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"abstract": "We report the cases of 2 patients who presented to our Myositis Center with myalgias and elevated creatine kinase levels. Muscle biopsy showed pathological features consistent with mitochondrial myopathy. In both cases, a single large deletion in mitochondrial DNA at low-level heteroplasmy was identified by next-generation sequencing in muscle tissue. In 1 case, the deletion was identified in muscle tissue but not blood. In both cases, the deletion was only identified on next-generation sequencing of muscle mitochondrial DNA and missed on array comparative genome hybridization testing. These cases demonstrate that next-generation sequencing of mitochondrial DNA in muscle tissue is the most sensitive method of molecular diagnosis for mitochondrial myopathy due to mitochondrial DNA deletions.",
"affiliations": "Center for Genetic Muscle Disorders at Kennedy Krieger Institute, Baltimore, MD.;Center for Genetic Muscle Disorders at Kennedy Krieger Institute, Baltimore, MD.;Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.;Genetic Testing for Mitochondrial Disorders, GeneDx, Gaithersburg, MD.;Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.;Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.",
"authors": "Leung|Doris G|DG|;Cohen|Julie S|JS|;Michelle|Elizabeth Harlan|EH|;Bai|Renkui|R|;Mammen|Andrew L|AL|;Christopher-Stine|Lisa|L|",
"chemical_list": "D004272:DNA, Mitochondrial",
"country": "United States",
"delete": false,
"doi": "10.1097/CND.0000000000000200",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-0443",
"issue": "19(3)",
"journal": "Journal of clinical neuromuscular disease",
"keywords": null,
"medline_ta": "J Clin Neuromuscul Dis",
"mesh_terms": "D000368:Aged; D004272:DNA, Mitochondrial; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D017240:Mitochondrial Myopathies; D018482:Muscle, Skeletal; D017384:Sequence Deletion",
"nlm_unique_id": "100887391",
"other_id": null,
"pages": "117-123",
"pmc": null,
"pmid": "29465611",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19546809;25991405;17276740;16258160;16909385;28749475;26633542;10888364;24011700;21519523;23473862;27386780;24277717;27659608;15313359;26530670;21867371;24843231;9266727;8163275;25526677;27912046;24186072;25203117",
"title": "Mitochondrial DNA Deletions With Low-Level Heteroplasmy in Adult-Onset Myopathy.",
"title_normalized": "mitochondrial dna deletions with low level heteroplasmy in adult onset myopathy"
} | [
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"companynumb": "US-DRREDDYS-USA/USA/18/0101174",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"activesubstance": {
"activesubstancename": "SIMVASTATIN"
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... |
{
"abstract": "Gas gangrene (GG) remains a life-threatening and deadly disease. Early recognition together with daily surgical debridement remains the mainstay of therapy. We sought to describe a fatal case of necrotizing soft tissue infection, which was a gas gagrene in this case. This case was remarkable as two main sites were infected simultaneously in geographical zones very far from each other making dissemination between both sites almost impossible. The other particularity was the fact that the infection was caused at the same time by four different bacteria that is atypical in GG similar to that in streptoccocal necrotizing fasciitis where one bacteria is the causative agent (Clostridium perfringens for GG and group A streptococcus for necrotizing fasciitis).",
"affiliations": "Emergency Department, Brugmann University Hospital, Brussels, Belgium.;Intensive care Departement, Brugmann University Hospital, Brussels, Belgium.;Pathology Department, Brugmann University Hospital, Brussels, Belgium.;Intensive care Departement, Brugmann University Hospital, Brussels, Belgium.;Surgery Department, Brugmann University Hospital, Brussels, Belgium.;Surgery Department, Brugmann University Hospital, Brussels, Belgium.;Intensive care Departement, Brugmann University Hospital, Brussels, Belgium.;Intensive care Departement, Brugmann University Hospital, Brussels, Belgium.",
"authors": "Preseau|Thierry|T|;Deviendt|Jacques|J|;Duttman|Ruth|R|;Attou|Rachid|R|;Franck|Diane|D|;Claeys|Ruben|R|;Honoré|Patrick M|PM|;De Bels|David|D|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.2478/jtim-2020-0009",
"fulltext": "\n==== Front\nJ Transl Int Med\nJ Transl Int Med\njtim\njtim\nJournal of Translational Internal Medicine\n2450-131X 2224-4018 Sciendo \n\njtim-2020-0009\n10.2478/jtim-2020-0009\nCase Report\nClostridium Perfringens in Gas Gangrene: Still a Smoked Gun!\nPreseau Thierry 1 Deviendt Jacques 2 Duttman Ruth 3 Attou Rachid 2 Franck Diane 4 Claeys Ruben 4 Honoré Patrick M. 2 Bels David De Dr. M.D.*2 1 Emergency Department, Brugmann University Hospital, Brussels, Belgium\n2 Intensive care Departement, Brugmann University Hospital, Brussels, Belgium\n3 Pathology Department, Brugmann University Hospital, Brussels, Belgium\n4 Surgery Department, Brugmann University Hospital, Brussels, Belgium\n* Dr. David De Bels, M.D., Intensive Care Department, Brugmann University Hospital, 4, Place A Van Gehuchten, B1020 Brussels, Belgium. david.debels@chu-brugmann.be\n3 2020 \n09 5 2020 \n8 1 54 56\n© 2020 Thierry Preseau, Jacques Deviendt, Ruth Duttman, Rachid Attou, Diane Franck, Ruben Claeys, Patrick M. Honoré, David De Bels, published by Sciendo2020Thierry Preseau, Jacques Deviendt, Ruth Duttman, Rachid Attou, Diane Franck, Ruben Claeys, Patrick M. Honoré, David De Bels, published by SciendoThis work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.Abstract\nGas gangrene (GG) remains a life-threatening and deadly disease. Early recognition together with daily surgical debridement remains the mainstay of therapy. We sought to describe a fatal case of necrotizing soft tissue infection, which was a gas gagrene in this case. This case was remarkable as two main sites were infected simultaneously in geographical zones very far from each other making dissemination between both sites almost impossible. The other particularity was the fact that the infection was caused at the same time by four different bacteria that is atypical in GG similar to that in streptoccocal necrotizing fasciitis where one bacteria is the causative agent (Clostridium perfringens for GG and group A streptococcus for necrotizing fasciitis).\n\nKey words\ngas gangrenepolymicrobialbifocal\n==== Body\nIntroduction\nGas gangrene (GG) caused by Clostridium species is a rare life-threatening infection with rapidly progressive invasion and destruction of soft tissue associated with gas production within tissues. Occasionaly, Clostridium is mixed with other aerobic and anaerobic bacteria.[1] It is usually caused by traumatic injury; however spontaneous gas gangrene (SGG) is also reported, nearby always in patients with underlying diseases, especially gastrointestinal disease, and is typically caused by Clostridium septicum.[2]\n\nWe describe the case of a patient with spontaneous bifocal GG caused by Clostridium perfringens associated with other bacteria, without evident underlying disease and with a fulminant and fatal course, despite rapid general tretment and surgical debridement. Surgical debridement remains the mainstay of the therapy for SGG.\n\nCase report\nA 62-year-old man without signifiant past medical or surgical history, no addiction, and taking no home medication presented to the emergency department (ED) with a history of pain and swelling of the left leg for 48 hours. On physical examination, the patient was pale, agitated, confused, and tachypneic and in distress from severe pain. Temperature was 37.8°C, pulse rate was 110/min, blood pressure was 185/100 mm Hg, and pulsed arterial oxygen saturation on room air was 96%. The left thigh and the right chest wall were notable for pain at palpation, for swelling, and of blue coloration (diffuse hematoma) with crepitus.\n\nThe laboratory studies revealed an anemia with an hemoglobin level of 4.6 (12–16) g/dL, a white blood cell count of 7.34 (4–12) K/μL, a platelet count of 198 (150–450) K/μL. INR was 1.39. There was a metabolic and lactic acidosis [pH: 7.24 (7.38–7.42); bicarbonate: 4.6 (24–28) mmol/L; lactate: 12.4 (0.66–2) mmol/L] and a renal failure [creatinine: 1.99 (0.7–1.3) mg/dL; urea: 10.5 (4.6–16.8) mmol/L]. C-reactive protein was 182 (<0.5) mg/dL, serum glucose was 333 (60–100) mg/dL, creatin kinase was 11,786 (<190) IU/L, troponine T (HS) was 6.4 (<14) ng/L, AST was 520 (<40) IU/L, ALT was 339 (<41) IU/L, alkaline phosphatases was 227 (40–129) IU/L, and total bilirubin was 6.7 (0.2–1.2) mg/dL.\n\nAn electrocardiogram showed a sinusal tachycardia without signifiant ST segment or T wave abnormalites.\n\nThe chest X-rays (Figure 1) showed an important soft tissue swelling predominant on the right chest wall with bilateral subcutaneous emphysema, without pulmonary parenchymatous lesions. The computed tomography scannner of chest, abdomen, and thighs (Figure 2a and b) showed the soft tissue and subcutaneous empysema of the chest wall and the same major lesions on the left thigh. There was no continuity between these two lesions.\n\nFigure 1 Chest X-ray showing soft tissue swelling with internal gas density predominant on the right chest wall.\n\nFigure 2 (a) CT scan showing massive infestation of the bilateral thoracic wall with sucutaneous emphysema. (b) CT scan showing massive myolysis of the left thigh with subcutaneous emphysema.\n\nThe diagnosis of necrotizing fasciitis and gas gangrene was considered, and emergent surgical consultation was obtained. Despite immediate intravenous antibiotherapy (clindamycin, amoxycillin–clavulanate acid, and amikacin 25 mg/kg), abundant perfusions of crystalloid and colloid fluids, and blood transfusions, the situation deteriorated rapidly necessitating instauration of mechanical ventilation and inotropic support.\n\nThirty minutes after the first medical contact, the patient was admitted to the operating room (OR), but cardiac arrest occurred on his admission in the OR. After cardiopulmoary resuscitation, the patient was momentarily stabilized with high doses of catecholamines, but a second cardiac arrest occured during surgery. The patient died 2 h after his admission to the hospital.\n\nLater C. perfringens (sensitive to clindamycin and penicillin), Escherichia coli (sensitive to amoxycillin–clavulanate acid and amikacine), and Enterococcus faecalis (sensitive to penicillin) were isolated from blood cultures. E. coli, E. faecalis, and Klebsiella pneumoniae (sensitive to amoxycillin–clavulanate acid and amikacine) were isolated from the cultures of tissue aspirated fluids in the OR.\n\nAn autopsy was performed and showed an extensive myonecrosis of the chest wall and thigh but neither neoplastic lesion nor perforation of the digestive tract.\n\nDiscussion\nSkin and soft tissue infections (SSTIs) are common and form a broad group of infections, ranging from mild to life-threatening ones. Necrotizing soft tissue infections (NSTIs) are the most severe form of SSTI, have a very rapid progression, and require immediate medical management and surgical debridement. NSTI remains uncommon with an incidence of 0.4/100.000 but seems to be increasing with a reported mortality as high as 73%.[3] NSTI can be mono- or polymicrobial, caused by aerobic, anaerobic, or a combination of aerobic and anaerobic microorganisms. Typically Group A (and sometimes group G ) Streptococcal necrotizing fasciitis[4, 5, 6] is monomicrobial as GG is caused by C. perfringens.\n\nGG is a life-threatening infection of the soft tissues, characterized by rapidly progressive muscular necrosis and gas production within the tissues. It is a well-recognized complication of trauma and penetrating (intrabdominal) wounds (e.g., war wounds, wounds caused by motor vehicle accident, and illegal abortion) or surgical intervention. In a literature review,[2] 49% of GG occurred after injury and 35% after surgery. It occurred spontaneously in only 16% of the cases.\n\nThe most frequently responsible pathogens are Clostridium species; six members of the clostridia species can invade muscle and cause myonecrosis in humans:[7]\nC. perfringens, C. septicum, Clostridium haemolyticum, Clostridium oedemateus, Clostridium Novyi, and Clostridium histolyticum.\n\nC. perfringens and C. septicum are responsible for the majority of the infections: C. perfringens accounts for 80–95% of cases after injury or surgery,[8] whereas SGG is almost exclusively caused by C. septicum.[7,8]\n\nClostridium are large gram-positive anaerobic bacilli and are nonpathogenic bacteria of the normal gut flora in humans. Spontaneous infections can be attributed in some of the cases to an impaired gut barrier (bowel malignancies, diverticulitis, translocation, etc.) and infections with C. septicum are linked to malignancy, immunosuppression, or diabetes mellitus.[7] SGG is also primarly found in the eldery. We did not measure the level of glycosylated hemoglobin. The patient had no antidiabetics or insulin before entering the hospital. However, we cannot rule out defintively that this was a GG secondary to an unknown diabetes mellitus.\n\nOur patient’s presentation is atypical by several aspects: possible spontaneous character of the infection, without traumatism or surgical intervention, the absence of evident underlying disease; although not fully certain regarding possible unknown diabetes mellitus, GG confirmed by the autopsy, multifocal localization, and the combination of four different microorganisms, aerobic and anaerobic, atypical in GG.\n\nThis case also draws attention to rare but increasing life-threatening infections that need immediate diagnosis and treatment with surgical debridement .\n\nConflict of Interest\n\nConflict of Interests: The authors declare to have no competing interests.\n==== Refs\nReferences\n1 Brook I Microbiolgy and management of soft tissue and muscle infections Int J Surg 2008 6 328 38 17720643 \n2 Yildiz T Gündeş S Willke A Solak M Toker K Spontaneous, nontraumatic gas gangrene due to Clostridium perfringens Int J Infect Dis 2006 10 83 5 16310394 \n3 Poromanski I Andriessen A Developing a tool to diagnose cases of necrotising fasciitis J Wound Care 2004 13 307 10 15469213 \n4 Zhao-Fleming H Dissanaike S Rumbaugh K Are anaerobes a major, underappreciated cause of necrotizing infections? Anaerobe 2017 45 65 70 28450145 \n5 Honoré PM Lozana A Dugernier T Harding D Jamez J Wauthier M et al Toxic shock syndrome due to Lancefield group A and G streptococci. Current concepts, clinical aspects and therapeutic challenges Med Mal Infect 1999 29 5 11 \n6 Honoré PM Lozana A Defalque D Efstratiou A Fatal septic shock due to Lancefield group G Streptococcus Acta Clin Belg 1996 51 57 60 8669163 \n7 Hartel M Kutup A Gehl A Zustin J Grossterlinden LG Rueger JM et al Foudroyant Course of an Extensive Clostridium septicum Gas Gangrene in a Diabetic Patient with Occult Carcinoma of the Colon Case Rep Orthop 2013 2013 216382 23864974 \n8 Lu J Wu XT Kong XF Tang WH Cheng JM et al Gas gangrene without wound: both lower extremities affected simultaneously Am J Emerg Med 2008 26 970 e3-4\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2224-4018",
"issue": "8(1)",
"journal": "Journal of translational internal medicine",
"keywords": "bifocal; gas gangrene; polymicrobial",
"medline_ta": "J Transl Int Med",
"mesh_terms": null,
"nlm_unique_id": "101673826",
"other_id": null,
"pages": "54-56",
"pmc": null,
"pmid": "32435613",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": "23864974;18926377;16310394;8669163;15469213;17720643;28450145",
"title": "Clostridium Perfringens in Gas Gangrene: Still a Smoked Gun!",
"title_normalized": "clostridium perfringens in gas gangrene still a smoked gun"
} | [
{
"companynumb": "BE-MICRO LABS LIMITED-ML2020-02025",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMIKACIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo assess the fetal outcome of three hypertensive women exposed to amlodipine. 5 mg/day, in the first trimester of pregnancy. CASE 1: The patient was treated with amlodipine until 7 weeks of gestation. She was also exposed to levosulpiride, aluminum hydroxide gel, magnesium carbonate, and Ginkgo biloba. At 38(+3) weeks of pregnancy, she delivered a 3750 g healthy female baby, and restarted taking amlodipine, 5 mg/day, while exclusively breastfeeding her daughter. At three months of age, the infant was healthy. CASE 2: The patient was treated with amlodipine from 2(+2) to 3(+4) weeks of pregnancy. Her treatment was modified to atenolol until the week 6(+4 weeks), when she declined any antihypertensive treatment. At 39(+4) weeks of pregnancy, the patient delivered a 2600 g baby. At 20 months old, the baby presented with intellectual delay and weakness in the left arm and hand grasp. These neurological alterations were not attributed to her exposure to amlodipine early in utero. CASE 3: The patient was treated with amlodipine from 7(+6) to 12 weeks of pregnancy. She was also taking sucralfate and lorazepam. At 12 weeks of amenorrhea, ultrasound revealed a 15.3 mm, single fetal pole in the gestational sac without cardiac activity. She underwent dilatation and evacuation of a dead embryo.\n\n\nCONCLUSIONS\nAs reported with other calcium-channel blockers, amlodipine does not appear to be teratogenic and it appears to be compatible with breastfeeding.",
"affiliations": "The Korean Motherisk Program, Cheil Hospital & Women's Health-care Center, Kwandong University School of Medicine, Seoul, Korea.",
"authors": "Ahn|Hyun Kyong|HK|;Nava-Ocampo|Alejandro A|AA|;Han|Jung Yeol|JY|;Choi|June Seek|JS|;Chung|Jin Hoon|JH|;Yang|Jae Hyug|JH|;Koong|Mi Kyoung|MK|;Park|Chong Taik|CT|",
"chemical_list": "D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D017311:Amlodipine",
"country": "England",
"delete": false,
"doi": "10.1080/10641950701204554",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1064-1955",
"issue": "26(2)",
"journal": "Hypertension in pregnancy",
"keywords": null,
"medline_ta": "Hypertens Pregnancy",
"mesh_terms": "D000328:Adult; D017311:Amlodipine; D000959:Antihypertensive Agents; D001794:Blood Pressure; D001942:Breast Feeding; D002121:Calcium Channel Blockers; D005260:Female; D047109:Fetal Development; D006801:Humans; D046110:Hypertension, Pregnancy-Induced; D011247:Pregnancy; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First",
"nlm_unique_id": "9421297",
"other_id": null,
"pages": "179-87",
"pmc": null,
"pmid": "17469008",
"pubdate": "2007",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Exposure to amlodipine in the first trimester of pregnancy and during breastfeeding.",
"title_normalized": "exposure to amlodipine in the first trimester of pregnancy and during breastfeeding"
} | [
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"companynumb": "KR-ALLERGAN-1721479US",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
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"actiondrug": "6",
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"activesubstancename": "SUCRALFATE"
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"drugadditional": null,
... |
{
"abstract": "This case series includes longitudinal clinical data of ten patients with Morquio A syndrome from south and southeastern parts of Turkey, which were retrospectively collected from medical records. All patients received enzyme replacement therapy (ERT). Clinical data collected included physical appearance, anthropometric data, neurological and psychological examinations, cardiovascular evaluation, pulmonary function tests, eye and ear-nose-throat examinations, endurance in the 6-min walk test and/or 3-min stair climb test, joint range of motion, and skeletal investigations (X-rays, bone mineral density).\n\n\n\nAt the time of ERT initiation, two patients were infants (1.8 and 2.1 years), five were children (3.4-7.1 years), and three were adults (16.5-39.5 years). Patients had up to 4 years follow-up. Most patients had classical Morquio A, based on genotypic and phenotypic data. Endurance was considerably reduced in all patients, but remained relatively stable or increased over time in most cases after treatment initiation. Length/height fell below normal growth curves, except in the two infants who started ERT at ≤ 2.1 years of age. All patients had skeletal and/or joint abnormalities when ERT was started. Follow-up data did not suggest improvements in skeletal abnormalities, except in one of the younger infants. Nine patients had corneal clouding, which resolved after treatment initiation in the two infants, but not in the other patients. Hepatomegaly was reported in seven patients and resolved with treatment in five of them. Other frequent findings at treatment initiation were coarse facial features (N = 9), hearing loss (N = 6), and cardiac abnormalities (N = 6). Cardiac disease deteriorated over time in three patients, but did not progress in the others.\n\n\n\nOverall, this case series with Morquio A patients confirms clinical trial data showing long-term stabilization of endurance after treatment initiation across ages and suggest that very early initiation of ERT optimizes growth outcomes.",
"affiliations": "Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, Faculty of Medicine, Çukurova University,, Adana, Turkey.;Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Çukurova University, Adana, Turkey.;Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, Faculty of Medicine, Çukurova University,, Adana, Turkey.;Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, Faculty of Medicine, Çukurova University,, Adana, Turkey.;Division of Pediatric Cardiology, Department of Pediatrics, Faculty of Medicine, Çukurova University, Adana, Turkey.;Department of Radiology, Faculty of Medicine, Çukurova University, Adana, Turkey.;Department of Ear, Nose and Throat Diseases, Faculty of Medicine, Çukurova University, Adana, Turkey.;Medical Genetics Department of Medical Faculty, Cukurova University AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center), Adana, Turkey.;Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, Faculty of Medicine, Çukurova University, 01130, Sarıçam, Adana, Turkey. munganhno@gmail.com.",
"authors": "Kılavuz|Sebile|S|0000-0002-7527-2620;Basaran|Sibel|S|;Kor|Deniz|D|0000-0001-7659-0500;Bulut|Fatma Derya|FD|0000-0003-0529-2404;Erdem|Sevcan|S|;Ballı|Hüseyin Tuğsan|HT|;Dağkıran|Muhammed|M|;Bisgin|Atil|A|0000-0002-2053-9076;Mungan|Halise Neslihan Önenli|HNÖ|0000-0001-7862-3038",
"chemical_list": "D002811:Chondroitinsulfatases",
"country": "England",
"delete": false,
"doi": "10.1186/s13023-021-01761-0",
"fulltext": "\n==== Front\nOrphanet J Rare Dis\nOrphanet J Rare Dis\nOrphanet Journal of Rare Diseases\n1750-1172\nBioMed Central London\n\n1761\n10.1186/s13023-021-01761-0\nResearch\nMorquio A syndrome and effect of enzyme replacement therapy in different age groups of Turkish patients: a case series\nhttp://orcid.org/0000-0002-7527-2620\nKılavuz Sebile dr.skilavuz@gmail.com\n\n1\nBasaran Sibel sbasaran@cu.edu.tr\n\n2\nhttp://orcid.org/0000-0001-7659-0500\nKor Deniz dozonur@yahoo.com\n\n1\nhttp://orcid.org/0000-0003-0529-2404\nBulut Fatma Derya deryaozduran@yahoo.com\n\n1\nErdem Sevcan hserdem@gmail.com\n\n3\nBallı Hüseyin Tuğsan tballi@cu.edu.tr\n\n4\nDağkıran Muhammed mdagkiran@cu.edu.tr\n\n5\nhttp://orcid.org/0000-0002-2053-9076\nBisgin Atil abisgin@cu.edu.tr\n\n6\nhttp://orcid.org/0000-0001-7862-3038\nMungan Halise Neslihan Önenli munganhno@gmail.com\n\n7\n1 grid.98622.37 0000 0001 2271 3229 Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, Faculty of Medicine, Çukurova University,, Adana, Turkey\n2 grid.98622.37 0000 0001 2271 3229 Department of Physical Medicine and Rehabilitation, Faculty of Medicine, Çukurova University, Adana, Turkey\n3 grid.98622.37 0000 0001 2271 3229 Division of Pediatric Cardiology, Department of Pediatrics, Faculty of Medicine, Çukurova University, Adana, Turkey\n4 grid.98622.37 0000 0001 2271 3229 Department of Radiology, Faculty of Medicine, Çukurova University, Adana, Turkey\n5 grid.98622.37 0000 0001 2271 3229 Department of Ear, Nose and Throat Diseases, Faculty of Medicine, Çukurova University, Adana, Turkey\n6 grid.98622.37 0000 0001 2271 3229 Medical Genetics Department of Medical Faculty, Cukurova University AGENTEM (Adana Genetic Diseases Diagnosis and Treatment Center), Adana, Turkey\n7 grid.98622.37 0000 0001 2271 3229 Division of Pediatric Metabolism and Nutrition, Department of Pediatrics, Faculty of Medicine, Çukurova University, 01130 Sarıçam, Adana, Turkey\n22 3 2021\n22 3 2021\n2021\n16 1445 11 2020\n25 2 2021\n© The Author(s) 2021\nOpen AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nThis case series includes longitudinal clinical data of ten patients with Morquio A syndrome from south and southeastern parts of Turkey, which were retrospectively collected from medical records. All patients received enzyme replacement therapy (ERT). Clinical data collected included physical appearance, anthropometric data, neurological and psychological examinations, cardiovascular evaluation, pulmonary function tests, eye and ear-nose-throat examinations, endurance in the 6-min walk test and/or 3-min stair climb test, joint range of motion, and skeletal investigations (X-rays, bone mineral density).\n\nResults\n\nAt the time of ERT initiation, two patients were infants (1.8 and 2.1 years), five were children (3.4–7.1 years), and three were adults (16.5–39.5 years). Patients had up to 4 years follow-up. Most patients had classical Morquio A, based on genotypic and phenotypic data. Endurance was considerably reduced in all patients, but remained relatively stable or increased over time in most cases after treatment initiation. Length/height fell below normal growth curves, except in the two infants who started ERT at ≤ 2.1 years of age. All patients had skeletal and/or joint abnormalities when ERT was started. Follow-up data did not suggest improvements in skeletal abnormalities, except in one of the younger infants. Nine patients had corneal clouding, which resolved after treatment initiation in the two infants, but not in the other patients. Hepatomegaly was reported in seven patients and resolved with treatment in five of them. Other frequent findings at treatment initiation were coarse facial features (N = 9), hearing loss (N = 6), and cardiac abnormalities (N = 6). Cardiac disease deteriorated over time in three patients, but did not progress in the others.\n\nConclusions\n\nOverall, this case series with Morquio A patients confirms clinical trial data showing long-term stabilization of endurance after treatment initiation across ages and suggest that very early initiation of ERT optimizes growth outcomes.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s13023-021-01761-0.\n\nKeywords\n\nElosulfase alfa\nEnzyme replacement therapy\nMucopolysaccharidosis IVA\nMorquio A syndrome\nhttp://dx.doi.org/10.13039/100008484 BioMarin Pharmaceutical No award number issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nMorquio A syndrome, also called mucopolysaccharidosis (MPS) IVA, is an ultra-rare autosomal recessive lysosomal storage disorder caused by deficient activity of the enzyme N-acetylgalactosamine-6-sulfatase (GALNS; EC 3.1.6.4), involved in the catabolism of the glycosaminoglycans (GAGs) keratan sulfate (KS) and chondroitin-6-sulfate [1]. The resulting accumulation of these GAGs in tissues and organs causes an array of multi-systemic and progressively worsening clinical manifestations [2].\n\nMorquio A is typically characterized by skeletal dysplasia (dysostosis multiplex, spinal cord compression), short trunk dwarfism, joint abnormalities, impaired respiratory function, cardiac abnormalities, impaired vision, hearing loss, hepatomegaly, and a reduced lifespan [3–6]. Clinical manifestations and progression rates differ considerably between patients. Onset of disease symptoms can vary from prior to 1 year of age in severely affected (classical) patients to the second decade of life in less severely affected (non-classical) patients [1].\n\nTherapeutic options for Morquio A syndrome include palliative symptom management and systemic therapies [7]. First-line therapy is elosulfase alfa, an enzyme replacement therapy (ERT), provided weekly (at 2 mg/kg) via intravenous infusions [8]. This therapy was developed to help correct the enzyme deficiency and restore cell function of Morquio A patients [9]. The pivotal phase 3 clinical trial of elosulfase alfa (MOR-004), including 176 patients ≥ 5 years of age, and its long-term extension (MOR-005) showed a statistically significant improvement in the distance walked in the 6-min walk test (6MWT), a rapid and sustained reduction in urine KS (uKS), and sustained numerical improvements in pulmonary function measures and activities of daily living after 120 weeks of treatment [8, 10–12]. Elosulfase alfa was generally well tolerated, with most drug-related adverse events being mild or moderate infusion-associated reactions [8, 10].\n\nIn Turkey, elosulfase alfa has been reimbursed since May 7, 2015 for patients > 60 months of age diagnosed with Morquio A by enzyme or mutation analysis, who can walk independently. On September 23, 2017, patients < 60 months of age and diagnosed by enzyme or mutation analysis also became eligible for reimbursement. To date, the Turkish Morquio A population and the impact of ERT on these patients have not been well defined.\n\nMethods\n\nAims\n\nThe aims of reporting these cases were to better characterize the phenotypic and genotypic features of a small group of Turkish Morquio A patients, and to describe the clinical outcomes of these patients after initiating ERT at different ages in real-life clinical practice.\n\nStudy design and participants\n\nClinical data of ten patients with a confirmed diagnosis of Morquio A syndrome who were followed up at the Çukurova University Balcalı Hospital in Adana, Turkey were retrospectively collected by a local clinical research officer from the patients’ medical records after ethical committee approval. Patients were selected as representatives of different age groups; and availability of clinical data was the second most important selection criterion. Clinical data that were collected included physical appearance, anthropometric data, neurological and mental/psychological examinations (Denver Developmental Screening Test II [up to age 6 years], Stanford-Binet test [children ≥ 2 years], Wechsler Intelligence Scale for Children Revised [WISC-R, 6–16 years], Wechsler Adult Intelligence Scale [WAIS, > 16 years]), cardiovascular evaluation, pulmonary function tests, eye and ear-nose-throat (ENT) examinations, endurance in the 6MWT and/or 3-min stair climb test (3MSCT) depending on age, joint range of motion, and skeletal investigations (X-rays, bone mineral density). All patients (and/or their parents) provided informed consent to publish clinical data of this case series.\n\nStatistical analysis\n\nAll data are presented descriptively and compared with normative data, where relevant and available. Z-scores (indicating how many standard deviation [SDs] a value deviates from the mean) were calculated for anthropometric data (length/height and weight).\n\nResults\n\nDemographics and patient characteristics\n\nThe case series included two infants (cases 1 and 2) aged 1.8 and 2.1 years, five children (cases 3–7) aged 3.4 to 7.1 years, and three adults (cases 8–10) aged 16.5 to 39.5 years at initiation of ERT (Table1). Consanguinity data showed that in all cases the patients’ parents were either first degree cousins (cases 1, 2, 4, 7, and 9), second degree cousins (cases 3, 5, 6 and 8) or distant relatives (case 10). Five patients (cases 1, 2, 3, 6, and 9) had a sibling with Morquio A syndrome.Table 1 Patient demographics and baseline characteristics\n\nPatient\tSex\tConsanguinity of parents\tAge at first symptoms (years)\tAge at diagnosis (years)\tAge at initiation of ERT (years)\tDuration of ERT (years)\tCurrent age (years)\tEnzyme level\nnmol/mg/17 h\n(45–240)a\tMutation\t\n1\tM\tYes\t1\t0.04 (2 weeks)b\t1.8\t2.5\t4.2\t13\tHomozygous: c.535 C > T (p. P179S)\t\n2\tM\tYes\t1.1\t1.5\t2.1\t4.2\t6.3\t0\tHomozygous: c.421 T > A (p.V141R)\t\n3\tF\tYes\t2\t3.2\t3.4\t2.2\t5.6\t12\tHomozygous: c.107 T > G (p.L36P)\t\n4\tF\tYes\t2.5\t3.7\t4.0\t2.9\t6.9\t0.1\tHomozygous: c.268C > T (p.R90W)\t\n5\tF\tYes\t2.8\t4.9\t5.2\t2.8\t8.0\t0.1\tHomozygous: c.922 T > C (p.C308R)\t\n6\tM\tYes\t1.9\t3.8\t5.2c\t3.0\t8.2\t18.8\tHomozygous: c.655A > T (p.R219X)\t\n7\tF\tYes\t1.5\t5.4\t7.1\t4.6\t11.7\t13\tHomozygous: c.421 T > A (p.W141R)\t\n8\tF\tYes\t3\t16.1\t16.5\t4.4\t20.9\t0\tHomozygous: c.922 T > C (p.C308R)\t\n9\tM\tYes\t7\t15.6\t16.6\t4.5d\t21.1\t26\tHomozygous: c.1417C > T (p.Q473X)\t\n10\tF\tYes\t0.8\t5.9\t39.5\t4.7\t44.2\t0\tHomozygous: c.1348G > A (p.E450K)\t\naDetermined before initiation of ERT; bTreatment of case 1 started late because the family could not be reached; cCase 6 was diagnosed in a different center, and his treatment was initially delayed due to hypersensitivity reactions; dCase 9 was not compliant to the weekly treatment; he discontinued treatment many times; ERT: enzyme replacement therapy; F: female; M: male; NA: not available\n\nData were collected between August 2008 and July 2020. The number of visits at which data were collected ranged from seven (subject 4) to 22 (subject 7), but not all assessments were performed at each visit. All patients had at least one visit per year since ERT was initiated.\n\nInfusion details\n\nAll patients received elosulfase alfa at 2 mg/kg/week. Eight patients did not miss any planned infusions, with exception of two or three recent infusions due to the COVID-19 pandemic. Case 6 missed six infusions due to hypersensitivity reactions. Case 9 missed one or two infusions per month in a 1-year period after the last follow-up visit due to familial problems, but resumed treatment thereafter.\n\nNone of the patients, except case 6, had anaphylactic reactions to ERT. After the 16th weekly infusion, case 6 presented with vomiting, nausea, hypotension, urticaria on the trunk, and angioedema on the eyelids, which developed in approximately 90 min. A skin prick test was performed and confirmed a strong IgE-dependent allergic reaction. A desensitization protocol was initiated. During the first day of desensitization, hypotension occurred, and ERT was discontinued for 1 month on the parents’ request. Desensitization was resumed successfully after 1 month without further incidents. The patient is currently (after a 1-year protocol) being treated with 4-h infusions without any premedication.\n\nDiagnosis\n\nAges at diagnosis ranged from 2 weeks in case 1 to 16.1 years in case 8 (Table 1). Cases 1 and 2 were diagnosed with Morquio A syndrome before the onset of symptoms, due to sibling history (older sibling previously diagnosed with the disease). In the other patients, first symptoms of Morquio A syndrome observed by the parents were pectus carinatum (cases 3, 4 and 7), scoliosis (case 4), kyphoscoliosis (case 6), and growth retardation (cases 5, 8, 9, and 10). Patients were referred for diagnosis by a pediatrician (cases 3, 5, 7, 8, 9) or by an orthopedic surgeon (cases 4, 6, and 10). All patients had homozygous mutations in the GALNS gene (Table 1). All mutations were previously defined as likely pathogenic or pathogenic.\n\nClinical findings before initiation of ERT\n\nTable 2 summarizes clinical data collected during physical and clinical examinations before treatment initiation. All patients had at least some joint and skeletal abnormalities at the time ERT was started. Other frequent observations were recurrent respiratory infections (N = 10), corneal clouding (N = 9), coarse facial features (N = 9), hearing loss (N = 6), hepato(spleno)megaly (N = 6), and cardiac abnormalities (N = 6). It should be noted that some clinical manifestations may have been missed due to the young age of the patient (e.g. inability to perform a visual acuity test) or a test not being performed before or at treatment initiation. For case 7, physical examination data reported at 0.3 years after treatment initiation are included since no earlier data were available, as ERT was started in a different center.Table 2 Clinical findings before or at initiation of enzyme replacement therapya\n\nCase\tCorneal clouding\tHearing loss\tJoint/skeletal abnormalities\tCoarse face\tAbdominal abnormalities\tCardiovascular disease\tOther\t\n1\tYes (mild)\tNo\tWrist laxity, shoulder stiffness, hip dysplasia, enlarged head, dysostosis multiplex, pectus carinatum\tNo\tHepatomegaly, umbilical hernia\tNo\tHypospadias, recurrent respiratory infections, CTS\t\n2\tYes\tConductive type C\tWrist laxity, genu valgum, pectus carinatum, increased lumbar lordosis, mild kyphosis, dysostosis multiplex\tYes (mild)\tNo\tNo\tRecurrent respiratory infections,\n\ntonsillar hypertrophy\n\n\t\n3\tNo\tNo\tWrist laxity, genu valgum,\n\nhip dysplasia,\n\npectus carinatum, minimal lumbar scoliosis, dysostosis multiplex\n\n\tYes (mild)\tNo\tNo\tRecurrent respiratory infections,\n\ntonsillar hypertrophy\n\n\t\n4\tYes (minimal)\tConductive\tWrist laxity, elbow stiffness, mild kyphosis, scoliosis, genu valgum, pectus carinatum, dysostosis multiplex\tYes (mild)\tHepatosplenomegaly\tMild mitral insufficiency\tRecurrent pulmonary infections\t\n5\tYes (mild)\tNA\tMild wrist laxity, hip dysplasia, genu valgum, pectus carinatum, mild kyphosis, dysostosis multiplex\tYes (mild)\tHepatomegaly, umbilical hernia\tMitral valve thickening, mild mitral/aortic insufficiency\tRecurrent respiratory infections,\n\nCTS, moderate upper airway obstruction due to adenoid and tonsillar hypertrophy, fecal incontinence\n\n\t\n6\tYes (minimal)\tConductive type B & C and sensorineural\tWrist laxity, mild joint stiffness, genu valgum, pectus carinatum, mild kyphoscoliosis, dysostosis multiplex\tYes (mild)\tHepatomegaly, umbilical hernia\tMitral/aortic valve thickening, mild mitral insufficiency, respiratory sinus arrhythmia,\tRecurrent respiratory infections,\n\nVA right eye 5/10, adenoid/tonsillar hypertrophy\n\n\t\n7\tYes\tNo\tWrist laxity, joint stiffness, genu valgum, pectus carinatum, kyphosis, dysostosis multiplex\tYes (moderate)\tNo\tNo\tRecurrent respiratory infections,\n\nVA 8/10 both eyes, papilledema, adenoid/tonsillar hypertrophy\n\n\t\n8\tYes (mild)\tConductive type B & C\tWrist laxity, mild joint stiffness, genu valgum, hip dysplasia, ankle deformities, mild pectus carinatum, mild kyphosis, thoracolumbar scoliosis, dysostosis multiplex\tYes (Moderate)\tHepatomegaly\tMild aortic and mitral insufficiency\tRecurrent respiratory infections,\n\nadenoid/tonsillar hypertrophy\n\n\t\n9\tYes (mild)\tSensorineural\tWrist laxity, joint stiffness, pectus excavatum, kyphoscoliosis, genu valgum, bilateral patellar dislocation, dysostosis multiplex\tYes\n\n(Moderate-Severe)\n\n\tHepatosplenomegaly\tAortic insufficiency, mild aortic stenosis, mild mitral insufficiency\tRecurrent respiratory infections,\n\nadenoid/tonsillar hypertrophy, muscle weakness\n\n\t\n10\tYes (mild)\tSensorineural\tWrist laxity, mild joint stiffness, genu valgum, pectus excavatum, thoracolumbar scoliosis, dysostosis multiplex\tYes (mild)\tHepatomegaly\tMild mitral insufficiency\tRecurrent respiratory infections,\n\nadenoid/tonsillar hypertrophy\n\n\t\naFor case 7, physical examination data were first reported at 0.3 years after treatment initiation\n\nCTS: carpal tunnel syndrome; NA: not available; VA: visual acuity\n\nEndurance\n\nAll reported 6MWT distances were considerably below normal values (i.e. below the mean 6MWT distance in healthy children at 4 years of age, which is 383 m) [13], but remained relatively stable or increased over time in most patients (Fig. 1a, b). 6MWT data at initiation of ERT (baseline) were available for three children (cases 4, 5 and 7) and all adults (cases 8–10). Cases 4, 5, 7, 8 and 10 showed increases in walking distance from baseline to last follow-up (case 4: from 150 to 245 m after 2.1 years; case 5: from 210 to 300 m after 1.7 years; case 7: from 150 to 250 m after 3.9 years; case 8: from 198 to 225 m after 3 years; case 10 from 42 to 110 m after 1.8 years). Case 9 had stable results in the first 2 years and a decline at 3 years (from 66 to 33 m after 3 years). This patient also required rest and support to perform the endurance tests. It should be noted that case 9 was diagnosed at 16.6 years old and he was not compliant to the weekly treatment (discontinued treatment many times).Fig. 1 Six-minute walk test (6MWT) distance over time in children (a) and adults (b) and 3-min stair climb test (3MSCT) results over time in children (c) and adults (d). Arrows indicate ages at initiation of enzyme replacement therapy (ERT). In cases 4, 5, 7, 8, 9, and 10, the first 6MWT measurement was recorded at or before initiation of ERT; baseline 3MSCT data were available for cases 4, 5, 8, and 10. All other data were collected after initiation of ERT. The dashed line in figure A represents normal 6MWT distances by age for children 4–11 years old [13]. Error bars represent standard deviations\n\n3MSCT results fluctuated considerably over time in the children, but increased between the first and the last measurement in all of them (Fig. 1c, d); 3MSCT results of the adults were relatively stable. Baseline 3MSCT data were available for cases 4, 5, 8 and 10. All these patients showed at least some improvement from baseline to last follow-up, except case 8 who showed a minor decline.\n\nEndurance data of cases 1 and 3 are not included in Fig. 1 as both patients had only one measurement, or two measurements with very short interval and no pre-ERT baseline. Results at last follow-up were 265 m in the 6MWT and 36.7 stairs/min in the 3MSCT for case 1 (at 3.7 years of age) and 125 m and 16 stairs/min, respectively, at 4.6 years of age for case 3.\n\nAnthropometrics\n\nHeight/length and weight data were available for all cases (Additional file 1). Data before treatment initiation were reported for all cases, except case 9.\n\nAmong the infants, who both started ERT around 2 years of age, case 1 had a length within 2 standard deviations of Centers for Disease Control and Prevention (CDC) reference curves at treatment initiation (z-score -0.97), while length was slightly below normal in case 2 (z-score −2.06). The older children had baseline height z-scores ranging between −2.56 and −4.97 (Additional file 1). Baseline weight z-scores were below normal (z-score < 2) in cases 5 and 6. All three adults (cases 8–10) had very short statures, with standing heights ranging from 99 to 103 cm (z-scores −8.5 to −9.7) and weights between 21 and 25 kg (z-scores −9.4 to −13.4). All patients > 2 years of age, except cases 7, 8 and 9, were overweight at baseline, which means that body mass index (BMI) was above the 85th percentile of CDC norms in patients of 2–20 years of age or > 25 kg/m2 in older patients (Additional file 1).\n\nAll infants and children showed increases in length/height after initiation of ERT (Fig. 2). Growth curves of the two infants (cases 1 and 2) appeared to follow CDC reference curves after treatment initiation. Length/height z-scores slightly increased from −0.97 to −0.63 after 1.5 years of treatment in case 1 and from −2.06 to −1.8 after 3.7 years in case 2. In the children who started ERT after 3 years of age, height increasingly deviated from reference growth curves over time despite treatment, and continued to follow Morquio A population curves (Fig. 2) [14]. All infants and children with follow-up data, except case 1, had low weight (z-score < −2.0) at last follow-up. Follow-up data in adults (cases 8 and 9) showed no increases in height after initiation of ERT and slight increases in weight. BMI remained relatively unchanged in most patients, with exception of case 4, who showed a normalization (from the 94th to the 52th percentile), case 7, who showed a reduction from the 80th to the 29th percentile, and case 9, who changed from the 79th to 90th percentile, after 2 to 4 years of treatment (Additional file 1).Fig. 2 Stature and weight over time. Length (0 to 2 years) and height (2 to 12 years) for age curves (a) and weight for age curves (b) in infants and children. Arrows indicate age at initiation of enzyme replacement therapy. Dashed and full black lines represent 3rd and 50th percentiles for healthy boys (CDC https://www.cdc.gov/growthcharts/clinical_charts.htm), respectively; full orange lines represent means for untreated Morquio A syndrome (boys) [14]. Reference curves for girls are not included as these largely overlap with the curves for boys in this age range\n\nSkeletal and joint abnormalities\n\nAll patients showed skeletal abnormalities before treatment initiation (Table 2). Frequent findings were wrist laxity (N = 10), pectus carinatum or excavatum (N = 10), genu valgum (knock knees; N = 9), kyphosis/scoliosis/kyphoscoliosis (N = 9), and joint stiffness (N = 7). Radiology examinations showed dysostosis multiplex in all patients. Although follow-up data were difficult to interpret, they did not suggest meaningful improvements in skeletal abnormalities over time. An exception was case 2, for whom an improvement of kyphosis was reported after 3.7 of 4.2 years of treatment. Follow-up data of the youngest patient (case 1) suggested progression of skeletal abnormalities. This patient showed mild joint stiffness and hyperlaxity and unilateral hip joint dysplasia at initiation of ERT at 1.8 years of age, but developed pectus carinatum, scoliosis and bilateral genu valgum within the next 1.5 years.\n\nJoint range of motion was mainly reported for shoulders, elbows, knees and hips. Case 2 maintained normal joint range of motion over 3.7 years of ERT. All other cases showed joint motion limitations at baseline, including genu valgum (cases 3, 4, 5, 6, 7, 8, 9, 10), and stiffness (flexion, extension, or rotation limitations) of the shoulders (cases 1, 6, 8, 10), elbows (cases 3, 4, 7, 9, 10), knees (cases 8, 10), and/or hips (cases 4, 5, 7, 9, 10). There was no improvement or worsening in joint range of motion over time in any of these patients.\n\nCardiorespiratory function\n\nAll echocardiographic investigations were performed by the same physician. Three children (cases 4, 5, and 6) and all three adults (cases 8–10) had mitral insufficiency before initiating ERT; cases 5, 6, 8, and 9 also had aortic insufficiency or valve thickening (Table 2). Cardiac valve disease resolved in case 6 after 1.8 years of treatment, and remained stable in cases 4 and 5. Case 8 showed mild aortic and mitral insufficiency when ERT was started and severe aortic insufficiency after 2.2 years of treatment. Case 9 had pulmonary hypertension, second-degree aortic insufficiency, mild aortic constriction and mild mitral insufficiency at baseline and at all follow-up examinations. Prophylactic penicillin use was recommended for infective endocarditis. In case 10, echocardiography revealed a diastolic relaxation of the left ventricle with slight mitral insufficiency and an ejection fraction of 72% at treatment initiation and second degree aortic insufficiency, and an ejection fraction of 70% after 2.5 years of treatment. Pulmonary hypertension resolved by last follow-up.\n\nFour patients (cases 1, 2, 3 and 7) initially had normal cardiovascular function. Of those, one (case 7) developed mitral, tricuspid and aortic valve insufficiency after 2 years on treatment. Cases 1, 2, and 3 kept normal cardiovascular function after 0.8, 3.7, and 1.2 years of ERT, respectively.\n\nPulmonary function tests were performed at regular intervals after initiating ERT in five patients (cases 4, 7, 8, 9, and 10) and showed restrictive pulmonary disease in four of them (cases 4, 8, 9, and 10). Restrictive pulmonary disease worsened over time in case 9, but no progression was seen in the other patients.\n\nEar, nose, throat\n\nHearing loss was reported for six patients (Table 2). Among these, four were diagnosed with conductive hearing loss (cases 2, 4, 6, and 8), mostly type B (likely due to otitis media) and/or type C (indicating Eustachian tube dysfunction). The two oldest patients (cases 9 and 10) and case 6 had sensorineural hearing loss. In addition, eight patients had upper airway obstruction due to adenoid and/or tonsillar hypertrophy (cases 2, 3, 5, 6, 7, 8, 9, and 10). Related to this, case 5 had ventilation tube insertions and adenoidectomy at 5.7 years of age, case 6 had three ventilation tube insertions and one adenoidectomy before 4 years of age, and case 8 had a tonsillectomy and an adenoidectomy at 16.5 years of age.\n\nHearing loss in case 8 and 10 remained stable. In case 8, otitis media was reported at 0.4 years after treatment initiation. Cases 6 and 10 started using hearing aids at 8 and 24 years of age, respectively. Follow-up ear/nose and throat investigations were planned, but have not yet been undertaken due to the COVID-19 pandemic.\n\nVision\n\nAll patients except case 3 had corneal clouding at first measurement. Cases 6 and 7 also showed reduced visual acuity (Table 2). Five patients had both baseline and follow-up data (cases 1, 2, 6, 8 and 10). Corneal clouding remained present in cases 6, 8, and 10 after around 2 to 3 years of treatment. Cases 1 and 2 had mild corneal clouding before initiation of treatment, which resolved in case 1 after 0.8 years and in case 2 after 3.7 years of treatment. The degree of corneal clouding was subjectively graded by a single physician as mild (+), moderate (++), or severe (+++).\n\nNeurological and mental function\n\nNeurological examination and/or spinal or brain magnetic resonance imaging (MRI) data were available for all patients except case 3, showing abnormalities in cases 1, 4, 5, 6, 7, 8, 9, and 10, and no abnormalities in case 2.\n\nCranial MRI in case 1 at 3.8 years of age revealed mild dilation of the third ventricle and perivascular spaces at the right frontal lobe. Cervical, thoracic, and lumbar MRI showed enlarged and biconcave vertebral bodies, but a normal spinal cord. In case 4, cranial and spine MRI at 4.6 years of age showed diffuse spinal cord compression on vertebral body and gibbus deformities in the lower thoracolumbar region and sacrococcygeal region, as well as craniocervical compression and myelomalacia. Case 5 had a cerebral MRI during a hospitalization for fecal incontinence shortly before initiatioin of ERT (at 5 years of age), showing spinal cord compression at C2 level but a normal cerebellum. An electromyogram (EMG) ruled out tethered cord syndrome. In case 6, spinal stenosis was reported at 2 years and spinal cord compression at 5 years of age (just before ERT was started), but without clinical symptoms. In case 7, spinal stenosis was reported at 8 years of age. In case 8, MRI results at 17 years of age showed spinal cord compression due to kyphosis at the upper thoracic region, and spinal cord compression and myelomalacia at the cranio-cervical region due to a narrow foramen magnum, causing hydrocephaly and some peripheral nervous system symptoms. At 18.6 years of age, a repeat spinal MRI in this patient showed worsening of spinal cord compression at the cranio-cervical region and hydrocephaly, requiring surgical decompression around 19 years. In case 9, a neurological examination at 17 years of age showed reduced muscle strength resulting in poor mobility. Deep tendon reflexes in this patient were minimal in the upper extremities and absent in the lower extremities. In case 10, MRI at 32 years of age showed spinal cord compression at the foramen magnum, upper cervical, lower thoracic and lumbar levels. Stenosis at the cranio-cervical junction resulted in myelomalacia. Spinal cord compression progressed over time; at last follow-up (40 year of age), an EMG showed patchy myogenic motor unit potentials, but otherwise no abnormalities.\n\nDenver Developmental Screening Test II data were reported at 2.6 years of age for case 1, at 1.7 years of age for case 2, and at 4.5 years of age for case 3. These showed a delay in fine motor skills, but otherwise no abnormalities in case 1, a delay in language and gross motor skills in case 2, and no abnormalities in case 3. Intelligence quotient, as determined by the Stanford-Binet test in cases 4, 5 and 6, the WISC-R in cases 7, 8 and 9, and the WAIS in case 10, was within normal limits in all children and adults, except case 9, who had cognitive impairment (intelligence quotient [IQ] 52) at 17.2 years of age, which was not considered associated with the diagnosed Morquio A syndrome [15].\n\nVisceral involvement\n\nLiver and spleen size were evaluated by physical examination and ultrasonography in all patients. Seven patients were reported to have hepatomegaly at treatment initiation (cases 1, 4, 5, 6, 8, 9 and 10) (Table 2). Case 9 and case 4 also had an enlarged spleen. Hepatomegaly resolved in cases 1, 4, 8, 9 and 10 at last follow-up, but persisted in cases 5 and 6.\n\nThree patients (cases 1, 5, and 6) had an umbilical hernia at the time treatment was initiated. For case 5, an inguinal hernia repair was also reported shortly after initiation of ERT.\n\nDiscussion\n\nThe present case series provides a better insight into the genotypic and phenotypic characteristics of a small group of Morquio A patients from Turkey, and provides real-life evidence on the long-term impact of ERT on the disease in clinical practice in a wide age range.\n\nMutational analysis and clinical data suggest that the majority of patients in the series had a classical (severe) Morquio A phenotype. Seven of the ten mutations reported in our case series have been described in previous publications [16–20]. Three of these i.e. p.P179S (case 1), p.W141R (case 7), and p.Q473X (case 9) were previously reported for Turkish patients [16–18], whereas p.C308R (case 3), p.L36P (case 4), p.R90W (case 5), and p.C308R (case 8) have been described in other countries [19, 20]. All these mutations have been associated with a classical phenotype, except L36P, which was linked to non-classical disease [16–20]. Our data support these genotype–phenotype correlations. In accordance with a classical Morquio A phenotype, cases 1 and 3 showed early onset of disease (before 2 years of age), including corneal clouding and skeletal dysplasia, and cases 5, 7, 8, and 9 showed short stature, poor mobility, skeletal dysplasia, corneal clouding, cardiac valve disease, and restrictive and obstructive respiratory disease. Case 4 showed less severe growth impairment, minimal corneal clouding, no ENT abnormalities, and minimal cardiac abnormalities, confirming a non-classical phenotype. To our knowledge, phenotypes associated with the mutations of case 2 (p.V141R), case 6 (p.R219X), and case 10 (p.E450K) have not been previously described in the literature. Based on their stature and clinical characteristics at initiation of ERT, cases 2, 6 and 10 can probably be classified as having a classical phenotype.\n\nAs could be expected based on the progressive natural history of Morquio A syndrome, the three adults in the case series showed more severe disability than the children. Endurance in the 6MWT and 3MSCT was most severely impaired in the adults, confirming findings from the Morquio A Clinical Assessment Program (MorCAP) natural history study, which show a decrease in these measures over time [21]. The adult patients also showed the greatest deviations from normative height and weight curves, confirming natural history data [2, 22]. In addition, they appeared to have more severe musculoskeletal, cardiorespiratory, and neurological manifestations than the younger patients. Corneal clouding, hearing impairment and skeletal and joint abnormalities (mainly kyphosis, pectus carinatum, and joint laxity) were also commonly observed in the younger patients, including the two infants, stressing the importance of these manifestations in the early diagnosis of Morquio A syndrome. Whereas most children had conductive hearing loss, sensorineural hearing loss was reported for two of three adults, suggesting development of conductive hearing loss (due to otitis media) in the early disease course, and mixed or sensorineural hearing loss later in life, as also reported for MPS II [23].\n\nOverall, the longitudinal data after initiation of ERT suggest an impact of treatment on the progression of some clinical manifestations. The endurance outcomes appear to largely confirm published data. In line with the pivotal elosulfase alfa clinical trial [10], the adult patients showed a stabilization in endurance after initiation of treatment for up to 3 years. In the children, overall endurance also appeared to stabilize or improve over time. The most relevant findings in the infants were related to growth. Despite their classical phenotype, cases 1 and 2 showed slight increases in height z-scores after treatment initiation at 1.8 and 2.1 years of age and maintained a length/height within normal limits (z-scores -0.63 and -1.8) up to around 3 and 6 years of age, respectively. In older children, who initiated ERT between 3.4 and 7.1 years of age, height was already significantly below normal at baseline and further deviated from normal growth curves after treatment initiation.\n\nOur growth data in the two infants are remarkable given the progressive deviation from normal growth curves after 2 years of age described for untreated patients with Morquio A syndrome [2, 14, 22]. These observations are particularly relevant considering the very limited data currently available for Morquio A patients starting ERT at this early age [22, 24, 25]. Our data confirm recent findings from a study of two siblings with Morquio A starting ERT at the ages of 54 months and 11 months. Over 4.5 years of treatment, growth of the youngest sibling deviated less from the norms than that of the older sibling, although a significant growth retardation was still seen after 2 years of age [24]. Other studies showed mixed results [22, 25]. A clinical study including 15 patients starting ERT at < 5 years of age also showed a trend towards improved growth versus untreated patients from the MorCAP study, although no increase in the mean z-score over time [22]. Another recent study including 12 patients starting ERT before 5 years of age, showed no effect of ERT on growth [25]. It is not clear why these studies have conflicting results. However, it should be noted that most patients that were included in both studies were older than 2 years when treatment was initiated. Together with our findings, the published data suggest that starting ERT very early in life can reduce, though not prevent, growth retardation in Morquio A patients. The earlier treatment is started, the better growth outcomes appear to be, although other factors such as genotype are also likely to have an impact. These findings support the international recommendation of starting treatment for Morquio IVA patients as early as possible [7].\n\nThe impact of (early) treatment initiation on other clinical manifestations was more difficult to determine. Apart from normal growth, case 2 also maintained normal joint range of motion and showed improvements in kyphosis and corneal clouding after 3.7 years of treatment. However, skeletal abnormalities continued to progress in the other cases after treatment initiation, although joint range of motion remained stable in all patients. Also, none of the other patients showed improvements in corneal clouding or vision, except case 1 in whom corneal clouding resolved after 0.8 years of ERT. The case series did not suggest a positive impact of ERT on cardiac function, with three patients showing a deterioration over time and the others showing no progression..\n\nIn conclusion, our case series provides real-life data on the natural history of Morquio A syndrome in patients from Turkey starting treatment with elosulfase alfa at different ages. Overall, our data appear to confirm clinical trial results showing a long-term stabilization of endurance after treatment initiation across ages [10]. In addition, growth data in the youngest patients suggest that very early intervention optimizes growth outcomes. This result provides support that a prompt diagnosis of this rare disease Morquio A, combined with the earliest initiation of ERT, would provide children the greatest potential improvement in health outcomes. Larger studies with long-term follow-up in infants are required to confirm these findings and to determine the long-term impact of early treatment initiation on other outcomes.\n\nSupplementary Information\n\nAdditional file 1: Length/height and weight z-scores at initiation of enzyme replacement therapy (ERT) and last follow-up. Description of data: Z-scores were calculated based on Centers for Disease Control and Prevention (CDC) growth charts (https://peditools.org/growthinfant/index.php for patients 0–2 years of age and https://peditools.org/growthpedi/index.php for older patients). Body mass index (BMI) percentiles were calculated using https://www.cdc.gov/healthyweight/bmi/calculator.html for patients 2–20 years and https://www.cdc.gov/healthyweight/assessing/bmi/adult_BMI/english_bmi_calculator/bmi_calculator.html for adults > 20 years.\n\nAbbreviations\n\n3MSCT 3-min stair climb test\n\n6MWT 6-min walk test\n\nCDC Centers for Disease Control and Prevention\n\nEMG Electromyogram\n\nENT Ear-nose-throat\n\nERT Enzyme replacement therapy\n\nGAGs Glycosaminoglycans\n\nGALNS N-acetylgalactosamine-6-sulfatase\n\nIQ Intelligence quotient\n\nKS Keratan sulfate\n\nMorCAP Morquio A Clinical Assessment Program\n\nMPS Mucopolysaccharidosis\n\nMRI Magnetic resonance imaging\n\nSD Standard deviation\n\nuKS Urinary keratan sulfate\n\nWAIS Wechsler Adult Intelligence Scale\n\nWISC-R Wechsler Intelligence Scale Revised test\n\nAcknowledgements\n\nThe authors are grateful to MonitorCRO for collecting the clinical data from the medical records and Ismar Healthcare NV for their assistance in the writing of this manuscript, which was funded by BioMarin Pharmaceutical Inc., Novato, CA, USA.\n\nAuthors' contributions\n\nHNÖM, SK, SB, DK, and FDB were involved in surgical and medical practices; HNÖM, SK, SB, DK, FDB, SE, HTB, MD, and AB were involved in data collection and processing; HNÖM and SK analyzed and interpreted the results. All authors read and approved the final manuscript.\n\nFunding\n\nThis work was supported by BioMarin Pharmaceutical, Inc. However, BioMarin was not involved in the data collection or writing process.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe study was approved by the Ethics in Research Committee of Çukurova University Faculty of Medicine, Adana, Turkey (approval number: 2020/96–01). All patients provided consent to participate in the study (Approval number: 2019/85–58).\n\nConsent for publication\n\nAll patients provided consent to publish clinical data.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Hendriksz CJ Harmatz P Beck M Jones S Wood T Lachman R Gravance CG Orii T Tomatsu S Review of clinical presentation and diagnosis of mucopolysaccharidosis IVA Mol Genet Metab 2013 110 54 64 10.1016/j.ymgme.2013.04.002 23665161\n2. Harmatz P Mengel KE Giugliani R Valayannopoulos V Lin SP Parini R Guffon N Burton BK Hendriksz CJ Mitchell J Martins A Jones S Guelbert N Vellodi A Hollak C Slasor P Decker C The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects Mol Genet Metab 2013 109 54 61 10.1016/j.ymgme.2013.01.021 23452954\n3. Hendriksz CJ Giugliani R Harmatz P Lampe C Martins AM Pastores GM Steiner RD Leão Teles E Valayannopoulos V Design, baseline characteristics, and early findings of the MPS VI (mucopolysaccharidosis VI) Clinical Surveillance Program (CSP) J Inherit Metab Dis 2013 36 373 384 10.1007/s10545-011-9410-9 22127392\n4. Hendriksz CJ Al-Jawad M Berger KI Hawley SM Lawrence R Mc Ardle C Summers CG Wright E Braunlin E Clinical overview and treatment options for non-skeletal manifestations of mucopolysaccharidosis type IVA J Inherit Metab Dis 2012 36 309 322 10.1007/s10545-012-9459-0 22358740\n5. Tomatsu S Averill LW Sawamoto K Mackenzie WG Bober MB Pizarro C Goff CJ Xie L Orii T Theroux M Obstructive airway in Morquio A syndrome, the past, the present and the future Mol Genet Metab 2016 117 150 156 10.1016/j.ymgme.2015.09.007 26432669\n6. Pizarro C Davies RR Theroux M Spurrier EA Averill LW Tomatsu S Surgical reconstruction for severe tracheal obstruction in Morquio A syndrome Ann Thorac Surg 2016 102 e329 331 10.1016/j.athoracsur.2016.02.113 27645974\n7. Akyol MU, Alden TD, Amartino H, Ashworth J, Belani K, Berger KI, Borgo A, Braunlin E, Eto Y, Gold JI, Jester A, Jones SA, Karsli C, Mackenzie W, Marinho DR, McFadyen A, McGill J, Mitchell JJ, Muenzer J, Okuyama T, Orchard PJ, Stevens B, Thomas S, Walker R, Wynn R, Giugliani R, Harmatz P, Hendriksz C, Scarpa M, Committee MPSCPS, Co-Chairs MPSCP. Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance. Orphanet J Rare Dis. 2019;14:137.\n8. Hendriksz CJ, Burton B, Fleming TR, Harmatz P, Hughes D, Jones SA, Lin SP, Mengel E, Scarpa M, Valayannopoulos V, Giugliani R, Slasor P, Lounsbury D, Dummer W, STRIVE Investigators. Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study. J Inherit Metab Dis. 2014;37:979–90.\n9. Hendriksz CJ, Giugliani R, Harmatz P, Mengel E, Guffon N, Valayannopoulos V, Parini R, Hughes D, Pastores GM, Lau HA, Al-Sayed MD, Raiman J, Yang K, Mealiffe M, Haller C, STRIVE Investigators. Multi-domain impact of elosufase alfa in Morquio A syndrome in the pivotal phase III trial. Mol Genet Metab. 2015;114:178–185.\n10. Hendriksz CJ Parini R AlSayed MD Raiman J Giugliani R Solano Villarreal ML Mitchell JJ Burton BK Guelbert N Stewart F Hughes DA Berger KI Slasor P Matousek R Jurecki E Shaywitz AJ Harmatz PR Long-term endurance and safety of elosulfase alfa enzyme replacement therapy in patients with Morquio A syndrome Mol Genet Metab 2016 119 131 143 10.1016/j.ymgme.2016.05.018 27380995\n11. Hendriksz CJ Berger KI Parini R AlSayed MD Raiman J Giugliani R Mitchell JJ Burton BK Guelbert N Stewart F Hughes DA Matousek R Jurecki E Decker C Harmatz PR Impact of long-term elosulfase alfa treatment on respiratory function in patients with morquio a syndrome J Inherit Metab Dis 2016 39 839 847 10.1007/s10545-016-9973-6 27553181\n12. Hendriksz CJ Parini R AlSayed M Raiman J Giugliani R Mitchell J Burton BK Guelbert N Stewart FJ Hughes DA Matousek R Hawley SM Decker C Harmatz PR Impact of long-term elosulfase alfa on activities of daily living in patients with morquio a syndrome in an open-label, multi-center, phase 3 extension study Mol Genet Metab 2018 123 127 134 10.1016/j.ymgme.2017.11.015 29248359\n13. Lammers AE Hislop AA Flynn Y Haworth SG The 6-minute walk test: normal values for children of 4–11 years of age Arch Dis Child 2008 93 464 468 10.1136/adc.2007.123653 17675356\n14. Montaño AM Tomatsu S Brusius A Smith M Orii T Growth charts for patients affected with Morquio A disease Am J Med Genet A 2008 146A 1286 1295 10.1002/ajmg.a.32281 18412124\n15. Borlot F Ricci Arantes P Robledo Quaio C da Silva Franco JF Marques Lourenço C Gomy I Romeo Bertola D Kim CA Mucopolysaccharidosis type IVA: evidence of primary and secondary central nervous system involvement Am J Med Genet A 2014 164A 1162 1169 10.1002/ajmg.a.36424 24478273\n16. Terzioglu M Tokatli A Coskun T Emre S Molecular analysis of Turkish mucopolysaccharidosis IVA (morquio a) patients: identification of novel mutations in the N-acetylgalactosamine-6-sulfate sulfatase (GALNS) gene Hum Mutat 2002 20 477 478 10.1002/humu.9088\n17. Bunge S Kleijer WJ Tylki-Szymanska A Steglich C Beck M Tomatsu S Fukuda S Poorthuis BJ Czartoryska B Orii T Gal A Identification of 31 novel mutations in the N-acetylgalactosamine-6-sulfatase gene reveals excessive allelic heterogeneity among patients with Morquio A syndrome Hum Mutat 1997 10 223 232 10.1002/(SICI)1098-1004(1997)10:3<223::AID-HUMU8>3.0.CO;2-J 9298823\n18. Khedhiri S Chkioua L Elcioglu N Laradi S Miled A Mutations and polymorphisms in N-acetylgalactosamine-6-sulfate sulfatase gene in Turkish morquio a patients Pathol Biol (Paris) 2014 62 38 40 10.1016/j.patbio.2013.10.001 24411403\n19. Dung VC Tomatsu S Montaño AM Gottesman G Bober MB Mackenzie W Maeda M Mitchell GA Suzuki Y Orii T Mucopolysaccharidosis IVA: correlation between genotype, phenotype and keratan sulfate levels Mol Genet Metab 2013 110 129 138 10.1016/j.ymgme.2013.06.008 23876334\n20. Tomatsu S Montaño AM Nishioka T Gutierrez MA Peña OM Trandafirescu GG Lopez P Yamaguchi S Noguchi A Orii T Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A) Hum Mutat 2005 26 500 512 10.1002/humu.20257 16287098\n21. Harmatz PR Mengel KE Giugliani R Valayannopoulos V Lin SP Parini R Guffon N Burton BK Hendriksz CJ Mitchell JJ Martins AM Jones SA Guelbert N Vellodi A Wijburg FA Yang K Slasor P Decker C Longitudinal analysis of endurance and respiratory function from a natural history study of Morquio A syndrome Mol Genet Metab 2015 114 186 194 10.1016/j.ymgme.2014.10.015 25582974\n22. Jones SA Bialer M Parini R Martin K Wang H Yang K Shaywitz AJ Harmatz P Safety and clinical activity of elosulfase alfa in pediatric patients with Morquio A syndrome (mucopolysaccharidosis IVA) less than 5 years Pediatr Res 2015 78 717 722 10.1038/pr.2015.169 26331768\n23. Keilmann A, Nakarat T, Bruce IA, Molter D, Malm G, HOS Investigators. Hearing loss in patients with mucopolysaccharidosis II: data from HOS - the Hunter Outcome Survey. J Inherit Metab Dis. 2012;35:343–353.\n24. Barak S, Anikster Y, Sarouk I, Stern E, Eisenstein E, Yissar T, Sherr-Lurie N, Raas-Rothschild A, Guttman D. Long-term outcomes of early enzyme replacement therapy for mucopolysaccharidosis IV: clinical case studies of two siblings. Diagnostics (Basel). 2020;10.\n25. Doherty C Stapleton M Piechnik M Mason RW Mackenzie WG Yamaguchi S Kobayashi H Suzuki Y Tomatsu S Effect of enzyme replacement therapy on the growth of patients with Morquio A J Hum Genet 2019 64 625 635 10.1038/s10038-019-0604-6 31019230\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1750-1172",
"issue": "16(1)",
"journal": "Orphanet journal of rare diseases",
"keywords": "Elosulfase alfa; Enzyme replacement therapy; Morquio A syndrome; Mucopolysaccharidosis IVA",
"medline_ta": "Orphanet J Rare Dis",
"mesh_terms": "D000328:Adult; D002648:Child; D002811:Chondroitinsulfatases; D056947:Enzyme Replacement Therapy; D006801:Humans; D009085:Mucopolysaccharidosis IV; D012189:Retrospective Studies; D014421:Turkey",
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"pubdate": "2021-03-22",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Morquio A syndrome and effect of enzyme replacement therapy in different age groups of Turkish patients: a case series.",
"title_normalized": "morquio a syndrome and effect of enzyme replacement therapy in different age groups of turkish patients a case series"
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"abstract": "The stiff person syndrome (SPS) is an extremely rare neurological disorder with primarily immune-mediated etiology. The cardinal symptoms are progressive, fluctuating axial/proximal limb muscle stiffness and spasms. The diagnosis is based on the clinical picture, electromyography examination and detection of antibodies to glutamic acid decarboxylase (anti-GAD). Adverse effects of medications might preclude its use or increase in dosing, therefore symptomatic and/or immunomodulatory medical therapy might be ineffective in acute exacerbation of the disease. We present a case of a 49-year-old female with exacerbation of SPS, in whom some standard pharmacotherapy could not be introduced (clonazepam, baclofen used in the past) and doses of existing standard medications could not be increased (diazepam, gabapentin, and levetiracetam) due to adverse effects. Moreover, a newly introduced medication (methylprednisolone) also led to a serious adverse effect (severe hyperglycemia). The patient underwent therapeutic plasma exchange (TPE) with good effect and no complications. We review the literature regarding the efficacy and safety profile of TPE in exacerbation of SPS unresponsive to medical therapy. The procedure seems to have a good safety profile as an adjunct therapy for exacerbation of SPS not responding to standard medical therapy in this patient population.",
"affiliations": "Department of Anaesthesiology and Intensive Care, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 14, Katowice, 40-752, Poland.;Department of Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 14, Katowice, 40-752, Poland.;Department of Anaesthesiology and Intensive Care, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 14, Katowice, 40-752, Poland.;Department of Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 14, Katowice, 40-752, Poland.;Department of Anaesthesiology and Intensive Care, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 14, Katowice, 40-752, Poland.",
"authors": "Czempik|Piotr F|PF|;Gawryluk|Justyna|J|;Wiórek|Agnieszka|A|;Krzystanek|Ewa|E|;Krzych|Łukasz J|ŁJ|",
"chemical_list": null,
"country": "Poland",
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"doi": "10.1515/med-2021-0220",
"fulltext": "\n==== Front\nOpen Med (Wars)\nOpen Med (Wars)\nmed\nOpen Medicine\n2391-5463\nDe Gruyter\n\nmed-2021-0220\n10.1515/med-2021-0220\nMini-Review\nEfficacy and safety of therapeutic plasma exchange in stiff person syndrome\nCzempik Piotr F. pczempik@sum.edu.pl\n\nGawryluk Justyna\nWiórek Agnieszka\nKrzystanek Ewa\nKrzych Łukasz J.\nDepartment of Anaesthesiology and Intensive Care, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 14, Katowice, 40-752, Poland\nDepartment of Neurology, Faculty of Medical Sciences in Katowice, Medical University of Silesia, Medyków 14, Katowice, 40-752, Poland\ntel: +48-505-087-875, fax:+48-32-252-59-55\n30 3 2021\n2021\n16 1 526531\n04 7 2020\n20 11 2020\n08 1 2021\n© 2021 Piotr F. Czempik et al., published by De Gruyter\n2021\nPiotr F. Czempik et al., published by De Gruyter\nThis work is licensed under the Creative Commons Attribution 4.0 International License.\n\nAbstract\n\nThe stiff person syndrome (SPS) is an extremely rare neurological disorder with primarily immune-mediated etiology. The cardinal symptoms are progressive, fluctuating axial/proximal limb muscle stiffness and spasms. The diagnosis is based on the clinical picture, electromyography examination and detection of antibodies to glutamic acid decarboxylase (anti-GAD). Adverse effects of medications might preclude its use or increase in dosing, therefore symptomatic and/or immunomodulatory medical therapy might be ineffective in acute exacerbation of the disease. We present a case of a 49-year-old female with exacerbation of SPS, in whom some standard pharmacotherapy could not be introduced (clonazepam, baclofen used in the past) and doses of existing standard medications could not be increased (diazepam, gabapentin, and levetiracetam) due to adverse effects. Moreover, a newly introduced medication (methylprednisolone) also led to a serious adverse effect (severe hyperglycemia). The patient underwent therapeutic plasma exchange (TPE) with good effect and no complications. We review the literature regarding the efficacy and safety profile of TPE in exacerbation of SPS unresponsive to medical therapy. The procedure seems to have a good safety profile as an adjunct therapy for exacerbation of SPS not responding to standard medical therapy in this patient population.\n\nKeywords\n\nglutamic acid decarboxylase\nprocedure efficacy\nprocedure safety\nstiff person syndrome\ntherapeutic plasma exchange\n==== Body\n1 Introduction\n\nThe stiff person syndrome (SPS) is a rare neurological disorder first reported in 1956 [1]. The incidence of the disease is 1/1,000,000, and it affects mostly women of 40–50 years of age [2]. SPS seems to have an autoimmune etiology, although its exact pathophysiologic mechanism remains unclear [3]. Most patients develop antibodies to the 65-kD isoform of glutamic acid decarboxylase (anti-GAD65), leading to a decrease in gamma-aminobutyric acid (GABA) [4]. Antibodies have been found to numerous other proteins: amphiphysin [5], gephyrin [6], Ri [7], dipeptidyl-peptidase-like protein-6, GABAA receptor-associated protein (GABAARAP), glycine receptor, and glycine transporter 2 [8]. The classic form of anti-GAD65-positive SPS is associated with other autoimmune disorders: insulin-dependent diabetes mellitus, Hashimoto’s thyroiditis, megaloblastic anemia, and celiac disease [9]. In the paraneoplastic form of SPS, associated with different types of cancers (breast, lung, thymus, colon, and lymphoma), antibodies to amphiphysin have been detected [5]. The typical presentation is progressive and fluctuating axial and proximal limb rigidity, lumbar hyperlordosis, postural instability, gait difficulties, falls, painful muscular cramps, spasms, and hyperactivity to stimuli [10,11]. Depression and generalized anxiety disorder are also common, sometimes even predominate [12]. Apart from classic and paraneoplastic forms of SPS, there are numerous variant forms: focal, segmental; progressive encephalomyelitis with rigidity and myoclonus; jerky SPS; and SPS comorbid with ataxia and epilepsy [10]. Diagnosis of SPS is based on the 2009 Dalakas criteria, electromyography examination (continuous motor unit activity at rest), and detection of specific antibodies [13].\n\nStandard symptomatic medical management includes GABA-ergic agonists (diazepam, clonazepam), baclofen, anticonvulsants, and physical therapy [14]. First-line immunomodulatory therapy includes corticosteroids, intravenous immunoglobulins (IVIGs) [15], and therapeutic plasma exchange (TPE) [16]. Second-line immunomodulatory therapy includes cyclophosphamide, mycophenolate mofetil, and rituximab [17].\n\nThe case presents an anti-GAD65-positive patient with marked deterioration of symptoms, in whom TPE was used successfully as an adjunct therapy. We performed a review of the available literature in the context of safety and efficacy of TPE in acute exacerbation of SPS.\n\n2 Case presentation\n\nA 49-year-old female patient with exacerbation of SPS was admitted to the intensive care unit (ICU) to undergo TPE. The patient was diagnosed with SPS in 2013, the first symptoms noticed were pain in the lower extremities with paroxysmal increase in muscle tone; forced, painful, upright positioning of the left limbs; and two falls due to sudden generalized stiffness triggered by external stimuli. The comorbidities included type 2 diabetes mellitus, Hashimoto’s thyroiditis, and dyslipidemia. Past medical history, along with adverse effects that the patient developed, is presented in Table 1.\n\nTable 1 Adverse effects to standard medical therapy and maximal tolerated dosing\n\nMedication\tAdverse effect\tMax. daily tolerated dose (mg)\t\nDiazepam\tVertigo, tachycardia, hypotension\t14\t\nClonazepam\tWorsened dystonia, speech difficulties\tNone\t\nBaclofen\tIncreased rigidity\tNone\t\nGabapentin\tVertigo, tachycardia, hypotension\t1,800\t\nLevetiracetam\tParadoxical convulsions\t1,500\t\nMethylprednisolone\tHyperglycemia\tNot tolerating therapeutic doses (1,500)\t\n\nIn 2018 and 2019, the patient had the erector spine muscle injected with botulinum toxin A (1,000 U), what reduced spasticity and improved patient’s gait. Over the previous 6 months, despite fixed daily oral doses of diazepam and gabapentin, the patient reported progression of symptoms: nystagmus, paresis, and spasticity of the left extremities; pain in the left lower extremity; paroxysmal axial rigidity; falls; dysphagia; and dyspnea. Due to exacerbation of the disease, the patient was admitted to the department of neurology for medical stabilization. IVIG was not used as it is not reimbursed by the Polish national healthcare insurer for the treatment of immune-mediated conditions. After an unsuccessful attempt at medical stabilization (5 days), the patient was admitted to the ICU to undergo TPE.\n\nAt the time of admission to the ICU, the concentration of anti-GAD65 was >2,000 U mL−1. Following admission to the ICU, the left radial artery was cannulated (Arterial Cannula 20 G; Becton Dickinson, Poland) and continuous, invasive arterial blood pressure monitoring was started along with minimally invasive pulse contour hemodynamic monitoring (LiDCO Rapid; LiDCO, United Kingdom). The right internal jugular vein was cannulated under ultrasound guidance (M7; Mindray, People’s Republic of China) and a 13 Fr dialysis catheter (GAMCATH HighFlow Dolphin Catheter; Baxter, Poland) was inserted. A standard continuous renal replacement therapy multifiltrate system (Fresenius Medical Care, Germany) along with plasmaFlux P2dry plasma filter (Fresenius Medical Care, Germany) was used. We used unfractionated heparin for anticoagulation and 4% human albumin as substitution fluid: a mixture of 20% human albumin and multiBic solution (Fresenius Medical Care) in the 1:5 ratio. The plasma volume exchanged was 1.5. We planned and performed 5 every-other-day procedures, no complications were reported. In the ICU, further two episodes of painful (pain sensation described as worse than labor pains) stiffness with muscle contractions occurred: at the time of a dialysis catheter insertion and spontaneously on day 2 of the ICU stay. Following the fourth procedure, a noticeable reduction in paresis/dystonic posturing and improved gait were noticed. The findings from neurological examination before and immediately following the course of TPE are presented in Table 2.\n\nTable 2 Neurologic symptoms before and following the course of therapeutic plasma exchange\n\nNeurological symptoms\tBefore therapeutic plasma exchange\tAfter therapeutic plasma exchange\t\nNystagmus\tTransient, low-phase, horizontal\tAbsent\t\nSpasticity\tLeft limbs, paraspinal (hyperlordosis)\tSignificant improvement\t\nDystonia (left foot), UDRS\t3\t1\t\nDystonia (left foot), GDS\t8\t4\t\nGait, TUG\t52 s (walking frame)\t23 s (no support)\t\nMuscle strength, mBMRC\t\nLeft upper limb\t4\t4/5\t\nLeft lower limb\t2/3\t4\t\nRight lower limb\t4/5\t5\t\nmBMRC – modified British Medical Research Council Scale, GDS – global dystonia severity rating scale, TUG – timed up and go, UDRS – unified dystonia rating scale.\n\nThe total hospital length of stay was 14 days. The concentration of anti-GAD65 stayed elevated following TPE (>2,000 U mL−1 twice after the completion of the last TPE), nevertheless improvement in clinical symptoms remained (12-month follow-up period).\n\nDue to the noninterventional design of the study, the Bioethics Committee approval was not needed. All patients’ data were obtained in accordance with the national law regulations of personal data management, after the written informed consent was given by the patient on hospital admission. The project was approved by the head of the institution and departments within which the work was undertaken; it conforms to the provisions of the Declaration of Helsinki (as revised in Fortaleza, Brazil, October 2013).\n\n3 Discussion\n\nWe present a case report of a patient diagnosed with a typical form of SPS with a high titer of anti-GAD65 (>2,000 U mL−1) and typical comorbidities (diabetes mellitus and thyroiditis). The patient experienced an exacerbation of SPS with an unsuccessful attempt at pharmacological stabilization. As an adjunct therapy, we performed TPE (ICU setting), which led to significant clinical improvement (Table 2). No complications of the procedure itself reported.\n\nThe role of TPE in SPS has not been clearly defined. The most recent guidelines from the American Society for Apheresis report on 367 SPS patients (6 case series: 344 patients; 21 case reports: 23 patients) [18]. The rationale for the use of TPE in SPS is based on mixed results of TPE treatment provided by individual physicians who came across the syndrome. In most cases, TPE was used as an adjunct to immunosuppressive therapy. Relief of the SPS symptoms with TPE, even partial, was reported in 50–60% of patients [18]. That is the reason why the American Society for Apheresis in its recent guidelines did not make a strong recommendation for TPE in SPS (Grade 2C, category III) [18]. Since then Albahra et al. showed that in 10 patients with acute exacerbation of SPS (8 of whom were anti-GAD65 positive), TPE led to complete resolution of disease in 3 patients, partial resolution in 5 patients, and 2 patients showed no improvement [19]. Our case report is in line with the previous reports showing that TPE might be beneficial in anti-GAD65-positive SPS patients. The summary of the published case series and case reports, in the context of TPE efficacy in SPS, is presented in Table 3.\n\nTable 3 Efficacy and safety profile of therapeutic plasma exchange in exacerbation of SPS\n\nPaper (author, year)\tAnti-GAD65 positive/total cases\tTPE frequency (procedure/time period)\tTPE efficacy (number of patients)\tComplications (number of patients)\t\nVicari et al., 1989 [22]\t1/1\t5/10 days\tImprovement (1)\tNot observed\t\nHarding et al., 1989 [23]\t2/2\t5/5 days\tNo improvement (2)\tNot observed\t\nGordon et al., 1991 [24]\t1/1\tNot reported\tNo improvement (1)\tNot reported\t\nBrashear and Phillips, 1991 [25]\t1/1\tNot reported\tImprovement (1)\tNot observed\t\nNakamagoe et al., 1995 [26]\t0/1\t4/8 days\tImprovement (1)\tNot observed\t\nFogan et al., 1996 [27]\t0/1\t6/14 days\tImprovement (1)\tNot observed\t\nBarker et al., 1998 [28]\t2/2\tNot reported\tNo improvement (2)\tNot observed\t\nHao et al., 1999 [29]\t1/1\tChronic: 3/week, 2/week, 1/week\tImprovement (1)\tCLABSI (1)\t\nHayashi et al., 1999 [30]\t0/1\t4/8 days\tImprovement (1)\tNot observed\t\nShariatmadar and Noto, 2001 [31]\t0/2\t6/12 days\tImprovement (1)\tNot observed\t\n5/10 days\tNo improvement (1)\t\nDe la Casa-Fages et al., 2012 [20]\t2/2\t1/week\tImprovement (2)\tNot observed\t\nMcKeon et al., 2012 [32]\t79/99\tNot reported\tImprovement (1)\tNot reported\t\nPagano et al., 2014 [33]\t6/9\t5/10 days (7 patients)\tImprovement (7)\tCLABSI (1)\t\n10/20 days (1 patient)\tNo improvement (2)\tHypotension (1)\t\n15/30 days (1 patient)\t\t\t\nGeorgieva and Parton, 2014 [34]\t1/1\t5/5 days (1 patient)\tImprovement (1)\tNot observed\t\nZdziarski et al., 2015 [35]\t1/1\t2 courses\tImprovement (1)\tLow albumin (1)\t\nAnemia (1)\t\nTachycardia (1)\t\nBuechner et al., 2015 [10]\t2/3\tAttempt (1 patient)\tNo improvement (1)\tThrombosis (1)\t\nPham and Williams, 2016 [36]\t2/2\t30/60 days\tImprovement (1)\tHypotension (1)\t\nNo improvement (1)\t\nAlbahra et al., 2019 [19]\t8/10\t5/10 days (10 patients)\tImprovement (8)\tNot observed\t\nChronic (6 patients)\tNo improvement (2)\t\nAnti-GAD65 – antibodies to the 65-kD isoform of glutamic acid decarboxylase, CLABSI – central line-associated bloodstream infection, SPS – stiff person syndrome, TPE – therapeutic plasma exchange.\n\nBased on the published literature (Table 3), out of the total number of 163 patients reported, 120 tested positive for anti-GAD65. Only 40 (25% of the total number) patients underwent TPE (30 seropositive and 10 seronegative for anti-GAD65). Following TPE, 28 (70%, 23 anti-GAD65-positive) patients showed marked improvement and 12 (30%, 7 anti-GAD65-positive) patients showed no improvement. Despite the concentration of anti-GAD65 following TPE may not decrease, clinical improvement is still possible [20].\n\nIn our patient, the concentration of anti-GAD65 also did not decrease following TPE (>2,000 U mL−1 a month after the completion of the last TPE), nevertheless improvement in clinical symptoms remained (12-month follow-up). Some authors suggest that the lack of effectiveness of TPE in SPS is due to the presence of antibodies other than anti-GAD65, such as anti-amphiphysin and anti-GABAARAP. Anti-GABARAP is a 14-kD postsynaptic protein that inhibits GABAA receptor expression in about 65% of SPS patients, making patients with anti-GABAARAP respond better to IVIG compared to other treatments [21].\n\nThe safety profile of TPE in SPS has not been accurately explored. The possible TPE complications include those associated with dialysis catheter insertion (local hematoma, pneumothorax, and hemothorax) and maintenance (local infection, central line-associated bloodstream infection [CLABSI], deep vein thrombosis) and complications associated with the procedure itself (tachycardia, hypotension, dyspnea, hypoalbuminemia, citrate toxicity, allergic reaction, and decreased humoral immunity).\n\nBased on the published literature (Table 3), the most frequent TPE complications were CLABSI (2 of 40 patients, 5%), hypotension (2 of 40 patients, 5%), citrate toxicity (1 of 40 patients, 2.5%), endocarditis (1 of 40 patients, 2.5%), thrombosis (1 of 40 patients, 2.5%), hypoalbuminemia (1 of 40 patients, 2.5%), and tachycardia (1 of 40 patients, 2.5%). In our opinion, infection is probably the most serious complication. It is a complication of the procedure itself during which patient’s serum (immunoglobulins) is replaced with an immunoglobulin-free solution. Moreover, the presence of a dialysis catheter is a risk factor for CLABSI. In order to reduce the risk infection, one should always exclude infection (in our case the patient’s C-reactive protein concentration before the procedure was 2 mg L−1). All other complications can be eliminated/minimized by a meticulous technique of dialysis catheter insertion (optimized coagulation profile, US guidance, aseptic technique, full barrier precautions, and skilled staff), proper maintenance of a dialysis catheter, and multimodal monitoring of a patient during procedure (ICU setting).\n\n4 Conclusion\n\nTherapeutic plasma exchange may be a useful adjunct therapy for exacerbation of SPS not responding to standard medical therapy. The frequency of complications seems low. The exact efficacy and safety profile of TPE in this clinical setting remains undetermined and requires further research.\n\nConflict of interest: Authors state no conflict of interest.\n\nData availability statement: The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n\n[1] Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome); report of a case and some observations in 13 other cases. Proc Staff Meet Mayo Clin. 1956;31:421–7.\nMoersch FP Woltman HW Progressive fluctuating muscular rigidity and spasm (“stiff-man” syndrome); report of a case and some observations in 13 other cases Proc Staff Meet Mayo Clin 1956 31 421 7 13350379\n[2] Murinson BB, Butler M, Marfurt K, Gleason S, De Camilli P, Solimena M. Markedly elevated GAD antibodies in SPS. 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J Clin Apher. 2014;30:8–14. 10.1002/jca.21342.\nFarooqi MS Lai Y Lancaster E Schmitt SE Sachais BS Therapeutic plasma exchange and immunosuppressive therapy in a patient with anti-GAD antibody-related epilepsy: quantification of the antibody response J Clin Apher 2014 30 8 14 10.1002/jca.21342 24961613\n[17] Baker MR, Das M, Isaacs J, Fawcett PR, Bates D. Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry. 2005;76:999–1001. 10.1136/jnnp.2004.051144.\nBaker MR Das M Isaacs J Fawcett PR Bates D Treatment of stiff person syndrome with rituximab J Neurol Neurosurg Psychiatry 2005 76 999 1001 10.1136/jnnp.2004.051144 15965211\n[18] Padmanabhan A, Connelly-Smith L, Aqui N, Balogun RA, Klingel R, Meyer E, et al. Guidelines on the use of therapeutic apheresis in clinical practice – evidence-based approach from the writing committee of the American society for apheresis: the eighth special issue. J Clin Apher. 2019;34:171–354. 10.1002/jca.21705.\nPadmanabhan A Connelly-Smith L Aqui N Balogun RA Klingel R Meyer E Guidelines on the use of therapeutic apheresis in clinical practice – evidence-based approach from the writing committee of the American society for apheresis: the eighth special issue J Clin Apher 2019 34 171 354 10.1002/jca.21705 31180581\n[19] Albahra S, Yates SG, Joseph D, De Simone N, Burner JD, Sarode R. Role of plasma exchange in stiff person syndrome. Transfus Apher Sci. 2019;58:310–2. 10.1016/j.transci.2019.03.015.\nAlbahra S Yates SG Joseph D De Simone N Burner JD Sarode R Role of plasma exchange in stiff person syndrome Transfus Apher Sci 2019 58 310 2 10.1016/j.transci.2019.03.015 30952585\n[20] De la Casa-Fages B, Anaya F, Gabriel-Ortemberg M, Grandas F. Treatment of stiff-person syndrome with chronic plasmapheresis. Mov Disord. 2012;28:396–7. 10.1002/mds.25167.\nDe la Casa-Fages B Anaya F Gabriel-Ortemberg M Grandas F Treatment of stiff-person syndrome with chronic plasmapheresis Mov Disord 2012 28 396 7 10.1002/mds.25167 23239368\n[21] Bhatti AB, Gazali ZA. Recent advances and review on treatment of stiff person syndrome in adults and pediatric patients. Cureus. 2015;7:e427. 10.7759/cureus.427.\nBhatti AB Gazali ZA Recent advances and review on treatment of stiff person syndrome in adults and pediatric patients Cureus 2015 7 e427 10.7759/cureus.427 26848416\n[22] Vicari AM, Folli F, Pozza G, Comi GC, Comola M, Canal N, et al. Plasmapheresis in the treatment of stiff-man syndrome. N Engl J Med. 1989;320:1499. 10.1056/nejm198906013202220.\nVicari AM Folli F Pozza G Comi GC Comola M Canal N Plasmapheresis in the treatment of stiff-man syndrome N Engl J Med 1989 320 1499 10.1056/nejm198906013202220\n[23] Harding AE, Thompson PD, Kocen RS, Batchelor JR, Davey N, Marsden CD. Plasma exchange and immunosuppression in the stiff man syndrome. Lancet. 1989;2:915. 10.1016/s0140-6736(89)91568-7.\nHarding AE Thompson PD Kocen RS Batchelor JR Davey N Marsden CD Plasma exchange and immunosuppression in the stiff man syndrome Lancet 1989 2 915 10.1016/s0140-6736(89)91568-7\n[24] Gordon MF, Pullman S, McDonald T, Fahn S. Plasmapheresis in the treatment of stiff-man syndrome. Neurology. 1991;41:223.\nGordon MF Pullman S McDonald T Fahn S Plasmapheresis in the treatment of stiff-man syndrome Neurology 1991 41 223 1992365\n[25] Brashear HR, Phillips HL II. Autoantibodies to gabaergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology. 1991;41:1588–92. 10.1212/wnl.41.10.1588.\nBrashear HR Phillips HL II Autoantibodies to gabaergic neurons and response to plasmapheresis in stiff-man syndrome Neurology 1991 41 1588 92 10.1212/wnl.41.10.1588 1922799\n[26] Nakamagoe K, Ohkoshi N, Hayashi A, Hisahara S, Shoji S. 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Efficacy of therapeutic plasma exchange for treatment of stiff-person syndrome. Transfusion. 2014;54:1851–6. 10.1111/trf.12573.\nPagano MB Murinson BB Tobian AA King KE Efficacy of therapeutic plasma exchange for treatment of stiff-person syndrome Transfusion 2014 54 1851 6 10.1111/trf.12573 24527774\n[34] Georgieva Z, Parton M. Cerebellar ataxia and epilepsy with anti-GAD antibodies: treatment with IVIG and plasmapheresis. BMJ Case Rep. 2014; pii:bcr2013202314. 10.1136/bcr-2013-202314.\nGeorgieva Z Parton M Cerebellar ataxia and epilepsy with anti-GAD antibodies: treatment with IVIG and plasmapheresis BMJ Case Rep 2014 ; pii:bcr2013202314. 10.1136/bcr-2013-202314\n[35] Zdziarski P. A case of stiff person syndrome: immunomodulatory effect of benzodiazepines: successful rituximab and tizanidine therapy. Medicine (Baltimore). 2015;94:e954. 10.1097/MD.0000000000000954.\nZdziarski P A case of stiff person syndrome: immunomodulatory effect of benzodiazepines: successful rituximab and tizanidine therapy Medicine (Baltimore) 2015 94 e954 10.1097/MD.0000000000000954 26061327\n[36] Pham HP, Williams LA 3rd. Therapeutic plasma exchange in two patients with stiff-person syndrome. J Clin Apher. 2016;31:493–4. 10.1002/jca.21431.\nPham HP Williams LA 3rd Therapeutic plasma exchange in two patients with stiff-person syndrome J Clin Apher 2016 31 493 4 10.1002/jca.21431 26407506\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "16(1)",
"journal": "Open medicine (Warsaw, Poland)",
"keywords": "glutamic acid decarboxylase; procedure efficacy; procedure safety; stiff person syndrome; therapeutic plasma exchange",
"medline_ta": "Open Med (Wars)",
"mesh_terms": null,
"nlm_unique_id": "101672167",
"other_id": null,
"pages": "526-531",
"pmc": null,
"pmid": "33821220",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "26848416;27262149;11756577;26061327;24529469;19210912;24961613;24926406;24419643;23186907;23239368;22332190;26407506;10851565;15596766;8797535;9810930;31019968;15984030;2571826;19150172;20177693;11258614;26106494;24527774;25511790;10460456;31180581;10839351;13350379;30952585;8665734;15965211;1922799;2716805",
"title": "Efficacy and safety of therapeutic plasma exchange in stiff person syndrome.",
"title_normalized": "efficacy and safety of therapeutic plasma exchange in stiff person syndrome"
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"abstract": "Chimeric antigen receptor T (CAR-T) cell therapy has proven to be very effective in patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). However, infections-related either due to lymphodepletion or the CAR-T cell therapy itself-can result in severe and potentially life-threatening complications, while side effects such as cytokine release syndrome (CRS) might complicate differential diagnosis. Sixty-seven dosings of CAR-T cells in sixty adult patients with NHL (85%) and ALL (15%) receiving CAR-T cell therapy were assessed for infectious complications. Almost two-thirds of patients (61%) developed fever following lymphodepletion and CAR-T cell dosing. Microbiological or radiological findings were observed in 25% of all cases (bacterial 12%, viral 5%, fungal 8%). Inpatient infections were associated with more lines of therapy and more severe CRS. However, overall serious complications were rare after CAR-T therapy, with one patient dying of infection. Pathogen detection after inpatient stay was infrequent and mostly occurred in the first 90 days after dosing. Infections in CAR-T cell treated patents are common. Fast and suitable identification and treatment are crucial in these heavily pretreated and immunocompromised patients. In most cases infectious complications are manageable. Nonetheless, standardized anti-infective prophylaxis and supportive therapy are mandatory to reduce morbidity and mortality in CAR-T cell therapy.",
"affiliations": "Department of Internal Medicine V-Hematology, Oncology & Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Internal Medicine V-Hematology, Oncology & Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Internal Medicine V-Hematology, Oncology & Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Internal Medicine V-Hematology, Oncology & Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Internal Medicine V-Hematology, Oncology & Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Internal Medicine V-Hematology, Oncology & Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Internal Medicine V-Hematology, Oncology & Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany.;Department of Internal Medicine V-Hematology, Oncology & Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany.",
"authors": "Korell|Felix|F|;Schubert|Maria-Luisa|ML|;Sauer|Tim|T|;Schmitt|Anita|A|;Derigs|Patrick|P|;Weber|Tim Frederik|TF|;Schnitzler|Paul|P|;Müller-Tidow|Carsten|C|;Dreger|Peter|P|;Schmitt|Michael|M|0000-0002-1579-1509",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3390/cancers13071684",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n10.3390/cancers13071684\ncancers-13-01684\nArticle\nInfection Complications after Lymphodepletion and Dosing of Chimeric Antigen Receptor T (CAR-T) Cell Therapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia or B Cell Non-Hodgkin Lymphoma\nKorell Felix 1*\nSchubert Maria-Luisa 1\nSauer Tim 1\nSchmitt Anita 1\nDerigs Patrick 1\nWeber Tim Frederik 2\nSchnitzler Paul 3\nMüller-Tidow Carsten 1\nDreger Peter 1\nhttps://orcid.org/0000-0002-1579-1509\nSchmitt Michael 1\nPabst Thomas Academic Editor\n1 Department of Internal Medicine V—Hematology, Oncology & Rheumatology, University Hospital Heidelberg, 69120 Heidelberg, Germany; maria-luisa.schubert@med.uni-heidelberg.de (M.-L.S.); Tim.Sauer@med.uni-heidelberg.de (T.S.); Anita.Schmitt@med.uni-heidelberg.de (A.S.); Patrick.Derigs@med.uni-heidelberg.de (P.D.); carsten.mueller-tidow@med.uni-heidelberg.de (C.M.-T.); Peter.Dreger@med.uni-heidelberg.de (P.D.); michael.schmitt@med.uni-heidelberg.de (M.S.)\n2 Department of Diagnostic and Interventional Radiology, University Hospital Heidelberg, 69120 Heidelberg, Germany; Tim.Weber@med.uni-heidelberg.de\n3 Department of Virology, University Hospital Heidelberg, 69120 Heidelberg, Germany; paul.schnitzler@med.uni-heidelberg.de\n* Correspondence: felix.korell@med.uni-heidelberg.de; Tel.: +49-6221-56-7989\n02 4 2021\n4 2021\n13 7 168415 3 2021\n29 3 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nChimeric antigen receptor T (CAR-T) cells have become clinical practice for the treatment of acute lymphoblastic leukemia and non-Hodgkin lymphoma. The aim of this retrospective study was to assess infection complications after lymphodepletion and CAR-T cell therapy. Infections were commonly detected, but manageable in most cases. Fast and appropriate identification as well as treatment were critical, especially in this very vulnerable patient group. Effective strategies to prevent infections as well as adequate medical management also include standardized prophylaxis and additional supportive therapy.\n\nAbstract\n\nChimeric antigen receptor T (CAR-T) cell therapy has proven to be very effective in patients with relapsed/refractory acute lymphoblastic leukemia (ALL) and non-Hodgkin lymphoma (NHL). However, infections—related either due to lymphodepletion or the CAR-T cell therapy itself—can result in severe and potentially life-threatening complications, while side effects such as cytokine release syndrome (CRS) might complicate differential diagnosis. Sixty-seven dosings of CAR-T cells in sixty adult patients with NHL (85%) and ALL (15%) receiving CAR-T cell therapy were assessed for infectious complications. Almost two-thirds of patients (61%) developed fever following lymphodepletion and CAR-T cell dosing. Microbiological or radiological findings were observed in 25% of all cases (bacterial 12%, viral 5%, fungal 8%). Inpatient infections were associated with more lines of therapy and more severe CRS. However, overall serious complications were rare after CAR-T therapy, with one patient dying of infection. Pathogen detection after inpatient stay was infrequent and mostly occurred in the first 90 days after dosing. Infections in CAR-T cell treated patents are common. Fast and suitable identification and treatment are crucial in these heavily pretreated and immunocompromised patients. In most cases infectious complications are manageable. Nonetheless, standardized anti-infective prophylaxis and supportive therapy are mandatory to reduce morbidity and mortality in CAR-T cell therapy.\n\nCAR-T cell\ninfection\nlymphodepletion\ncytokine release syndrome\n==== Body\n1. Introduction\n\nFor patients with relapsed or refractory (r/r) B-lineage acute lymphoblastic leukemia (ALL) or r/r B-cell non-Hodgkin lymphoma (NHL), chimeric antigen receptor T (CAR-T) cell therapy has shown clinical efficacy [1,2,3]. In Europe, two CAR-T cell products are commercially available—axicabtagene ciloleucel (Axi-Cel; Yescarta®) and tisagenlecleucel (Tisa-Cel; Kymriah®). Axi-Cel is EMA-approved for r/r primary mediastinal B cell lymphoma (PMBCL) and diffuse large B cell lymphoma (DLBCL), while Tisa-Cel is approved for r/r DLBCL as well as r/r B-ALL in children and young adolescents (≤25 years).\n\nPatients undergoing CAR-T cell therapy are at risk of bacterial, viral and fungal infections. Besides the underlying disease compromising immune response in affected patients, more than four prior chemotherapeutic treatment regimens, use of lymphodepleting chemotherapy, a higher dose of administered CAR-T cells and ALL as underlying disease are risk factors for infection after CAR-T cell treatment, as are cytopenia with a baseline absolute neutrophil count (ANC) below 500 cells/mm3 and b cell aplasia [4,5,6]. Moreover, treatment of CAR-T cell toxicities, i.e., the use of anti-cytokine treatment with tocilizumab or steroids, further compromises the immune response in respective patients [4,5] Due to similar symptoms of infections and cytokine release syndrome (CRS), differential diagnosis until pathogen detection can be difficult.\n\nHere, we evaluated the frequency of infections in patients receiving CAR-T cell therapy during the initial hospitalization phase. Simultaneous occurrence of CRS and infectious disease (ID) as well as complications from infection were analyzed. Furthermore, we assessed infection in patients until six months after CAR-T cell therapy. The investigation period was divided into two parts: after discharge until day 90 (early follow-up) and day 90 until day 180 (late follow-up). Additionally, we also investigated patient immune status with B cell and white blood cell (WBC) counts, cumulative steroid dosage during hospitalization and CAR-T cell expansion as potential influencing factors for infection during both follow-up periods.\n\n2. Materials and Methods\n\n2.1. Patients\n\nFrom September 2018 until September 2020, 60 patients at our center received CAR-T cells. Informed consent had been signed prior to treatment. Seven patients received two separate CAR-T cell dosings, resulting in a total of 67 dosings. Following CAR-T cell products being administered, the second-generation CAR-T cell products Axi-Cel comprising CD28 as costimulatory domain in a total dose of 0.4–2 × 108 CAR-T cells, Tisa-Cel comprising 4-1BB (CD137) as costimulatory domain in a total dose of 0.6–6 × 108 CAR-T cells and the third-generation CAR-T cell product (CD28 and 4-1BB costimulatory domains) were used within the clinical HD-CAR-1 trial at the Heidelberg University Hospital (EudraCT: 2016-004808-60; NCT: NCT03361748) [1,2,7]. 30 r/r DLBCL patients, two r/r PMBCL patients and one r/r mantle cell lymphoma (MCL) patient (as a compassionate use) received Axi-Cel. Tisa-Cel was administered to seven r/r DLBCL patients. The HD-CAR-1 product was administered in doses from 1 to 20 × 106 CAR-T cells/m2 body surface area to four r/r DLBCL patients, three r/r MCL patients, two r/r follicular lymphoma (FL) patients, two r/r chronic lymphocytic leukemia (CLL) patients and nine ALL patients in an escalating dose form [7]. All patients received a lymphodepleting chemotherapy with fludarabine and cyclophosphamide prior to CAR-T cell administration. According to the Declaration of Helsinki, written informed consent for all patients was obtained. Ethical approval and approvals from the local and federal competent authorities were granted. HD-CAR-1 trial protocol received Institutional Review Board approval from the Ethics Committee (Medical Faculty of Heidelberg University, reference number: AFmu-405/2017) in October 2017.\n\n2.2. Anti-Infective Prophylaxis\n\nUniform evidence-based guidelines for prophylaxis before and after CAR-T cell therapy have not yet been established. Similar to patients receiving autologous or allogeneic stem cell transplantation, prophylaxis for herpes simplex (HSV) and varicella zoster (VZV), as well as prophylaxis for pneumocystis jirovecii, are widely recommended until recovery of a CD4+ T-cell count above 200/µL and/or up to one year after CAR-T cell dosing [8,9]. Prophylaxis for bacterial or fungal infection varies among CAR-T cell centers and there is currently no standard use in all CAR-T cell patients, although in neutropenic patients it is strongly recommended [8,10]. Anti-infective prophylaxis at the Heidelberg University Hospital is summarized in Table 1.\n\nDetection and Categorization of Infection\n\nA standard-of-care (SOC) algorithm for fever after CAR-T cell treatment at the Heidelberg University Hospital included the following: after drawing blood cultures (from peripheral and, if available, central blood lines), appropriate antibiotic therapy was started (in neutrophil patients piperacillin/tazobactam was applied according to our standard operative procedure (SOP)). In cases of fever persistence or unclear fever beyond 48 h after antibiotic initiation, radiologic diagnostics, i.e., computed tomography (CT) of the chest, was carried out. Tests for pathogenic bacterial germs besides regular blood cultures included also other possible sources of infection such as catheter tips, which were also sent in for microbiological examination.\n\nConsidering viral infections, panel testing in case of respiratory symptoms including screening for respiratory syncytial virus (RSV), influenza and parainfluenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was carried out. Furthermore, at regular intervals in case of immunosuppressive therapy (e.g., after allogeneic hematopoietic cell transplantation) in patient history, before initiating lymphodepletion or in case of suspicion during the hospitalization, the patient’s blood was tested for infections with hepatis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV) as well as herpes virus species like herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV) or cytomegalovirus (CMV).\n\nFungal infections were diagnosed according to the 2008 revised European Organization for Research and Treatment of Cancer (EORTC) Consensus Group criteria including computed tomography (CT) of the chest to determine presence of typical imaging features, with proven, probable and possible invasive fungal disease [11].\n\n2.3. Cytokine Release Syndrome Grading\n\nCRS severity was graded according to consensus criteria [12].\n\n2.4. CAR-T Cell Expansion\n\nVector copy numbers of CAR-T cells for all used products (Axi-Cel, Tisa-Cel and HD-CAR-1) were assessed by single copy gene-based duplex-quantitative polymerase chain reaction (PCR) assay approach using standardized procedures [13,14].\n\n2.5. Data Analysis\n\nMicrosoft Excel® was used for the statistical analysis and data collection. Data were analyzed by standard statistical measures, including median and range (minimum/maximum). IBM SPSS 20 for Windows (IBM Corp., Armonk, NY, USA) was used to calculate significance using the Students T-test. For all tests, 95%-confidence interval was calculated (denoted as CI) and p-values < 0.05 were considered statistically significant.\n\n3. Results\n\n3.1. Patients Characteristics\n\nOf the 60 patients included in this study, 40 were male and 20 were female; 51 patients (85%) were diagnosed with lymphoma and 9 patients (15%) with ALL. Of all lymphoma patients, 41 patients (69%) had diffuse large B cell lymphoma (DLBCL), 4 (7%) mantle cell lymphoma (MCL), 2 (3%) chronic lymphocytic leukemia (CLL), 2 (3%) follicular lymphoma (FL) and 2 (3%) patients had primary mediastinal B-cell lymphoma (PMBCL) (Table 2). 33 (49%) of 69 CAR-T dosings were performed with Axi-Cel, 27 (40%) with the HD-CAR-1 product and seven (11%) with Tisa-Cel (Figure 1). All seven patients receiving a second CAR-T cell dosing were HD-CAR-1 patients.\n\n3.2. Baseline and Disease Analysis\n\nAge (56 years, range 20–74), Body mass index (24.4, range 15.9–45.5) and Karnovsky index (90, range 50–100) of the patients receiving CAR-T cells by gender (male 66.6%) are summarized in Table 2. Patients had received a median of 5 prior therapy lines (range 2–10) and had a median hospitalization duration of 20 days (range 14–110) following CAR-T cell administration. Four patients died after CAR-T cell therapy, three due to progressive disease and one by infection with CMV.\n\n3.3. Fever and Cytokine Release Syndrome (CRS)\n\nOverall, after 41 CAR-T cell dosings (61.2%) fever occurred (Table 3). In 11.9% of cases (8 dosings) fever developed after administration of lymphodepleting therapy before CAR-T cell dosings. CRS was diagnosed after 33 (49.2%) CAR-T cell dosings. Grade I CRS (64 %/n = 21) and grade II CRS (30%/n = 10) were most common, whereas grade III and IV were rarely observed (3%/each n = 1).\n\n3.4. Bacterial Infection and Antibiotic Treatment\n\nAfter eight dosings (11.9%), bacterial pathogens were identified (Table 3). Here, staphylococci (8.9%/n = 6) with subgroups S. epidermidis (7.5%/n = 5) and S. haemolyticus (1.4%/n = 1), Klebsiella pneumoniae and Escherichia coli (each 1.4%/n = 1) were detected. According to our on-house SOP, all patients who experienced fever received antibiotic therapy (61.2%/n = 41). Median duration of antibiotic treatment was 10 days (range 4–40). Of the aforementioned eight dosings with confirmed pathogens, five patients were simultaneously diagnosed with CRS (Figure 2).\n\n3.5. Viral Infection and Antiviral Treatment\n\nViral infections were observed after three dosings (4.5%), all after the CAR-T cell had been administered (Table 3). Detected viral pathogens were CMV (2.9/n = 2) and RSV (1.4%/n = 1), with a median treatment (CMV: foscarnet; RSV: ribavirin) duration of 15 days (range 8–30). Two of the abovementioned patients (one diagnosed with reactivated CMV and one with detected RSV) developed CMV and RSV pneumonia, respectively (see case report in Section 3.8). Laboratory values of CMV copies and creatinine of both patients are displayed in Figure 3, as both developed acute kidney failure, most likely related to foscarnet treatment. In two patients with viral infections (2.9%), CRS was simultaneously diagnosed (Figure 2).\n\n3.6. Fungal Infection and Antifungal Treatment\n\nFive patients (7.5%) developed a suspected fungal infection after CAR-T cell dosing (Table 3). Anti-fungal treatment had a duration of 13 days (range 12–19). In four cases, radiological evaluations were suspected to be of fungal origin and classified as possible invasive fungal disease according to EORTC criteria. In the other patient, additional to radiological findings, aspergillus fumigatus in bronchoalveolar lavage (BAL) was detected (probable invasive fungal disease classification). Concomitant CRS was evident after all five dosings (7.5%) (Figure 2).\n\n3.7. Overview of Infections and Complications\n\nOverall, in 16 CAR-T cell dosings (23.8%) a pathogen or cause for infection was detected. Occurrence of bacterial, viral and fungal infections was equally distributed (bacterial/viral: 8 [CI 3–10] vs. 3 [CI 1–6], p = 0.1; bacterial/fungal: 8 [CI 3–10] vs. 5 [CI 3–9], p = 0.2; viral/fungal: 3 [CI 1–6] vs. 5 [CI 3–9], p = 0.2). Furthermore, a comparable duration of therapy was observed (bacterial/viral: 10 [CI 10–15] vs. 15 [CI 5–30] days, p = 0.2; bacterial/fungal: 10 [CI 10–15] vs. 13 [CI 10–19] days, p = 0.3; viral/fungal: 15 [CI 5–30] vs. 13 [CI 10–19] days, p = 0.3). DLBCL was the underlying disease in 12 of 16 cases, followed by FL and ALL (each 2). For the group of patients with infection, three patients developed sepsis (all with a sequential organ failure assessment (SOFA) score >8) and required catecholamine therapy with noradrenaline for circulatory support as well as invasive ventilation. In addition, post-infection kidney failure occurred in eight of these patients where infection had been confirmed. When compared to all other dosings without infection, all the abovementioned complications were found to be significantly more frequent in patients with infection (catecholamine usage: 3 [CI 3–5] vs. 2 [CI 2–3], p = 0.02; invasive ventilation: 3 [CI 2–4] vs. 1 [CI 0–1], p = 0.004; post-fever kidney failure: 8 [CI 6–10] vs. 1 [CI 0–3], p < 0.001). Catecholamine use and invasive ventilation occurred significantly more often in patients with fungal compared to those with bacterial infection (2 [CI 2–3] vs. 0 [CI 0–1], p = 0.03 each), whereas other parameters, i.e., age or gender, did not influence the rate of catecholamine use. Furthermore, infection was not associated with administered CAR-T cell dosage (p = 0.2). However, CAR-T cell dose was significantly correlated with a higher grade of CRS (median grades 2 [CI 2–4] vs. 0 [CI 0–1], p < 0.001) and a higher number of prior therapies (median 6 [CI 5–10] vs. 3 [CI 2–4], p = 0.01).\n\n3.8. Case Reports:\n\n(a) CMV pneumonia: male patient, 71 years old, DLBCL, treated with Axi-Cel.\n\nOn day 29 after administration of CAR-T cells (extended inpatient stay after severe neurotoxicity—ICANS IV), the patient developed fever and an increasing need for oxygen supplementation. After drawing of blood cultures and initiation of antibiotic treatment with piperacillin/tazobactam, a CT scan revealed diffuse bronchocentric pulmonary ground-glass opacities predominantly in the left lower and left upper lobe (Figure 4). In addition, examination of both serum and BAL specimens were positive for CMV, strongly indicating CMV reactivation. Due to pancytopenia, antiviral therapy with foscarnet was initiated. However, the patient died due to multiple organ failure induced by pneumogenic sepsis on day + 7 after CMV detection.\n\n(b) RSV-B pneumonia: male patient, 68 years old, DLBCL, treated with Axi-Cel.\n\nA chest CT scan (day 5 before CAR-T dosing) showed bronchocentric consolidation and ground-glass opacities in the right upper lobe as well as areas with centrilobular nodules and tree-in-bud pattern in both lungs. On the third day after receiving the lymphodepleting therapy, the patient developed an increase in inflammation markers and a body temperature raised up to 38.2 °C. With a rapidly developing and increasing cough, a second set of CT scans was carried out without evidence of an infiltrate. However, a panel examination for respiratory viruses as additional diagnostics confirmed RSV-B in the throat swab. According to our in-house SOP, a therapy with ribavirin was initiated. Ribavirin could be discontinued after 31 days of treatment following negative panel testing for RSV and the patient was released in good general health condition 50 days after receiving CAR-T cells.\n\n3.9. Infection within the First 180 Days—Overall Occurance and Evaluation of Risk Factors\n\nPatients were intensively monitored after discharge and medical records were obtained from 56 dosings (83.5%), with unavailability in the other 11 dosings either due to death or loss of follow-up. For early follow-up, infections were observed in four patients—three of bacterial (two patients with S. epidermidis and one with E. coli) and one of viral (parainfluenza) origin. Another infection was identified in the late follow-up period: here, radiological evaluations were suspected to be of fungal origin and were classified as possible invasive fungal disease according to EORTC criteria, leading to a total of five patients with post-discharge infections in the overall follow-up after CAR-T cell dosing. B cell and white blood cells were comparable in both infection and non-infection cohorts (p = 0.14 and p = 0.48, respectively) (Figure 5).\n\nCumulative steroid dosages (in cortisone equivalence dosage) were also assessed, showing no significant differences in patients with (median 0.5 g [CI 0.0–2.5]) and without (median 0.1 g [CI 0.0–3.8]; p = 0.27) infection (Figure 6A). In addition, we analyzed CAR-T cell expansion in both groups at different time points (day 7, day 14, day 30, day 60, day 90 and day 180). Here, copy numbers per µL were comparable over the investigated time period (p = 0.16). (Figure 6B).\n\n4. Discussion\n\nInfectious complications constitute a risk for hospitalized cancer patients, particularly those treated with lymphodepleting chemotherapy as conditioning before CAR-T cell therapy. In this study on 67 CAR-T dosings in 60 patients with r/r ALL and NHL, the risk of infection was associated with the extent of prior treatment and the severity of CRS. Requirement of vasopressors and invasive ventilation was more frequent in patients with infection. However, overall lethal complications were rare.\n\nIn prior studies, infectious complications after CAR-T cell dosing were common, with bacterial, viral and fungal pathogens being the most frequent causes [15,16,17,18]. Particularly, infections with bacterial pathogens were shown to be frequent, occurring in about 15–20% of cases in previous studies on patients who had received CAR-T cell therapy [5,16]. The spectrum of pathogens has been described as very broad, with both gram-positive and negative, anaerobic and mycoplasm being detected. Neutropenic patients generally have a different pathogen environment than immunocompetent patients [19]. Our findings are comparable to the abovementioned studies. Of the 35 dosings with fever, only in eight patients a bacterial strain could be isolated (22.8%), similar to evaluations in other studies in patients with leukopenia (10 to 25%) [19,20]. Oftentimes, these arose from the patients’ endogenous flora [21]. Of the pathogens detected, staphylococcus species (with S. epidermidis and S. haemolyticus being known endogenous skin flora) was found in 75%.\n\nMost viral infections in patients after CAR-T cell therapy have been associated with respiratory viruses such as RSV, rhinoviruses, influenza and parainfluenza virus [16]. In some cases, viral infection is a reactivation of previous viral infections. Causes described in studies include HBV, HSV, VZV, EBV or CMV [12,15,22]. In our cohort, infections with CMV and RSV were detected, causing severe pneumonia in two cases. Both patients suffering from CMV were negative in screen testing before lymphodepletion chemotherapy and in additional regular testing for CM-viremia during their respective hospitalization. This illustrates the difficulties regarding early detection of virus reactivation. Therefore, regular tests should be performed at fixed intervals.\n\nFungal pathogens were also identified as probable cause for infection after lymphodepletion and CAR-T cell administration in several studies. Frequently detected pathogens were Aspergillus, Candida, Fusarium or Coccidioides spp. [18,23]. In one patient in our cohort, Aspergillus fumigatus was detected in the BAL fluid, while all other four patients had possible invasive fungal disease diagnosed by CT imaging.\n\nOverall, most infections occurred early after CAR–T cell infusion during hospitalization or in the first 90 days after dosing. In our study, B cell and WBC counts were not associated with higher risk for infection in patient follow-up, while steroid dosages and CAR-T cell expansion were also shown to be comparable in both groups. However, copy numbers were higher in early measurements on days 7 and 14 in patients without infection, warranting further investigation with more timepoints and in bigger cohorts.\n\nDifferential diagnosis of fever in patients receiving CAR-T cells is complex. Firstly, the patients might develop fever due to different causes such as the abovementioned bacterial, viral or fungal pathogens. As differential diagnosis, an incipient CRS must always be taken into account, which is statistically more frequent than a pathogen detection. High-grade CRS (grade ≥ 3) itself has been described as a risk factor for infection [4,5,15,24,25]. On the other hand, earlier studies as well as our evaluation underline the need for prophylaxis. These have shown to prevent infections as well as mitigate possible serious disease courses. In addition, adequate and rapid treatment of infections as a “hit hard and early” approach is important. This can reduce serious complications and the risk of fatal courses, especially in the immunocompromised host.\n\nAll of these evaluations show the need for special precautions and planning for patient follow-up care [26,27]. After administration of CAR-T cells, extensive monitoring is necessary until complete immune reconstitution. In this respect, follow-up of CAR-T cell patients should be performed in analogy of follow-up strategies for patients after allogeneic hematopoietic cell transplantation (alloHCT). Both patient groups share similarities regarding their immuno-reconstitution as well as potential complications. Because of this, regular follow-up testing should include testing, for example, of virus copies for CMV and EBV in order to detect reactivations at an early stage and treat them promptly before possible complications occur. In addition, this follow-up should also include other measures such as vaccination, e.g., for seasonal influenza or pneumococcus spp., as well as booster vaccinations for low titers. In the case of recurrent pneumonia, early control CT scans and early use of BAL should be considered. Moreover, this report as well as other evaluations of potential infections in patients receiving CAR-T cells underline the importance of standardized approaches to antimicrobial prophylaxis regimens in CAR–T cell recipients as well as special supportive care guidelines [8,10,24]. The approach in this study, with CAR-T dosing according to our SOP providing infection prevention with antibiotic, -viral and -fungal prophylaxis as well as “hit hard and early” anti-infective therapy in case of fever or other signs of infection, proved effective. However, with rates of prophylaxis before and after CAR-T cell therapy (Table 4) of only 13% antibiotic, 55% antiviral and 61% antifungal prophylaxis CAR-T cell dosing (61%, 88% and 90% afterwards, respectively), this leaves further room for improvement. Future goals include the identification of additional risk factors for infection and its timeframes as well as assessment of influencing factors in the pathogenesis of infection such as gut microbiota [28]. Moreover, evaluation of infections occurring before lymphodepletion and those after the infusion of CAR-T cells is necessary because of potential connections between the two. This further analysis could provide additional development and strengthening and improvement of infection prevention systems, as well as for safer therapy delivery and better patient outcomes.\n\nThis study included CAR–T cell recipients with six disease types as well as three different CAR-T cell products, standardized supportive-care measures and infection monitoring for the full duration of hospitalization. Also included was a full analyses of preexisting baseline and post-CAR–T cell infusion risk factors for infection with a follow-up of 180 days.\n\nLimitations include missing evaluation of infection beyond the follow-up period of 180 days. The results obtained are subject to limitations as a retrospective analysis, and with 67 CAR-T cell dosings, there was a small number of examined patients and infection events, both for hospitalization and follow-up, compared to the approval studies. All the findings of this analysis therefore need to be further evaluated and confirmed in randomized prospective studies or in a large meta-analyses.\n\n5. Conclusions\n\nWhile infectious complications commonly occur after lymphodepletion and CAR-T cell dosing, incidence and type of infections were consistent with those seen in patients treated for other r/r B-cell malignancies. Overall, infections (24%) were manageable, when supported by fast identification and initiation of treatment. Fatal infections were rarely observed (1.5%), especially among patients receiving optimized lymphodepletion chemotherapy and CAR–T cell dosing regimens. Standardized strategies to reduce risk and prevent infections in immunocompromised patients are pivotal for successful CAR-T cell dosing and should therefore be firmly established analogous to other hematological therapies such as alloHCT.\n\nAcknowledgments\n\nThe authors acknowledge financial support by Deutsche Forschungsgemeinschaft within the funding program Open Access Publishing, by the Baden-Württemberg Ministry of Science, Research and the Arts and by Ruprecht-Karls-Universität Heidelberg.\n\nAuthor Contributions\n\nF.K. and M.S. designed the research project. F.K., M.-L.S., P.D. (Peter Dreger) and M.S. acquired and analyzed the data. M.-L.S., M.S., P.D. (Peter Dreger) and F.K. discussed the data and the organization of the manuscript. F.K. wrote the manuscript. F.K., M.-L.S., T.S., A.S., P.D. (Patrick Derigs), T.F.W., P.S., C.M.-T., P.D. (Peter Dreger) and M.S. critically reviewed the manuscript, M.S., M.-L.S., and P.D. (Peter Dreger) edited the manuscript. M.S. supervised the work. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki, and approved by the Ethics Committee of the Medical Faculty of Heidelberg University (reference number: AFmu-405/2017 in October 2017).\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nThe data presented in this study are available in this article.\n\nConflicts of Interest\n\nM.S.: funding for collaborative research from Apogenix, Hexal and Novartis, travel grants from Hexal and Kite, financial support for educational activities and conferences from bluebird bio, Kite and Novartis, board member for MSD and (co-)PI of clinical trials of MSD, GSK, Kite and BMS, as well as co-Founder and shareholder of TolerogenixX Ltd. A.S.: travel grants from Hexal and Jazz Pharmaceuticals, research grant from Therakos/Mallinckrodt and co-founder of TolerogenixX LtD. C.M.-T.: consultancy Advisory Board for Pfizer and Janssen, and has received grants and research support from Pfizer, Daiichi Sankyo, BiolineRx and Bayer AG. P.D. (Peter Dreger): consultancy for AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche; speakers bureau for AbbVie, Gilead, Novartis, Riemser, Roche; research support from Neovii and Riemser. M.-L.S.: consultancy for Gilead. The other authors declare no conflict of interest.\n\nFigure 1 Distribution of CAR-T cell dosings by product. The main share of patients was treated with Axi-Cel (n = 33, 49%) and as part of the HD-CAR-1 study (n = 27, 40%). Seven patients received Tisa-Cel (11%).\n\nFigure 2 Distribution of infection and CRS. This graphic shows the distribution of infections—divided into bacterial (n = 8, 11.9%), viral (n = 3, 4.5%) and fungal (n = 5, 7.5%) origin and CRS (n = 33, 49.2%). Furthermore, infections with simultaneous CRS (n = 12, 17.9%) are displayed.\n\nFigure 3 Laboratory values (CMV-DNA, measured by PCR, and creatinine). Laboratory values of CMV copies and creatinine of patient (A) and patient (B) are displayed. Both patients developed acute kidney failure, most likely as an adverse effect from foscarnet.\n\nFigure 4 CMV pneumonia. CT scan with diffuse bronchocentric pulmonary ground-glass opacities predominantly in the left lower and left upper lobe.\n\nFigure 5 Immune status by measurement of B cell and WBC counts (median and CI). For assessment and comparison of immune status, B cell (A) and WBC (B) counts (per nanoliter; nL) of patients with and without infection after inpatient stay are shown at different timepoints ranging from day 30 to 180.\n\nFigure 6 Comparison of cumulative steroid dosages and CAR-T cell expansion (median and CI). Comparison of steroid dosages (A) received during hospitalization in patients with or without infection (in gram; g). Additionally, CAR-T expansion levels (B) in both subgroups are displayed.\n\ncancers-13-01684-t001_Table 1 Table 1 Recommended prophylaxis at Heidelberg University Hospital.\n\nAntibiotic\tOral: rifaximin 200 mg 2 × 1 until neutrophil regeneration\t\nAntiviral\tOral: aciclovir 2 × 400 mg daily until CD4 regeneration\nIntravenous: aciclovir 2 × 5 mg/kg daily\t\nAntifungal\tOral: co-trimoxazole 960 mg 1 × 1 only Mon, Wed, Fri for PCP prophylaxis (from day 0, accompanying folic acid 5 mg 2×/week) up to CD4 regeneration; fluconazole 200 mg, 0-1-0 until neutrophil regeneration (or if there is anamnestic evidence of fungal pneumonia: posaconazole: day 1: 100 mg 3-0-3; from day 2: 300 mg 0-1-0)\nIntravenous: co-trimoxazole 960 mg Mon, Wed, Fri for PCP prophylaxis (from day 0, accompanying folic acid 5 mg 2×/week until regeneration); fluconazole 200 mg 0-2-0\t\nThe dosages should be adjusted to the current kidney function. Alternative preparations should be used in the event of intolerance. PCP = pneumocystis pneumonia (also known as PJP for pneumocystis jiroveci pneumonia).\n\ncancers-13-01684-t002_Table 2 Table 2 Baseline and disease characteristics.\n\nBaseline Characteristics\tAll Patients\nn = 60\tMale\nn = 40\tFemale\nn = 20\t\nAge (years), median (range)\t56 (20–74)\t57 (20–71)\t47 (20–74)\t\nBody mass index, median (range)\t24.4 (15.9–45.5)\t26.4 (18.7–45.5)\t21.7 (15.9–41.1)\t\nKarnofsky index (percent), median (range)\t90 (50–100)\t90 (50–100)\t90 (50–100)\t\nDisease characteristics\tAll patients\nn = 60\t\t\t\nDisease\nPrior therapy lines median (range)\tDLBCL (69%), ALL (15%), MCL (7%), CLL (3%), FL (3%), PMBCL (3%)\n5 (2–10)\t\nDuration in-patient stay (days), median (range)\t20 (14–110)\t\nDLBCL = Diffuse large B-cell lymphoma, ALL = Acute lymphoblastic leukemia, MCL = Mantle cell lymphoma, CLL = chronic lymphocytic leukemia, FL = Follicular lymphoma, PMBCL = Primary mediastinal B-cell lymphoma.\n\ncancers-13-01684-t003_Table 3 Table 3 Microbiological characteristics and events.\n\nEvents\tOccurrence\t\t\t\nFever (in %/n)\t61.2/41\t\t\t\nCytokine release syndrome\n(in %/n)\t49.2/33:\ngrade I 64%/21, grade II 30%/10, grade III 3% & grade IV 3%/each 1\t\n\tBacterial infection\tViral infection\tFungal infection\t\nTreatment * (in %/n)\t61.2/41\t4.5/3\t7.5/5\t\ndays of application median (range)\t10 (4–40)\t15 (8–30)\t13 (12–19)\t\nCultured pathogen detected/suspected radiological diagnosis (in %, n)\t11.9/8\t4.5/3\t7.5/5\t\nsimultaneous CRS (in %, n)\t7.5/5\t3.0/2\t7.5/5\t\n* Either antibiotic/antiviral/antifungal, no prophylactic applications.\n\ncancers-13-01684-t004_Table 4 Table 4 Anti-infective prophylaxis before and after hospitalization.\n\n\tPrior Admission (in %, n)\tAfter Discharge (in %, n) †\t\nAntibacterial prophylaxis *\t13.4/9\t60.9/40\t\nAntiviral prophylaxis **\t55.2/37\t88.0/59\t\nAntifungal prophylaxis\tC 61.1/41, F 17.9/12, P 2.9/2, V 2.9/2\tC 89.5/60, F 62.6/42, P 4.4/3, V 4.4/3\t\n* = Either rifaximin, ciprofloxacin or amoxicillin/clavulanic acid; ** = acyclovir, † = in 5.9% of applications patient deceased during stationary stay and therefore received no further medication; C = co-trimoxazole, F = fluconazole, P = posaconazole: V = voriconazole (if both: C and either F/P/V).\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Wang X. Sénéchal B. Curran K.J. Sauter C. Wang Y. Santomasso B. Mead E. Long-Term Follow-up of CD19 CAR Therapy in Acute Lymphoblastic Leukemia N. Engl. J. Med. 2018 378 449 459 10.1056/NEJMoa1709919 29385376\n6. Fried S. Avigdor A. Bielorai B. Meir A. Besser M.J. Schachter J. Shimoni A. Nagler A. Toren A. Jacoby E. Early and late hema-tologic toxicity following CD19 CAR-T cells Bone Marrow Transpl. 2019 54 1643 1650 10.1038/s41409-019-0487-3\n7. Schubert M.-L. Schmitt A. Sellner L. Neuber B. Kunz J. Wuchter P. Kunz A. Gern U. Michels B. Hofmann S. Treatment of patients with relapsed or refractory CD19+ lymphoid disease with T lymphocytes transduced by RV-SFG CD19.CD28.4-1BBzeta retroviral vector: A unicentre phase I/II clinical trial protocol BMJ Open 2019 9 e026644 10.1136/bmjopen-2018-026644\n8. Mahmoudjafari Z. Hawks K.G. Hsieh A.A. Plesca D. Gatwood K.S. Culos K.A. American Society for Blood and Marrow Trans-plantation Pharmacy Special Interest Group Survey on Chimeric Antigen Receptor T Cell Therapy Administrative, Logistic, and Toxicity Management Practices in the United States Biol. Blood Marrow Transpl. 2019 25 26 33 10.1016/j.bbmt.2018.09.024\n9. Kansagra A.J. Frey N.V. Bar M. Laetsch T.W. Carpenter P.A. Savani B.N. Heslop H.E. Bollard C.M. Komanduri K.V. Gastineau D.A. Clinical Utilization of Chimeric Antigen Receptor T Cells in B Cell Acute Lymphoblastic Leukemia: An Expert Opinion from the European Society for Blood and Marrow Transplantation and the American Society for Transplantation and Cellular Therapy Biol. Blood Marrow Transpl. 2019 25 e76 e85 10.1016/j.bbmt.2018.12.068\n10. Yakoub-Agha I. Chabannon C. Bader P. Basak G.W. Bonig H. Ciceri F. Corbacioglu S. Duarte R.F. Einsele H. Hudecek M. Management of adults and children undergoing chimeric antigen receptor T-cell therapy: Best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) Haematologica 2019 105 297 316 10.3324/haematol.2019.229781\n11. De Pauw B. Walsh T.J. Donnelly J.P. Stevens D.A. Edwards J.E. Calandra T. Pappas P.G. Maertens J. Lortholary O. Kauffman C.A. Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2008 46 1813 1821\n12. Lee D.W. Gardner R. Porter D.L. Louis C.U. Ahmed N. Jensen M.C. Grupp S.A. Mackall C.L. Current concepts in the diagnosis and management of cytokine release syndrome Blood 2014 124 188 195 10.1182/blood-2014-05-552729 24876563\n13. Schubert M.-L. Kunz A. Schmitt A. Neuber B. Wang L. Hückelhoven-Krauss A. Langner S. Michels B. Wick A. Daniel V. Assessment of CAR T Cell Frequencies in Axicabtagene Ciloleucel and Tisagenlecleucel Patients Using Duplex Quantitative PCR Cancers 2020 12 2820 10.3390/cancers12102820\n14. Kunz A. Gern U. Schmitt A. Neuber B. Wang L. Hückelhoven-Krauss A. Michels B. Hofmann S. Müller-Tidow C. Dreger P. Optimized Assessment of qPCR-Based Vector Copy Numbers as a Safety Parameter for GMP-Grade CAR T Cells and Monitoring of Frequency in Patients Mol. Ther. Methods Clin. Dev. 2020 17 448 454 10.1016/j.omtm.2020.02.003 32201711\n15. Logue J.M. Zucchetti E. Bachmeier C.A. Krivenko G.S. Larson V. Ninh D. Grillo G. Cao B. Kim J. Chavez J.C. Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma Haematologica 2020 10.3324/haematol.2019.238634\n16. Hill J.A. Li D. Hay K.A. Green M.L. Cherian S. Chen X. Riddell S.R. Maloney D.G. Boeckh M. Turtle C.J. Infectious complications of CD19-targeted chimeric antigen receptor–modified T-cell immunotherapy Blood 2018 131 121 130 10.1182/blood-2017-07-793760 29038338\n17. Grupp S. Hu Z.-H. Zhang Y. Keating A. Pulsipher M.A. Philips C. Margossian S.P. Rosenthal J. Salzberg D. Schiff D.E. Tisagenlecleucel Chimeric Antigen Receptor (CAR) T-Cell Therapy for Relapsed/Refractory Children and Young Adults with Acute Lymphoblastic Leukemia (ALL): Real World Experience from the Center for International Blood and Marrow Trans-plant Research (CIBMTR) and Cellular Therapy (CT) Registry Blood 2019 134 Suppl. 1 2619\n18. Cordeiro A. Bezerra E.D. Hirayama A.V. Hill J.A. Wu Q.V. Voutsinas J. Sorror M.L. Turtle C.J. Maloney D.G. Bar M. Late Events after Treatment with CD19-Targeted Chimeric Antigen Receptor Modified T Cells Biol. Blood Marrow Transpl. 2020 26 26 33 10.1016/j.bbmt.2019.08.003\n19. Freifeld A.G. Bow E.J. Sepkowitz K.A. Boeckh M.J. Ito J.I. Mullen C.A. Raad I.I. Rolston K.V. Young J.A. Wingard J.R. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious dis-eases society of america Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2011 52 e56 e93 10.1093/cid/cir073\n20. Wood A.J. Pizzo P.A. Management of Fever in Patients with Cancer and Treatment-Induced Neutropenia N. Engl. J. Med. 1993 328 1323 1332 10.1056/NEJM199305063281808 8469254\n21. Schimpff S.C. Young V.M. Greene W.H. Vermeulen G.D. Moody M.R. Wiernik P.H. Origin of infection in acute nonlymphocytic leukemia. Significance of hospital acquisition of potential pathogens Ann. Intern. Med. 1972 77 707 714 10.7326/0003-4819-77-5-707 4628214\n22. Wei J. Zhu X. Mao X. Huang L. Meng F. Zhou J. Severe early hepatitis B reactivation in a patient receiving anti-CD19 and anti-CD22 CAR T cells for the treatment of diffuse large B-cell lymphoma J. Immunother. Cancer 2019 7 315 10.1186/s40425-019-0790-y 31753002\n23. Haidar G. Dorritie K. Farah R. Bogdanovich T. Nguyen M.H. Samanta P. Invasive Mold Infections After Chimeric Antigen Receptor–Modified T-Cell Therapy: A Case Series, Review of the Literature, and Implications for Prophylaxis Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 2019 71 672 676 10.1093/cid/ciz1127 31756246\n24. Schubert M.L. Schmitt M. Wang L. Ramos C.A. Jordan K. Müller-Tidow C. Dreger P. Side-effect management of chimeric an-tigen receptor (CAR) T-cell therapy Ann. Oncol. Off. J. Eur. Soc. Med. Oncol. 2020 32 34 48 10.1016/j.annonc.2020.10.478\n25. Park J.H. Romero F.A. Taur Y. Sadelain M. Brentjens R.J. Hohl T.M. Seo S.K. Cytokine Release Syndrome Grade as a Predictive Marker for Infections in Patients with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukemia Treated with Chimeric Antigen Receptor T Cells Clin. Infect. Dis. 2018 67 533 540 10.1093/cid/ciy152 29481659\n26. Gudiol C. Lewis R.E. Strati P. Kontoyiannis D.P. Chimeric antigen receptor T-cell therapy for the treatment of lymphoid malignancies: Is there an excess risk for infection? Lancet Haematol. 2021 8 e216 e228 10.1016/S2352-3026(20)30376-8 33460558\n27. Baird J.H. Epstein D.J. Tamaresis J.S. Ehlinger Z. Spiegel J.Y. Craig J. Claire G.K. Frank M.J. Muffly L. Shiraz P. Immune reconstitution and infectious complications following axicabtagene ciloleucel therapy for large B-cell lymphoma Blood Adv. 2021 5 143 155 10.1182/bloodadvances.2020002732 33570626\n28. Blumenberg V. Schubert M.-L. Zamir E. Schmidt S. Rohrbach R. Waldhoff P. Bozic D. Pock H. Elinav E. Schmidt C. An-tibiotic Therapy and Low Gut Microbiome Diversity Is Associated with Decreased Response and High Toxicity in BCP-ALL and DLBCL Patients after Treatment with CD19. CAR T-Cells Blood 2020 136 Suppl. 1 33 34 10.1182/blood-2020-141210\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2072-6694",
"issue": "13(7)",
"journal": "Cancers",
"keywords": "CAR-T cell; cytokine release syndrome; infection; lymphodepletion",
"medline_ta": "Cancers (Basel)",
"mesh_terms": null,
"nlm_unique_id": "101526829",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33918340",
"pubdate": "2021-04-02",
"publication_types": "D016428:Journal Article",
"references": "24876563;32327504;30809033;31753002;21258094;8469254;33098993;18462102;29434335;33570626;31756246;31019670;29481659;29038338;31110096;30501490;33460558;30576834;30266675;4628214;31419568;29385376;29226797;31753925;32201711;33007926",
"title": "Infection Complications after Lymphodepletion and Dosing of Chimeric Antigen Receptor T (CAR-T) Cell Therapy in Patients with Relapsed/Refractory Acute Lymphoblastic Leukemia or B Cell Non-Hodgkin Lymphoma.",
"title_normalized": "infection complications after lymphodepletion and dosing of chimeric antigen receptor t car t cell therapy in patients with relapsed refractory acute lymphoblastic leukemia or b cell non hodgkin lymphoma"
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"abstract": "We describe a Chinese family with severe autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) and psychiatric problems in whom whole-exome family trio sequencing identified a heterozygous mutation in the potassium channel subfamily T, member 1 (KCNT1), a sodium-gated potassium channel gene, which was a novel missense mutation c.2153A>T (p. Asp718Val). The typical characteristics of the three patients in the family were refractory epilepsy, acquired cognitive impairment, and psychiatric problems, which include hallucinations and suicidal thoughts and behaviors. The age at onset was found to be earlier in son and daughter of the proband than that of the proband, as proven by the proband's history of an epileptic seizure at the age of 16 years and her son's and daughter's history of seizures at the age of 8 years. Magnetic resonance imaging findings were negative for any abnormalities. Because of psychiatric symptoms, these three patients were administered risperidone at different times during their illness. The protestor's son had tried fenofibrate treatment, but clinical remission was unclear. In summary, our findings broadened the mutation database in relation to KCNT1 and implicated the sodium-gated potassium channel complex in ADNFLE, more broadly, in the pathogenesis of focal epilepsies.",
"affiliations": "Department of Neurology, Anyang District Hospital of Puyang City, Henan, China.;Department of Neurology, Henan Provincial People's Hospital, Zhengzhou, Henan, China.;Department of Neurology, Anyang District Hospital of Puyang City, Henan, China.;Department of Neurology, Anyang District Hospital of Puyang City, Henan, China.;Department of Neurology, Anyang District Hospital of Puyang City, Henan, China.;Department of Neurology, Anyang District Hospital of Puyang City, Henan, China.;Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.",
"authors": "Xie|Na|N|;Qin|Weiwei|W|;Deng|Jianzhong|J|;Qi|Jinxing|J|;Niu|Dewang|D|;Lu|Guifeng|G|;Wang|Qun|Q|",
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"doi": "10.1515/tnsci-2020-0182",
"fulltext": "\n==== Front\nTransl Neurosci\nTransl Neurosci\ntnsci\nTranslational Neuroscience\n2081-3856\n2081-6936\nDe Gruyter\n\ntnsci-2020-0182\n10.1515/tnsci-2020-0182\nCase Report\nA novel KCNT1 mutation in a Chinese family with severe autosomal-dominant nocturnal frontal lobe epilepsy\nXie Na 15037267397@163.com\n\nQin Weiwei\nDeng Jianzhong\nQi Jinxing\nNiu Dewang\nLu Guifeng\nWang Qun wangq@ccmu.edu.cn\n\nDepartment of Neurology, Anyang District Hospital of Puyang City, Henan, China\nDepartment of Neurology, Henan Provincial People’s Hospital, Zhengzhou, Henan, China\nDepartment of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China\n07 9 2021\n01 1 2021\n12 1 330334\n24 4 2021\n20 8 2021\n20 8 2021\n© 2021 Na Xie et al., published by De Gruyter\n2021\nNa Xie et al., published by De Gruyter\nhttps://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License.\n\nAbstract\n\nWe describe a Chinese family with severe autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE) and psychiatric problems in whom whole-exome family trio sequencing identified a heterozygous mutation in the potassium channel subfamily T, member 1 (KCNT1), a sodium-gated potassium channel gene, which was a novel missense mutation c.2153A>T (p. Asp718Val). The typical characteristics of the three patients in the family were refractory epilepsy, acquired cognitive impairment, and psychiatric problems, which include hallucinations and suicidal thoughts and behaviors. The age at onset was found to be earlier in son and daughter of the proband than that of the proband, as proven by the proband’s history of an epileptic seizure at the age of 16 years and her son’s and daughter’s history of seizures at the age of 8 years. Magnetic resonance imaging findings were negative for any abnormalities. Because of psychiatric symptoms, these three patients were administered risperidone at different times during their illness. The protestor’s son had tried fenofibrate treatment, but clinical remission was unclear. In summary, our findings broadened the mutation database in relation to KCNT1 and implicated the sodium-gated potassium channel complex in ADNFLE, more broadly, in the pathogenesis of focal epilepsies.\n\nKeywords\n\nKCNT1\nsevere ADNFLE\nautosomal dominant\nrefractory epilepsy\npsychiatric symptoms\n==== Body\npmc1 Introduction\n\nADNFLE is a childhood-onset focal epilepsy syndrome characterized by clusters of motor seizures arising from sleep, usually occurring in individuals with normal intellect [1].\n\nMutations of the KCNT1 have recently been identified in three families and a sporadic case with severe ADNFLE associated with intellectual and psychiatric problems [2].\n\nIn this report, we describe a family in which autosomal-dominant transmission of ADNFLE was explained by a novel mutation in KCNT1.\n\n2 Case reports\n\nProband: female, 47 years old, since the age of 16, suddenly felt suffocated and felt throat discomfort after falling asleep. She stared to the left, raised the left upper limb, sometimes moved both upper limbs, and straightened both lower limbs for a few seconds to 2 min. There were several attacks per day. Later episodes were frequent, sometimes manifested as turning the head to the left and staring to the left of the eyes, and these symptoms resolved in about 10 s. Sometimes the performance of the activity suddenly stopped or both hands twist spasm, both hands overstretch, left turn in circles. Each time lasted for tens of seconds. Sometimes, they present as tonic-clonic seizures in the extremities, lasting about a few minutes for relief, which was possibly induced and exacerbated by her menstruation. Prior to this, the patient did not receive any regular treatment, and her cognitive level was also found to be adequate for her work. In the past year, the frequency of seizures ranged from 2 to 3 times a day or 3 to 10 times a month to 4–5 times daily. Seizures evolved to frequent status epilepticus resulting in hospitalization. Then, she was given sodium valproate (0.4 g) three times a day; however, her epilepsy was not controlled. She was admitted to our hospital emergency department for frequent status epilepticus and psychiatric symptoms for 2 days. Mental motor development was normal. The patient was born in a healthy, non-inbred marriage with two healthy brothers and two healthy sisters. The obstetric history of the patient was normal, following an unremarkable pregnancy. Neuropsychological assessment revealed mild cognitive impairment [Montreal Cognitive Assessment (MoCA) 21/30] [3]. The scores of each parameter of the MoCA were as follows: visuospatial/executive (2/5), naming (2/3), attention (5/6), language (1/3), abstraction (1/2), delayed recall (5/5), and orientation (5/6). Other neurological examinations were normal and an MRI of the head showed no abnormality. The EEG showed normal background activity. High-amplitude spines and slow waves of 4 Hz occurred in the bilateral frontal regions in each sleep phase, sometimes affecting the anterior temporal and bilateral central regions (Figure 1c). Seizures are now better controlled after being on a regimen of carbamazepine 600 mg/day, valproate 1,500 mg/day, and risperidone 1 mg/day. Furthermore, risperidone was withdrawn when the psychiatric symptoms subsided.\n\nFigure 1 (a) Family pedigree in a novel mutation in KCNT1. The Chinese family includes three affected adults (II: 1, female, 47 years old; III: 1, female, 26 years old, III: 2, male, 17 years old). All subjects (II: 1, III: 1, III: 2) were tested by next generation sequencing. Comparison of the clinical features of the patients with missense mutation at c.2153A>T. (b) The DNA sequencing profile shows the c.2153A>T (p.Asp718Val) mutation in KCNT1. (c) The proband: interictal EEG shows double temporal apical slow waves. (d) The son: ictal EEG examined at 16-year-old. A short EEG seizure discharge begins at the right frontal region. The right anterior temporal, middle temporal, and right sphenoid spike rhythm lasted about 20 s, and then changed to full lead spike rhythm for about 40 s. Paroxysmal clinical manifestations: Sit up suddenly in sleep, lie down 20 s later, and gaze down with excessive movement of torso and proximal limbs, hands flexion and stiff, head left and right wobble, unconsciousness, last for about 48 s, and several similar episodes at night.\n\nProband’s son, 17 years old: At the age of 8, there was a sudden feeling of breath-holding, throat failure, spitting during sleep without obvious inducement, and then panic, with double upper limbs dance-like movements, kicking, continue for 1–2 min to relieve. Every day or several days in a cluster attack, a dozen times to dozens of times each time. During the daytime, after strenuous activity or having a meal, had an attack, the head to one side askew (left and right sides have), consciousness was clear or fuzzy, stiff limbs shook, lasting about 5–6 min. At the age of 16, he developed mental symptoms, such as fear, locking the door back, cutting his wrists with scissors, and cutting his belly. His father was a healthy civil servant. Intelligence and neurological examination were normal. The ictal electroencephalogram (EEG) of the proband’s son was examined at 16 years of age (Figure 1d). The EEG showed normal background activity, moderate and high-amplitude sharp slow waves in the double frontal region, and the right anterior temporal lead during each sleep period. Several episodes were recorded in the monitoring, which was manifested as a sleep state, suddenly sitting up during the episode, lying down for 20 s, and staring with both eyes, accompanied by excessive movement of the trunk and proximal limbs, head shaking from side to side, and no response to calls, which lasted for about 40 s, synchronized with EEG, and fast wave rhythm was observed in the right midfrontal lead 5 s before the onset.\n\nProband’s daughter, 17 years old. When she was 8 years old, she often suddenly cried out, twisted her body, and sometimes suddenly felt sick or sat up for 1–2 min after falling asleep. They occurred in clusters at night. Sometimes, they were tonic-clonic seizures of the limbs. Seizures were more likely to occur during menstruation. The EEG background activity was normal, and the sleep EEG suggested a single spike in the forehead.\n\nThe proband’s son and daughter were admitted to the hospital emergency department for frequent status epilepticus and psychiatric symptoms several times. Her daughter had three suicide attempts, whereas her son had one when his mood fluctuated. Her daughter’s seizures were more controlled than before, but she still experienced an attack even after the combined use of sodium valproate 2,000 mg/day, carbamazepine 1,600 mg/day, and clonazepam 2 mg/day in the evening. In addition, her son’s seizures were also more controlled than before since the frequency and degree of the seizures were less than those in the past. He still experienced an attack even after the combined use of oxcarbazepine 1,800 mg/day, valproate 2,000 mg/day, levetiracetam 1,000 mg/day, and fenofibrate 0.1 g/day. Her daughter’s neurological examination upon admission revealed cognitive impairment and her neuropsychological assessment revealed mild cognitive impairment [Montreal Cognitive Assessment (MoCA) 19/30]. The MoCA scores were as follows: visuospatial/executive (4/5), naming (3/3), attention (5/6), language (3/3), abstraction (0/2), delayed recall (1/5), and orientation (3/6). On the other hand, her son’s neurological examination results were found to be unremarkable.\n\nBlood DNA was extracted from the patient’s children to serve as the amplification template. Targeted sequence capture and next-generation sequencing technologies were used to sequence epilepsy-related genes. The results revealed a novel missense mutation in the KCNT1 gene, which was a novel missense mutation c.2153A>T (p. Asp718Val). This mutation was found in the patient as well as her children (Figure 1a and b).\n\nThis variant was predicted by Sorting Intolerant From Tolerant (SIFT) and by MutationTaster to be damaging. The novel missense mutation c.2153A>T (p.Asp718Val) may disrupt protein function. This variant was predicted by MutationTaster, CADD score of 25.74, and SIFT score of 0.005 to be disease-causing. This mutation was not reported in HGMD Pro or PubMed. On the other hand, it was reported in either 1,000 genomes or the ExAC database.\n\n3 Discussion\n\nHerein, we describe members of a Chinese family with severe autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE), who were identified with a novel KCNT1 gene mutation. The variant is not reported in ClinVar. The varian is of unknown significance in ACMG classification. However, the clinical manifestations, EEG, and genetic characteristics of this family were consistent with ADNFLE.\n\nKCNT1, a gene that encodes a sodium-activated potassium channel that is highly expressed in the nervous system [4,5,6], is found in neurons of the frontal lobe [4]. Although it is not widely expressed in the cortex, it is consistent with its role in the pathogenesis of ADNFLE. It has also been thought to regulate hyperpolarization following repetitive firing. The C-terminal cytoplasmic domain of KCNT1 interacts with a protein network, including the Fragile X mental retardation protein, thus stimulating the KCNT1 channel [7]. KCNT1 mutations were identified in three families and in a sporadic case with severe ADNFLE and psychiatric features in 2012. These mutations include the following: c.2782C>T (p.Arg928Cys) in an Australian British descent family, c.2386T>C (p.Tyr796His) in an Italian family, c.1193G>A (p.Arg398Gln) in the Israeli family, c.2688G>A (p.Met896Ile), and c.2688G>A (p.Met896Ile) in a sporadic case of severe sporadic nocturnal frontal lobe epilepsy (NFLE) and psychiatric problems [2]. In addition, KCNT1 mutations have also been reported in medial temporal lobe epilepsy. Hansen reported a novel phenotype with TLE, intellectual disability with early-adulthood onset being associated, and cerebellar ataxia in the KCNT1 channel. The mutation was heterozygous c.1694G>A mutation (p.Arg565His). The two patients in this report had hippocampal sclerosis and amygdala enlargement. Imaging lesions may be the structural cause of MTL epilepsy [8].\n\nTo date, heterozygous pathogenic variants of ADNFLE have been found in CHRNA4, CHRNB2, CHRNA2, KCNT1, DEPDC5, and CRH. Heron thinks that the age at onset of a seizure and the comorbidities associated with intellectual disability and psychiatric features in epileptic patients may be different between mutations affecting the nicotinic acetylcholine receptors (nAChRs) and KCNT1 [2]. Although intellectual disability and psychiatric disorders have been reported in ADNFLE [9,10], they are uncommon in families with ADNFLE that are associated with nAChR alterations. The phenotype associated with KCNT1 mutations differs from that associated with mutations affecting the nAChRs. Individuals carrying KCNT1 mutations have an earlier age at the onset of a seizure and frequently have significant comorbidities of intellectual disability and psychiatric features [2]. In contrast with the cases reported in the literature, our proband carrying KCNT1 mutation has a later age at onset of a seizure, which is 18 years of age. The clinical manifestations of this family member were refractory epilepsy and psychiatric symptoms. Genetic counseling is important for families carrying KCNT1 mutations.\n\nPsychiatric comorbidity and cognitive impairment may occur, even if clinical neurologic examination and intelligence in ADNFLE are normal. The manifestations of the disease may vary greatly in the same family, and our patients had normal intelligence prior to the onset of seizures while some present with decreased intelligence with frequent seizures. It is still unknown whether the intellectual disability is the result of frequent seizures, gene mutations, or antiepileptic drugs. The onset of our proband was reduced at 48-year-old. This is consistent with the literature reports that ADNFLE is not progressive and that the attacks may become milder and less frequent as patients reach middle age.\n\nADNFLE is characterized by clusters of nocturnal motor seizures, varying from simple arousals from sleep to dramatic. The seizures of all members of the family were stereotyped and brief (several seconds to 5 min), which are often bizarre hyperkinetic events with dystonic or tonic features. The son and the proband may experience the aura of vomiting and laryngeal discomfort, respectively; the daughter and the proband possibly experienced an exacerbation of their menses.\n\nADNFLE is sensitive to the treatment of carbamazepine. However, carbamazepine alone does not control the symptoms. The proband’s son still had seizures after the combination of anti-epileptics. Fenofibrate, as an adjunctive therapy, reduced the seizure frequency in individuals with pharmaco-resistant ADNFLE/NFLE [11]. We tried to give fenofibrate to the proband’s son but clinical remission was unclear. In addition, Milligan reported that exposure to quinidine significantly reduces the gain of function for KCNT1 pathogenic variants implicated in ADNFLE and EIMFS [12]. Carbamazepine is the main therapeutic drug and it is often given at low doses; however, individuals with the CHRNA4 pathogenic variant p.Ser284Leu were found to be more responsive to zonisamide. Approximately 30% of individuals are resistant to AEDs. All patients in the family suffered from medically refractory epilepsy. The dosages of carbamazepine and oxcarbazepine were very high in all three patients, and the individuals required a trial of more than two appropriate AEDs. Addition of large amounts of anti-epileptic drugs did not address the seizures of our proband’s son leading us to switch to adjunctive fenofibrate therapy. After the addition of fenofibrate, the seizure attacks appeared to be more controlled than before, but clinical remission was unclear. Fenofibrate was discontinued after 3 months because the father thought it was a lipid-lowering drug. Owing to the short duration, the exact efficacy of fenofibrate in this patient could not be evaluated. All three patients had mental-related symptoms, and all of them were cured after short-term treatment with a small dose of risperidone. One year later, the protestor went to the doctor because of decreased interest and appetite. She was reexamined for hypothyroidism and has improved after receiving supplemental adenosin tablets. The protestor was clinical seizure-free. The protester’s son and daughter continued to have intermittent seizures. During the follow-up 2 years later, the protestor’s son had a suicide attempt and after being administered an adjusted antipsychotic medication, his condition improved. Reexamination of the protester’s son showed a slightly higher TSH level (8.03 µIU/mL) and normal TF3 and FT4 levels of thyroid function. The psychiatrist tried to add levothyroxine sodium tablets. At follow-up 2 years later, the protestor’s daughter had a slightly higher TSH level (7.25 µIU/mL) and normal TF3 and FT4 levels. Considering her low mood, we added a small dose of levothyroxine sodium tablets.\n\nIn conclusion, we identified a novel missense mutation in KCNT1 in a Chinese family with ADNFLE. All members of this family had refractory epilepsy and severe mental symptoms. The thyroid function was normal at the beginning of the disease. However, it was not clear whether the different degrees of thyroid dysfunction in the follow-up were related to the disease. This finding provides additional evidence in understanding KCNT1 pathogenesis better.\n\nAcknowledgement\n\nWe would like to extend our deepest appreciation to the patients and their families receiving care in our department of neurology.\n\nEthical approval: The research related to human use has been complied with all the relevant national regulations, institutional policies, and in accordance with the tenets of the Helsinki Declaration, and has been approved by the authors’ institutional review board or equivalent committee.\n\nInformed consent: Informed consent has been obtained from all individuals included in this study.\n\nFunding information: The study was financially supported by the Capital Health Research and Development of Special grants (2016-1-2011 and 2020-1-2013), and the Beijing Natural Science Foundation (Z200024), and the science and technology project of Puyang (No. 1805069).\n\nConflict of interest: The authors state no conflict of interest.\n\nData availability statement: All data generated or analyzed during this study are included in this published article.\n==== Refs\nReferences\n\n[1] Scheffer IE, Bhatia KP, Lopes-Cendes I, Fish DR, Marsden CD, Andermann E, et al. Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder. Brain. 1995 Feb;118(Pt 1):61–73.\nScheffer IE Bhatia KP Lopes-Cendes I Fish DR Marsden CD Andermann E Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder Brain 1995 Feb 118 Pt 1 61 73 7895015\n[2] Heron SE, Smith KR, Bahlo M, Nobili L, Kahana E, Licchetta L, et al. Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet. 2012 Nov;44(11):1188–90.\nHeron SE Smith KR Bahlo M Nobili L Kahana E Licchetta L Missense mutations in the sodium-gated potassium channel gene KCNT1 cause severe autosomal dominant nocturnal frontal lobe epilepsy Nat Genet 2012 Nov 44 11 1188 90 23086396\n[3] Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al. The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695–9. Erratum in: J Am Geriatr Soc. 2019 Sep;67(9):1991.\nNasreddine ZS Phillips NA Bédirian V Charbonneau S Whitehead V Collin I The montreal cognitive assessment, MoCA: a brief screening tool for mild cognitive impairment J Am Geriatr Soc 2005 Apr 53 4 695 9 Erratum in: J Am Geriatr Soc. 2019 Sep;67(9):1991. 15817019\n[4] Bhattacharjee A, Gan L, Kaczmarek LK. Localization of the Slack potassium channel in the rat central nervous system. J Comp Neurol. 2002 Dec;454(3):241–54.\nBhattacharjee A Gan L Kaczmarek LK Localization of the Slack potassium channel in the rat central nervous system J Comp Neurol 2002 Dec 454 3 241 54 12442315\n[5] Bhattacharjee A, von Hehn CA, Mei X, Kaczmarek LK. Localization of the Na+ -activated K+ channel Slick in the rat central nervous system. J Comp Neurol. 2005 Mar;484(1):80–92.\nBhattacharjee A von Hehn CA Mei X Kaczmarek LK Localization of the Na+ -activated K+ channel Slick in the rat central nervous system J Comp Neurol 2005 Mar 484 1 80 92 15717307\n[6] Barcia G, Fleming MR, Deligniere A, Gazula VR, Brown MR, Langouet M, et al. De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy. Nat Genet. 2012 Nov;44(11):1255–9.\nBarcia G Fleming MR Deligniere A Gazula VR Brown MR Langouet M De novo gain-of-function KCNT1 channel mutations cause malignant migrating partial seizures of infancy Nat Genet 2012 Nov 44 11 1255 9 23086397\n[7] Brown MR, Kronengold J, Gazula VR, Chen Y, Strumbos JG, Sigworth FJ, et al. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat Neurosci. 2010 Jul;13(7):819–21.\nBrown MR Kronengold J Gazula VR Chen Y Strumbos JG Sigworth FJ Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack Nat Neurosci 2010 Jul 13 7 819 21 20512134\n[8] Hansen N, Widman G, Hattingen E, Elger CE, Kunz WS. Mesial temporal lobe epilepsy associated with KCNT1 mutation. Seizure. 2017 Feb;45:181–3.\nHansen N Widman G Hattingen E Elger CE Kunz WS Mesial temporal lobe epilepsy associated with KCNT1 mutation Seizure 2017 Feb 45 181 3 28081520\n[9] Khatami R, Neumann M, Schulz H, Kölmel HW. A family with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation. J Neurol. 1998 Dec;245(12):809–10.\nKhatami R Neumann M Schulz H Kölmel HW A family with autosomal dominant nocturnal frontal lobe epilepsy and mental retardation J Neurol 1998 Dec 245 12 809 10 9840354\n[10] Magnusson A, Stordal E, Brodtkorb E, Steinlein O. Schizophrenia, psychotic illness and other psychiatric symptoms in families with autosomal dominant nocturnal frontal lobe epilepsy caused by different mutations. Psychiatr Genet. 2003 Jun;13(2):91–5.\nMagnusson A Stordal E Brodtkorb E Steinlein O Schizophrenia, psychotic illness and other psychiatric symptoms in families with autosomal dominant nocturnal frontal lobe epilepsy caused by different mutations Psychiatr Genet 2003 Jun 13 2 91 5 12782965\n[11] Puligheddu M, Melis M, Pillolla G, Milioli G, Parrino L, Terzano GM, et al. Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy. Epilepsia. 2017 Oct;58(10):1762–70.\nPuligheddu M Melis M Pillolla G Milioli G Parrino L Terzano GM Rationale for an adjunctive therapy with fenofibrate in pharmacoresistant nocturnal frontal lobe epilepsy Epilepsia 2017 Oct 58 10 1762 70 28766701\n[12] Milligan CJ, Li M, Gazina EV, Heron SE, Nair U, Trager C, et al. KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine. Ann Neurol. 2014 Apr;75(4):581–90.\nMilligan CJ Li M Gazina EV Heron SE Nair U Trager C KCNT1 gain of function in 2 epilepsy phenotypes is reversed by quinidine Ann Neurol 2014 Apr 75 4 581 90 24591078\n\n",
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"title": "A novel KCNT1 mutation in a Chinese family with severe autosomal-dominant nocturnal frontal lobe epilepsy.",
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"affiliations": "Psychiatry and Behavioral Sciences Research Center, Department of Psychiatry, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.;Pharmaceutical Sciences Research Center, Faculty of Pharmacy, Mazandaran University of Medical Sciences, Sari, Iran.",
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"abstract": "Drugs including some of the antimicrobial agents (AMAs) can cause mild to severe intensity of hypokalemia, which leads to cardiac, muscular, renal, gastrointestinal, and metabolic manifestations.\nTo explore the possible association of AMAs use and the development of hypokalemia as an adverse drug reaction (ADR).\nRetrospective analysis of spontaneously individual case safety reports (ICSRs) received during January 2015 to September 2017 for any reduction in serum potassium levels following the use of AMAs. Such ICSRs were further analyzed for age, gender, seriousness and severity of hypokalemia, outcome, concomitant drugs, management of hypokalemia, and causality assessment using WHO-UMC causality assessment scale.\nOut of total 2,880 spontaneous ICSR, 53 had report title of hypokalemia. In almost half of these (27) ICSRs, AMAs were suspected to induced hypokalemia. Ceftriaxone (24.5%) and azithromycin (10.5%) were most suspected AMAs. Females (74.19%) aged between 21 years and 40 years experienced more AMA induced hypokalemia. The mild, moderate, and severe hypokalemia was present in 53.8%, 40.7%, and 7.4% of ICSRs, respectively. Drug-drug interaction of AMA with either furosemide, hydrocortisone and/or deriphyllin was present in six ICSRs. Causal association of all the ICSRs with AMA induced hypokalemia was possible.\nAntimicrobial agents (especially ceftriaxone and azithromycin)-induced hypokalemia alert needs to be investigated. Further, healthcare professionals are advocated to take caution by monitoring serum potassium levels routinely for such patients.\nRehan HS, Hotha P, Antimicrobial Agentsinduced Hypokalemia: A Possible Causality Association. Indian J Crit Care Med 2019;23(4):175-177.",
"affiliations": "Department of Pharmacology, Lady Hardinge Medical College, New Delhi, India.;Department of Pharmacology, Lady Hardinge Medical College, New Delhi, India.",
"authors": "Singh Rehan|Harmeet|H|;Hotha|Priyanka|P|",
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"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XJaypee Brothers Medical Publishers 10.5005/jp-journals-10071-23148Original ArticleAntimicrobial Agents-induced Hypokalemia: A Possible Causality Association Singh Rehan Harmeet 1Hotha Priyanka 21,2 Department of Pharmacology, Lady Hardinge Medical College, New Delhi, IndiaHarmeet Singh Rehan, Department of Pharmacology, Lady Hardinge Medical College, New Delhi, India, e-mail: harmeetrehan@hotmail.com4 2019 23 4 175 177 Copyright © 2019; Jaypee Brothers Medical Publishers (P) Ltd.2019This work is licensed under a Creative Commons Attribution 4.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ABSTRACT\nBackground\nDrugs including some of the antimicrobial agents (AMAs) can cause mild to severe intensity of hypokalemia, which leads to cardiac, muscular, renal, gastrointestinal, and metabolic manifestations.\n\nObjective\nTo explore the possible association of AMAs use and the development of hypokalemia as an adverse drug reaction (ADR).\n\nMethodology\nRetrospective analysis of spontaneously individual case safety reports (ICSRs) received during January 2015 to September 2017 for any reduction in serum potassium levels following the use of AMAs. Such ICSRs were further analyzed for age, gender, seriousness and severity of hypokalemia, outcome, concomitant drugs, management of hypokalemia, and causality assessment using WHO-UMC causality assessment scale.\n\nResult\nOut of total 2,880 spontaneous ICSR, 53 had report title of hypokalemia. In almost half of these (27) ICSRs, AMAs were suspected to induced hypokalemia. Ceftriaxone (24.5%) and azithromycin (10.5%) were most suspected AMAs. Females (74.19%) aged between 21 years and 40 years experienced more AMA induced hypokalemia. The mild, moderate, and severe hypokalemia was present in 53.8%, 40.7%, and 7.4% of ICSRs, respectively. Drug–drug interaction of AMA with either furosemide, hydrocortisone and/or deriphyllin was present in six ICSRs. Causal association of all the ICSRs with AMA induced hypokalemia was possible.\n\nConclusion\nAntimicrobial agents (especially ceftriaxone and azithromycin)-induced hypokalemia alert needs to be investigated. Further, healthcare professionals are advocated to take caution by monitoring serum potassium levels routinely for such patients.\n\nHow to cite this article\nRehan HS, Hotha P, Antimicrobial Agentsinduced Hypokalemia: A Possible Causality Association. Indian J Crit Care Med 2019;23(4):175-177.\n\nKeywords\nAdverse drug reactionAntimicrobial agentsHypokalemia\n==== Body\nINTRODUCTION\nIntra- and extracellular homeostasis of potassium is important to maintain physiological function of several human cells including cardiac muscle, skeletal muscle, and nerve cells.1 Increase and decrease of serum potassium levels may be potentially fatal.2 Hypokalemia may result from the shift of potassium ions from the extracellular to the intracellular space, increased potassium excretion in urine, and/or poor potassium intake. Among the hospitalized patients, almost 20% of the patients may develop all cause hypokalemia leading to cardiac, muscular, renal, gastrointestinal, and metabolic manifestations.3 In addition, few drugs may also precipitate hypokalemia. Hypokalemia associated with antibiotic use is rare but it is a recognized complication of dicloxacillin, ampicillin,4 amphotericin B,5 aminoglycosides,6 and penicillin7 especially when administered to patients with renal or hepatic insufficiency. Recently, Pharmacovigilance Programme of India (PvPI) has also issued a drug alert that piperacillin-tazobactam may induce hypokalemia.8 In view of this, AMAs use dependent hypokalemia may concern the clinicians. Hence, this retrospective analyze of spontaneously ICSR was carried out to explore any possible association between AMA use and the development of hypokalemia.\n\nMETHOD\nAll the spontaneous ICSRs with suspected drugs-induced hypokalemia including AMAs received at ADR monitoring center (AMC) under the aegis of PvPI between January 2015 to September-2017 were analyzed. ICSRs without the mention of serum potassium values were excluded from the analysis. The severity of hypokalemia was graded as mild (3–3.5 mEq/L), moderate (2.5–3 mEq/L), and severe (below 2.5 mEq/L).9 ICSRs with AMA-induced hypokalemia were further analyzed for patient information (age and gender), suspected adverse reaction (seriousness, severity, outcome, and management), suspected medication (concomitant drugs and drug–drug interactions), and causality assessment. Causality assessment between suspected AMA and hypokalemia was assessed by using WHO-UMC causality scale.10 Data were presented in numbers and proportions.\n\nRESULT\nA total number of 2,880 spontaneous ICSRs were received by the AMC during the study period. Of these, 53 ICSRs contained 120 drugs, which were suspected to induce hypokalemia, with an average of 2.26 suspected drugs per ICSR. Further analysis revealed that there were 27 ICSRs which contained 57 AMA and were suspected to cause hypokalemia. The possible AMA-induced hypokalemia was 0.9% of study. AMAs (47.5%) were the most frequently alleged to cause hypokalemia followed by antineoplastic agents (11.6%) and corticosteroids (9.1%) (Table 1).\n\nTable 1 Suspected groups of drugs alleged to cause hypokalemia in 53 ICSRs with a total of 120 drugs\n\nS. No\tGroup of drugs\tNumber (%)\t\n1\tAntimicrobial Agents\t57 (47.5)\t\na\tCeftriaxone\t14 (24.5)\t\nb\tAzithromycin\t06 (10.5)\t\nc\tMetronidazole\t05 (08.7)\t\nd\tCiprofloxacin\t03 (05.2)\t\ne\tOthers\t29 (50.8)\t\n2\tAntineoplastic agents\t14 (11.6)\t\na\tCisplatin\t04 (28.5)\t\nb\tCyclophosphamide\t02 (14.2)\t\nc\tOthers\t08 (57.1)\t\n3\tCorticosteroids\t11 (09.1)\t\na\tHydrocortisone\t05 (45.4)\t\nb\tPrednisolone\t02 (18.1)\t\nc\tOthers\t04 (36.3)\t\n4\tβ2 receptor agonist\t09 (07.5)\t\na\tSalbutamol\t09 (07.5)\t\n5\tDiuretics\t08 (06.6)\t\na\tFurosemide\t06 (75.0)\t\nb\tHydrochlorothiazide\t02 (25.0)\t\n6\tOthers\t21 (17.5)\t\nIn our study, ceftriaxone (24.5%) and azithromycin (10.5%) were frequently suspected AMAs to induce hypokalemia (Table 2). Out of 27 ICSRs with suspected AMA-induced hypokalemia, nine patients were aged between 21 years and 40 years and majority (74.19%) of these was females. Out of 27 ICSRs, three (11.1%) patients experienced serious adverse events as their hospital stay was prolonged but their severity of hypokalemia was moderate and did not require and instruct to correct it. The causality assessment for all suspected AMAs was possible.\n\nTable 2 Analysis of 27 ICSRs containing 53 AMAs for suspected adverse drug reactions\n\nAMAs (n)\tRoute of administration\tSeverity of hypokalemia\tOutcome\tCausality assessment\t\nIV\tPO\tMild\tModerate\tSevere\tRecovered\tContinued\t\nCeftriaxone (14)\t13\t00\t10\t03\t01\t02\t12\tPossible\t\nAzithromycin (06)\t01\t05\t05\t01\tNil\t01\t05\tPossible\t\nMetronidazole (05)\t03\t02\t02\t03\tNil\t00\t05\tPossible\t\nCiprofloxacin (03)\t02\t01\tNil\t03\tNil\t00\t03\tPossible\t\nOthers (29)\t13\t16\t12\t16\t01\t01\t28\tPossible\t\nTable 3 Two ICSRs with suspected severe hypokalemia due to concomitant medications prescribed with AMA (Total ICSRs-6)\n\nS. No.\tAMA\tConcomitant drug(s)\tSerum K+ level mEq/L\tAction taken\tIndication\tOutcome\tCausality assessment\t\n1\tAmphotericin B\tDexamethasone\t1.5\tAmphotericin B stopped\n\nHypokalemia managed with KCl\tKala azar\tRecovered\tPossible\t\n2\tCeftriaxone\tPrednisolone,\n\nFurosemide\t2\tCeftriaxone dose reduced\n\nHypokalemia managed with KCl\tNephrotic syndrome\tRecovered\tPossible\t\nIn 14(53.8%), 11(40.7%), and 02(7.4%) ICSRs, the severity of hypokalemia was mild, moderate, and severe, respectively. The severity of hypokalemia was of higher intensity when AMAs were administered parentally than orally. In three ICSRs with moderate to severe hypokalemia were managed by potassium supplementation. In six ICSRs, the possible reason of hypokalemia was drug–drug interaction of AMAs like ceftriaxone, azithromycin, amphotericin B, and vancomycin with concomitant medications like furosemide, hydrocortisone, dexamethasone, and deriphyllin. The severity of hypokalemia in these cases ranged from mild to severe (Table 3).\n\nDISCUSSION\nThe potassium loss from the urinary tract, hypomagnesemia, ketonuria, bicarbonaturia, renal tubular acidosis, hyperaldosteronism, and drugs can cause hypokalemia in patients.11 Patients with mild hypokalemia are usually asymptomatic,12 whereas patients with moderate-to-severe hypokalemia present with generalized weakness, cardiac arrhythmias and acute respiratory failure, hepatic encephalopathy, etc.13 In our study, 0.9% of the patients who required AMAs developed hypokalemia. Though the prevalence of hypokalemia in admitted patients irrespective of the cause has been reported to be varying between 3.5214 and 20%15 which is high.\n\nIn this study, six ICSRs had mid to severe grade of hypokalemia as AMAs viz. ceftriaxone and azithromycin were coadministered with hydrocortisone, furosemide, and or deriphyllin. These concomitantly administered drugs are established to cause hypokalemia (Table 3). Due to retrospective nature of this analysis, it was not possible to retrieve the information on the other associated causes of potassium loss like diarrhea, hyperaldosteronism, and serum acid–base balance imbalance.\n\nIn a report vancomycin also induced progressive K+ reductions.16 Further, its use concomitantly with furosemide for the treatment of infection at site of amputation,6 rifampicin in combination with other antitubercular drugs for treatment of vertebral brucellosis,17 sodium penicillin for treatment of coxitis,18 flucloxacillin for treatment of spondylodiskitis,19 and piperacillin/tazobactam for prophylaxis after hip fracture20 was associated with mild to severe intensity of hypokalemia. Recently, National Coordination Centre–Pharmacovigilance Programme of India (NCC–PvPI), Central Drugs Standard Control Organization (CDSCO), Ministry of Health and Family Welfare, Government of India has issued a drug alert that the administration of piperacillin-tazobactam may cause hypokalemia.21 Several researchers have reported the association of ceftriaxone, azithromycin, and ciprofloxacin with the development hypokalemia by increasing the urinary potassium excretion.22–24\n\nThis finding attracts the attention of healthcare professionals to plan focused pharmacovigilance of patients receiving AMAs by monitoring serum K+ levels and any sign and symptoms of hypokalemia especially when administered parentally.\n\nCONCLUSION\nAntimicrobial agent induced hypokalemia was frequent in females. Mild hypokalemia was more common in patients taking AMAs only. Severe hypokalemia was prevalent in patients receiving concomitant medications known to cause hypokalemia. This signal needs further investigation.\n\nSource of support: Nil\n\nConflict of interest: None\n==== Refs\nREFERENCES\n1. Palmer BF. Regulation of Potassium Homeostasis. Clin J Am Soc Nephrol. 2015; 10 (6): 1050- 1060. 24721891 \n2. Pun PH, Goldstein BA, et al. Serum Potassium Levels and Risk of Sudden Cardiac Death Among Patients With Chronic Kidney Disease and Significant Coronary Artery Disease. Kidney Int Rep. 2017; 2 (6): 1122- 1131. 29270520 \n3. Daly K, Farrington E. Hypokalemia and hyperkalemia in infants and children: Pathophysiology and treatment. J Pediatr Health Care. 2013; 27 (6): 486- 496. 24139581 \n4. Gill MA, DuBé JE, et al. Hypokalemic, metabolic alkalosis induced by high-dose ampicillin sodium. Am J Hosp Pharm. 1977; 34 (5): 528- 531. 326044 \n5. Kim YW. Antimicrobial-induced Electrolyte and Acid-Base Disturbances. Electrolyte Blood Press. 2007; 5 (2): 111- 115. 24459509 \n6. Siau K. Hypokalaemia and cardiac arrest complicating vancomycin and furosemide therapy. Cases J. 2009; 2: 8244. 19830061 \n7. Zaki SA, Lad V. Piperacillin-tazobactam-induced hypokalemia and metabolic alkalosis. Indian J Pharmacol. 2011; 43 (5): 609- 610. 22022014 \n8. Kalaiselvan V, Thota P, et al. Pharmacovigilance Programme of India: Recent developments and future perspectives. Ind J Pharmacol. 2016; 48 (6): 624- 628. \n9. Medscape. (2017). Hypokalemia in Emergency Medicine: Background, Pathophysiology, Epidemiology. [online] Available from: https://emedicine.medscape.com/article/767448-overview (Last Accessed April, 2019). \n10. Zaki SA. Adverse drug reaction and causality assessment scales. Lung India. 2011; 28 (2): 152- 153. 21712934 \n11. Falcone C, Compostella L, et al. Hypokalemia during antibiotic treatment for bone and joint infections. Eur J Orthop Surg Traumatol. 2018; 28 (3): 389- 395. 29018986 \n12. Medscape. (2017). Hypokalemia: Practice Essentials, Pathophysiology, Etiology. [online] Available from: https://emedicine.medscape.com/article/242008-overview [Last Accessed April, 2019]. \n13. Lee JW. Fluid and Electrolyte Disturbances in Critically Ill Patients. Electrolyte Blood Press. 2010; 8 (2): 72- 81. 21468200 \n14. Janko O, Seier J, Zazgornik J. Hypokalemia—incidence and severity in a general hospital. Wien Med Wochenschr. 1992; 142 (4): 78- 81. 1604881 \n15. Mandal AK. Hypokalemia and Hyperkalemia. Med Clin North Am. 1997; 81 (3): 611- 639. 9167648 \n16. Pazhayattil GS, Shirali AC. Drug-induced impairment of renal function. Int J Nephrol Renovasc Dis. 2014; 7: 457- 468. 25540591 \n17. Torun AN, Eren MA, et al. Recurrent symptomatic hypocalcemia during rifampicin therapy for brucellosis. Wien Klin Wochenschr. 2011; 123 (17-18): 566- 568. 21739210 \n18. Brunner FP, Frick PG. Hypokalaemia, metabolic alkalosis, and hypernatraemia due to “massive” sodium penicillin therapy. Br Med J. 1968; 4 (5630): 550- 552. 5722316 \n19. Hoorn EJ, Zietse R. Severe hypokalaemia caused by flucloxacillin. J Antimicrob Chemother. 2008; 61 (6): 1396- 1398. 18388113 \n20. Hussain S, Syed S, et al. Electrolyte imbalance: a rare side effect of piperacillin/tazobactam therapy. J Coll Physicians Surg Pak. 2010; 20 (6): 419- 420. 20642978 \n21. Issuu. Indian Journal of Clinical Practice March 2016. [online] Available from: https://issuu.com/ijcp6/docs/ijcp_march_2016_web [Last Accessed April, 2019]. \n22. eHealthMe. Will you have Hypokalemia with Ceftriaxone—from FDA reports. [online] Available from: https://www.ehealthme.com/ds/ceftriaxone/hypokalemia/ [Last Accessed April, 2019]. \n23. eHealthMe. Will you have Hypokalemia with Azithromycin—from FDA reports. [online] Available from: https://www.ehealthme.com/ds/azithromycin/hypokalemia/ [Last Accessed April, 2019]. \n24. eHealthMe. Will you have Hypokalemia with Ciprofloxacin—from FDA reports. Available from: https://www.ehealthme.com/ds/ciprofloxacin/hypokalemia/ [Last Accessed April, 2019].\n\n",
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"issue": "23(4)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Adverse drug reaction; Antimicrobial agents; Hypokalemia",
"medline_ta": "Indian J Crit Care Med",
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"title": "Antimicrobial Agents-induced Hypokalemia: A Possible Causality Association.",
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"abstract": "Clopidogrel is an adenosine diphosphate receptor antagonist used for the prevention of vascular events in patients with atherothrombotic diseases manifested by recent myocardial infarction, ischemic stroke or peripheral arterial disease. Diarrhoea, rash and pruritus are rather common side effects of clopidogrel. Other side effects include epistaxis, nausea, abdominal pain, vomiting, gastritis, gastric and duodenal ulcer. Thrombocytopenia is the most common laboratory abnormality. Leucopenia and neutropenia are rare. We report three cases of purpuric herpes zoster in patients in therapy with clopidogrel. To our knowledge, only one case of haemorrhagic herpes zoster has been published in a patient in therapy with this drug.",
"affiliations": "Department of Pathophysiology and Transplantation, Università degli Studi di Milano, I.R.C.C.S. Foundation, Cà Granda Ospedale Maggiore Policlinico, Milan, Italy. Electronic address: stefano.veraldi@unimi.it.;Department of Pathophysiology and Transplantation, Università degli Studi di Milano, I.R.C.C.S. Foundation, Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Pathophysiology and Transplantation, Università degli Studi di Milano, I.R.C.C.S. Foundation, Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.",
"authors": "Veraldi|S|S|;Vaira|F|F|;Nazzaro|G|G|",
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"journal": "Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology",
"keywords": "Clopidogrel; HIV; Haemorrhagic herpes zoster; Herpes zoster; Purpuric herpes zoster",
"medline_ta": "J Clin Virol",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D000998:Antiviral Agents; D000077144:Clopidogrel; D005260:Female; D006562:Herpes Zoster; D006801:Humans; D008297:Male; D011537:Pruritus; D013988:Ticlopidine; D016896:Treatment Outcome; D000077483:Valacyclovir; D014633:Valine",
"nlm_unique_id": "9815671",
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"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
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"title": "Purpuric herpes zoster in patients in therapy with clopidogrel.",
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"abstract": "We report a case of intraoperative severe bradycardia that resulted in asystole and cardiac arrest shortly after (<2 min) intravenous granisetron 1mg for postoperative nausea and vomiting prophylaxis, that occurred in a female patient who underwent an elective total thyroidectomy. After two cycles of cardiopulmonary resuscitation and defibrillation, spontaneous circulation and sinus rhythm returned successfully. Postoperatively, the patient was diagnosed with a drug-induced long QT syndrome. At the time of the event, granisetron was the only medication administered. Furthermore, there was no reason to suspect electrolyte abnormalities. We explore the association of the onset of severe sinus bradycardia with the intravenous administration of granisetron.",
"affiliations": null,
"authors": "Al Harbi|Mohammed|M|;Al Rifai|Derar|D|;Al Habeeb|Hassan|H|;Wambi|Freddie|F|;Geldhof|Georges|G|;Dimitriou|Vassilios|V|",
"chemical_list": "D000932:Antiemetics; D017829:Granisetron",
"country": "Lebanon",
"delete": false,
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"issue": "23(4)",
"journal": "Middle East journal of anaesthesiology",
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"medline_ta": "Middle East J Anaesthesiol",
"mesh_terms": "D000932:Antiemetics; D005260:Female; D017829:Granisetron; D006323:Heart Arrest; D006801:Humans; D007431:Intraoperative Complications; D008875:Middle Aged",
"nlm_unique_id": "8604187",
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"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A CASE OF GRANISETRON ASSOCIATED INTRAOPERATIVE CARDIAC ARREST.",
"title_normalized": "a case of granisetron associated intraoperative cardiac arrest"
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{
"abstract": "BACKGROUND\nMyeloid sarcoma (MS) is a rare hematologic malignancy defined as an extramedullary tumor of immature granulocytic cells. It can occur as primary or de novo and be associated with myelodysplasia or myeloproliferative neoplasms. The most frequent locations are the skin, lymph nodes and bones. The case of a patient with a diagnosis of primary granulocytic de novo gastric MS is reported.\n\n\nMETHODS\nA 19-year-old female patient with MS, whose abdominal computed tomography showed a bulky tumor of 16.5 cm in the gastric chamber with infiltration in the retroperitoneal, pancreatic and bile duct region; the histological study showed gastric mucosa diffusely infiltrated by mononucleated cells and the immunohistochemistry expressed myeloperoxidase. After receiving induction chemotherapy based on the 3 + 7 regimen (daunorubicin/cytarabine), the patient developed severe hematological toxicity and neutropenic typhlitis which required a prolonged medical treatment. She presented a rapid disease progression. Although she received supportive treatment, the patient died.\n\n\nCONCLUSIONS\nGastric primary de novo MS is a rare and aggressive course neoplasm, fostering knowledge is very important to decide its management and to promote more approaches focused on understanding this pathology and its particularities in our population.",
"affiliations": "Department of Oncology Medicine, Instituto Nacional de Enfermedades Neoplásicas, Lima 15000, Peru.;Department of Oncology Medicine, Instituto Nacional de Enfermedades Neoplásicas, Lima 15000, Peru.;Department of Surgical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15000, Peru. jorgelunaabanto@gmail.com.;Universidad Privada San Juan Bautista, Filial Chincha 11702, Peru.;Universidad Privada San Juan Bautista, Lima 15000, Peru.",
"authors": "Rioja|Patricia|P|;Macetas|Jackeline|J|;Luna-Abanto|Jorge|J|;Tirado-Hurtado|Indira|I|;Enriquez|Daniel J|DJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5306/wjco.v12.i10.960",
"fulltext": "\n==== Front\nWorld J Clin Oncol\nWJCO\nWorld Journal of Clinical Oncology\n2218-4333\nBaishideng Publishing Group Inc\n\njWJCO.v12.i10.pg960\n10.5306/wjco.v12.i10.960\nCase Report\nGastric myeloid sarcoma: A case report\nRioja P et al. Gastric myeloid sarcoma: A case report\nRioja Patricia Department of Oncology Medicine, Instituto Nacional de Enfermedades Neoplásicas, Lima 15000, Peru\n\nMacetas Jackeline Department of Oncology Medicine, Instituto Nacional de Enfermedades Neoplásicas, Lima 15000, Peru\n\nLuna-Abanto Jorge Department of Surgical Oncology, Instituto Nacional de Enfermedades Neoplásicas, Lima 15000, Peru. jorgelunaabanto@gmail.com\n\nTirado-Hurtado Indira Universidad Privada San Juan Bautista, Filial Chincha 11702, Peru\n\nEnriquez Daniel J Universidad Privada San Juan Bautista, Lima 15000, Peru\n\nAuthor contributions: Rioja P, Macetas J and Enriquez DJ participated in the clinical management of the patient, the conception of the case report, and writing; Tirado-Hurtado I and Luna-Abanto J participated with the writing and critical review of the manuscript.\n\nCorresponding author: Jorge Luna-Abanto, MD, Surgical Oncologist, Department of Oncological Surgery, Instituto Nacional de Enfermedades Neoplásicas, Av. Angamos Este 2520, Lima 15000, Peru. jorgelunaabanto@gmail.com\n\n24 10 2021\n24 10 2021\n12 10 960965\n21 4 2021\n26 7 2021\n19 9 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/\nBACKGROUND\n\nMyeloid sarcoma (MS) is a rare hematologic malignancy defined as an extramedullary tumor of immature granulocytic cells. It can occur as primary or de novo and be associated with myelodysplasia or myeloproliferative neoplasms. The most frequent locations are the skin, lymph nodes and bones. The case of a patient with a diagnosis of primary granulocytic de novo gastric MS is reported.\n\nCASE SUMMARY\n\nA 19-year-old female patient with MS, whose abdominal computed tomography showed a bulky tumor of 16.5 cm in the gastric chamber with infiltration in the retroperitoneal, pancreatic and bile duct region; the histological study showed gastric mucosa diffusely infiltrated by mononucleated cells and the immunohistochemistry expressed myeloperoxidase. After receiving induction chemotherapy based on the 3 + 7 regimen (daunorubicin/cytarabine), the patient developed severe hematological toxicity and neutropenic typhlitis which required a prolonged medical treatment. She presented a rapid disease progression. Although she received supportive treatment, the patient died.\n\nCONCLUSION\n\nGastric primary de novo MS is a rare and aggressive course neoplasm, fostering knowledge is very important to decide its management and to promote more approaches focused on understanding this pathology and its particularities in our population.\n\nMyeloid sarcoma\nGranulocytic sarcoma\nStomach\nChemotherapy\nPeru\nCase report\n==== Body\npmc Core Tip: This case report describes a gastric primary de novo myeloid sarcoma (MS) which is a very rare hematological neoplasm with poor prognosis in a young and symptomatic patient. After receiving chemotherapy, she presented severe toxicity (neutropenic typhlitis) and rapid disease progression. This case highlights the importance of detecting gastric primary MS as a rare form of extramedullary myeloid leukemia presentation. Moreover, management of gastric primary MS could lead to interventions to avoid deterioration of gastrointestinal system during treatment. There is limited information of management and outcomes regarding gastric primary MS. Furthermore, there is very limited data about de novo MS in Peruvian patients.\n\nINTRODUCTION\n\nMyeloid sarcoma (MS) is defined as a myeloblast tumor produced in an anatomical place different from the bone marrow that destroys the original architecture of the local tissue. These tumors are also known as granulocytic sarcomas, chloromas or extramedullary myeloid tumors[1,2]. MS occurs more frequently in males and young individuals; its location is variable, and cerebral, mammary, testicular, gastrointestinal involvement has been reported, among other visceral organs, and it appears more frequently in the skin, lymph nodes and bones[3].\n\nMS occurrence is frequently associated with acute myeloid leukemia (AML), affecting between 2.5% and 9% of patients. When the disease is detected without clinical signs of leukemia and in association with a negative bone marrow biopsy, it is classified as de novo MS[2], the incidence of which is 2 cases per million adults[2,4]. Gastrointestinal presentation is uncommon and shows nonspecific symptoms related to the effect of tumor mass[3,5].\n\nCASE PRESENTATION\n\nChief complaints\n\nThe patient was a 19-year-old female without a relevant history.\n\nHistory of present illness\n\nThe patient was admitted to the hospital with nausea, vomiting and early satiety of 5 mo of evolution associated with an episode of hematemesis.\n\nPhysical examination\n\nThe patient showed low body weight, a regular general condition, distended abdomen, ascites, and a poorly defined bulky mass located in the upper hemiabdomen.\n\nLaboratory examinations\n\nLaboratory tests at admission revealed moderate anemia (Hb: 9 g/dL), hypoalbuminemia (albumin: 2.5 g/dL), grade 4 hyperbilirubinemia (total bilirubin: 2.5 mg/dL, indirect bilirubin: 1.8 g/dL), grade 2 hypertransaminasemia (aspartate aminotransferase: 90 IU/L, alanine aminotransferase: 100 IU/L), and elevated alkaline phosphatase (360 IU/L).\n\nImaging examinations\n\nAbdominal computed tomography showed a bulky tumor of 16.5 cm in the gastric chamber, which infiltrated the retroperitoneal, pancreatic and bile duct regions, with dilation of the latter. In addition, peritoneal thickening, free fluid, splenomegaly and bilateral hydronephrosis were observed (Figure 1). Upper digestive endoscopy was reported at the level of the infiltrated gastric mucosal body with decreased contractility, thickened gastric folds, and infiltration of the duodenal bulb throughout its length. The colonoscopy showed no lesions.\n\nFigure 1 Abdominal computed tomography scan used a part of diagnosis. Computed tomography scan showing extensive intra-abdominal bulky tumor of 16.5 cm at diagnosis with the presence of ascitis.\n\nPathology\n\nThe histological study showed gastric mucosa diffusely infiltrated by mononucleated cells, which were intermediate in size with eosinophilic cytoplasm and blast-like nuclei (Figure 2). Immunohistochemistry indicated that these cells expressed myeloperoxidase (MPO) (+), CD117 (+) CD34 (+), CD20 (-), CD3 (-), CD68 (-), CD38 (-), CD30 (-), DTT (-), and Ki67: 80% (Figure 3). Bone marrow analysis by cytomorphology and flow cytometry was negative for infiltration by myeloid blasts. The bone marrow karyotype was 46 XX, and it was not possible to demonstrate the presence of the AML1-ETO, CBFB-MYH11, NPM1 mut A, and FLT3-ITD genes or mutations in exons 8 and 17 of the c-kit gene in bone marrow and the primary tumor.\n\nFigure 2 Hematoxylin-eosin staining of gastric myeloid sarcoma. A: There is mucosa with diffuse infiltration of monomorphic medium cells (× 10 magnification); B: At higher magnification (× 40 magnification) the cells show eosinophilic cytoplasm and nucleus with fine chromatin (blast).\n\nFigure 3 Immunohistochemistry. A: Positive staining for myeloperoxidase (× 40 magnification); B: Positive staining for CD34 (× 40 magnification); C: Positive staining for CD117 (× 40 magnification); D: Strong staining for Ki-67 (proliferation index), around 80% (× 40 magnification).\n\nFINAL DIAGNOSIS\n\nThis case final diagnosis is primary gastric de novo granulocytic MS.\n\nTREATMENT\n\nThe patient began induction treatment based on the 3 + 7 regimen (daunorubicin 60 mg/m2 for 3 d + citarabine 200 mg/m2 for 7 d). She developed severe hematological toxicity and neutropenic typhlitis requiring antibiotic and antifungal coverage, parenteral nutritional support and a prolonged stay.\n\nOUTCOME AND FOLLOW-UP\n\nIn the reassessment of the disease 30 d after treatment, the patient reached a partial response. A second cycle of 3 + 7 regimen treatment was scheduled, and regular tolerance and rapid disease progression were observed, thus she received supportive treatment; however, the patient died.\n\nDISCUSSION\n\nThe case of a 19-year-old woman with a final diagnosis of gastric granulocytic type MS is presented. The symptoms were similar to those reported in other cases of gastric MS, which was conditioned by the extensive intra-abdominal involvement of the neoplasm (Figure 1)[2,6,7]. The differential histopathological diagnosis was based on morphological and immunohistochemical characteristics, which included non-Hodgkin lymphoma, Burkitt lymphoma, diffuse large B-cell lymphoma, lymphoblastic lymphoma, and Ewing's sarcoma, among others[3,8]. The present case had a blast type histology. Classically, MS expresses myeloid markers such as CD13, CD33 and MPO, but these markers are not present in all cases. For example, the expression of MPO, one of the most frequent markers, has been reported to be between 83.6% and 64.1% in different series[9]. On the other hand, the expression of CD68, a marker related to lymphocyte lineage and lysosome leakage, was positive in our patient; its presence has been reported in up to 100% of patients with MS[8]. Other markers, such as CD33, CD13 and related to line B, are less consistent in these patients[4,8,9]. It can be distinguished from other round cell neoplasms, such as Ewing sarcoma or neuroendocrine tumors, with specific markers, such as CD99-specific neuronal enolase and CD99, respectively. It has been reported that the anomaly of the nucleus binding factor (translocation between chromosomes 8 and 21) is the most frequent in patients with de novo MS; this has been reported in 38% of cases in an North American study[8]. In contrast, translocation 8; 21 was only found in 3% of patients in an Italian series[9]. This translocation was not found in the present case, and there is probably a different frequency of it in our population.\n\nDue to the rarity of MS, there are no prospective studies that guide its management[3,4,8,10], with induction therapy and postadmission therapy for AML being the only current alternatives to treatment. The prognosis of these patients is poor, and a 12-month survival has been reported for patients with MS without treatment and progression within 1 year to leukemia[3]. However, retrospective series such as that of Pileri et al[4] and Kawamoto et al[9] report that systemic treatment, including daunorubicin and cytarabine, offers longer progression-free survival than local treatments (surgery and radiotherapy). In addition, promising results have been achieved with hematopoietic progenitor (TPH) transplantation; Movassaghian et al[10] reported a median OS of 16.7 mo in a retrospective series of 22 patients with allogeneic post-PHT MS. However, despite this, the majority of the patients had disease progression in less than 6 mo[5,7].\n\nCONCLUSION\n\nIn conclusion, gastric primary de novo MS is a rare neoplasm with an aggressive course. The differential diagnosis depends on the histological and immunohistochemical characteristics. Chemotherapy is the standard treatment, and important results have been reported with bone marrow transplantation. However, further collaborative studies are necessary to understand this pathology and its particularities in our population.\n\nInformed consent statement: Informed written consent was obtained from the patient for publication of this manuscript, also the accompanying images.\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: April 21, 2021\n\nFirst decision: July 16, 2021\n\nArticle in press: September 19, 2021\n\nSpecialty type: Oncology\n\nCountry/Territory of origin: Peru\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Gupta S S-Editor: Gao CC L-Editor: A P-Editor: Wu RR\n==== Refs\n1 Klco JM Welch JS Nguyen TT Hurley MY Kreisel FH Hassan A Lind AC Frater JL State of the art in myeloid sarcoma Int J Lab Hematol 2011 33 555 565 21883967\n2 Huang XL Tao J Li JZ Chen XL Chen JN Shao CK Wu B Gastric myeloid sarcoma without acute myeloblastic leukemia World J Gastroenterol 2015 21 2242 2248 25717265\n3 Almond LM Charalampakis M Ford SJ Gourevitch D Desai A Myeloid Sarcoma: Presentation, Diagnosis, and Treatment Clin Lymphoma Myeloma Leuk 2017 17 263 267 28342811\n4 Pileri SA Ascani S Cox MC Campidelli C Bacci F Piccioli M Piccaluga PP Agostinelli C Asioli S Novero D Bisceglia M Ponzoni M Gentile A Rinaldi P Franco V Vincelli D Pileri A Jr Gasbarra R Falini B Zinzani PL Baccarani M Myeloid sarcoma: clinico-pathologic, phenotypic and cytogenetic analysis of 92 adult patients Leukemia 2007 21 340 350 17170724\n5 Ravulapati S Siegel C Dara A Lionberger JM Myeloid sarcoma without circulating leukemia mimicking gastrointestinal malignancy and lymphoma Hematol Rep 2018 10 7040 30046410\n6 Bhat I A Chloroma at the Gastric Cardia Am J Gastroenterol 2016 111 1226\n7 Yu T Xu G Xu X Yang J Ding L Myeloid sarcoma derived from the gastrointestinal tract: A case report and review of the literature Oncol Lett 2016 11 4155 4159 27313759\n8 Vachhani P Bose P Isolated gastric myeloid sarcoma: a case report and review of the literature Case Rep Hematol 2014 2014 541807 25105036\n9 Kawamoto K Miyoshi H Yoshida N Takizawa J Sone H Ohshima K Clinicopathological, Cytogenetic, and Prognostic Analysis of 131 Myeloid Sarcoma Patients Am J Surg Pathol 2016 40 1473 1483 27631510\n10 Movassaghian M Brunner AM Blonquist TM Sadrzadeh H Bhatia A Perry AM Attar EC Amrein PC Ballen KK Neuberg DS Fathi AT Presentation and outcomes among patients with isolated myeloid sarcoma: a Surveillance, Epidemiology, and End Results database analysis Leuk Lymphoma 2015 56 1698 1703 25213180\n\n",
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"issue": "12(10)",
"journal": "World journal of clinical oncology",
"keywords": "Case report; Chemotherapy; Granulocytic sarcoma; Myeloid sarcoma; Peru; Stomach",
"medline_ta": "World J Clin Oncol",
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"nlm_unique_id": "101549149",
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"pages": "960-965",
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"pmid": "34733617",
"pubdate": "2021-10-24",
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"references": "27313759;27631510;21883967;25105036;17170724;30046410;27580768;25213180;28342811;25717265",
"title": "Gastric myeloid sarcoma: A case report.",
"title_normalized": "gastric myeloid sarcoma a case report"
} | [
{
"companynumb": "PE-Hisun Pharmaceuticals-2122122",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DAUNORUBICIN HYDROCHLORIDE"
},
"drugad... |
{
"abstract": "We report a case of severe amnestic syndrome following theophylline overdose. A woman in her early 30s was admitted to hospital where she developed status epilepticus following an intentional overdose of theophylline and lansoprazole. She developed a profound acidosis and required intubation in the intensive care unit. Following extubation the patient was noted to have a severe amnestic syndrome with poor short-term memory. A work-up to exclude infectious, autoimmune and paraneoplastic causes for encephalitis was undertaken. Cerebrospinal fluid analysis was normal and autoimmune encephalitis titres were negative. Initial MRI brain imaging demonstrated hyperintensities of the mesial temporal lobes bilaterally. Follow-up imaging at 4 months identified further interval reduction but persistent hippocampal hyperintensities. Theophylline toxicity with corresponding amnestic syndrome and hippocampal hyperintensities has been rarely reported. We believe this case with persistent abnormal Montreal Cognitive Assessment Score at 12 months correlates with persistent hippocampal abnormalities seen on imaging.",
"affiliations": "Neurology, University Hospital Galway, Galway, Ireland eimearm.joyce@hse.ie.;Neurology, University Hospital Galway, Galway, Ireland.;Department of Anatomy, University of Dublin Trinity College, Dublin, Ireland.;Neurology, University Hospital Galway, Galway, Ireland.",
"authors": "Joyce|Eimear|E|;Olszewska|Diana Angelika|DA|;Davy|Shane|S|;Counihan|Timothy J|TJ|",
"chemical_list": "D013806:Theophylline",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-240273",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "drugs: CNS (not psychiatric); memory disorders; toxicology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D004660:Encephalitis; D005260:Female; D050031:Hashimoto Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D059906:Neuroimaging; D013806:Theophylline",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33952564",
"pubdate": "2021-05-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe amnestic syndrome due to theophylline toxicity.",
"title_normalized": "severe amnestic syndrome due to theophylline toxicity"
} | [
{
"companynumb": "IE-INVENTIA-000481",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "THEOPHYLLINE ANHYDROUS"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nAcromegaly associated to schizophrenia was first reported ~60 years ago, and so far, it is unclear whether this association is causal or not. Our aim was to report new cases with both clinical entities and to discuss the potential pathophysiological mechanisms of this association.\n\n\nMETHODS\nThree new cases and data from literature are reviewed.\n\n\nRESULTS\nWe report 2 males and 1 female diagnosed with schizophrenia and treated for several years with antipsychotics who developed acromegaly due to a growth hormone (GH)-secreting pituitary macroadenoma. In all cases, the diagnosis of schizophrenia preceded acromegaly with mean disease duration of ~12 years. Antipsychotic therapy was different in every patient. Two patients underwent transsphenoidal surgery. Histopathological study showed mixed GH- and prolactin-secreting adenoma in 1 patient and pure GH-secreting adenoma in the other patient. Several pathophysiological mechanisms related to alterations in dopaminergic neurotransmission due to psychiatric disease itself or its pharmacological treatment are proposed and discussed as likely linkage between schizophrenia and acromegaly.\n\n\nCONCLUSIONS\nThese case reports suggest that schizophrenia and/or its antipsychotic therapy in the long term might be in relation with the development of GH-secreting pituitary adenomas.",
"affiliations": "Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain; piglo65@gmail.com.;Department of Endocrinology, Hospital 12 de Octubre, Madrid, Spain.;Department of Endocrinology, Hospital Ramón y Cajal, Madrid, Spain;",
"authors": "Iglesias|Pedro|P|;Bernal|Carmen|C|;Díez|Juan J|JJ|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "United States",
"delete": false,
"doi": "10.1093/schbul/sbu028",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0586-7614",
"issue": "40(4)",
"journal": "Schizophrenia bulletin",
"keywords": "acromegaly; dopamine; growth hormone; pituitary adenoma; schizophrenia",
"medline_ta": "Schizophr Bull",
"mesh_terms": "D000236:Adenoma; D000328:Adult; D014150:Antipsychotic Agents; D005260:Female; D049912:Growth Hormone-Secreting Pituitary Adenoma; D006801:Humans; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia",
"nlm_unique_id": "0236760",
"other_id": null,
"pages": "740-3",
"pmc": null,
"pmid": "24603061",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "18514488;5550122;23983960;8911225;18562408;11081170;6401459;3080462;17167139;21325455;13103105;16490410;948738;12500753;16716128;23246411;19700006;4575024",
"title": "Curious cases: Acromegaly and schizophrenia: an incidental association?",
"title_normalized": "curious cases acromegaly and schizophrenia an incidental association"
} | [
{
"companynumb": "ES-JNJFOC-20140715243",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PALIPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nBesides major clinical/biochemical features, neutropenia and inflammatory bowel disease (IBD) constitute common complications of Glycogen storage disease type Ib (GSD Ib). However, their management is still challenging. Although previous reports have shown benefit of empagliflozin administration on neutropenia, no follow-up data on bowel (macro/microscopic) morphology are available. We herein present for the first time longitudinal assessment of bowel morphology in a GSD Ib child suffering from Crohn disease-like enterocolitis treated with empagliflozin.\n\n\nMETHODS\nA 14-year-old boy with GSD Ib and severe IBD was (off-label) treated with empagliflozin (20 mg/day) after informed oral and written consent was obtained from the patient's parents. No adverse events were noted. Clinical symptoms and stool frequency improved within the first week of treatment. Pediatric Crohn disease activity index (PCDAI) normalised within the first month of treatment. Abdomen magnetic resonance imaging (MRI) performed 3 months after treatment initiation showed dramatic decrease in disease activity and length. Similar findings were reported on histology at 5.5 months. At 7.5 months hemoglobin levels normalised and fecal calprotectin almost normalised. Improved neutrophil count, metabolic control and quality of life were also noted. G-CSF dose was decreased by 33% and the patient was partly weaned from tube feeding.\n\n\nCONCLUSIONS\nThis is the first report presenting extensive gastrointestinal morphology follow-up in a GSD Ib patient receiving empagliflozin. The present case suggests that empagliflozin can be safe and effective in inducing IBD remission in GSD Ib patients and can even postpone surgery. Future studies are required to confirm its effect over time and assess its benefit in various disease stages. The development of an international collaborating networks for systematic data collection is worthy.",
"affiliations": "Department of Translational Medical Sciences, Section of Pediatrics, University of Naples \"Federico II\", Naples, Italy. alessandro.rossi@unina.it.;Department of Translational Medical Sciences, Section of Pediatrics, University of Naples \"Federico II\", Naples, Italy.;Department of Translational Medical Sciences, Section of Pediatrics, University of Naples \"Federico II\", Naples, Italy.;Groupe de Recherches Metaboliques, de Duve Institute, UC Louvain (Université Catholique de Louvain), B-1200, Brussels, Belgium.;Department of Translational Medical Sciences, Section of Pediatrics, University of Naples \"Federico II\", Naples, Italy.;Section of Medical Imaging, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.;Section of Pathology, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy.;Department of Translational Medical Sciences, Section of Pediatrics, University of Naples \"Federico II\", Naples, Italy.;Department of Translational Medical Sciences, Section of Pediatrics, University of Naples \"Federico II\", Naples, Italy.;Section of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.;Department of Translational Medical Sciences, Section of Pediatrics, University of Naples \"Federico II\", Naples, Italy.;Department of Translational Medical Sciences, Section of Pediatrics, University of Naples \"Federico II\", Naples, Italy.",
"authors": "Rossi|Alessandro|A|http://orcid.org/0000-0002-1689-4948;Miele|Erasmo|E|;Fecarotta|Simona|S|;Veiga-da-Cunha|Maria|M|;Martinelli|Massimo|M|;Mollica|Carmine|C|;D'Armiento|Maria|M|;Mozzillo|Enza|E|;Strisciuglio|Pietro|P|;Derks|Terry G J|TGJ|;Staiano|Annamaria|A|;Parenti|Giancarlo|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13052-021-01100-w",
"fulltext": "\n==== Front\nItal J Pediatr\nItal J Pediatr\nItalian Journal of Pediatrics\n1824-7288\nBioMed Central London\n\n1100\n10.1186/s13052-021-01100-w\nCase Report\nCrohn disease-like enterocolitis remission after empagliflozin treatment in a child with glycogen storage disease type Ib: a case report\nhttp://orcid.org/0000-0002-1689-4948\nRossi Alessandro alessandro.rossi@unina.it\na.rossi@umcg.nl\n\n12\nMiele Erasmo 1\nFecarotta Simona 1\nVeiga-da-Cunha Maria 3\nMartinelli Massimo 1\nMollica Carmine 4\nD’Armiento Maria 5\nMozzillo Enza 1\nStrisciuglio Pietro 1\nDerks Terry G. J. 2\nStaiano Annamaria 1\nParenti Giancarlo 16\n1 grid.4691.a 0000 0001 0790 385X Department of Translational Medical Sciences, Section of Pediatrics, University of Naples “Federico II”, Naples, Italy\n2 grid.4830.f 0000 0004 0407 1981 Section of Metabolic Diseases, Beatrix Children’s Hospital, University Medical Center Groningen, University of Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands\n3 grid.7942.8 0000 0001 2294 713X Groupe de Recherches Metaboliques, de Duve Institute, UC Louvain (Université Catholique de Louvain), B-1200 Brussels, Belgium\n4 grid.4691.a 0000 0001 0790 385X Section of Medical Imaging, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy\n5 grid.4691.a 0000 0001 0790 385X Section of Pathology, Department of Advanced Biomedical Sciences, University of Naples Federico II, Naples, Italy\n6 grid.410439.b 0000 0004 1758 1171 Telethon Institute of Genetics and Medicine, Pozzuoli, Italy\n2 7 2021\n2 7 2021\n2021\n47 14916 4 2021\n3 6 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nBesides major clinical/biochemical features, neutropenia and inflammatory bowel disease (IBD) constitute common complications of Glycogen storage disease type Ib (GSD Ib). However, their management is still challenging. Although previous reports have shown benefit of empagliflozin administration on neutropenia, no follow-up data on bowel (macro/microscopic) morphology are available. We herein present for the first time longitudinal assessment of bowel morphology in a GSD Ib child suffering from Crohn disease-like enterocolitis treated with empagliflozin.\n\nCase presentation\n\nA 14-year-old boy with GSD Ib and severe IBD was (off-label) treated with empagliflozin (20 mg/day) after informed oral and written consent was obtained from the patient’s parents. No adverse events were noted. Clinical symptoms and stool frequency improved within the first week of treatment. Pediatric Crohn disease activity index (PCDAI) normalised within the first month of treatment. Abdomen magnetic resonance imaging (MRI) performed 3 months after treatment initiation showed dramatic decrease in disease activity and length. Similar findings were reported on histology at 5.5 months. At 7.5 months hemoglobin levels normalised and fecal calprotectin almost normalised. Improved neutrophil count, metabolic control and quality of life were also noted. G-CSF dose was decreased by 33% and the patient was partly weaned from tube feeding.\n\nConclusions\n\nThis is the first report presenting extensive gastrointestinal morphology follow-up in a GSD Ib patient receiving empagliflozin. The present case suggests that empagliflozin can be safe and effective in inducing IBD remission in GSD Ib patients and can even postpone surgery. Future studies are required to confirm its effect over time and assess its benefit in various disease stages. The development of an international collaborating networks for systematic data collection is worthy.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s13052-021-01100-w.\n\nKeywords\n\nGlycogen storage disease type Ib\nInflammatory bowel disease\nNeutropenia\n1,5-anhydroglucitol\nEmpagliflozin\nContinuous glucose monitoring\nVitaflo ItaliaAssociazione Italiana Glicogenosi01/2020 Rossi Alessandro issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nGlycogen storage disease type Ib (GSD Ib, MIM#232220) is an inherited disorder of carbohydrate metabolism due to microsomal glucose-6-phosphate transporter (G6PT) deficiency (SLC37A4 gene). The ubiquitously expressed G6PT transports glucose 6-phosphate (G6P) from cytosol to endoplasmic reticulum (ER) where it is oxidized to glucose to ensure glucose homeostasis. G6PT defect results into both glycogenolysis and gluconeogenesis defect [1]. Major clinical features of GSD Ib include fasting hypoglycaemia, hyperlactatemia, hyperuricemia, hyperlipidaemia, hepatomegaly, growth retardation, renal disease [2]. Additionally, GSD Ib patients show neutropenia/neutrophil dysfunction [3] and increased risk of inflammatory bowel disease (IBD) (i.e., Crohn disease-like enterocolitis) [4], and autoimmune disorders [5, 6].\n\nDespite the progress in the (medical and dietary) treatment of GSD Ib over the past years, such immunological complications still heavily impact on patients’ prognosis and quality of life. While evidence regarding the pathogenesis of neutropenia/neutrophil dysfunction and autoimmune disorders has accumulated [7–9], the pathomechanism of IBD in GSD Ib is still unclear; the disturbed immune response may play a role in its pathogenesis [4]. Granulocyte-colony stimulating factor (G-CSF) for neutropenia and conventional drugs for IBD and autoimmune disorders still constitute the current treatment options for most GSD Ib patients. For IBD, conventional treatments are sometimes ineffective and/or associated with side effects and patients might eventually need surgery [1]. Notably, improved prevention/treatment of IBD in GSD Ib ranked as a top priority for research in the international priority setting partnership for liver glycogen storage diseases [10].\n\nRecent evidence has shown a major role for plasma 1,5-anhydroglucitol (1,5AG) in causing neutropenia/neutrophil dysfunction in GSD Ib. 1,5AG enters neutrophils where it is phosphorylated to 1,5-anhydroglucitol-6-phosphate (1,5AG6P). 1,5AG6P is transported by G6PT into the ER, where it is physiologically dephosphorylated. G6PT defect results into cytosolic toxic 1,5AG6P accumulation thus affecting neutrophils survival and function [11].\n\nEmpagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes which reduces renal 1,5AG resorption by increasing urinary glucose excretion. Notably, empagliflozin administration decreased 1,5AG (plasma) and 1,5AG6P (neutrophils) concentrations in GSD Ib mice [11]. Two recent reports have shown same effect in GSD Ib patients with improved neutrophil count/function. Possible benefit on gastrointestinal symptoms have also been reported [12, 13]. However, no follow-up data on bowel (macro/microscopic) morphology are available.\n\nWe herein present for the first time longitudinal assessment of bowel morphology in a GSD Ib child suffering from Crohn disease-like enterocolitis treated with empagliflozin.\n\nCase presentation\n\nMethods\n\nStudy design\n\nEmpagliflozin is a SGLT2-inhibitor registered and marketed for type 2 diabetes in adults. Its most common adverse effects include low blood pressure and urogenital infections [14]. In the case herein described informed oral and written consent for the off-label treatment with empagliflozin was obtained from the patient and patient’s parents after discussing potential benefits and adverse effects of such treatment. Baseline data were collected 1 (day − 1) or 2 (day − 2) days before starting the treatment during in-hospital admission under medical supervision (day 0). Vital parameters were checked every 2 h within the first 12 h after treatment initiation and subsequently every 8 h. The patient was discharged on day + 5. Regular assessments of his GSD Ib and related conditions were performed at the outpatient clinic every 1 week within the first 2 months of treatment; subsequent evaluations were performed based on the patient’s conditions and medical advice. Blood samples were collected at the maximum distance after last C-GSF administration (day − 2 to day 30: 48 h; day 37 to day 51: 72 h; day 64 to day 71: 96 h; day 78 to day 115: 72 h). Physical examination included: weight, height and body mass index, signs/symptoms of infections, abdominal pain, mouth ulcers and perianal lesions. Adverse events were also recorded. For all results, the specific day of collection (i.e., day before/after starting the treatment) is reported in the main text, tables or figures.\n\nGastrointestinal assessment\n\nAn expert endoscopist performed the colonoscopy. During colonoscopy, 4 biopsies were taken from each colonic segment and from the terminal ileum, if entered. The histologic features were assessed by an experienced IBD pathologist, who was blinded to the endoscopic features and clinical history of the patients. Magnetic Resonance Imaging (MRI) was performed by an experienced IBD radiologist (who was blinded to the morphological features and clinical history of the patient) using a high-field (3.0-Tesla) scanner (Trio, Siemens) using a body coil with four channels; the following sequences were acquired: T2-weighted HASTE triggered on the axial plane (TR/TE 2000/91 ms; thickness 6 mm; flip angle 150; matrix: 256 × 157; acquisition time: 64 s), T2-weighted HASTE triggered on the coronal plane (TR/TE 2000/92 ms; thickness 4 mm; flip angle 121; matrix 320 × 256; acquisition time 80 s) with and without fat saturation, T1-weighted in-phase on the axial plane (TR/TE 1500/2.3 ms; thickness 6 mm; flip angle 20; matrix 256 × 154; acquisition time 50 s), T1- weighted out-of-phase on the axial plane (TR/TE 1500/1.37 ms; thickness 3.5 mm; flip angle 20; matrix 256 × 160; acquisition time 58 s) before and after intravenous injection of paramagnetic contrast (gadopentetate dimeglumine, Magnevist, Bayer HealthCare Pharmaceuticals). Disease activity was assessed using the pediatric Crohn disease activity index (PCDAI) [15]. Stool consistency was assessed with the Bristol stool chart.\n\nBiochemical tests\n\nFecal calprotectin was assessed through ELISA assay. Plasma 1,5AG and granulocytes 1,5AG6P were assessed as previously described [12]. Blood (glucose, lactate, cholesterol, triglycerides (TG), uric acid, AST, ALT, albumin, complete blood count, absolute neutrophil count (ANC), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) within the first hour, creatinine, blood urea nitrogen) and urine tests (creatinine, (24 h-proteins, 24 h-glucose, urinalysis) were performed by using assays with commercially available kits.\n\nGlucose monitoring\n\nBesides capillary glucose measurements, flash glucose monitoring (FGM) was performed through an intermittent scanning FGM device (Freestyle Libre2) during the following time frames: 1) baseline to day + 10; 2) + 3 months; 3) + 5.5 months; 4) + 7.5 months; 5) + 8 months. Low-glucose threshold was set at 3.3 mmol/L. In case of glucose concentrations below threshold, capillary glucose was also checked. Hypoglycemia was defined as capillary glucose < 3.3 mmol/L. Due to possible interference of daily life activities, physical activity and the risk of temporary sensor disconnection, both 24-h and night-time (1 a.m. to 5 a.m.) FGM data were analyzed for each time frame by using descriptive statistics. Only days with > 15 time points available were considered for the analysis. Time below range (TBR), time in range (TIR) and time above range (TAR) were defined according to current consensus glucose monitoring recommendations [16].\n\nQuality of life (QoL)\n\nHealth-related QoL was assessed at baseline and on day + 232 through the Italian version of the Short Form Health Survey (SF-36) questionnaire which has been previously used for GSDI patients. The SF-36 questionnaire consists of 36 items combined into eight scaled scores. The raw score is transformed into a 0–100 scale to generate a summary measure, with higher scores indicating better QoL [17].\n\nCase presentation\n\nA 14-year-old boy was diagnosed with GSD Ib at age 7 months due to fasting hypoketotic hypoglycemia with high lactate, enlarged liver and neutropenia. The molecular diagnosis of the SLC37A4 gene showed homozygosity for the mutation c.742C > T (p.Gln248X). A diet based on frequent meals and nocturnal gastric drip-feeding was started and the patient was included in a follow-up program at Section of Pediatrics, University of Naples “Federico II”. Several unsuccessful attempts with uncooked cornstarch were made in order to extend his fasting time (all associated with diarrhea, abdominal pain, vomiting). After such attempts, the patient developed avoidant/restrictive food intake disorder. Starting from age 6 years, 24-h gastric drip feeding (GDF) was required. Due to neutropenia, he was also started with i.m. G-CSF.\n\nDuring the follow-up several complications appeared. At 9 years of age juvenile idiopathic arthritis was diagnosed following the development of arthralgia and arthritis in the right knee and hip. From that age he also experienced recurrent aphthous stomatitis. Since Naproxen (15 mg/Kg/day) administration showed no benefit, i.m. methotrexate (15 mg/m2 every 1–3 weeks) was started. At age 13 limitation of range of motion and arthritis in the left knee required intra-articular injection of triamcinolone acetonide. At age 14 hyperuricemia was detected, requiring allopurinol administration (200 mg twice per day). Kidney function was regularly assessed and found normal. Plasma cholesterol (range 1.4–2.5 mmol/L) and TG (range 0.4–1.3 mmol/L) concentrations were constantly decreased.\n\nSince 10 years of age, he suffered from Crohn-like IBD (PCDAI:75 at the diagnosis). Chronic anemia was also detected requiring several (partly beneficial) intravenous iron infusions (Hb 7.6–10.5 g/dL). Despite methotrexate (15 mg/m2 every 1–3 weeks) administration, he experienced 2 disease relapses during the following 3 years. At age 13 switching to adalimumab (40 mg every 2 weeks) was decided after additional bowel and joint relapse. At age 14, further relapse occurred: moderate/severe abdominal pain, 2–5 liquid stools (with mucus) per day, perineal pain due to anal fissure, pain in the left foot with limitation of range of motion due to left metatarsal joints arthritis. No oral lesions were noted. Therefore, the patient was admitted, and extensive reassessment was performed (Table 1). Stricture at the ileocecal valve was detected at ileocolonoscopy (Fig. 1A). Histology showed active disease with crypt abscesses (Fig. 1B). Abdomen Magnetic resonance imaging (MRI) showed active disease with increased wall thickness and contrast enhancement in the distal ileum (total length:15–20 mm) with ileal stricture (Fig. 1C). 7-day ciprofloxacin (2 mg/Kg/day) and metronidazole (15 mg/Kg/day) treatment showed no benefit. Ibuprofen patch was partly effective on arthralgia. Since anti-adalimumab antibodies together with undetectable plasma adalimumab were also detected (Table 1), this treatment was withdrawn (hospital day 5) and ileocecal resection was proposed. 4.8 μg G-CSF/Kg every other day (i.e., 2.4 μg G-CSF/Kg/day) was continued. Table 1 Baseline clinical and biochemical data\n\n\tResult\tReferenceRange\t\nWeight (Kg)\t50\t–\t\nWeight (Z-score)\t−0.46\t−2 − + 2\t\nHeight (cm)\t159\t–\t\nHeight (Z-score)\t−1.10\t−2 − + 2\t\nBMI\t20\t–\t\nBMI (Z-score)\t0.10\t−2 − + 2\t\nPCDAI\t50\t< 10\t\nStool consistency type\t6\t3–4\t\nGlucose (mmol/L)\t4.5\t3.3–6.1\t\nLactate (mmol/L)\t1.8\t< 2.2\t\nTotal cholesterol (mmol/L)\t1.4\t3.4–5.3\t\nTriglycerides (mmol/L)\t0.4\t0.5–1.6\t\nUric acid (mmol/L)\t0.26\t0.13–0.39\t\nAST (U/L)\t12\t0–34\t\nALT (U/L)\t7\t0–55\t\nAlbumin (g/L)\t37\t34–48\t\nCreatinine (mg/dL)\t0.66\t0.60–1.10\t\nBlood Urea Nitrogen (mg/dL)\t13\t18–45\t\neGFR (ml/min/1.73 m2)\t132.6\t100.9–133.3\t\nWhite blood cells (WBC)/μL\t3010\t5000–15,000\t\nNeutrophils/μL\t1490\t1300–8500\t\nLymphocytes/μL\t1370\t1300–8500\t\nHemoglobin (g/dL)\t8.8\t11.5–14.0\t\nHematocrit (%)\t33\t33–35\t\nPlatelets/μL\t274,000\t140,000–440,000\t\nFibrinogen (mg/dL)\t233\t160–350\t\n1,5AG (μM)\t155\t–\t\n1,5AG6P (μM)\t1.35\t–\t\nCRP (mg/dL)\t2.8\t< 0.5\t\nESR (mm/h)\t35\t< 20\t\nAdalimumab (μg/ml)\t< 0.5\t5–10\t\nAnti-adalimumab IgG (ng/ml)\t62.3\t< 2.5\t\n24-h urine protein (mg/24 h)\t< 200\t< 200\t\n24-h urine glucose (mg/24 h)\tnot detected\tnot detected\t\nFecal calprotectin (μg/g)\t253\t< 100\t\nPCDAI: Pediatric Crohn’s Disease Activity Index; eGFR: estimated glomerular filtration rate; 1,5AG:1,5-anhydroglucitol; 1,5AG6P: 1,5-anhydroglucitol-6-phosphate; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate within the first hour\n\nFig. 1 Bowel morphology at baseline. A Ileocolonoscopy: ulcerated and ileocecal valve stricture with impossibility to pass through with the scope (Paris classification A1b, L1, B2, G0; SES-CD: 3). B Histology (colonic mucosa): architectural irregularity and a mild patchy increase of lamina propria cells with neutrophilic and eosinophilic infiltration, crypt abscesses (red arrow) and an epithelioid cell granuloma (black arrow) indicating active disease. C Abdomen MRI: active disease with increased wall thickness (max: 10 mm), diffusion restriction and contrast enhancement in the distal ileum (total length:15–20 cm) and ileal stricture; mesenteric hypertrophy (creeping fat) and lymphadenopathy and conglomerated bowel loops (right lower quadrant) are also shown. SES-CD: simplified endoscopic score for Crohn’s disease\n\nOff-label treatment with empagliflozin was also discussed with the patient’s family. After oral and written informed consent for this individual treatment, ileocecal resection was postponed, and the patient was started with empagliflozin (day 0, hospital day 16). The starting dose was 5 mg/day (0.1 mg/Kg/day); the dose was further increased to 5 mg twice a day (0.2 mg/Kg/day) on day + 3 and 10 mg twice a day (0.4 mg/Kg/day) on day + 7. Ciprofloxacin was stopped on day − 1; metronidazole was withdrawn on day + 3. The dietary regimen was continued as usual (24-h GDF). No significant changes in vital signs and no serious adverse events were observed. On day + 22 urinary nitrites (with no leukocytes) were detected, with no associated symptoms. Urine culture was ordered and oral cefixime (8 mg/Kg/day) was started (being urinary tract infections common side effects of empagliflozin and considering the risk of metabolic decompensation in case of infection). On day + 27 urine culture tested negative and oral cefixime was withdrawn. Subsequent urinalysis tested normal. 24-h urine glucose was absent on day − 2 and tested constantly increased after treatment initiation (range 13,212–30,775 mg/24 h).\n\nPerineal pain and anal fissure improved after 3 days of treatment and disappeared on day + 6. On day + 3 pain in the left foot improved and on day + 5 metatarsal swelling was reduced; starting from day + 20 no signs or symptoms of arthritis were noted. On day + 232 his weight (Z-score: − 0.49), height (Z-score: − 1.03) and BMI (Z-score:0.01) were comparable to baseline. The stool frequency went down to 1–2 x day after 1 week of treatment and 1 x every 2 days after 1 month of treatment. The stool consistency switched from type 6 to type 5 after 2 weeks of treatment and type 4 after 1 month of treatment. The PCDAI decreased from 50 (day − 1) to 20 (day + 7) to 5 (day + 15). Fecal calprotectin increased up to + 40% during the first month of treatment with subsequent decrease. 7.5 months after starting with empagliflozin its value was − 48% compared to baseline and almost normalised (Fig. 2A). Similarly, CRP values increased during the first 2 week of treatment and eventually normalised (occasional spikes occurred). ESR values decreased by 34% after 2 weeks of treatment and normalised after 3 months of treatment. Hemoglobin concentrations constantly increased from the first week of treatment and eventually normalised 5.5 months after starting with empagliflozin (Fig. 2B). Fig. 2 PCDAI and biochemical assessment before and after empagliflozin. A PCDAI (light grey triangles) and fecal calprotectin (dark grey circles) values before and after empagliflozin (upper references values for PCDAI (10) and fecal calprotectin (100) are underlined; B Hemoglobin (light grey triangles), ESR (Black circle) and CRP (dark grey squares) values before and after empagliflozin (upper reference values for ESR (20) and CRP (0.5) and lower reference value for Hb (11.5) are underlined. PCDAI: Paediatric Crohn’s Disease Activity Index; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate within the first hour\n\nAbdomen MRI performed at + 85 days showed − 45% wall thickness and − 63% disease length in the distal ileum (total length 5.5 cm) together with ileal stricture (Fig. 3A). At + 161 days ileocolonoscopy showed unchanged stricture at the ileocecal valve (Fig. 3B); histology showed no signs of active disease (Fig. 3C). At the time no significant change in spleen longitudinal diameter was noted (Z-score: baseline: + 8.75; + 161 days: + 7.52). Fig. 3 Bowel morphology after empagliflozin treatment. A MRI (day + 85): decreased wall thickness (max 6.5 mm), decreased diffusion restriction, decreased contrast enhancement in the distal ileum (total length: 5.5 cm) together with ileal stricture; stable mesenteric hypertrophy (creeping fat) and lymphadenopathy with no evidence of conglomerated bowel loops (right lower quadrant) are also shown. B-C. Ileocolonoscopy (day + 161): ileocecal valve ulcer and stricture with the impossibility to pass through with the scope (Paris classification A1b, L1, B2, G0; SES-CD: 3). D Histology (day + 161, colonic mucosa): minimal architectural distortion, increase of lamina propria, associated with muscularis mucosae hypertrophy (black arrow) and adequate gland representation indicating chronic mild colitis with histologic remission. SES-CD: simplified endoscopic score for Crohn’s disease\n\nOn day + 163 oral refeeding was proposed. Following discussion with the family, the patient was switched from 24-h (5 mg carbohydrates/Kg/min) to 19-h (4 p.m.-11 a.m.) (5 mg carbohydrates/Kg/min) GDF. In the “GDF-free” hours one morning snack (11 a.m.) and lunch (01.30 p.m.) were included in the hospital setting, providing an overall carbohydrate intake of 2.2 g/Kg (i.e., 7.6 mg carbohydrates/Kg/min). With such a scheme, the patient’s fasting time changed from 0 to 2.5 h during the “GDF-free” hours. Capillary glucose concentrations (checked every 30 min on 3 consecutive days during the 5 h without gastric drip feeding) were > 3.9 mmol/L (range 4.9–7.2 mmol/L). Neither gastrointestinal symptoms/signs nor changes in stool frequency/features were reported during the subsequent 2-month follow-up; on day + 232 fecal calprotectin almost normalised (Fig. 2A).\n\nANC showed wide variations before empagliflozin (340–4720/μL) with reduced fluctuations (580–2990/μL) after empagliflozin was started. 1,5-AG and 1,5-AG6P concentrations are presented in Additional file 1. The G-CSF dose was gradually decreased and finally set to 4.8 μg G-CSF/Kg every 3 days (i.e. 1.6 μg G-CSF/Kg/day). Lactate concentrations stayed within the reference range (1.3–2.3 mmol/L). A slight increase in cholesterol and TG concentrations (which reached the reference range) was observed (Additional file 2A). Uric acid concentrations stayed normal and allopurinol was gradually discontinued (Additional file 2B). Liver and kidney function were regularly checked and tested normal.\n\nCapillary glucose values were below < 3.3 mmol/L (range 2.6–3.3 mmol/L) on 20/32 low-glucose events measured by FGM within the first week of treatment and promptly increased upon glucose administration via the feeding tube. No signs or symptoms of hypoglycemia were reported. Occasional (2–4 times per month) asymptomatic mild hypoglycemias (range 2.7–3.3 mmol/L) occurred during the subsequent 6-month capillary glucose self-monitoring. Data on FGM monitoring are shown in Additional file 3. A substantial decrease in TBR as well as an increase in TIR were observed (also after oral refeeding was started). The patient’s QoL score improved from 37.64 (baseline) to 74.44 (day + 232).\n\nDiscussion and conclusions\n\nThe management of IBD is still challenging in GSD Ib as its pathogenesis remains [1, 3]. Conventional treatments (i.e., corticosteroids, immunomodulators, biological agents) are sometimes ineffective and/or associated with side effects (e.g. leucopenia, anemia, diarrhea) and patients might eventually need surgery [18]. Being the cornerstone of treatment for neutropenia, G-CSF has also led to IBD remission in some GSD Ib patients [19]. However, its efficacy is variable and long-term G-CSF administration may cause side effects (e.g. enlarged spleen) and increased risk for malignancies (e.g. acute myeloid leukemia, myelodysplastic syndrome) [20, 21]. Therefore, more effective treatments are required to improve patients prognosis and quality of life.\n\nAlthough previous reports have shown possible benefit of empagliflozin on gastrointestinal symptoms [12, 13], follow-up data on bowel (macro/microscopic) morphology are not available. In the case herein reported, we presented comprehensive gastrointestinal assessment in a child with GSD Ib, showing clear benefit of empagliflozin administration on Chron disease-like enterocolitis. No symptomatic hypoglycemias and no adverse events were associated with empagliflozin administration.\n\nClinical improvement was noted within the first week of treatment and eventually led to normal stool frequency/consistency and PCDAI normalisation. Clinical remission occurred within the first month of treatment. Biochemical improvement occurred within the first 2 weeks of treatment and remission was documented after 2 months of treatment. Strikingly, the benefit on clinical picture and hemoglobin concentrations appeared as soon as the end of the first week. Morphology studies also showed partial IBD remission within 3–6 months of treatment. Notably, a dramatic improvement in the disease length and activity was documented on the abdomen MRI after 3 months of treatment as well as histologic remission after 5.5 months of treatment. Empagliflozin allowed to postpone ileocecal resection (and possibly decrease the length of the bowel segment to be resected) in the present case. However, no major endoscopic changes were noted 5.5 months after starting treatment. Those data show that empagliflozin may be effective in healing the inflammatory lesions/strictures but might not be able to reverse fibrotic strictures once established. Such conclusion suggests early empagliflozin administration in GSD Ib patients with IBD before the onset of (irreversible) intestinal fibrosis. 0.4 mg/Kg/day empagliflozin were administered in the present case. Previous study showed 0.3–0.7 mg/Kg/day to lay within the therapeutic window for neutropenia [12]. It is still unclear if higher doses can be more effective or whether a specific dose range might exert special benefit on other disease complications (e.g., IBD, arthritis). Future studies should address this issue.\n\nBesides the effect on IBD, decreased 1,5AG and 1,5AG6P concentrations as well as higher/more stable neutrophil count were also documented after starting with empagliflozin. Based on those data, the G-CSF dose was decreased by 33% in the present case. Undoubtedly, reducing G-CSF dose can decrease the risk of side effects and malignancies associated with its long-term administration. However, not all GSD Ib patients treated with empagliflozin are able to discontinue G-CSF [12]. The reason for such discrepancy is still unclear. Possible role of additional factors contributing to empagliflozin response (e.g., genotype, renal function, glycosylation status) should be further addressed for optimal patient selection. The results herein reported also support possible role of disrupted immune response in the pathogenesis of IBD in GSD Ib. Indeed, a role for 1,5AG and 1,5AG6P in modulating other peripheral blood mononuclear cells has been postulated [11].\n\nDespite 33% reduction in G-CSF dose, no change in spleen size was observed in the current patient. In 3 out of the 5 previous GSD Ib patients that have been previously described to be treated with empagliflozin and who presented with splenomegaly, 2 showed decreased spleen size only 9 months after starting empagliflozin (G-CSF was discontinued or decreased by 81%, respectively). Despite G-CSF discontinuation, 1 patient showed stable spleen size 3 months after starting empagliflozin [12]. Longer follow-up studies are warranted to clarify when to expect benefit on splenomegaly.\n\nAdditionally, improved metabolic control was noted in the present case. Increase of (low) cholesterol and TG levels and reversal of hyperuricemia (leading to allopurinol discontinuation) were detected after empagliflozin administration. Likely, normalisation of plasma cholesterol and TG were secondary to intestinal healing in the present case. FGM data showed stable glucose levels and eventually no hypoglycemia was detected. Strikingly, the patient also experienced (limited) amount of time in the “above-range” (Additional file 3). Such findings are in line with previous report [12] suggesting that IBD might concur to metabolic control in GSD Ib patients by limiting intestinal glucose absorption. Interestingly, recent research has shown the impact of life-long diet on gut microbiota in GSD Ib [22]. FGM may constitute an additional, minimally invasive monitoring tool for GSD Ib patients.\n\nNot only led empagliflozin to improved clinical conditions and biochemical/morphological markers but also allowed drug dose reduction/discontinuation in the present case. As a matter of fact, the patient was switched from 4-drug (i.e., adalimumab, allopurinol, G-CSF, ibuprofen patch) to 2-drug (G-CSF, empagliflozin) regimen with a simplified drug schedule. Notably, the number of painful G-CSF injections was decreased. Benefits on healthcare costs (empagliflozin is less expensive than G-CSF and biologic therapies for IBD) as well as reduced healthcare use by GSD Ib patients can also be expected. Indeed, the gross monthly financial burden for medication decreased by 59% in the present case (3586 € vs 1467€).\n\nImproved QoL was also observed after empagliflozin administration. Patients with IBD show increased prevalence of psychological disturbances like depression and anxiety [23]. In the present case, the patient agreed on restarting oral feeding after 8 years, allowing (in part) weaning from tube feeding. This result suggests that, by improving the IBD-related symptoms, empagliflozin can also exert a positive effect on psychosocial health and well-being in patients with GSD Ib.\n\nAlthough renal function was constantly normal in the present case, future studies should assess the effect of empagliflozin on renal function in GSD Ib patients [24, 25].\n\nOverall, the present case shows that empagliflozin administration is safe and effective in inducing IBD remission in GSD Ib patients and can postpone surgery. It also improves neutrophil count and metabolic control. Since this is the first case documenting comprehensive longitudinal IBD morphology follow-up in a patient with GSD Ib treated with empagliflozin, future studies are needed to confirm its safety and efficacy over time and assess its benefit in various disease stages. As empagliflozin has the potential to change the natural history and management of GSD Ib patients, the development of an international collaborating networks for systematic data collection on its safety and efficacy is worthy.\n\nSupplementary Information\n\nAdditional file 1. Neutrophil count (light grey triangles), 1,5AG (black circles) and 1,5AG6P (dark grey squares) before and after empagliflozin. Plasma 1,5-AG concentration dropped from ±250 μM before treatment to ±50 μM after 2 weeks on empagliflozin. Concentration of 1,5-AG stayed relatively constant until day + 164, before a change in the diet introducing a daily oral intake of carbohydrates. On day + 232, approximately 2 months after this change, plasma 1,5-AG was only very slightly increased to 60 μM. After treatment, 1,5-AG6P present in leukocytes and measured in whole blood samples was reduced by 4- to 5-fold when compared to values before starting empagliflozin. 1,5AG: 1,5-anhydroglucitol; 1,5AG6P: 1,5-anhydroglucitol-6-phosphate.\n\nAdditional file 2. (A) Plasma cholesterol (grey triangles) and TG (black circles) before and after empagliflozin (reference values for cholesterol (3–5) and TG (0.5–1.5) are underlined); (B) Plasma uric acid concentrations before and after empagliflozin (reference values are underlined). TG: triglycerides.\n\nAdditional file 3. Flash glucose monitoring data.\n\nAbbreviations\n\nANC Absolute neutrophil count\n\nCRP C-reactive protein\n\nESR Erythrocyte sedimentation rate\n\nFGM Flash glucose monitoring\n\nGSD Ib Glycogen storage disease type Ib\n\nIBD Inflammatory bowel disease\n\nPCDAI Pediatric Crohn disease activity index\n\nQoL Quality of life\n\nTG Triglycerides\n\n1,5AG 1,5-anhydroglucitol\n\n1,5AG6P 1,5-anhydroglucitol-6-phosphate\n\nAcknowledgements\n\nThe authors would like to thank Rosaria Tuzzi and Carmen Rosano for their support with the collection of samples.\n\nAuthors’ contributions\n\nAR, EM, SF, MM, CM, MDA, EM were involved in data collection, analysed and interpreted the patient data and wrote the first draft of the manuscript. MVDC, PS, TGJD, AS, GP were involved in data collection, analysed and interpreted the patient data and critically revised the manuscript. All the authors made substantial contributions to the conception or design of the work. All authors read and approved the final manuscript.\n\nFunding\n\nThis work was supported by a research funding donation from Vitaflo Italia to AR and GP (no award/grant number) and the 01/2020 scholarship from Associazione Italiana Glicogenosi to AR and TGJD.\n\nAvailability of data and materials\n\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nWritten informed consent was obtained from the patient’s parents. A copy of the written consent is available for being reviewed by the Editor-in-Chief of this journal.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient’s parents. A copy of the written consent is available for being reviewed by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that there is no potential conflict of interest related to this work. There are no prior publications or submissions with any overlapping information, including studies and patients.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Kishnani PS Austin SL Abdenur JE Diagnosis and management of glycogen storage disease type I: a practice guideline of the American College of Medical Genetics and Genomics Genet Med 2014 128 1 29 10.1038/gim.2014.128\n2. Rake JP Visser G Labrune P Leonard JV Ullrich K Smit Guidelines for management of glycogen storage disease type I – European study on glycogen storage disease type I (ESGSD I) Eur J Pediatr 2002 161 1 S112 S119 10.1007/BF02680007 12373584\n3. Visser G Rake J Labrune P Consensus guidelines for management of glycogen storage disease type 1b - European study on glycogen storage disease type 1 Eur J Pediatr 2003 161 S120 S123\n4. Visser G Rake JP Fernandes J Labrune P Leonard JV Moses S Ullrich K Smit GP Neutropenia, neutrophil dysfunction, and inflammatory bowel disease in glycogen storage disease type Ib: results of the European study on glycogen storage disease type I J Pediatr 2000 137 2 187 191 10.1067/mpd.2000.105232 10931410\n5. Melis D Pivonello R Parenti G Della Casa R Salerno M Lombardi G Increased prevalence of thyroid autoimmunity and hypothyroidism in patients with glycogen storage disease type I J Pediatr 2007 150 3 300 305 10.1016/j.jpeds.2006.11.056 17307551\n6. Melis D Della Casa R Balivo F Minopoli G Rossi A Salerno M Involvement of endocrine system in a patient affected by glycogen storage disease 1b: speculation on the role of autoimmunity Ital J Pediatr 2014 40 1 30 10.1186/1824-7288-40-30 24646511\n7. Jun HS Weinstein DA Lee YM Mansfield BC Chou JY Molecular mechanisms of neutrophil dysfunction in glycogen storage disease type Ib Blood. 2014 123 18 2843 2853 10.1182/blood-2013-05-502435 24565827\n8. Melis D Carbone F Minopoli G La Rocca C Perna F De Rosa V Cutting edge: increased autoimmunity risk in glycogen storage disease type 1b is associated with a reduced engagement of glycolysis in T cells and an impaired regulatory T cell function J Immunol 2017 198 10 3803 3808 10.4049/jimmunol.1601946 28389590\n9. Rossi A Simeoli C Salerno M Ferrigno R Della Casa R Colao A Strisciuglio P Parenti G Pivonello R Melis D Imbalanced cortisol concentrations in glycogen storage disease type I: evidence for a possible link between endocrine regulation and metabolic derangement Orphanet J Rare Dis 2020 15 1 99 10.1186/s13023-020-01377-w 32306986\n10. 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"keywords": "1,5-anhydroglucitol; Continuous glucose monitoring; Empagliflozin; Glycogen storage disease type Ib; Inflammatory bowel disease; Neutropenia",
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"title": "Crohn disease-like enterocolitis remission after empagliflozin treatment in a child with glycogen storage disease type Ib: a case report.",
"title_normalized": "crohn disease like enterocolitis remission after empagliflozin treatment in a child with glycogen storage disease type ib a case report"
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"abstract": "Crizotinib is an oral small-molecule anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor for the treatment of ALK-positive non-small-cell lung cancer (NSCLC). A 63-year old woman with postoperative relapsed ALK-positive NSCLC was treated with crizotinib. Erythema multiforme (EM) occurred one week after initiation of crizotinib therapy. Skin biopsy specimen showed compatible drug eruption. The discontinuation of crizotinib improved her eruption within one week. This report presented the first case of crizotinib-associated EM, which is the preclinical stage of Stevens-Johnson syndrome. Although crizotinib is clinically available, we should be aware of its potential severe skin adverse event.",
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"authors": "Sawamura|Soichiro|S|;Kajihara|Ikko|I|;Ichihara|Asako|A|;Fukushima|Satoshi|S|;Jinnin|Masatoshi|M|;Yamaguchi|Emi|E|;Kohrogi|Hirotsugu|H|;Ihn|Hironobu|H|",
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"title": "Crizotinib-associated erythema multiforme in a lung cancer patient.",
"title_normalized": "crizotinib associated erythema multiforme in a lung cancer patient"
} | [
{
"companynumb": "JP-PFIZER INC-2018510324",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CRIZOTINIB"
},
"drugadditional": "1",
... |
{
"abstract": "We present a normotensive, pregnant woman with severe haemolytic anaemia in the third trimester of pregnancy. Owing to normal platelet count diagnoses other than HELLP syndrome were considered and investigated. The patient was treated with nitrofurantoin 3 weeks before presentation and she turned out to have a deficiency of glucose-6-phosphate dehydrogenase. After treatment with blood transfusion, vitamin B12 and folic acid the patient recovered completely. Caesarean delivery was performed because of maternal hypertension and fetal distress at 33 weeks' gestation.",
"affiliations": "Department of Obstetrics & Gynecology, Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands.",
"authors": "van de Mheen|Lidewij|L|;Smits|Simone M|SM|;Terpstra|Wim E|WE|;Leyte|Anja|A|;Bekedam|Dick J|DJ|;van den Akker|Eline S A|ES|",
"chemical_list": "D009582:Nitrofurantoin; D005492:Folic Acid; D014805:Vitamin B 12",
"country": "England",
"delete": false,
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"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000743:Anemia, Hemolytic; D001803:Blood Transfusion; D002585:Cesarean Section; D005260:Female; D005492:Folic Acid; D005955:Glucosephosphate Dehydrogenase Deficiency; D017359:HELLP Syndrome; D006801:Humans; D009582:Nitrofurantoin; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic; D011256:Pregnancy Outcome; D011263:Pregnancy Trimester, Third; D011295:Prenatal Care; D018570:Risk Assessment; D014552:Urinary Tract Infections; D014805:Vitamin B 12",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24789148",
"pubdate": "2014-04-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16430460;8765269;19245695;17698825;12659;7943089;19233695",
"title": "Haemolytic anaemia after nitrofurantoin treatment in a pregnant woman with G6PD deficiency.",
"title_normalized": "haemolytic anaemia after nitrofurantoin treatment in a pregnant woman with g6pd deficiency"
} | [
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"companynumb": "NL-ACTAVIS-2015-00874",
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"abstract": "Post-transplant lymphoproliferative disorder (PTLD) describes a spectrum of conditions with highest incidence in the first year post-solid organ transplant in pediatric patients. Central nervous system (CNS) involvement with PTLD carries high mortality risk with no consensus on optimal therapeutic regimen. We present the case of a 7-year old heart transplant patient diagnosed with widespread monomorphic, CD20+, Epstein-Barr virus-positive PTLD, including CNS involvement. In addition to immunosuppression reduction and rituximab, she was treated with multiagent systemic and intrathecal chemotherapy. She achieved a prompt and complete clinical and radiologic remission, which has been sustained for over 46 months since diagnosis.",
"affiliations": "Department of Pediatrics, Lucile Packard Children's Hospital, Palo Alto, California.",
"authors": "Mahapatra|Sidharth|S|;Chin|Clifford C|CC|;Iagaru|Andrei|A|;Heerema-McKenney|Amy|A|;Twist|Clare J|CJ|",
"chemical_list": "D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "61(11)",
"journal": "Pediatric blood & cancer",
"keywords": "Epstein-Barr virus (EBV); central nervous system post-transplant lymphoproliferative disorder (CNS PTLD); chemotherapy; heart transplant",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D001853:Bone Marrow; D002490:Central Nervous System; D002648:Child; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D008232:Lymphoproliferative Disorders; D008727:Methotrexate",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "2107-9",
"pmc": null,
"pmid": "25066638",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of systemic and central nervous system post-transplant lymphoproliferative disorder without the use of high-dose methotrexate or radiation.",
"title_normalized": "successful treatment of systemic and central nervous system post transplant lymphoproliferative disorder without the use of high dose methotrexate or radiation"
} | [
{
"companynumb": "US-ROCHE-1572447",
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{
"actiondrug": "2",
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"activesubstancename": "DOXORUBICIN"
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{
"abstract": "BACKGROUND\nMidodrine is widely used in the treatment of hypotensive states, there have been no reports of myoclonus associated with midodrine use in hypotension with chronic kidney disease.\nWe report a 58-year-old female patient with chronic kidney disease (CKD) presenting with involuntary tremor 2 h after taking midodrine, which became more frequent after 6 h. Brain CT and neurological examination did not yield findings of note. Blood chemistry showed serum albumin of 3.1 g/L, ALT of 19 U/L, AST of 22 U/L, SCr of 273.9 μmol/L, K of 2.94 mmol/L, Ca of 1.63 mmol/L, and Mg of 0.46 mmol/L. Her BP was maintained at 83-110/56-75 mmHg. Her urine volume was 600-1000 mL/d, and her heart rate was within a range of 90-100 beats/min.\n\n\nMETHODS\nChronic kidney disease (CKD), hypotension, metabolic acidosis, hypocalcemia, hypokalemia, and hypomagnesemia.\n\n\nMETHODS\nMidodrine treatment was stopped and the patient was treated with intravascular rehydration and furosemide. Myoclonus ceased one day after midodrine withdrawal.\n\n\nCONCLUSIONS\nOral midodrine is widely used in the treatment of orthostatic hypotension, recurrent reflex syncope and dialysis-associated hypotension and the adverse effects are mostly mild. However, clinicians should be alert for midodrine-induced myoclonus, especially in patients with CKD.",
"affiliations": "Department of Pharmacy, Zhejiang Provincial People's Hospital.;Department of Pharmacy, The First People's Hospital of Yancheng City, Yancheng 224005, Jiangsu.;State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Rd.;Department of Pharmacy, Third Affiliated hospital of Wenzhou Medical University.;Department of Nephrology, Zhejiang Provincial People's Hospital.;Department of Nephrology, Zhejiang Provincial People's Hospital.;Department of Pharmacy, Zhejiang Provincial People's Hospital.;Department of Pharmacy, Zhejiang Provincial People's Hospital.;Department of Nephrology, Zhejiang Provincial People's Hospital.",
"authors": "Ye|Xiaolan|X|;Ling|Bai|B|;Wu|Jian|J|;Wu|Shujuan|S|;Ren|Yan|Y|;Zhang|Hongjuan|H|;Song|Feifeng|F|;Xuan|Zixue|Z|;Chen|Maosheng|M|",
"chemical_list": "D058646:Adrenergic alpha-1 Receptor Agonists; D008879:Midodrine",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000021533",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-19-09020\n10.1097/MD.0000000000021533\n21533\n4200\nResearch Article\nClinical Case Report\nCase report: severe myoclonus associated with oral midodrine treatment for hypotension\nYe Xiaolan MDab∗ Ling Bai MDc∗ Wu Jian MDd Wu Shujuan MDe Ren Yan MDfg Zhang Hongjuan MDfg Song Feifeng MDab Xuan Zixue BSab Chen Maosheng MD PhDfg∗ Saranathan. Maya a Department of Pharmacy, Zhejiang Provincial People's Hospital\nb Department of Pharmacy, People's Hospital of Hangzhou Medical College, Hangzhou 310014\nc Department of Pharmacy, The First People's Hospital of Yancheng City, Yancheng 224005, Jiangsu\nd State Key Laboratory for the Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Rd.\ne Department of Pharmacy, Third Affiliated hospital of Wenzhou Medical University\nf Department of Nephrology, Zhejiang Provincial People's Hospital\ng Department of Nephrology, People's Hospital of Hangzhou Medical College, Hangzhou 310014, People's Republic of China.\n∗ Correspondence: Maosheng Chen, Department of Nephrology, Zhejiang Provincial People's Hospital, No. 158 Shangtang Road, Xiacheng District, Hangzhou 310014, People's Republic of China (e-mail: chenmaosheng@hmc.edu.cn).\n02 10 2020 \n02 10 2020 \n99 40 e2153318 11 2019 8 6 2020 1 7 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nMidodrine is widely used in the treatment of hypotensive states, there have been no reports of myoclonus associated with midodrine use in hypotension with chronic kidney disease.\n\nPatient concerns:\nWe report a 58-year-old female patient with chronic kidney disease (CKD) presenting with involuntary tremor 2 h after taking midodrine, which became more frequent after 6 h. Brain CT and neurological examination did not yield findings of note. Blood chemistry showed serum albumin of 3.1 g/L, ALT of 19 U/L, AST of 22 U/L, SCr of 273.9 μmol/L, K+ of 2.94 mmol/L, Ca2+ of 1.63 mmol/L, and Mg2+ of 0.46 mmol/L. Her BP was maintained at 83–110/56–75 mmHg. Her urine volume was 600–1000 mL/d, and her heart rate was within a range of 90–100 beats/min.\n\nDiagnosis:\nChronic kidney disease (CKD), hypotension, metabolic acidosis, hypocalcemia, hypokalemia, and hypomagnesemia.\n\nInterventions:\nMidodrine treatment was stopped and the patient was treated with intravascular rehydration and furosemide. Myoclonus ceased one day after midodrine withdrawal.\n\nLessons:\nOral midodrine is widely used in the treatment of orthostatic hypotension, recurrent reflex syncope and dialysis-associated hypotension and the adverse effects are mostly mild. However, clinicians should be alert for midodrine-induced myoclonus, especially in patients with CKD.\n\nKeywords\nmidodrinemyoclonushypotensionchronic kidney diseaseOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nMidodrine is widely used in the treatment of hypotensive states, particularly in orthostatic hypotension.[12] To our knowledge, this is the first reported case of myoclonus caused by midodrine. The pharmacological mechanisms leading to this adverse drug reaction (ADR) have not been established.\n\n2 Case Report\nA 58-year-old female patient with chronic kidney disease (CKD) was treated with laser lithotripsy. After 20 days, her serum creatinine (SCr) had increased from 200 to 280.2 μmol/L, at which point she was admitted to the hospital. SCr continued to increase to 393.0 μmol/L over the course of the next 16 days. Upon admission, she was fatigued, weak, and consistently dizzy. Blood pressure (BP) was 106/63 mmHg. Blood chemistry showed albumin of 3.1 g/L, ALT at 19 U/L, AST at 22 U/L, SCr at 273.9 μmol/L, K+ at 2.94 mmol/L, Ca2+ at 1.63 mmol/L, and Mg2+ at 0.46 mmol/L. She was diagnosed with metabolic acidosis, hypocalcemia, hypokalemia, and hypomagnesemia, and was treated with intravenous calcium gluconate, oral potassium sodium hydrogen citrate granules, potassium, and magnesium aspartate. Three days after treatment, the patient still complained of dizziness and physical weakness. Her BP was maintained at 83–110/56–75 mmHg, her urine volume was 600–1000 mL/d, and her heart rate had a range of 90–100 beats/min. Since she suffered from hypotension, she was given oral midodrine (2.5 mg three times daily). She took midodrine for the first time at 19:00 pm, and felt intermittent involuntary tremors after 2 h. Tremors became more frequent after 6 h. There were no observations of salivation, urination, or biting of the tongue, and she was able to obey verbal commands. The patient reported that she could not control her arms to keep them still. Blood gas analysis indicated a pH of 7.46, with Ca2+ of 0.93 mmol/L. Despite continuous supplementary intravenous calcium, the symptoms were not relieved. After taking midodrine for the second and third time, the patient had a generalized myoclonic seizure and paresthesia, described as the sensation of crawling ants on her skin. She reported that the clonus was less painful if she lay down, and she was unable to walk by herself. There were no additional significant abnormalities in her brain CT scan or neurological examination, although she was dehydrated from hemodialysis. She was given oral diazepam to relieve anxiety, but this was also ineffective. After evaluating the patient's medicines and manifestations, a clinical pharmacist suggested that the myoclonus reflected a rare ADR of midodrine, and midodrine was withdrawn immediately. Since the patient's blood pressure was still low, intravascular rehydration and furosemide were given without an alpha-1-receptor antagonist. Her symptoms improved gradually, and myoclonus ceased a day after midodrine withdrawal, although her ionized calcium remained abnormal. Myoclonus did not recur during hospitalization, and the patient did not report any further symptoms at the outpatient clinic one month later. The event was evaluated as Naranjo Scale[7] is 7, and we therefore suspect it to be an adverse drug reaction.\n\n3 Discussion\nMidodrine is a direct-acting sympathomimetic with selective alpha-1-agonist activity. Its main active moiety is its major metabolite, deglymidodrine, which reaches peak plasma concentration about 1 h after oral administration, the half-life (t1/2) of deglymidodrine is about 3 h, and the duration of drug action is 4–6 h.[23] Midodrine is mainly excreted through the urine as metabolites and a small amount of unchanged form.[234]\n\nMidodrine is widely used in the treatment of orthostatic hypotension, recurrent reflex syncope, and dialysis-associated hypotension,[12345] and raises blood pressure by acting on arterial and venous smooth muscle contraction.[6] Notable side effects include supine and sitting hypertension, paresthesia, pruritus (mainly of the scalp), goosebumps, chills, urinary urge, urinary retention, and urinary frequency. Though the FDA label of midodrine mentions leg cramps as a rare ADR,[4] we were unable to find other cases reports of generalized myoclonus in Medline, PubMed, or Clinical Trial Data Review. Despite this rareness, the Naranjo Scale[7] indicated score of 7, or a probable relationship between the patient's development of myoclonus and use of midodrine (Table 1).\n\nTable 1 The Naranjo adverse drug reaction probability scale.\n\nThe exact mechanisms this ADR cannot yet be characterized. Several studies have indicated that anxiety, fear, restlessness, insomnia, confusion, irritability, psychotic states, and other central nervous system effects may occur with all sympathomimetics. Some sympathomimetics which do not cross the blood-brain barrier appear to be a somatic response to their central effects. In addition, epinephrine can facilitate neuromuscular transmission followed by a prolonged rapid stimulation of motor nerves.[2] Some studies have found that the stimulation of receptors causes a more rapid increase in transmitter release from the somatic motor neuron, perhaps due to the enhanced influx of Ca2+. These responses are most likely mediated by alpha-1 receptors.[2]\n\nIn treating or preventing midodrine alpha-mediated ADRs such as hypertension, a rapidly-acting alpha blocker such as phentolamine may be given. However, it is not known whether this could affect ADRs such as myoclonus, especially for patients with hypotension. As such, supportive care may be more suitable. In our case, the patient had chronic renal insufficiency, with decreased urine output at admission, and midodrine excretion was delayed. As a result, the myoclonus ADR lasted for one day after drug withdrawal.\n\n4 Conclusion\nThis case is the first reported case of myoclonus as a serious and unexpected adverse drug reaction to midodrine. Our experience suggests that careful attention should be given to patients taking midodrine, especially for those with CKD, since they may be more susceptible to midodrine side effects.\n\nAuthor contributions\n\nConceptualization: Xiaolan Ye, Bai Ling, Yan Ren, Hongjuan Zhang.\n\n\nData curation: Hongjuan Zhang, Feifeng Song, Zixue Xuan.\n\n\nInvestigation: Xiaolan Ye, Shujuan Wu, Feifeng Song, Zixue Xuan, Maosheng Chen.\n\n\nMethodology: Xiaolan Ye, Yan Ren, Maosheng Chen.\n\n\nProject administration: Xiaolan Ye.\n\n\nResources: Xiaolan Ye, Maosheng Chen.\n\n\nSupervision: Hongjuan Zhang.\n\n\nWriting – original draft: Xiaolan Ye.\n\n\nWriting – review & editing: Bai Ling, Jian Wu, Maosheng Chen.\n\nAbbreviations: ADR = adverse drug reaction, ALT = alanine aminotransferase, AST = aspartate aminotransferase, BP = blood pressure, CKD = chronic kidney disease, SCr = serum creatinine.\n\nHow to cite this article: Ye X, Ling B, Wu J, Wu S, Ren Y, Zhang H, Song F, Xuan Z, Chen M. Case report: severe myoclonus associated with oral midodrine treatment for hypotension. Medicine. 2020;99:40(e21533).\n\nXY and BL contributed equally to this work.\n\nInformed consent: The patient agreed to the publication of this case report by signing an informed consent form.\n\nThe authors have no funding and conflicts of interest to disclose.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n==== Refs\nReferences\n[1] Izcovich A González Malla C Manzotti M \nMidodrine for orthostatic hypotension and recurrent reflex syncope: a systematic review\n. Neurology \n2014 ;83 :1170 –7\n.25150287 \n[2] Sweetman SC \nMartindale: the complete drug reference\n. 38th ed London : Pharmaceutical Press ; 2014 .\n[3] Laurence L Bjorn C Hilal-Dandan R \nGoodman & Gilman's: the pharmacological basis of therapeutics\n. 13th ed London : McGraw-Hill ; 2017 .\n[4] Midodrine (prescribing information). Princeton, NJ: Sandoz Inc; October 2019 .\n[5] Perazella M \nEfficacy and safety of midodrine in the treatment of dialysis-associated hypotension\n. Expert Opin Drug Saf \n2003 ;2 :37 –47\n.12904123 \n[6] McClellan KJ Wiseman LR Wilde MI \nMidodrine: a review of its therapeutic use in the management of orthostatic hypotension\n. Drugs Aging \n1998 ;12 :76 .9467688 \n[7] Naranjo CA Busto U Sellers EM \nA method for estimating the probability of adverse drug reactions\n. Clin Pharmacol Ther \n1981 ;30 :239 –45\n.7249508\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "99(40)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000284:Administration, Oral; D058646:Adrenergic alpha-1 Receptor Agonists; D005260:Female; D006801:Humans; D007022:Hypotension; D008875:Middle Aged; D008879:Midodrine; D009207:Myoclonus; D051436:Renal Insufficiency, Chronic",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e21533",
"pmc": null,
"pmid": "33019383",
"pubdate": "2020-10-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case report: severe myoclonus associated with oral midodrine treatment for hypotension.",
"title_normalized": "case report severe myoclonus associated with oral midodrine treatment for hypotension"
} | [
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{
"actiondrug": "1",
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"activesubstancename": "MIDODRINE HYDROCHLORIDE"
},
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{
"abstract": "OBJECTIVE\nTo evaluate the utility of quantifying CD64 expression on neutrophils in rheumatoid arthritis patients with malignancy, especially its diagnostic role in lymphoma.\n\n\nMETHODS\nWe used flow cytometry to quantify CD64 expression on neutrophils from patients diagnosed with malignancy during the follow-up period prior to initiating treatment.\n\n\nRESULTS\nNeutrophils from 18 patients with lymphoma expressed significantly higher levels of CD64 (9635.6 ± 2123.7 molecules/cell) than those from 32 patients with other solid cancers (carcinoma) (1250.5 ± 91.1 molecules/cell) (p < 0.001). When the cutoff value was set at 2060 molecules/cell, the sensitivity and specificity of CD64 for diagnosing lymphoma was 88.9% and 94.4%, respectively.\n\n\nCONCLUSIONS\nThe quantitative measurement of neutrophil CD64 by flow cytometry may be useful as a subsidiary diagnostic marker in patients with suspected lymphoma. Although neutrophil CD64 is currently a well-known marker of infection, it is necessary to bear in mind that lymphoma is also a candidate in differential diagnosis when CD64 expression on neutrophils is upregulated.",
"affiliations": "a Department of Clinical Laboratory , Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .;b Department of Rheumatology , Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .;b Department of Rheumatology , Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .;b Department of Rheumatology , Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .;c Department of Rheumatology , Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .;b Department of Rheumatology , Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .;b Department of Rheumatology , Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .;d Department of Rehabilitation , Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan , and.;b Department of Rheumatology , Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .;c Department of Rheumatology , Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .;b Department of Rheumatology , Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .;e Department of Urology , Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan.;c Department of Rheumatology , Clinical Research Center for Allergy and Rheumatology, Sagamihara National Hospital, National Hospital Organization , Kanagawa , Japan .",
"authors": "Komiya|Akiko|A|;Matsui|Toshihiro|T|;Horie|Koichiro|K|;Fukuda|Hidefumi|H|;Iwata|Kanako|K|;Tsuno|Hirotaka|H|;Ogihara|Hideki|H|;Ikenaka|Tatsuoh|T|;Kawakami|Misato|M|;Furukawa|Hiroshi|H|;Hashimoto|Atsushi|A|;Hirai|Kotaro|K|;Tohma|Shigeto|S|",
"chemical_list": "D015415:Biomarkers; D017452:Receptors, IgG",
"country": "England",
"delete": false,
"doi": "10.3109/14397595.2015.1078986",
"fulltext": null,
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"issn_linking": "1439-7595",
"issue": "26(2)",
"journal": "Modern rheumatology",
"keywords": "CD64; Flow cytometry; Neutrophil; Rheumatoid arthritis; lymphoma",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid; D015415:Biomarkers; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008223:Lymphoma; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D009504:Neutrophils; D017452:Receptors, IgG; D012680:Sensitivity and Specificity; D015854:Up-Regulation",
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "216-23",
"pmc": null,
"pmid": "26381527",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Neutrophil CD64 is upregulated in RA patients with lymphoma but not in other solid cancers.",
"title_normalized": "neutrophil cd64 is upregulated in ra patients with lymphoma but not in other solid cancers"
} | [
{
"companynumb": "JP-JNJFOC-20160316570",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nEvidence supporting routine postoperative antiepileptic drug (AED) prophylaxis following oncologic neurosurgery is limited, and actual practice patterns are largely unknown beyond survey data.\n\n\nOBJECTIVE\nTo describe patterns and predictors of postoperative AED prophylaxis following intracranial tumor surgery.\n\n\nMETHODS\nThe MarketScan Database was used to analyze pharmacy claims data and clinical characteristics in a national sample over a 5-year period.\n\n\nRESULTS\nAmong 5895 patients in the cohort, levetiracetam was the most widely used AED for prophylaxis (78.5%) followed by phenytoin (20.5%). Prophylaxis was common but highly variable for patients who underwent open resection of supratentorial intraparenchymal tumors (62.5%, reference) or meningiomas (61.9%). In multivariate analysis, biopsies were less likely to receive prophylaxis (44.8%, OR 0.47, 95% CI 0.33-0.67), and there was near consensus against prophylaxis for infratentorial (9.7%, OR 0.07, CI 0.05-0.09) and transsphenoidal procedures (0.4%, OR 0.003, CI 0.001-0.010). Primary malignancies (52.1%, reference) and secondary metastases (42.2%) were more likely to receive prophylaxis than benign tumors (23.0%, OR 0.63, CI 0.48-0.83), as were patients discharged with home services and patients in the Northeast. There was a large spike in duration of AED use at approximately 30 days.\n\n\nCONCLUSIONS\nUse of seizure prophylaxis following intracranial biopsies and supratentorial resections is highly variable, consistent with a lack of guidelines or consensus. Current practice patterns do not support a clear standard of care and may be driven in part by geographic variation, availability of post-discharge services, and electronic prescribing defaults rather than evidence. Given uncertainty regarding effectiveness, indications, and appropriate duration of AED prophylaxis, well-powered trials are needed.",
"affiliations": "Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA. bey2103@cumc.columbia.edu.;Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA.;Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.;Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.;Department of Neurology, Columbia University Medical Center, New York, NY, USA.;Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA.;Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA.;Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.;Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.;Department of Neurological Surgery, Columbia University Medical Center, New York, NY, USA.",
"authors": "Youngerman|Brett E|BE|http://orcid.org/0000-0002-4792-3190;Joiner|Evan F|EF|;Wang|Xianling|X|;Yang|Jingyan|J|;Welch|Mary R|MR|;McKhann|Guy M|GM|;Wright|Jason D|JD|;Hershman|Dawn L|DL|;Neugut|Alfred I|AI|;Bruce|Jeffrey N|JN|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-019-03362-1",
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"keywords": "Antiepileptic drugs; Brain tumor; Glioma; Meningioma; Oncologic neurosurgery; Postoperative seizures; Seizure prophylaxis",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000927:Anticonvulsants; D001932:Brain Neoplasms; D003399:Craniotomy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D008577:Meningeal Neoplasms; D008579:Meningioma; D008875:Middle Aged; D019635:Neurosurgical Procedures; D010672:Phenytoin; D010818:Practice Patterns, Physicians'; D011379:Prognosis; D012189:Retrospective Studies; D012640:Seizures; D015173:Supratentorial Neoplasms; D055815:Young Adult",
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"title": "Patterns of seizure prophylaxis after oncologic neurosurgery.",
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"abstract": "Nephrogenic fibrosing dermatopathy (NFD) is a systemic disorder of unknown etiology. Recent reports have associated the development of NFD with the use of gadolinium-enhanced magnetic resonance imaging (MRI). Here, we present the case of an adolescent with end-stage renal disease who died of biopsy-proven NFD and also developed cardiac calcification and clinical manifestations of pulmonary fibrosis with pulmonary hypertension. Only five cases of NFD have been reported in children, all of which were prior to the information regarding the consequences of using gadolinium. Here, we report a patient with NFD who received gadolinium while on chronic hemodialysis, 16 months prior to the onset of symptoms. Because he succumbed to this disease, we stress on the importance of eliminating the use of gadolinium-enhanced MRI examinations in children with impaired kidney function until the etiology of NFD is clarified.",
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"authors": "Sharma|J|J|;Mongia|A|A|;Schoenaman|M|M|;Chang|S|S|;D'Angelo|A|A|;Rao|M|M|",
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"fulltext": "\n==== Front\nIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications India IJN-18-7010.4103/0971-4065.42340Case ReportNephrogenic fibrosing dermatopathy, cardiac calcification and pulmonary hypertension in an adolescent on chronic hemodialysis Sharma J. Mongia A. 1Schoenaman M. 1Chang S. 1D'Angelo A. 1Rao M. 2Division of Pediatric Cardiology, Jamaica Hospital Medical Center, Jamaica, NY 11418, USA1 Division of Nephrology, The Children Hospital at Downstate/SUNY, Brooklyn, NY 11203 USA2 Division of Pulmonology, The Children Hospital at Downstate/SUNY, Brooklyn, NY 11203 USAAddress for correspondence: Dr. Jayendra Sharma, 45, Wiltshire Road, Scarsdale, NY 10583, USA. E-mail: jsharma@jhmc.org4 2008 18 2 70 73 © Indian Journal of Nephrology2008This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Nephrogenic fibrosing dermatopathy (NFD) is a systemic disorder of unknown etiology. Recent reports have associated the development of NFD with the use of gadolinium-enhanced magnetic resonance imaging (MRI). Here, we present the case of an adolescent with end-stage renal disease who died of biopsy-proven NFD and also developed cardiac calcification and clinical manifestations of pulmonary fibrosis with pulmonary hypertension. Only five cases of NFD have been reported in children, all of which were prior to the information regarding the consequences of using gadolinium. Here, we report a patient with NFD who received gadolinium while on chronic hemodialysis, 16 months prior to the onset of symptoms. Because he succumbed to this disease, we stress on the importance of eliminating the use of gadolinium-enhanced MRI examinations in children with impaired kidney function until the etiology of NFD is clarified\n\nCardiac calcificationgadoliniumnephrogenic fibrosing dermatopathy\n==== Body\nNephrogenic fibrosing dermatopathy (NFD) is a recently identified sclerosing skin disorder of unknown etiology in patients with a history of renal insufficiency. Recently, Food and Drug Administration has received reports on adverse events affecting 75 patients with moderate to end-stage renal disease (ESRD) who developed NFD after receiving a gadolinium-based contrast agent for magnetic resonance imaging (MRI) studies.1 In fact, recent reviews of the literature imply that NFD may develop only in patients who received gadolinium-enhanced MRI examinations while suffering from severely impaired renal function.23\n\nOnly five pediatric cases have been reported, all prior to the information about the consequences of using gadolinium.4 None of these case reports address the issue of gadolinium-enhanced MRI examinations. However, further investigation in two of these patients revealed that both had received gadolinium prior to the emergence of NFD.5\n\nHere, we present the case of an adolescent with ESRD who died of biopsy-proven NFD and developed cardiac calcification and clinical manifestations of pulmonary fibrosis with pulmonary hypertension. A thorough review of his clinical course revealed that he was exposed to gadolinium only once, while on chronic hemodialysis, 16 months before the onset of NFD.\n\nCase Report\nA 14-year-old Hispanic male with ESRD due to congenital cystic renal dysplasia presented, after being on chronic hemodialysis for almost 10 years, with a 10-month history of right knee pain and a two-month history of worsening brawny hyperpigmentation of the skin of the distal extremities and painful contractures of the fingers and wrists. A 4-mm punch biopsy from the dorsum of the right foot revealed prominent dermal collagen bundles and an increased number of banal CD34/procollagen dual positive spindles (compatible with NFD).\n\nPrior to the age of two years, the patient was on peritoneal dialysis. Between two and three years of age, he received a cadaveric kidney transplant that failed within one year. Since then, he has remained on hemodialysis three times a week. Other medical history includes renal osteodystrophy, seizure disorder and reactive airway disease. He took multiple medications, including Procardia XL, calcitriol, aspirin, erythropoietin, a Fentanyl patch, folic acid, iron, vitamins, flovent and albuterol.\n\nPhysical examination showed a debilitated wheel-chair-bound adolescent with heart rate of 130 beats/min; respiration rate, 30/min and blood pressure, 140/84 mmHg. He was afebrile and hemodynamically stable, but with mild respiratory distress. Chest auscultation showed an S3 gallop, diminished air entry at the right base and bibasilar crepitations. He also had moderate hepatomegaly and ascites. Diffuse areas of thickened skin with hyperpigmentation were associated with painful contractures of the hands, knees and feet [Fig. 1].\n\nFig. 1 (A-B)Lesions consisting of areas of indurated plaques and nonpitting edema on the dorsal surface of the hand and foot with flexural contractures of the fingers\n\nLaboratory data were remarkable with erythrocyte sedimentation rate (ESR), 98 mm/h; C-reactive protein (CRP), 5.89 U; and negative serologic antibody testing for ANA, anti-smith, anti-SSA/SSB, lupus anticoagulant, anticardiolipin and anti-SCL-70. Serum intact parathyroid hormone levels and serum calcium levels over the previous 2-4 years were 580-1160 and 9-11 mg/dl, respectively. Chest x-ray demonstrated mild cardiomegaly, increased pulmonary vascular markings and a right pleural effusion. A two-dimensional-echo Doppler study demonstrated moderate concentric left ventricular hypertrophy, mild mitral regurgitation, small discrete areas of calcification in the interventricular septum and mild tricuspid regurgitation with a gradient of 64 mmHg and an estimated pulmonary artery pressure of 70 mmHg (concomitant blood pressure, 130/80 mmHg) [Fig. 2]. Chest computed tomography (CT) showed a moderate right pleural effusion, large discrete areas of pulmonary calcification and cardiac calcification involving the aortic root, proximal coronary arteries, left atrium and mitral valve ring [Fig. 3].\n\nFig. 2 Parasternal long-axis view showing discrete small areas of calcification in interventricular septum\n\nFig. 3 Chest CT scan showing cardiac calcification involving left atrium aortic root, proximal coronaries and mitral valve ring\n\nWithin one year of the confirmed diagnosis of NFD, lung function testing showed an obstructive component with a progressive deterioration of the restrictive lung disease. It was not possible to determine whether the restriction was secondary to fibrosis, poor muscle mass, weakening muscle strength or pulmonary hypertension. Corresponding chest CT demonstrated diffuse nodules as large as 5 mm, bilateral pleural effusion and air trapping. The treatment for pulmonary vascular hypertension was initiated with sildenafil.\n\nHis condition deteriorated despite providing UVB phototherapy and physical therapy. He underwent renal transplantation, but the graft failed because of acute rejection and he returned to chronic hemodialysis. His cardio-pulmonary function steadily deteriorated and he died at the age of 16 years.\n\nA thorough review of his previous radiology examinations revealed that, due to complications in vascular access, he had undergone a gadolinium-enhanced MRI study 16 months prior to the onset of the symptoms of NFD. He was receiving a regular three-times-a-week hemodialysis at that time.\n\nDiscussion\nNFD was first reported in 2000 by Cowper et al., in 15 adult patients with a history of either hemodialysis or renal transplant.6 NFD typically presents with indurated skin plaques with brawny hyperpigmentation predominantly on distal extremities and trunk with sparing of the face. This skin thickening can result in contraction flexures with significant restriction in mobility. The typical histopathology of NFD closely resembles scleromyxedema except that NFD patients do not exhibit paraproteinemia or mucin deposition in other organs.7 Laboratory data also did not show eosinophilia and autoantibodies, as observed in other fibrosing conditions. The differential diagnosis of NFD includes scleromyxedema, scleroderma (morphea), eosinophilic fasciitis, porphyria cutanea tarda, B2 microglobulin amyloidosis, fibroblastic rheumatism, rapeseed oil ingestion and L-tryptophan ingestion.6\n\nRenal failure is a common underlying risk factor for NSF/NFD. Although the specific etiological agent remains unclear, infection, auto-immunity, toxic effects of dialysate and failed kidney transplants have been considered to be the possible contributing factors.48 Most recently, an association with gadolinium-enhanced contrast agents used during MRI examinations in patients with moderate to severe renal insufficiency has been reported.2 Further, gadolinium has been detected in the tissues of renal failure patients with NFD with a history of gadolinium exposure.9 It is recommended that health care professionals carefully weigh the risks and benefits associated with a gadolinium-based contrast agent and, although not proven helpful, prompt dialysis after gadolinium administration is recommended to reduce the burden of this agent in the body.2 Our patient had undergone the study before the association between gadolinium exposure and NFD had been identified. Although he was on regular hemodialysis sessions following his first gadolinium exposure, he went on to develop the clinical features of NFD.\n\nManagement of NFD is purely empirical but includes oral steroids, photopheresis, plasmapheresis, cyclophosphamide, thalidomide, ultraviolet therapy and physical therapy.49–10 Our patient presented with typical clinical features, confirmed by histopathology on skin biopsy. The changes in NFD have been reported to be reversible with successful renal transplant. For this reason, we attempted renal transplantation even though he was highly sensitized and required multiple plasmapheresis episodes.\n\nPatients with ESRD are at a risk of tissue calcification as a result of deranged mineral metabolism and secondary hyperparathyroidism of renal osteodystrophy. Coronary artery calcification correlates with an increased risk of cardiovascular events in adults.11 The usual locations for cardiac metastatic calcium deposition in patients with chronic hyperparathyroidism secondary to ESRD include AV valve/valve rings, aortic root and proximal coronaries. Our patient had a myocardial calcification involving interventricular septum as demonstrated by echocardiogram and calcification of aortic root, left atrium and proximal coronaries, as observed on CT scan.\n\nOur patient also had significant pulmonary hypertension. Children with ESRD on chronic hemodialysis via arteriovenous access often develop unexplained pulmonary hypertension as adults.12 Pulmonary hypertension in such patients is usually secondary to LVH/diastolic dysfunction, uremic cardiomyopathy or recurrent thromboembolism. Pulmonary calcification and NFD are not linked to pathophysiology of pulmonary hypertension.\n\nConclusion\nIn this study, we present the case of an adolescent with ESRD on chronic hemodialysis who developed NFD after exposure to gadolinium, complicated with myocardial calcification and pulmonary hypertension. Because of the morbidity and mortality associated with NFD, we suggest that gadolinium exposure be avoided in children with impaired kidney function, despite the ongoing hemodialysis, until the etiology of NFD is clarified.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nReferences\n1 Perazella MA Nephrogenic systemic fibrosis, kidney disease and gadolinium: Is there a link? Clin J Am Soc Nephrol 2007 2 200 2 17699407 \n2 Anon Gadolinium-based contrast agents for magnetic resonance imaging scans (marketed as Omniscan, OptiMARK, Magnevist, ProHance and MultiHance) 2007 Available from: http://www.fda.gov/cder/drug/advisory/gadolinium_agents.htm \n3 Grobner T Gadolinium: A specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006 21 1104 8 16431890 \n4 Jain SM Wesson S Hassanein A Canova E Hoy M Fennell RS Dharnidharka VR Nephrogenic fibrosing dermopathy in pediatric patients Pediatr Nephrol 2004 19 467 70 14872332 \n5 Dharnidharka VR Wesson SK Fennell RS Gadolinium and nephrogenic fibrosing dermopathy in pediatric patients Pediatr Nephrol 2007 22 1395 17180360 \n6 Cowper SE Robins HS Steinberg SM Scleromyxoedema like cutaneous disease in renal dialysis patients Lancet 2000 356 1000 1 11041404 \n7 Mackay-Wiggan JM Cohen DJ Hardy MA Knobler EH Grossman ME Nephrogenic fibrosing dermatopathy J Am Acad Dermatol 2003 48 55 60 12522371 \n8 Baron PW Cantos K Hillebrand DJ Hu KQ Ojogho ON Nehlsen-Cannarella S Nephrogenic fibrosing dermopathy after liver transplantation successfully treated with plasmapheresis Am J Dermatopathol 2003 25 204 9 12775982 \n9 High WA Ayers RA Chandler J Zito G Cowper SE Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis J Am Acad Dermatol 2007 56 21 6 17097388 \n10 Streams BN Liu V Liegeois N Moschella SM Clinical and pathologic features of nephrogenic fibrosing dermatopathy: A report of two cases J Am Acad Dermatol 2003 48 42 7 12522369 \n11 Russo D Palmiero G De Blasio AP Balletta MM Andreucci VE Coronary artery calcification in patients with CRF not undergoing dialysis Am J Kidney Dis 2004 44 1024 30 15558523 \n12 Yigla M Keidar Z Safadi I Tov N Reisner SA Nakhoul F Pulmonary calcification in hemodialysis patients: Correlation with pulmonary artery pressure values Kidney Int 2004 66 806 10 15253737\n\n",
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"issue": "18(2)",
"journal": "Indian journal of nephrology",
"keywords": "Cardiac calcification; gadolinium; nephrogenic fibrosing dermatopathy",
"medline_ta": "Indian J Nephrol",
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"title": "Nephrogenic fibrosing dermatopathy, cardiac calcification and pulmonary hypertension in an adolescent on chronic hemodialysis.",
"title_normalized": "nephrogenic fibrosing dermatopathy cardiac calcification and pulmonary hypertension in an adolescent on chronic hemodialysis"
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"abstract": "Immune checkpoint inhibitors (ICIs) have been used as immunotherapeutic agents in several malignancies because of their ability to modify the T cell-mediated response against tumor cells. Dual checkpoint inhibition improves remission rates in patients with metastatic melanoma compared to monotherapy. However, a higher incidence of toxicity, including immune-related colitis, has been reported before. A 54-year-old female was diagnosed with malignant melanoma on her left upper arm. Because of progressive metastatic disease, a rescue therapy with nivolumab (Opdivo®) 1 mg/kg and ipilimumab (Yervoy®) 3 mg/kg was initiated and a clinical and radiological remission was achieved. Two weeks after completing the third cycle of the ICI therapy, the patient presented with persistent hemorrhagic diarrhea, nausea and abdominal pain. A diagnostic colonoscopy revealed multiple ulcerative lesions and hemorrhagic colitis of the sigmoid and rectum. Due to the ongoing treatment with nivolumab and ipilimumab, the diagnosis of a checkpoint inhibitor-induced colitis was made and immunosuppression with local and systemic steroids, such as mesalazine was initiated. In order to achieve a long-lasting steroids reduction, we decided to start with infliximab (Remicade® 5 mg/kg body weight i.v. every 2 weeks). Clinical remission was achieved and prednisolone could be subsequently discontinued. Infliximab, in combination with mesalazine, could successfully induce a long-lasting remission without steroids. The treatment of ICI-induced colitis did not lead to a reoccurrence of malignant melanoma after 2 years of follow-up.",
"affiliations": "Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Department of Gastroenterology, Endocrinology, Diabetology and General Medicine, Klinikum Kassel, Kassel, Germany.;Department of Dermatology, Klinikum Kassel, Kassel, Germany.;Department of Gastroenterology, Endocrinology, Diabetology and General Medicine, Klinikum Kassel, Kassel, Germany.;Department of Gastroenterology, Endocrinology, Diabetology and General Medicine, Klinikum Kassel, Kassel, Germany.",
"authors": "Paparoupa|Maria|M|;Stupperich|Sophie|S|;Goerg-Reifenberg|Lisa|L|;Wittig|Andreas|A|;Schuppert|Frank|F|",
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"fulltext": "\n==== Front\nCase Rep Gastroenterol\nCase Rep Gastroenterol\nCRG\nCase Reports in Gastroenterology\n1662-0631 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n10.1159/000511252\ncrg-0014-0554\nSingle Case\nSuccessful Treatment of an Immune-Mediated Colitis Induced by Checkpoint Inhibitor Therapy in a Patient with Advanced Melanoma\nPaparoupa Maria a* Stupperich Sophie b Goerg-Reifenberg Lisa c Wittig Andreas b Schuppert Frank b 1Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany\n2Department of Gastroenterology, Endocrinology, Diabetology and General Medicine, Klinikum Kassel, Kassel, Germany\n3Department of Dermatology, Klinikum Kassel, Kassel, Germany\n*Maria Paparoupa, Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, DE–20246 Hamburg (Germany), maria.paparoupa@yahoo.com; m.paparoupa@uke.de\nSep-Dec 2020 \n29 10 2020 \n29 10 2020 \n14 3 554 560\n26 8 2020 31 8 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Immune checkpoint inhibitors (ICIs) have been used as immunotherapeutic agents in several malignancies because of their ability to modify the T cell-mediated response against tumor cells. Dual checkpoint inhibition improves remission rates in patients with metastatic melanoma compared to monotherapy. However, a higher incidence of toxicity, including immune-related colitis, has been reported before. A 54-year-old female was diagnosed with malignant melanoma on her left upper arm. Because of progressive metastatic disease, a rescue therapy with nivolumab (Opdivo®) 1 mg/kg and ipilimumab (Yervoy®) 3 mg/kg was initiated and a clinical and radiological remission was achieved. Two weeks after completing the third cycle of the ICI therapy, the patient presented with persistent hemorrhagic diarrhea, nausea and abdominal pain. A diagnostic colonoscopy revealed multiple ulcerative lesions and hemorrhagic colitis of the sigmoid and rectum. Due to the ongoing treatment with nivolumab and ipilimumab, the diagnosis of a checkpoint inhibitor-induced colitis was made and immunosuppression with local and systemic steroids, such as mesalazine was initiated. In order to achieve a long-lasting steroids reduction, we decided to start with infliximab (Remicade® 5 mg/kg body weight i.v. every 2 weeks). Clinical remission was achieved and prednisolone could be subsequently discontinued. Infliximab, in combination with mesalazine, could successfully induce a long-lasting remission without steroids. The treatment of ICI-induced colitis did not lead to a reoccurrence of malignant melanoma after 2 years of follow-up.\n\nKeywords\nImmune checkpoint inhibitorNivolumabIpilimumabInfliximabImmune-related adverse events\n==== Body\nIntroduction\nImmune checkpoint inhibitors (ICIs) are becoming increasingly important as therapeutic agents in several malignancies because of their ability to modify the T cell-mediated immune response against tumor cells. The programmed death-1 co-receptor (PD-1) or ligand (PD-L1) and the cytotoxic T lymphocyte-associated protein 4 (CTLA-4) are well-established checkpoint targets. Nivolumab, an IgG4 anti-PD-1 antibody, and ipilimumab, an anti-CTLA-4 antibody, have been approved as a rescue therapy in advanced melanoma, leading to rapid and long-term durable clinical responses [1].\n\nA number of immune-related adverse events (irAEs) are associated with the use of ICIs. Clinicians using these agents should be aware of the spectrum and the incidence of irAEs, in order to recognize and treat them properly. According to a study by Almutairi et al. [2] in patients with advanced melanoma receiving ICIs, ipilimumab was related to irAEs affecting the gastrointestinal system (diarrhea, 29%; and colitis, 8%), skin (rash, 31%; pruritus, 27%; and dermatitis, 10%) and the hypophysis (hypophysitis, 4%), while nivolumab caused more often maculopapular rash (13%), erythema (4%), hepatitis (3%), and infusion-related reactions (3%) [2]. Our group has recently published a study describing the wide clinical spectrum of autoimmune hypophysitis related to the use of checkpoint inhibitors [3].\n\nImmune-related adverse events affecting the digestive system are colitis, hepatitis and pancreatitis. A T cell-mediated immune response is probably involved in the ICI-induced colitis, as infiltration with CD8+ cells and T-bet expressing CD4+ cells has been observed in the colon biopsies of patients receiving nivolumab [4]. A meta-analysis by Tian et al. [5] reported an increased incidence risk of all grade colitis in patients with solid tumors receiving ICIs, compared to those undergoing chemotherapy or chemotherapy and ICIs. The lower incidence risk was observed under monotherapy with nivolumab [5].\n\nSteroids are generally recommended as first-line treatment against all kinds of ICI-induced adverse events [6]. Infliximab and vedolizumab have been successfully used in patients with immune-mediated colitis, being refractory to steroids [7, 8]. However, data regarding the side effects of the concomitant administration of nivolumab and ipilimumab are rare and prospective, controlled clinical trials are still lacking in this field. Furthermore, it is generally believed that immunosuppression may adversely affect the antitumor efficacy of the ICIs therapy [9].\n\nWe describe the case of a patient with advanced melanoma treated with nivolumab and ipilimumab and who subsequently developed a steroid-refractory immune-mediated colitis. The patient was successfully treated with infliximab and mesalazine and has remained progression-free for 2 years.\n\nCase Presentation\nA 54-year-old otherwise healthy female was diagnosed with a malignant melanoma on her left upper arm. The lesion was entirely removed with a margin of 2 cm. After 6 months on adjuvant therapy with interferon alpha-2a (Roferon®), progressive metastatic disease was observed. A radical axillary lymphadenectomy and radiation of the left axillary region (50 Gray) were performed. The patient then developed a mild autoimmune hyperthyroidism with subsequent hypothyroidism, requiring substitution therapy with L-thyroxine 75 µg/day. An autoimmune insufficiency of the pituitary gland was excluded by testing all five regulatory pathways. During restaging, she presented with disseminated lung, liver and peritoneal metastasis, forming the indication for a rescue therapy with nivolumab (Opdivo®) 1 mg/kg and ipilimumab (Yervoy®) 3 mg/kg and discontinuation of interferon alpha-2a.\n\nAfter three cycles of nivolumab and ipilimumab in the course of 3 months, restaging investigations still showed pulmonary, hepatic and lymphatic metastases. In addition, the patient presented with persistent hemorrhagic diarrhea, nausea and abdominal pain 2 weeks after completing the third cycle of ICI therapy. A diagnostic colonoscopy revealed multiple ulcerative lesions and hemorrhagic colitis of the sigmoid and rectum (Fig. 1). The rest of the colon showed edematous mucosa, while the terminal ileum and ileocecal valve were macroscopically intact (Fig. 2). A series of sequential mucosal biopsies were taken from the proximal to the distal colon. Histological analysis confirmed an acute and chronic inflammatory mucosal alteration which was compatible with inflammatory bowel disease (IBD) with a high apoptosis rate. Calprotectin was elevated to >800 μg/g stool. Due to the ongoing treatment with nivolumab and ipilimumab, the diagnosis of an ICI-induced colitis was made.\n\nAfter excluding an infection with cytomegalovirus by RT-PCR in serum and colonic tissue, an immunosuppression with local hydrocortisone acetate (Colifoam® rectal foam once daily) and oral steroids (prednisolone 80 mg daily in the morning) was initiated. Furthermore, the patient received mesalazine locally (Salofalk® Enema 4 g/60 mL once daily in the evening) and orally (Salofalk® gastro-resistant prolonged-release granules 3 g once daily in the morning).\n\nAfter a short clinical remission of 2 months, symptoms relapsed when a reduction of systemic steroids below 30 mg daily was attempted. Prednisolone was increased to 150 mg/day and symptoms improved. It was slowly tapered again, but symptoms related to a flare-up of the colonic inflammation, like bloody diarrhea, nausea and abdominal pain, relapsed after reaching a dose of less than 30 mg/day. Positively, 6 months after discontinuation of nivolumab and ipilimumab, radiological remission of metastatic disease was documented for the first time.\n\nIn order to induce remission of the colitis without long-term steroid therapy, we decided to start an immunosuppressive therapy with infliximab (300 mg Remicade®, 5 mg/kg body weight i.v. every 2 weeks). Infliximab was combined with the previously started corticosteroid and mesalazine therapy. Prednisolone was gradually reduced to 30 mg/day. Already 1 month after initiation of infliximab, our patient was free of symptoms. Two weekly cycles of intravenous infliximab were continued for 6 months until the next routine examination, where calprotectin was in the normal range (6 months earlier >800 μg/g stool) and remission of metastatic disease was still in place. At the same time, prednisolone could be gradually reduced to a minimum of 2.5 mg/day and subsequently discontinued altogether. During endoscopic follow-up, only minimal residual inflammation was seen, so that a 4-weekly scheme of infliximab was decided.\n\nAfter a total of 17 infliximab administrations, in overall 12 months, clinical remission of gastrointestinal symptoms, undetectable calprotectin and complete mucosal healing in colonoscopy (Fig. 3) were achieved. Infliximab was therefore discontinued. Administration of mesalazine orally (Salofalk® gastro-resistant prolonged-release granules 3 g once daily in the morning) is continued until today, since an attempt to discontinuation led to an increase of stool frequency. Hydrocortisone locally (Colifoam® rectal foam) was first tapered to a single application every other day and then applied only as needed which so far was never necessary. A recent colonoscopy showed healthy colonic tissue. The patient is still in full remission of metastatic melanoma, 2 years after discontinuation of nivolumab and ipilimumab.\n\nDiscussion\nDual checkpoint inhibition induced by combination therapy with nivolumab and ipilimumab improves response rates in patients with metastatic melanoma compared to monotherapy. However, a higher rate of toxicity, including immune-related colitis, seems to be present under this regimen showing itself as ICI-induced diarrhea [5, 10]. Diagnostic colonoscopy and multiple colonic biopsies are necessary for the diagnosis of ICI-induced colitis, as a diversity of clinical, endoscopic and histological manifestations have been observed in patients with ICI-induced diarrhea [10]. In our case, erythema, erosions and ulcerations mimicking IBD were described during colonoscopy and histological examination revealed acute inflammatory infiltration of the mucosa with cryptitis and apoptosis. The most prominent macroscopic damage was located in the left colonic segments (sigmoid and rectum) as already described in the literature [11].\n\nHigh-dose steroid therapy is the milestone in the treatment of ICI-induced colitis, but cases of steroid-refractory colitis have been registered before. Recently, Tidwell and Gutnik [7] have reported on a 66-year-old female with advanced melanoma, who developed a steroid-resistant colitis secondary to administration of nivolumab and ipilimumab, which was successfully treated with infliximab [7]. Our case has many similarities to that of Tidwell and Gutnik, as every time an attempt was made to reduce the daily prednisolone dosage below 30 mg, symptomatic colitis re-emerged.\n\nAccording to other case reports, protocols of a broad immunosuppressive therapy in patients with refractory colitis under steroids and infliximab have been implemented before. Randhawa et al. [12] have recently presented the case of a 27-year-old female with severe colitis, refractory to methylprednisolone, infliximab and mycophenolate mofetil, who responded to vedolizumab, which is a humanized monoclonal antibody against α4β7 integrin [12]. On the other hand, Alcantar et al. [13] presented the case of a patient in whom clinical remission was observed under steroids and mycophenolate after high-dose steroids, infliximab, and vedolizumab failed to achieve a resolution of the patients' symptoms [13]. Nevertheless, we decided to keep our immunosuppression regime limited to steroids and infliximab because of the induction of a remarkable clinical remission, even though a daily mesalazine dose is necessary in order to preserve this effect.\n\nThe use of local steroids and mesalazine has already been described in the literature as treatment strategies beyond systemic steroids in order to reduce the high burden of side effects. Beclomethasone has already been used in ICI-induced colitis with isolated histological features in the absence of macroscopic disease. Sustained clinical and histological remission was induced without adverse effects [14]. Mesalazine has been implemented in the treatment of relapsed nivolumab-associated colitis as maintenance therapy, as well as remission induction for long-term survival [15]. In our case, mesalazine was well tolerated and successfully administered up to now, in order to maintain remission for a period of more than 2 years.\n\nConclusion\nOur case shows that ICI-induced colitis can become clinically apparent, even after ICI therapy, in this case with nivolumab and ipilimumab, has been discontinued. Furthermore, we support the notion that infliximab, in combination with mesalazine, can successfully induce a long-lasting remission in patients who have responded to steroids, but clinical deterioration re-emerges by every attempt to achieve a dosage reduction. It is important to note that successful treatment of ICI-induced colitis did not lead to reoccurrence of malignant melanoma after 2 years of follow-up.\n\nStatement of Ethics\nThe research was conducted ethically in accordance with the World Medical Association Declaration of Helsinki. A written informed consent for publication, including images, has been obtained from the patient.\n\nConflict of Interest Statement\nThe authors have disclosed that they have no significant relationship with or financial interest in any commercial companies pertaining to this article.\n\nFunding Sources\nNo funding was received.\n\nAuthor Contributions\nMaria Paparoupa and Sophie Stupperichcollected all needed data and wrote the manuscript. Lisa Goerg-Reifenberg, AndreasWittig and Frank Schuppert treated the patient throughout time. Frank Schuppert reviewed the manuscript and provided consultation regarding intellectual argumentation. All authors have read and approved the submitted version of the manuscript.\n\nFig. 1 Diagnostic colonoscopy revealing multiple ulcerative lesions and hemorrhagic colitis of the sigmoid and rectum.\n\nFig. 2 Terminal ileum and ileocecal valve are macroscopically intact.\n\nFig. 3 Diagnostic colonoscopy showing full remission of endoscopic findings under immunosuppressive therapy.\n==== Refs\nReferences\n1 Mearns ES Bell JA Galaznik A Puglielli SM Cichewicz AB Boulanger T Gastrointestinal adverse events with combination of checkpoint inhibitors in advanced melanoma: a systematic review Melanoma Manag 2018 1 5 (1) MMT01 30190927 \n2 Almutairi AR McBride A Slack M Erstad BL Abraham I Potential Immune-Related Adverse Events Associated With Monotherapy and Combination Therapy of Ipilimumab, Nivolumab, and Pembrolizumab for Advanced Melanoma: A Systematic Review and Meta-Analysis Front Oncol 2020 2 10 91 32117745 \n3 Hartmann A Paparoupa M Volkmer BG Rompel R Wittig A Schuppert F Autoimmune hypophysitis secondary to therapy with immune checkpoint inhibitors: four cases describing the clinical heterogeneity of central endocrine dysfunction J Oncol Pharm Pract 2020 3 1078155220910202 1078155220910202 \n4 Yoshino K Nakayama T Ito A Sato E Kitano S Severe colitis after PD-1 blockade with nivolumab in advanced melanoma patients: potential role of Th1-dominant immune response in immune-related adverse events: two case reports BMC Cancer 2019 10 19 (1) 1019 31664934 \n5 Tian Y Zhang Z Yang X Li D Zhang L Li Z The Risk Ratio of Immune-Related Colitis, Hepatitis, and Pancreatitis in Patients With Solid Tumors Caused by PD-1/PD-L1 Inhibitors: A Systematic Review and Meta-Analysis Front Oncol 2020 2 10 261 32181158 \n6 Puzanov I Diab A Abdallah K Bingham CO 3rd Brogdon C Dadu R Society for Immunotherapy of Cancer Toxicity Management Working Group Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for Immunotherapy of Cancer (SITC) Toxicity Management Working Group J Immunother Cancer 2017 11 5 (1) 95 29162153 \n7 Tidwell C Gutnik S Treatment of Immune Checkpoint Inhibitor Induced Colitis with Infliximab S D Med 2019 10 72 (10) 454 8 31816206 \n8 Abu-Sbeih H Ali FS Alsaadi D Jennings J Luo W Gong Z Outcomes of vedolizumab therapy in patients with immune checkpoint inhibitor-induced colitis: a multi-center study J Immunother Cancer 2018 12 6 (1) 142 30518410 \n9 González-Rodríguez E Rodríguez-Abreu D Spanish Group for Cancer Immuno-Biotherapy (GETICA) Immune Checkpoint Inhibitors: Review and Management of Endocrine Adverse Events Oncologist 2016 7 21 (7) 804 16 27306911 \n10 Yanai S Nakamura S Kawasaki K Toya Y Akasaka R Oizumi T Immune checkpoint inhibitor-induced diarrhea: clinicopathological study of 11 patients Dig Endosc 2019 \n11 Wright AP Piper MS Bishu S Stidham RW Systematic review and case series: flexible sigmoidoscopy identifies most cases of checkpoint inhibitor-induced colitis Aliment Pharmacol Ther 2019 6 49 (12) 1474 83 31035308 \n12 Randhawa M Gaughran G Archer C Pavli P Morey A Ali S Vedolizumab in combined immune checkpoint therapy-induced infliximab-refractory colitis in a patient with metastatic melanoma: A case report World J Clin Oncol 2019 10 10 (10) 350 7 31799150 \n13 Alcantar D Al-Jaashaami L Giron F A Case of Immune Checkpoint Inhibitor Refractory Colitis Treated with Mycophenolate and High-dose Steroids Cureus 2019 12 11 (12) e6392 31938669 \n14 Ibraheim H Green M Papa S Powell N Topical beclometasone dipropionate in the management of immune checkpoint inhibitor-induced microscopic colitis BMJ Case Rep 2019 4 12 (4) e226481 \n15 Kikuchi H Sakuraba H Akemoto Y Murai Y Fukutoku Y Asari T A case of nivolumab-associated colitis, which relapsed after mucosal healing and was then successfully treated with mesalazine Immunol Med 2019 3 42 (1) 39 44 30917094\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "14(3)",
"journal": "Case reports in gastroenterology",
"keywords": "Immune checkpoint inhibitor; Immune-related adverse events; Infliximab; Ipilimumab; Nivolumab",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "554-560",
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"pmid": "33250697",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
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"title": "Successful Treatment of an Immune-Mediated Colitis Induced by Checkpoint Inhibitor Therapy in a Patient with Advanced Melanoma.",
"title_normalized": "successful treatment of an immune mediated colitis induced by checkpoint inhibitor therapy in a patient with advanced melanoma"
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"abstract": "OBJECTIVE\nTo explore efficacy and side effects of intrapleural or intraperitoneal lobaplatin for treating patients with malignant pleural or peritoneal effusions.\n\n\nMETHODS\nPatients in Jiangsu Cancer Hospital and Research Institute with cytologically confirmed solid tumors complicated with malignant pleural effusion or ascites were enrolled into this study. Lobaplatin (20-30 mg/m2) was intrapleurally or intraperitoneally infused for patients with malignant pleural effusion or ascites.\n\n\nRESULTS\nFrom 2012 to 2013, intrapleural or intraperitonea lobaplatin was administered for patients with colorectal or uterus cancer who were previous treated for malignant pleural effusion or ascites. Partial response was achieved for them. Main side effects were nausea/vomiting, and bone marrow suppression. No treatment related deaths occurred.\n\n\nCONCLUSIONS\nIntrapleural or intraperitoneal infusion of lobaplatin is a safe treatment for patients with malignant pleural effusion or ascites, and the treatment efficacy is encouraging.",
"affiliations": "Department of Chemotherapy, JiangSu Cancer Hospital, Nanjing, Jiangsu, China. huangxinen06@ymail.com",
"authors": "Huang|Xin-En|XE|;Wei|Guo-Li|GL|;Huo|Jie-Ge|JG|;Wang|Xiao-Ning|XN|;Lu|Yan-Yan|YY|;Wu|Xue-Yan|XY|;Liu|Jin|J|;Xiang|Jin|J|;Feng|Ji-Feng|JF|",
"chemical_list": "D000970:Antineoplastic Agents; D003503:Cyclobutanes; D009944:Organoplatinum Compounds; C066228:lobaplatin",
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"doi": "10.7314/apjcp.2013.14.4.2611",
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"issue": "14(4)",
"journal": "Asian Pacific journal of cancer prevention : APJCP",
"keywords": null,
"medline_ta": "Asian Pac J Cancer Prev",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000970:Antineoplastic Agents; D001201:Ascites; D003503:Cyclobutanes; D004333:Drug Administration Routes; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D016066:Pleural Effusion, Malignant; D011379:Prognosis; D002583:Uterine Cervical Neoplasms",
"nlm_unique_id": "101130625",
"other_id": null,
"pages": "2611-4",
"pmc": null,
"pmid": "23725184",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intrapleural or intraperitoneal lobaplatin for treatment of patients with malignant pleural effusion or ascites.",
"title_normalized": "intrapleural or intraperitoneal lobaplatin for treatment of patients with malignant pleural effusion or ascites"
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"abstract": "OBJECTIVE\nThis study aimed to assess the evaluation of clinical outcomes and consequences of complications after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the peritoneal carcinomatosis (PC) from colorectal cancer.\n\n\nMETHODS\nA total 26 patients underwent CRS and HIPEC for PC from colorectal cancer between March 2009 and April 2018. All the patients underwent CRS with the purpose of complete or near-complete cytoreduction. Intraoperative HIPEC was performed simultaneously after the CRS. Mitomycin C was used as chemotherapeutic agent for HIPEC.\n\n\nRESULTS\nMedian disease-free survival was 27.8 months (range, 13.4-42.2 months). Median overall survival was 56.0 months (range, 28.6-83.5 months). The mean peritoneal cancer index (PCI) was 8.73 ± 5.54. The distributions thereof were as follows: PCI <10, 69.23%; PCI 10-19, 23.08%; and PCI ≥20, 7.69%. The completeness of cytoreduction was 96.2% of patients showed CC-0, with 3.8% achieved CC-1. The mean operation time was 8.5 hours, and the mean postoperative hospital stay was 21.6 days. The overall rate of early postoperative complications was 88.5%; the rate of late complications was 34.6%. In the early period, most complications were grades I-II complications (65.4%), compared to grades III-V (23.1%). All late complications, occurring in 7.7% of patients, were grades III-V. There was no treatment-related mortality.\n\n\nCONCLUSIONS\nAlthough the complication rate was approximately 88%, but the rate of severe complication rate was low. In selective patients with peritoneal recurrence, more aggressive strategies for management, such as CRS with HIPEC, were able to be considered under the acceptable general condition and life-expectancy.",
"affiliations": "Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.;Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.;Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.;Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.;Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.;Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.;Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.;Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.;Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.;Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea.",
"authors": "Roh|Seung Jae|SJ|;Park|Sung Chan|SC|;Choi|Jaehee|J|;Lee|Joon Sang|JS|;Lee|Dong Woon|DW|;Hong|Chang Won|CW|;Han|Kyung Su|KS|;Park|Hyoung Chul|HC|;Sohn|Dae Kyung|DK|;Oh|Jae Hwan|JH|",
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"doi": "10.3393/ac.2019.04.30",
"fulltext": "\n==== Front\nAnn Coloproctol\nAnn Coloproctol\nAC\nAnnals of Coloproctology\n2287-9714 2287-9722 Korean Society of Coloproctology \n\n32146785\n10.3393/ac.2019.04.30\nac-2019-04-30\nOriginal Article\nCytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy With Mitomycin C Used for Colorectal Peritoneal Carcinomatosis\nRoh Seung Jae http://orcid.org/0000-0003-3949-7862Park Sung Chan Choi Jaehee Lee Joon Sang Lee Dong Woon Hong Chang Won Han Kyung Su Park Hyoung Chul Sohn Dae Kyung Oh Jae Hwan \nCenter for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, Goyang, Korea\nCorrespondence to: Sung Chan Park, M.D. Center for Colorectal Cancer, Research Institute and Hospital, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea Tel: +82-32-920-1041, Fax: +82-32-920-1148 E-mail: sungchan@ncc.re.kr\n2 2020 \n29 2 2020 \n36 1 22 29\n18 2 2019 30 4 2019 Copyright © 2020 The Korean Society of Coloproctology2020This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nThis study aimed to assess the evaluation of clinical outcomes and consequences of complications after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for the peritoneal carcinomatosis (PC) from colorectal cancer.\n\nMethods\nA total 26 patients underwent CRS and HIPEC for PC from colorectal cancer between March 2009 and April 2018. All the patients underwent CRS with the purpose of complete or near-complete cytoreduction. Intraoperative HIPEC was performed simultaneously after the CRS. Mitomycin C was used as chemotherapeutic agent for HIPEC.\n\nResults\nMedian disease-free survival was 27.8 months (range, 13.4–42.2 months). Median overall survival was 56.0 months (range, 28.6–83.5 months). The mean peritoneal cancer index (PCI) was 8.73 ± 5.54. The distributions thereof were as follows: PCI <10, 69.23%; PCI 10–19, 23.08%; and PCI ≥20, 7.69%. The completeness of cytoreduction was 96.2% of patients showed CC-0, with 3.8% achieved CC-1. The mean operation time was 8.5 hours, and the mean postoperative hospital stay was 21.6 days. The overall rate of early postoperative complications was 88.5%; the rate of late complications was 34.6%. In the early period, most complications were grades I–II complications (65.4%), compared to grades III–V (23.1%). All late complications, occurring in 7.7% of patients, were grades III–V. There was no treatment-related mortality.\n\nConclusion\nAlthough the complication rate was approximately 88%, but the rate of severe complication rate was low. In selective patients with peritoneal recurrence, more aggressive strategies for management, such as CRS with HIPEC, were able to be considered under the acceptable general condition and life-expectancy.\n\nColorectal neoplasmsPeritoneal carcinomatosisCytoreductive surgeryHyperthermic intraperitoneal chemotherapy\n==== Body\nINTRODUCTION\nPeritoneal metastasis of colorectal cancer is the fourth most common recurrence site in all colorectal cancer patients, occurring in about 10% of colorectal cancer patients [1]. This is related to the poor prognosis of the patient and the 5-year survival rate is reported to be about 20%–30% despite treatment with chemotherapy. After cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) was first introduced by Sugarbaker et al. [2, 3], several studies have reported that the 5-year survival rate of patients undergoing CRS and HIPEC is over 45% [4-6].\n\nHowever, CRS and HIPEC are technically challenging and require a well-trained team, with high postoperative complications and a long learning curve compared to other surgeries [7-9]. Although CRS and HIPEC have been extensively used in Western Europe and US treatments, they are also known to have high morbidity in centers with experienced surgeons. In the United States, about 10% of patients undergoing CRS and HIPEC undergo reoperation and the incidence of major complications is reported to be approximately 33% [10]. Complications related to CRS can be caused by the long operation time and hemodynamic changes due to the resection of multiple sites. CRS and HIPEC may increase the risk of surgical complications and toxicity, which may lead to postoperative bleeding, anastomosis leak, bowel perforation wound dehiscence, etc. HIPEC may lead to nephrotoxicity or hepatotoxicity [7].\n\nThe purpose of this study was to evaluate the safety and efficacy for patients with peritoneal metastasis after examining clinical prognosis and postoperative complications on patients underwent CRS and HIPEC in our hospital.\n\nMETHODS\nPreoperative Diagnosis and Patient Selection\nFrom February 2008 to April 2018, CRS and HIPEC were performed in 26 patients with peritoneal metastasis or pseudomyxoma peritonei in colorectal cancer and retrospectively analyzed. Patients underwent thoracic and abdominal computed tomography and esophagogastroduodenoscopy and colonoscopy to confirm peritoneal metastasis and other metastases before surgery. When computed tomography was difficult to diagnose or suspicion of nonabdominal metastasis, positron emission tomography-computed tomography was also considered. Inclusion criteria were defined as patients who were predicted to be able to undergo complete resection due to only metastasis within the abdominal cavity confirmed by preoperative computed tomography or positron emission tomography-computed tomography, among patients with suspected peritoneal metastasis in histologically proven colorectal cancer. The exclusion criteria were patients whose peritoneal metastases were unresectable or underwent emergency surgery, patients with extraperitoneal metastases, patients with unresectable hepatic metastases, and patients with poor overall system status at 2 or more points in the Eastern Cooperative Oncology Group. This study was approved by the Institutional Review Board (IRB) of the National Cancer Center (NCC2019-0016). And informed consent was not obtained because this was a retrospective study using clinical practice data.\n\nData Forms\nPatient characteristics, history, peritoneal metastasis, complications, short follow-up data were studied retrospectively. Peritoneal cancer index score was measured by abdominal exploration during surgery. Abdominal cavity was divided into 13 compartments and subdivided into 0–3 points according to the size of peritoneal metastasis (0 points, absence of tumor; 1 point, tumor less than 0.5 cm; 2 points, tumor from 0.5 cm to 5 cm; and 3 points, tumor larger than 5 cm). The scores were marked from 0 to 39 in total [11]. Peritoneal cancer index score was divided into 3 groups according to the score, and was divided into less than 10 points, between 10 points and 19 points, and more than 20 points. Completeness of cytoreduction after surgery was subdivided according to the size of residual tumor (CC-0, complete removal of visible tumor; CC-1, remnant tumor less than 0.25 cm; CC-2, residual tumor between 0.25 cm and 2.5 cm; and CC-3, visible tumor larger than 2.5 cm in diameter). Complications were classified into 5 grades according to the Clavien-Dindo grade classification. Class 0 to II were classified as mild cases and grade III and above were classified as serious complications.\n\nCRS and HIPEC Procedure\nIn case of patients with synchronous peritoneal metastasis, primary tumor resection was performed at the same time. In case of patients with metachronous peritoneal metastasis, patients with metastasis during the postoperative chemotherapy or follow-up of the primary tumor underwent resection after receiving full explanation and consent. As suggested by Sugarbaker, CRS was carried out to remove the cancer cells by mechanical means through the naked eye and minimize the peritoneal cancer index score [12]. Peritoneal resection was performed selectively according to the location of peritoneal metastasis, such as anterior peritonectomy (right and left), Epigastric peritonectomy, right subdiaphragmatic peritonectomy, left subdiaphragmatic peritonectomy, greater omentectomy, lesser omentectomy, pelvic peritonectomy, cholecystectomy & resection of the omental bursa, etc\n\nHIPEC was prepared by mixing mitomycin C with 15 mg/m2 of body surface area in 4,500 mL of physiological saline. The mixed solution was circulated through a HIPEC pump (The Belmont Hyperthermic Pump) at a rate of 800 to 1,000 mL/min for 90 minutes while maintaining the 42°C to 43°C. The patient’s central body temperature, inflow temperature, and outflow temperature were checked every 5 minutes, and the target temperature was controlled through the inlet temperature of the HIPEC pump. All patients underwent more than one day of follow-up in intensive care unit. When the vital sign was stable and there was no change in the drainage tube or clinical examination results, patients were transferred to the general ward. Most of the Levin tubes were removed immediately after surgery or the next day. Water intake started the day after surgery. All patients underwent a total of 4 drainage tubes in the pelvic cavity and bilateral diaphragmatic space after the operation. Abdominal computed tomography was performed on the 7th postoperative day to confirm the absence of abnormalities and tubes were removed.\n\nStatistical Analysis\nStatistical analysis was performed using IBM SPSS Statistics ver. 22.0 (IBM Co., Armonk, NY, USA). Categorical variables are described as frequency and percentage, and continuous variables as mean and standard error, minimum and maximum values. Crossover analysis was used for the comparison of complications, and a P-value less than 0.05 was considered statistically significant.\n\nRESULTS\nA total of 26 patients underwent CRS and HIPEC (Table 1). The average age of the patients was 55.3 years, 35% were males and 65% were females. Body mass index was 22.32 ± 3.97 kg/m2 (range, 17.8–32.3 kg/m2). American Society of Anesthesiologists physical status classification was I in 42.3%, II in 53.8% and III in 3.8%. The primary tumor sites were most common in sigmoid colon, synchronous peritoneal metastasis in 9 patients (34.6%) and metachronous peritoneal metastasis in 17 patients (65.4%). The preoperative chemotherapy was used in 17 patients (65.4%). Twelve patients among them underwent surgery in the progression disease state during chemotherapy, 5 underwent surgery in stable disease state after finding peritoneal metastasis and chemotherapy. Of the 9 patients with synchronous peritoneal metastasis, 1 patient who underwent stenting with colonic obstruction, and 1 patient who was transferred to our hospital after chemotherapy in other hospitals, the remaining 7 patients did not undergo neoadjuvant chemotherapy. Preoperative chemotherapy was performed in 15 of 17 patients with metachronous peritoneal metastasis patients.\n\nSome patients had accompanied resection during surgery due to metastasis to the other organs; 2 had liver metastasis and 1 had spleen. Histopathologic type was adenocarcinoma in 15, infiltrating cell carcinoma in 1, and mucinous carcinoma in 10. Preoperative carcinoembryonic antigen was 192.13 ± 812.33 ng/mL (range, 1.0–4,160.6 ng/mL) and it was 7.25 ± 17.23 ng/mL (range, 0.6–82.7 ng/mL) after 1 of operation\n\nThe peritoneal cancer index score of the patients was as follows; less than 10 points in 18 patients (69%), 10–19 points in 6 patients, and more than 20 points in 2 patients (Table 2). The CRS completion score (CC score) was 0 in all except 1 patient. In the case of patient with 1 score, residual tumor occurred due to severe adhesions\n\nOperative transfusion was performed in 8 patients. The average operation time was 507 minutes and blood loss was 652 mL on average. All patients underwent surgery. Total 3 ostomies were performed: 1 case for permanent ileostomy in patient underwent total proctocolectomy, 1 case for temporary ileostomy in patient underwent low anterior resection, and 1 case for permanent colostomy in patient underwent abdominoperineal resection.\n\nThe average postoperative hospital stay was 21 days (Table 3), and they started to eat porridge within an average of 1 week. Postoperative chemotherapy was recommended for all patients, but it was performed in 12 patients due to complication or rejection and started after average 52 days after surgery (range, 31–105 days). And 5 patients were treated coadministration with Bevacizumab and FOLFIRI.\n\nPostoperative complications occurred in 88.5% in early period within 30 days and in 34.6% in late period (Table 4). Complications were recorded in duplicate and more than the total number of patients, 26. In early period, 3 patients had no complication and 17 patients had grade I to II complications. Among them, 9 (34.6%) had ileus, which was the most frequent complication. Severe complications of grade III or higher occurred in 6 patients and most were associated with postoperative wound infection or suture. One patient underwent delayed wound closure due to deep incisional infection, 1 patient underwent percutaneous drainage due to deep organ infection, and 2 underwent primary closure with wound dehiscence. One patient had septicemia due to colonic-rectal anastomosis leaks during low anterior resection of CRS but recovered after percutaneous drainage and controlled fistula. There was no death. The complications after 30 days of operation were 9 patients (34.6%), 2 intestinal obstruction due to intestine adhesions, 3 dysuria, 1 erectile dysfunction, 1 pelvic abscess, 1 ureteral stenosis, 1 rectal stenosis. There were 2 patients with serious complications.\n\nWith regard to postoperative complications, 6 patients with severe complications were compared to 20 patients without complications or mild complications. The factors associated with complications were investigated (Table 5). Patient characteristics and outcomes were compared. There was a significant difference in the presence of transfusion during surgery (P = 0.004). There was no difference in the amount of blood loss during the operation between the mild and severe complications. In the mild complication group only red blood cells (RBC) or fresh frozen plasma (FFP) was transfused. In the severe complication group, 1 patient was injected platelet only, 1 patient was in RBC only, and 3 patients were injected RBC and FFP at the same time Operative transfusion was performed in 8 patients. One patient had no complications. Of 7 patients with complications, 5 patients had severe complications. As mind complication, there were 3 cases of urinary retention. Two cases of ileus, 1 case of pleural effusion, hydrocele, etc. Severe complications included septicemic due to anastomosis leak, deep incisional infection, deep organ infection, wound dehiscence, urinary leak of bladder, for one case respectively.\n\nAmong 26 CRS and HIPEC patients, 15 patients had recurrence and 6 patients died. The median follow-up period was 15 months (range, 1–100 months). The median disease-free survival was 27.8 months (range, 13.4–42.2 months). The median overall survival was 56.0 months (range, 28.6–83.5 months) for 3 deaths except for 3 patients who were discharged to other hospitals or lost to follow-up. The cancer-specific survival rates of 2 and 3 years were 57% and 36%, respectively.\n\nDISCUSSION\nThe treatment of patients with metastatic colorectal cancer has been continuously studied. In patients with colorectal cancer with unresectable metastases, systemic chemotherapy has been shown to increase median survival to more than 24 months [13], and the resection of metastatic masses in the lung and liver also increases survival rate [14]. As with these reasons, CRS and HIPEC of peritoneal metastatic colorectal cancer are one of the treatment options for patients with colorectal cancer metastasis and has increased the survival rate [4-10, 12].\n\nHowever, the criteria for the selection of patients who can perform CRS and HIPEC have not been studied yet because sufficient clinical randomized trial has not been done yet. Goéré et al. [15] retrospectively reviewed the patients who underwent CRS and intraperitoneal chemotherapy and found that the 5-year survival rate was significantly higher when PCI score was less than 10. Elias et al. [16] reported that PCI score was independent prognostic factor for overall survival. In this study, the average postoperative PCI score was 8.73 points, and 8 patients (30.1%) had a score of 10 points or more. The CC score was reported to be an important prognostic factor in patients undergoing CRS and HIPEC as well as the PCI score [16, 17]. In this study, all patients except for 1 (3.8%) showed CC-0, and neither PCI score nor CC score was significantly correlated with survival.\n\nIn this study, mean operation time was 507 minutes (range, 285–950 minutes) and mean hospital stay was 21.6 days (range, 9–73 days). Polanco et al. [18] showed that the mean operation time was 430 minutes in 370 patients with CRS and HIPEC and 15.86 days in mean hospital stay, which is shorter than the results of this study. However, in the case of Kusamura et al. [19] while investigating 420 patients underwent CRS and HIPEC, the mean operation time was 563 minutes and the mean hospital stay was 22 days, which was longer than this study.\n\nIn this study, mortality was 0% but morbidity was as high as 88.5%. However, complications of grade III or higher were low and usually mild complications occurred. Postoperative mortality was reported to be less than 1% in the high-volume center [20], and other studies reported up to 4% to 8% [17, 21-24]. CRS and HIPEC are highly skilled procedures, and the learning curve is high enough to require 100 to 140 cases compared to other procedures. Morbidity tends to decrease as the surgical experience accumulates, resulting in about 12%–52% morbidity [19, 25]. In this study, morbidity was higher than other studies, but mortality was close to other high-volume centers.\n\nHIPEC has the advantage of high cytotoxic effect on intra-abdominal metastatic tumor cells and less systemic cytotoxic effect compared with systemic chemotherapy [26], but it does not suggest it is harmless. The chemotherapeutic agent used in HIPEC is mitomycin C, which is known to induce bone marrow suppression and nephrotoxicity when administered intraperitoneally [23], however, no associated complications were found in this study.\n\nIn this study, blood transfusion was associated with severity of complication. Baratti et al. [23] reported no association with severe complications and transfusions in patients undergoing CRS and HIPEC. However, Saxena et al. [27] reported that in 936 patients undergoing CRS and HIPEC, more than 5 units of allogenic blood transfusion increased hospital mortality and morbidity above grade III. However, this study did not show any correlation with those who received more than 5 units of blood transfusion. The mechanism of transfusion-related complications was strongly correlated with the biological effect associated with transfusion-related immunomodulation, and that the soluble mediator stored prior to transfusion may also cause posttransfusion complications [28]. In patients receiving transfusions, it was reported that alloantigens in donor cells can lead to cytokine mediators and induce cellular responses that affect inflammatory mediators, which cause complications due to change of immune system [29]. Therefore, to reduce the postoperative severe complications incidence, it is necessary to try to reduce the transfusion such as minimizing intraoperative bleeding and avoiding unnecessary transfusion.\n\nThe limitations of this study are as follows. First, it was a small retrospective study. Second, CRS and HIPEC were first performed in 2008, but since 2017, the research has been conducted in earnest and no significant factors related to the survival rate have been identified. Third, there was a selection bias in patient.\n\nIn conclusion, CRS and HIPEC are the treatments that are still being studied. However, complication incidence is high and highly skilled procedure are required. However, this can be overcome through intensive training and the accumulation of continuous surgical experience.\n\nNo potential conflict of interest relevant to this article was reported.\n\nThis work was supported by a National Cancer Center Grant (grant number: 1810191).\n\nTable 1. Demographics and characteristics of patients\n\nCategory\tNo. (%)\t\nAge\t55.27 ± 11.06 (35–69)\t\nSex\t\t\n Male\t9 (34.6)\t\n Female\t17 (65.4)\t\nBody mass index (kg/m2)\t22.32 ± 3.97 (17.8–32.3)\t\nASA PS classification\t\t\n I\t11 (42.3)\t\n II\t14 (53.8)\t\n III\t1 (3.8)\t\nPrimary cancer\t\t\n Ascending colon cancer\t4 (15.4)\t\n Hepatic flexure cancer\t1 (3.8)\t\n Transverse colon cancer\t1 (3.8)\t\n Descending colon cancer\t2 (7.7)\t\n Sigmoid colon cancer\t8 (30.8)\t\n Rectal cancer\t6 (23.1)\t\n Appendiceal cancer\t4 (15.4)\t\nPrevious abdominal surgery\t\t\n Yes\t21 (80.8)\t\n No\t5 (19.2)\t\nPrevious colorectal cancer surgery\t\t\n Yes\t17 (65.4)\t\n Cecectomy\t1\t\n Right hemicolectomy\t5\t\n Left hemicolectomy\t2\t\n Anterior resection\t5\t\n Low anterior resection\t4\t\n Time interval since last surgery (mo)\t24.56 ± 10.9 (1–50)\t\n No\t7 (26.9)\t\nPresentation of peritoneal carcinomatosis\t\t\n Synchronous\t8 (30.8)\t\n Metachronous\t17 (65.4)\t\nPrevious chemotherapy\t\t\n Yes\t17 (65.4)\t\n 1st line\t9 (34.6)\t\n 2nd line\t6 (23.1)\t\n 3rd line\t2 (7.7)\t\n No\t9 (34.6)\t\nSynchronous organ metastasis\t\t\n Liver\t2 (7.7)\t\n Spleen\t1 (3.8)\t\nHistology of primary colorectal cancer\t\t\n WD\t3 (11.5)\t\n MD\t9 (34.6)\t\n PD\t3 (11.5)\t\n Signet ring cell\t1 (3.8)\t\n Mucinous\t10 (38.5)\t\nPreop CEA (ng/mL)\t192.13 ± 812.33 (1.0–4,160.6)\t\nPostop CEA (<7 days) (ng/mL)\t7.25 ± 17.23 (0.6–82.7)\t\nValues are presented as number (%) or mean ± standard deviation (range).\n\nASA PS, American Society of Anesthesiologists physical status; WD, well differentiated; MD, moderately differentiated; PD, poorly differentiated; CEA, carcinoembryonic antigen.\n\nTable 2. Intraoperative outcomes\n\nVariable\tNo. (%)\t\nPCI score\t\t\n <10\t18 (69.23)\t\n 10–19\t6 (23.08)\t\n ≥20\t2 (7.69)\t\n Mean ± SD\t8.73 ± 5.54\t\nCC score\t\t\n 0\t25 (96.2)\t\n 1\t1 (3.8)\t\n 2\t0 (0)\t\n 3\t0 (0)\t\nIntraoperative transfusion\t\t\n Yes\t8 (30.8)\t\n No\t18 (69.2)\t\nOperative time (yr)\t507.69 ± 152.46 (285–950)\t\nEstimated blood loss (mL)\t651.92 ± 786.06 (50–3,000)\t\nNo. of anastomosis\t\t\n 0\t3 (11.5)\t\n 1\t12 (43.2)\t\n 2\t7 (26.9)\t\n 3\t4 (15.4)\t\nCombined resection organ\t\t\n Liver (tumorectomy)\t2 (7.7)\t\n Gall bladder\t3 (11.5)\t\n Stomach\t3 (11.5)\t\n Spleen\t7 (26.9)\t\n Uterus and ovary\t7 (26.9)\t\n Bladder\t1 (3.8)\t\nFecal diversion\t\t\n None\t23 (88.5)\t\n Ileostomy\t2 (7.7)\t\n Colostomy\t1 (3.8)\t\nValues are presented as number (%) or mean ± standard deviation (range) unless otherwise indicated.\n\nPCI, peritoneal cancer index; SD, standard deviation; CC, completeness of cytoreduction.\n\nTable 3. Postoperative clinical outcomes\n\nCategory\tValue\t\nLength of ICU stay (day)\t0.92 ± 0.56 (0–2)\t\nLength of postoperative day\t21.58 ± 13.51 (9–73)\t\nDays to 1st sips of water\t1.80 ± 1.39 (1–6)\t\nDays to 1st soft diet\t7.19 ± 3.05 (4–16)\t\nDays to removal of Levin tube\t0.85 ± 1.32 (0–6)\t\nDays to removal of JP drain\t15.42 ± 13.46 (7–72)\t\nPostoperative chemotherapy\t\t\n Yes\t12 (46.2)\t\n No\t14 (53.8)\t\nRegimen of 1st postoperative chemotherapy\t\t\n Bevacizumab + FOLFIRI\t5 (19.2)\t\n Bevacizumab + FOLFOX\t2 (7.7)\t\n FOLFOX\t4 (15.4)\t\n Capecitabine\t1 (3.3)\t\nValues are presented as mean ± standard deviation (range) or number (%).\n\nICU, intensive care unit; JP, Jackson-Pratt.\n\nTable 4. Postoperative complications (n = 26)\n\nClavien-Dindo grade & complications\tNo. (%)\t\nEarly postoperative complication (≤postoperative 30 days)\t23 (88.5)\t\n Grade I\t19 (73.1)\t\n Ileus\t9\t\n Urinary retention\t7\t\n Hydrocecle\t1\t\n Pleural effusion\t1\t\n Chyle\t1\t\n Grade II\t4 (15.4)\t\n Wound seroma\t2\t\n Urinary tract infection\t1\t\n Deep vein thrombosis\t1\t\n Grade IIIa\t4 (15.4)\t\n Wound dehiscence\t2\t\n Deep incisional infection\t1\t\n Deep organ infection\t1\t\n Grade IIIb\t2 (7.7)\t\n Anastomotic leak\t1\t\n Urinary leak from Bladder\t1\t\n Grade IV\t\t\n Sepsis\t1 (3.8)\t\n Grade V\t\t\n -\t-\t\nLate postoperative complication (>postoperative 30 days)\t9 (34.6)\t\n Grade I\t5 (19.2)\t\n Urinary difficulty\t3\t\n Ileus\t2\t\n Grade II\t2 (7.7)\t\n Impotence\t1\t\n Pelvic abscess\t1\t\n Grade IIIa\t\t\n Ureter stricture\t1 (3.8)\t\n Grade IIIb\t\t\n Rectovaginal fistula\t1 (3.8)\t\n Grade IV\t\t\n -\t-\t\n Grade V\t\t\n -\t\t\nTable 5. Factors associated severe early complications (≤postoperative 30 days)\n\nVariable\t<CIII (n = 20)\t≥CIII (n = 6)\tP-value\t\nAge (yr)\t54.45 ± 9.83\t58.00 ± 15.26\t0.609\t\nSex\t\t\t1.000\t\n Male\t7 (35.0)\t2 (33.3)\t\t\n Female\t13 (65.0)\t4 (66.7)\t\t\nBody mass index (kg/m2)\t23.67 ± 3.74\t22.17 ± 4.87\t0.428\t\nASA PS classification\t\t\t0.232\t\n I\t10 (50.0)\t1 (16.7)\t\t\n II\t9 (45.0)\t5 (83.3)\t\t\n II\t1 (5.0)\t0 (0)\t\t\nPrimary cancer location\t\t\t1.000\t\n Right colon\t8 (40.0)\t2 (33.3)\t\t\n Left colon\t7 (35.0)\t3 (50.0)\t\t\n Rectum\t5 (25.0)\t1 (16.7)\t\t\nPresentation of peritoneal carcinomatosis\t\t\t1.000\t\n Synchronous\t8 (40.0)\t2 (33.3)\t\t\n Metachronous\t12 (60.0)\t4 (66.7)\t\t\nHistology\t\t\t0.065\t\n WD/MD\t7 (35.0)\t5 (83.3)\t\t\n PD/signet/mucinous\t13 (65.0)\t1 (16.7)\t\t\nPrevious abdominal surgery\t\t\t1.000\t\n Yes\t16 (80.0)\t5 (83.3)\t\t\n No\t4 (20.0)\t1 (16.7)\t\t\nPreoperative CEA (ng/mL)\t237.67±926.49\t40.33 ± 40.15\t0.354\t\nPostoperative CEA (7 days) (ng/mL)\t7.64 ± 20.21\t6.23 ± 4.41\t0.870\t\nPCI score\t9.00 ± 5.94\t7.83 ± 4.26\t0.660\t\n <10\t15 (75.0)\t4 (66.7)\t0.529\t\n ≥10\t5 (25.0)\t2 (33.3)\t\t\nIntraoperative transfusion\t\t\t0.004\t\n Yes\t3 (15.0)\t5 (83.3)\t\t\n No\t17 (85.0)\t1 (16.7)\t\t\nOperative time (min)\t499.75±150.19\t534.17±171.51\t0.637\t\nEstimated blood loss (mL)\t517.50±661.00\t1,100.00 ± 1,056.41\t0.113\t\nFecal diversion\t\t\t1.000\t\n Yes\t2 (10.0)\t1 (16.7)\t\t\n No\t18 (90.0)\t5 (83.3)\t\t\nNo. of anastomosis\t1.5 ± 1.0\t1.33 ± 0.52\t0.701\t\nNo. of organ resected\t1.45 ± 1.36\t1.83 ± 0.75\t0.388\t\nValues are presented as mean ± standard deviation or number (%).\n\nASA PS, American Society of Anesthesiologists physical status; CTx, chemotherapy; WD, well differentiated; MD, moderately differentiated; PD, poorly differentiated; CEA, carcinoembryonic antigen; PCI, peritoneal cancer index; EBL, estimated blood loss.\n==== Refs\nREFERENCES\n1 Elferink MA de Jong KP Klaase JM Siemerink EJ de Wilt JH Metachronous metastases from colorectal cancer: a population-based study in North-East Netherlands Int J Colorectal Dis 2015 30 205 12 25503801 \n2 Sugarbaker PH Landy D Jaffe G Pascal R Histologic changes induced by intraperitoneal chemotherapy with 5-fluorouracil and mitomycin C in patients with peritoneal carcinomatosis from cystadenocarcinoma of the colon or appendix Cancer 1990 65 1495 501 2107021 \n3 Sugarbaker PH Peritonectomy procedures Ann Surg 1995 221 29 42 7826158 \n4 Kuijpers AM Mirck B Aalbers AG Nienhuijs SW de Hingh IH Wiezer MJ Cytoreduction and HIPEC in the Netherlands: nationwide long-term outcome following the Dutch protocol Ann Surg Oncol 2013 20 4224 30 23897008 \n5 Elias D Lefevre JH Chevalier J Brouquet A Marchal F Classe JM Complete cytoreductive surgery plus intraperitoneal chemohyperthermia with oxaliplatin for peritoneal carcinomatosis of colorectal origin J Clin Oncol 2009 27 681 5 19103728 \n6 Désolneux G Mazière C Vara J Brouste V Fonck M Béchade D Cytoreductive surgery of colorectal peritoneal metastases: outcomes after complete cytoreductive surgery and systemic chemotherapy only PLoS One 2015 10 e0122816 25825874 \n7 Canda AE Sokmen S Terzi C Arslan C Oztop I Karabulut B Complications and toxicities after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy Ann Surg Oncol 2013 20 1082 7 23456387 \n8 Kuijpers AM Hauptmann M Aalbers AG Nienhuijs SW de Hingh IH Wiezer MJ Cytoreduction and hyperthermic intraperitoneal chemotherapy: the learning curve reassessed Eur J Surg Oncol 2016 42 244 50 26375923 \n9 Chua TC Yan TD Saxena A Morris DL Should the treatment of peritoneal carcinomatosis by cytoreductive surgery and hyperthermic intraperitoneal chemotherapy still be regarded as a highly morbid procedure?: a systematic review of morbidity and mortality Ann Surg 2009 249 900 7 19474692 \n10 Jafari MD Halabi WJ Stamos MJ Nguyen VQ Carmichael JC Mills SD Surgical outcomes of hyperthermic intraperitoneal chemotherapy: analysis of the american college of surgeons national surgical quality improvement program JAMA Surg 2014 149 170 5 24352601 \n11 Jacquet P Sugarbaker PH Clinical research methodologies in diagnosis and staging of patients with peritoneal carcinomatosis Cancer Treat Res 1996 82 359 74 8849962 \n12 Sugarbaker PH Management of peritoneal metastases - Basic concepts J BUON 2015 20 Suppl 1 S2 S11 26051329 \n13 Koppe MJ Boerman OC Oyen WJ Bleichrodt RP Peritoneal carcinomatosis of colorectal origin: incidence and current treatment strategies Ann Surg 2006 243 212 22 16432354 \n14 Esquivel J Current status of colorectal cancer with peritoneal carcinomatosis Ann Surg Oncol 2010 17 1968 9 20186492 \n15 Goéré D Malka D Tzanis D Gava V Boige V Eveno C Is there a possibility of a cure in patients with colorectal peritoneal carcinomatosis amenable to complete cytoreductive surgery and intraperitoneal chemotherapy? Ann Surg 2013 257 1065 71 23299520 \n16 Elias D Gilly F Boutitie F Quenet F Bereder JM Mansvelt B Peritoneal colorectal carcinomatosis treated with surgery and perioperative intraperitoneal chemotherapy: retrospective analysis of 523 patients from a multicentric French study J Clin Oncol 2010 28 63 8 19917863 \n17 Glehen O Gilly FN Boutitie F Bereder JM Quenet F Sideris L Toward curative treatment of peritoneal carcinomatosis from nonovarian origin by cytoreductive surgery combined with perioperative intraperitoneal chemotherapy: a multi-institutional study of 1,290 patients Cancer 2010 116 5608 18 20737573 \n18 Polanco PM Ding Y Knox JM Ramalingam L Jones H Hogg ME Institutional learning curve of cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion for peritoneal malignancies Ann Surg Oncol 2015 22 1673 9 25377640 \n19 Kusamura S Baratti D Deraco M Multidimensional analysis of the learning curve for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in peritoneal surface malignancies Ann Surg 2012 255 348 56 22202584 \n20 Gusani NJ Cho SW Colovos C Seo S Franko J Richard SD Aggressive surgical management of peritoneal carcinomatosis with low mortality in a high-volume tertiary cancer center Ann Surg Oncol 2008 15 754 63 18080166 \n21 Verwaal VJ van Ruth S de Bree E van Sloothen GW van Tinteren H Boot H Randomized trial of cytoreduction and hyperthermic intraperitoneal chemotherapy versus systemic chemotherapy and palliative surgery in patients with peritoneal carcinomatosis of colorectal cancer J Clin Oncol 2003 21 3737 43 14551293 \n22 Levine EA Stewart JH 4th Russell GB Geisinger KR Loggie BL Shen P Cytoreductive surgery and intraperitoneal hyperthermic chemotherapy for peritoneal surface malignancy: experience with 501 procedures J Am Coll Surg 2007 204 943 53 17481516 \n23 Baratti D Kusamura S Iusco D Bonomi S Grassi A Virzì S Postoperative complications after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy affect long-term outcome of patients with peritoneal metastases from colorectal cancer: a two-center study of 101 patients Dis Colon Rectum 2014 57 858 68 24901687 \n24 Glehen O Kwiatkowski F Sugarbaker PH Elias D Levine EA De Simone M Cytoreductive surgery combined with perioperative intraperitoneal chemotherapy for the management of peritoneal carcinomatosis from colorectal cancer: a multi-institutional study J Clin Oncol 2004 22 3284 92 15310771 \n25 Moradi BN 3rd Esquivel J Learning curve in cytoreductive surgery and hyperthermic intraperitoneal chemotherapy J Surg Oncol 2009 100 293 6 19697425 \n26 Yan TD Cao CQ Munkholm-Larsen S A pharmacological review on intraperitoneal chemotherapy for peritoneal malignancy World J Gastrointest Oncol 2010 2 109 16 21160929 \n27 Saxena A Valle SJ Liauw W Morris DL Allogenic blood transfusion is an independent predictor of poorer peri-operative outcomes and reduced long-term survival after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a review of 936 cases J Gastrointest Surg 2017 21 1318 27 28560703 \n28 Vamvakas EC Blajchman MA Transfusion-related immunomodulation (TRIM): an update Blood Rev 2007 21 327 48 17804128 \n29 Kao KJ Mechanisms and new approaches for the allogeneic blood transfusion-induced immunomodulatory effects Transfus Med Rev 2000 14 12 22 10669937\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2287-9714",
"issue": "36(1)",
"journal": "Annals of coloproctology",
"keywords": "Colorectal neoplasms; Cytoreductive surgery; Hyperthermic intraperitoneal chemotherapy; Peritoneal carcinomatosis",
"medline_ta": "Ann Coloproctol",
"mesh_terms": null,
"nlm_unique_id": "101605121",
"other_id": null,
"pages": "22-29",
"pmc": null,
"pmid": "32146785",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": "19474692;20737573;24352601;19103728;25503801;25825874;23456387;23897008;28560703;26375923;19917863;17481516;15310771;18080166;19697425;25377640;14551293;22202584;24901687;20186492;7826158;21160929;10669937;2107021;23299520;16432354;8849962;17804128;26051329",
"title": "Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy With Mitomycin C Used for Colorectal Peritoneal Carcinomatosis.",
"title_normalized": "cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with mitomycin c used for colorectal peritoneal carcinomatosis"
} | [
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"companynumb": "KR-ACCORD-177329",
"fulfillexpeditecriteria": "1",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MITOMYCIN"
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{
"abstract": "Baboon syndrome is a special form of systemic contact dermatitis to systemic or local administration of contact allergens. Baboon syndrome without known previous cutaneous sensitisation was also described as drug-related baboon syndrome or symmetrical drug-related intertriginous and flexural exanthema (SDRIFE). The major drugs causing SDRIFE was beta-lactam antibiotic such as amoxicillin and ampicillin. We report a case of 16-year-old woman who developed pruritic eruptions after oral metronidazole treatment for diarrhea. She was diagnosed SDRIFE according to her clinical and histopathological findings. To our knowledge, our patient is the first case who developed SDRIFE due to metronidazole in the literature.",
"affiliations": "Department of Dermatology and.",
"authors": "Şikar Aktürk|Aysun|A|;Bayramgürler|Dilek|D|;Salman|Selma|S|;Yıldız|Kürşat Demir|KD|;Odyakmaz Demirsoy|Evren|E|",
"chemical_list": "D000994:Antitrichomonal Agents; D008795:Metronidazole",
"country": "England",
"delete": false,
"doi": "10.3109/15569527.2013.823981",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9527",
"issue": "33(4)",
"journal": "Cutaneous and ocular toxicology",
"keywords": "Baboon syndrome; drug eruption; metronidazole",
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000293:Adolescent; D000994:Antitrichomonal Agents; D002081:Buttocks; D003967:Diarrhea; D003875:Drug Eruptions; D005076:Exanthema; D005260:Female; D006801:Humans; D008795:Metronidazole; D012867:Skin",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "337-8",
"pmc": null,
"pmid": "24938451",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Symmetrical drug-related intertriginous and flexural exanthema (SDRIFE) induced by oral metronidazole.",
"title_normalized": "symmetrical drug related intertriginous and flexural exanthema sdrife induced by oral metronidazole"
} | [
{
"companynumb": "PHHY2014TR165292",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
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"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to assess the efficacy and tolerability of trabectedin given every 10 days as a single agent in recurrent ovarian cancer after 3 prior regimens.\n\n\nMETHODS\nTrabectedin 0.6 mg/m2 was administered as a 3-h infusion every 10 days on a 21-day cycle. The study population was compared to patients treated with weekly paclitaxel 80 mg/m2 intravenously on days 1, 8, 15, and 22 every 4 weeks.\n\n\nRESULTS\nWe identified 34 patients previously submitted to at least 3 lines of chemotherapy who received single-agent trabectedin between 2010 and 2015. They were matched with a historical series of 34 patients who received weekly paclitaxel. No significant differences in response rate were found. Median progression-free survival was 4 months; 5 months in the trabectedin group and 4 months in the paclitaxel group. Overall survival (OS) was 13 months for the trabectedin group and 7 months for the paclitaxel group (p = 0.015). Patients who received platinum after trabectedin had a significant OS increase compared to those who received platinum after paclitaxel (18 vs. 9 months, respectively; p = 0.009). The most frequent drug-related grade 3/4 toxicities were reversible hepatic toxicity, neutropenia, anemia, thrombocytopenia, and gastrointestinal toxicity.\n\n\nCONCLUSIONS\nSingle-agent trabectedin every 10 days is an active treatment with a manageable toxicity profile in heavily pretreated advanced relapsed ovarian cancer patients.",
"affiliations": "Department of Gynecological-Obstetrical and Urological Sciences, Sapienza University of Rome, Rome, Italy.",
"authors": "Marchetti|Claudia|C|;Musella|Angela|A|;Romito|Alessia|A|;Vertechy|Laura|L|;Palaia|Innocenza|I|;Di Donato|Violante|V|;Boccia|Serena|S|;De Felice|Francesca|F|;Monti|Marco|M|;Muzii|Ludovico|L|;Benedetti Panici|Pierluigi|P|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D004149:Dioxoles; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin; D017239:Paclitaxel",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000475668",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "93(6)",
"journal": "Oncology",
"keywords": "Chemotherapy; Ovarian cancer; Paclitaxel; Recurrence; Trabectedin",
"medline_ta": "Oncology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018906:Antineoplastic Agents, Alkylating; D000972:Antineoplastic Agents, Phytogenic; D016022:Case-Control Studies; D004149:Dioxoles; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008875:Middle Aged; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D012189:Retrospective Studies; D044005:Tetrahydroisoquinolines; D000077606:Trabectedin",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "359-366",
"pmc": null,
"pmid": "28946142",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Short-Infusion Trabectedin in Heavily Pretreated Ovarian Cancer Patients: A Single-Institution Experience.",
"title_normalized": "short infusion trabectedin in heavily pretreated ovarian cancer patients a single institution experience"
} | [
{
"companynumb": "IT-JNJFOC-20161122973",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
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"drugadditional": null,
... |
{
"abstract": "The prognosis of several lymphoid malignancies has improved through development of novel therapies, combination with traditional chemotherapies, and investigation of appropriate therapeutic sequencing. Toxicities that are arising because of prolonged or multiple sequential therapeutic interventions are becoming increasingly impactful. Among the broad spectrum of complications that patients with lymphoid malignancies may experience, cardiovascular toxicities are significant in terms of morbidity and mortality. The entire cardiovascular system can be affected, but cardiomyopathy, heart failure, and arrhythmias remain of greatest concerns with the use of anthracyclines, hematopoietic stem cell transplantation, and radiation therapy in patients with lymphoid malignancies. These aspects will be covered in this article within the framework of case-based discussions. Key to the management of cardiovascular complications in patients with lymphoid malignancies is awareness and preparedness across the cancer continuum. Baseline risk stratification helps to direct surveillance and early intervention efforts before, during and after cancer therapy, which are paramount for best possible outcomes. Along these lines, the overall goal is to enable the best possible therapies for lymphoid malignancies without the complications of clinically significant cardiovascular events.",
"affiliations": "Mayo Clinic, Rochester, Minnesota, United States.;Mayo Clinic, Rochester, Minnesota, United States.;Mayo Clinic, Rochester, Minnesota, United States.",
"authors": "Herrmann|Joerg|J|;McCullough|Kristen|K|0000-0003-4252-2619;Habermann|Thomas M|TM|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1182/blood.2019003893",
"fulltext": null,
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"abstract": "Background: German authorities reimburse migraine prevention with erenumab only in patients who previously did not have therapeutic success with at least five oral prophylactics or have contraindications to such. In this real-world analysis, we assessed treatment response to erenumab in patients with chronic migraine (CM) who failed five oral prophylactics and, in addition, onabotulinumtoxinA (BoNTA). Methods: We analyzed retrospective data of 139 CM patients with at least one injection of erenumab from two German headache centers. Patients previously did not respond sufficiently or had contraindications to β-blockers, flunarizine, topiramate, amitriptyline, valproate, and BoNTA. Primary endpoint of this analysis was the mean change in monthly headache days from the 4-weeks baseline period over the course of a 12-weeks erenumab therapy. Secondary endpoints were changes in monthly migraine days, days with severe headache, days with acute headache medication, and triptan intake in the treatment period. Results: Erenumab (starting dose 70 mg) led to a reduction of -3.7 (95% CI 2.4-5.1) monthly headache days after the first treatment and -4.7 (95% CI 2.9-6.5) after three treatment cycles (p < 0.001 for both). All secondary endpoint parameters were reduced over time. Half of patients (51.11%) had a >30% reduction of monthly headache days in weeks 9-12. Only 4.3% of the patients terminated erenumab treatment due to side effects. Conclusion: In this treatment-refractory CM population, erenumab showed efficacy in a real-world setting similar to data from clinical trials. Tolerability was good, and no safety issues emerged. Erenumabis is a treatment option for CM patients who failed all first-line preventives in addition to BoNTA.",
"affiliations": "Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.;Praxis Gendolla, Essen, Germany.;Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany.",
"authors": "Raffaelli|Bianca|B|;Kalantzis|Rea|R|;Mecklenburg|Jasper|J|;Overeem|Lucas Hendrik|LH|;Neeb|Lars|L|;Gendolla|Astrid|A|;Reuter|Uwe|U|",
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"doi": "10.3389/fneur.2020.00417",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2020.00417\nNeurology\nOriginal Research\nErenumab in Chronic Migraine Patients Who Previously Failed Five First-Line Oral Prophylactics and OnabotulinumtoxinA: A Dual-Center Retrospective Observational Study\nRaffaelli Bianca 12* Kalantzis Rea 1 Mecklenburg Jasper 1 Overeem Lucas Hendrik 1 Neeb Lars 1 Gendolla Astrid 3 Reuter Uwe 1 1Department of Neurology, Charité Universitätsmedizin Berlin, Berlin, Germany\n2Clinician Scientist Program, Berlin Institute of Health (BIH), Berlin, Germany\n3Praxis Gendolla, Essen, Germany\nEdited by: Massimiliano Valeriani, Bambino Gesù Children Hospital (IRCCS), Italy\n\nReviewed by: Paolo Martelletti, Sapienza University of Rome, Italy; Lanfranco Pellesi, Rigshospitalet, Denmark; Fayyaz Ahmed, Hull University Teaching Hospitals NHS Trust, United Kingdom\n\n*Correspondence: Bianca Raffaelli bianca.raffaelli@charite.deThis article was submitted to Headache Medicine and Facial Pain, a section of the journal Frontiers in Neurology\n\n\n28 5 2020 \n2020 \n11 41727 2 2020 20 4 2020 Copyright © 2020 Raffaelli, Kalantzis, Mecklenburg, Overeem, Neeb, Gendolla and Reuter.2020Raffaelli, Kalantzis, Mecklenburg, Overeem, Neeb, Gendolla and ReuterThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Background: German authorities reimburse migraine prevention with erenumab only in patients who previously did not have therapeutic success with at least five oral prophylactics or have contraindications to such. In this real-world analysis, we assessed treatment response to erenumab in patients with chronic migraine (CM) who failed five oral prophylactics and, in addition, onabotulinumtoxinA (BoNTA).\n\nMethods: We analyzed retrospective data of 139 CM patients with at least one injection of erenumab from two German headache centers. Patients previously did not respond sufficiently or had contraindications to β-blockers, flunarizine, topiramate, amitriptyline, valproate, and BoNTA. Primary endpoint of this analysis was the mean change in monthly headache days from the 4-weeks baseline period over the course of a 12-weeks erenumab therapy. Secondary endpoints were changes in monthly migraine days, days with severe headache, days with acute headache medication, and triptan intake in the treatment period.\n\nResults: Erenumab (starting dose 70 mg) led to a reduction of −3.7 (95% CI 2.4–5.1) monthly headache days after the first treatment and −4.7 (95% CI 2.9–6.5) after three treatment cycles (p < 0.001 for both). All secondary endpoint parameters were reduced over time. Half of patients (51.11%) had a >30% reduction of monthly headache days in weeks 9–12. Only 4.3% of the patients terminated erenumab treatment due to side effects.\n\nConclusion: In this treatment-refractory CM population, erenumab showed efficacy in a real-world setting similar to data from clinical trials. Tolerability was good, and no safety issues emerged. Erenumabis is a treatment option for CM patients who failed all first-line preventives in addition to BoNTA.\n\nchronic migrainepreventioncalcitonin gene-related peptideerenumabonabotulinumtoxinA\n==== Body\nIntroduction\nMigraine prevention is hampered by poor tolerability of available oral drugs, low therapeutic adherence, and insufficient efficacy in a substantial percentage of patients (1, 2). Prior to the approval of the calcitonin gene-related peptide (CGRP)-(receptor) monoclonal antibodies (mAbs), topiramate, and onabotulinumtoxinA (BoNTA) had been the only approved preventative medications in the United States and Europe for the prophylaxis of chronic migraine (CM) (3). mAbs have shown in clinical trials a favorable profile in terms of safety and efficacy, along with significant improvement in daily functioning and quality of life (4, 5). They have several potential advantages compared to standard oral preventives, including a rapid onset of efficacy, ease of use, persistent therapeutic effect, and lack of pharmacological interactions with other medications (6–8).\n\nErenumab, which blocks the calcitonin gene-related peptide (CGRP) receptor, was launched in Germany in November 2018 and is approved by the European Medicine Agencies (EMA) for the treatment of CM (9). Approval was based on the phase II registration trial (NCT02066415) (10). In this trial, both erenumab doses (70 and 140 mg) led to a significantly greater reduction of monthly migraine days (MMD) than placebo in the last four of the 12 study weeks (−6.6 days for erenumab vs. −4.2 for placebo) (10). Over two-thirds (73.8%) of the patients in the trial had tried at least one prior preventive treatment, and 92.1% of these reported at least one treatment failure due to poor efficacy or tolerability (11). Of note, 66.5% of patients who had previously tried BoNTA therapy for CM had failed this treatment (11). Failure to respond to more than three preventives previously was an exclusion criterion in this trial (10). Erenumab and other CGRP antibodies have not been studied in a migraine population with more than four treatment failures.\n\nOwing to the lack of evidence that erenumab or any other CGRP mAb is superior to established first-line migraine preventive drugs, the European Headache Federation (EHF) and other international guidelines as well as expert opinion suggest the use of mAbs in patients who failed at least two previous oral prophylactic therapies or BoNTA in CM (6, 12, 13). In Germany, the German Federal Joint Committee (Gemeinsamer Bundesausschuss = GBA), a board that sets medical therapy regulations for the public health insurance sector, has identified a specific group of patients for whom the treatment with a mAb will be reimbursed (14). The suitable group consists of patients who previously failed or had contraindications for at least five different anti-migraine treatment classes. According to the authorities, these include the following first-line preventives: one beta blocker (metoprolol or propranolol), flunarizine, topiramate, amitriptyline, and valproate (14). In CM patients, previous failure to BoNTA is additionally required for the reimbursement of erenumab (14). The rationale for these six recommended classes is not based on rigorous scientific data, but rather on the responsible body's (GBA) majority decision (14). This rule applies to the public health insurance sector, which covers the costs of 90% of the population in Germany. Although not favorable to the patients, the GBA's ruling allows us the real-world analysis of data from a patient population that has, at least to our knowledge, never been studied in a clinical migraine trial.\n\nTherefore, we conducted an analysis of CM patients on erenumab therapy who had previously failed or had contraindications to all first-line oral preventives and additionally BoNTA.\n\nMaterials and Methods\nWe analyzed the pharmacy prescriptions for erenumab between November 1, 2018 and April 30, 2019 of the headache center at the Charité—Universitätsmedizin Berlin and the headache specialist's practice Praxis Gendolla in Essen, Germany, retrospectively. This was followed by the review of the electronic chart of every patient with a registered erenumab order and the diagnosis of CM. Other headache diagnoses were exclusion criteria. Only patients who received at least one erenumab s.c. injection and also had history of a non-successful BoNTA therapy following the PREEMPT protocol (15) were included in this analysis. In addition, all patients had failed five first-line migraine preventive medications (metoprolol/propranolol, flunarizine, topiramate, amitriptyline, and valproate) or were unsuitable for these therapies due to contraindications.\n\nIn line with a recent study (16), failure to previous medications including BoNTA was defined as treatment discontinuation due to lack of efficacy and/or tolerability reasons as self-reported by patient and/or according to physician decision as documented in the patients' chart.\n\nHeadache Characteristics and Clinical Evaluation\nWe collected headache data for the following periods: 4 weeks before erenumab treatment (baseline), weeks 1–4 after treatment initiation, weeks 5–8 (after the second treatment cycle), and weeks 9–12 (after the third treatment cycle).\n\nPatients recorded their headaches in headache diaries, which are routinely used and collected in our headache centers. The standard headache diary used by our patients is provided by the German Migraine and Headache Society (Deutsche Migräne- und Kopfschmerzgesellschaft, DMKG) and is available in different languages at http://www.dmkg.de/patienten/dmkg-kopfschmerzkalender.html. When headache diaries were not available, we used the electronic documentation of headache data by the treating physician. Headache data in headache diaries or per electronic documentation included the following discrete numerical variables: monthly headache days (MHD), MMD, monthly days with severe headache (MDSH), monthly days with acute medication use (AMD), and monthly days with triptan use (TriD). We collected side effects and dosing information (70 or 140 mg) as categorical variables using the electronic documentation of the treating physician. Only patients with complete information about at least MHD during baseline were included in the efficacy analysis, i.e., analysis of headache characteristics over time. Patients with missing headache data were excluded from the efficacy analysis, but still included in the analysis of side effects.\n\nA headache day was defined as any day on which a patient recorded any type of headache. We classified a headache day as migraine day if the ICHD-3 criteria of probable migraine applied (17), or when headache was preceded by an aura, and/or improved after triptan intake. We defined headache intensity ≥7/10 on a numeric analog scale as severe. All headache data were averaged across the respective 4-weeks period (i.e., at baseline, weeks 1–4, weeks 5–8, and weeks 9–12).\n\nWe also assessed multiple demographic and anamnestic features of the study population. This included the categorical variables sex (female or male), family history for headaches (positive or negative), and history of aura (positive or negative), the continuous numeric variables age, and age at migraine onset. For all previous prophylactic medications, we collected the numeric variable treatment duration, and time interval prior to erenumab treatment, and the categorical variable reasons for treatment failure (side effects or lack of efficacy). For BoNTA, we also recorded the number of treatment cycles and documented the side effects in detail.\n\nStatistical Analysis\nDemographic and anamnestic variables were examined using descriptive statistics. The primary endpoint of our analysis was the change in MHD from baseline over the course of a 12-weeks treatment. The secondary endpoints were changes in MMD, MDSH, AMD, and TriD in the same time period. Normal distribution of data was assessed with the Kolmogorov–Smirnov test. Since all variables were normally distributed, we compared the 4-weeks baseline phase with the 4-weeks period following each treatment cycle using paired-samples t-tests (i.e., baseline vs. weeks 1–4, baseline vs. weeks 5–8, and baseline vs. weeks 9–12). Patients included in each pairwise comparison varied depending on available headache information. We reported the number of included patients for each analysis. Statistical analysis was performed with IBM SPSS Statistics, version 25. A value of p ≤ 0.05 was considered statistically significant. Test for significance was corrected for multiple comparisons using Bonferroni correction. Categorical data were reported as percentage, numerical data as mean (±standard deviation or 95% confidence interval). Owing to the retrospective design of the study, we did not perform a sample size calculation but included all patients fulfilling the inclusion criteria treated at our headache centers between November 1, 2018 and April 30, 2019.\n\nResults\nDemography\nWe included 139 CM patients in the analysis (Figure 1). All patients were eligible for erenumab therapy according to the authorities' regulations. Both headache centers contributed patient data in equal numbers [n = 71 in Essen (51.1%) vs. n = 68 in Berlin (48.9%)].\n\nFigure 1 Flowchart of patient selection.\n\nPatients were mostly female (n = 116, 83.5%) with an average age of 53.4 ± 10.2 years; age at migraine onset was 20.0 ± 13.6 years. A history of aura was reported in 31 patients (22.3%), and a large majority (n = 115, 82.7%) had a positive family history for migraine. Demographic variables were not different for patients in Berlin and in Essen (Table 1).\n\nTable 1 Selected demographic and anamnestic characteristics of patients in our two headache centers.\n\n\tBerlin\tEssen\tp\t\nN\t71\t68\t\t\nFemale (%)\t78.9\t88.2\t>0.999\t\nAge\t52.5 ± 9.7\t54.3 ± 10.6\t>0.999\t\nAge at migraine onset\t19.5 ± 17.0\t20.7 ± 9.0\t>0.999\t\nHistory of aura\t23.4%\t23.9%\t>0.999\t\nFamily history for headaches\t96.2%\t76.4%\t0.140\t\nn, number of patients; p, Bonferroni adjusted p-value for multiple (= 5) comparisons.\n\nMigraine Prophylactic Treatments\nIn addition to BoNTA, patients had on average 3.6 ± 1.2 non-successful prior treatment attempts due to lack of either efficacy or tolerability issues. This number does not include medications for which contraindications exist. This was in the majority of cases valproate in women with childbearing potential. The reasons for treatment termination are shown in Table 2.\n\nTable 2 Characteristics of previous prophylactic treatment.\n\nMedication\tn (%)\tTreatment duration (months)\tEnd of onabotulinumtoxinA (BoNTA) therapy to erenumab initiation in years\tReason for treatment discontinuation\t\n\t\t\t\tSide effects\tLack of efficacy\t\nβ-Blocker\t90.6\t29.9 ± 47.9\t6.6 ± 5.9\t40.3%\t95.1%\t\nTopiramate\t87.1\t20.2 ± 31.1\t5.9 ± 4.9\t72.4%\t81.4%\t\nFlunarizine\t65.5\t5.2 ± 7.6\t6.0 ± 6.3\t52.0%\t89.8%\t\nValproate\t36.0\t3.2 ± 2.9\t6.1 ± 6.2\t82.6%\t91.3%\t\nAmitriptyline\t77.4\t17.1 ± 26.6\t5.2 ± 5.1\t61.7%\t92.2%\t\nA large majority of patients (n = 111, 79.9%) also failed further prophylactic medications of second or third choice (18), most commonly venlafaxine (n = 48), candesartan (n = 31), or opipramol (n = 28).\n\nTwenty patients (14.4%) continued one other concomitant migraine prophylactic treatment (n = 7 metoprolol, n = 10 topiramate, and n = 2 amitriptyline) during erenumab therapy. Three more patients stayed on metoprolol due to arterial hypertension, and seven on amitriptyline because of concomitant depression.\n\nHistoric OnabotulinumtoxinA Treatment\nPatients in this analysis had received 4.1 ± 3.8 BoNTA treatment cycles following the PREEMPT protocol (15). Side effects of BoNTA were reported by 17.3% of patients, among which neck pain was the most frequent (37.5%), followed by facial paralysis or ptosis (25.0%), and injection site pain (16.7%). The discontinuation rate due to side effects was 11.5%; all other patients terminated BoNTA due to insufficient headache response. All patients who discontinued BoNTA primarily due to side effects had received either one or two treatment cycles and had not reported a relevant migraine improvement until treatment discontinuation.\n\nErenumab Treatment\nBetween November 2018 and April 2019, n = 14 patients had received at least one erenumab treatment cycle: n = 26 two, n = 32 three, and n = 67 more than three treatment cycles in a monthly subcutaneous regimen. Average time interval between the last BoNTA treatment cycle and the first erenumab treatment was 34.8 ± 37.1 months. Patients started erenumab therapy with a dose of 70 mg s.c. without any exception. Dosage escalation to 140 mg was done in 7.3% of patients after 4 weeks (second treatment) and in 29.5% after 8 weeks (third erenumab cycle). A small majority of patients (52.8%) who continued erenumab after the third cycle received thereafter a dose of 140 mg.\n\nHeadache Characteristics During Erenumab Treatment\nEighty-four patients completed headache diaries during the four baseline weeks and reported 18.2 MHD (95% CI 16.8–19.65). MHD at baseline were similar in patients in Berlin (17.7, 95% CI 15.8–19.6) and in Essen (18.9, 95% CI 16.55–21.33, p = 0.405). Erenumab led on average to a reduction of MHD by 21.5% (95% CI −30.8−12.1) in weeks 1–4 (n = 68), by 31.1% (95% CI −40.1−22.2) in weeks 5–8 (n = 60), and by 27.2% (95% CI −37.9−16.4) in weeks 9–12 (n = 45, n = 25 with 70 mg and n = 20 with 140 mg).\n\nAlmost 40% of patients (n = 27/68) reported a reduction of >30% in weeks 1–4, 53.3% (n = 32/60) in weeks 5–8, and 51.1% (n = 23/45) in weeks 9–12. A 50% response to erenumab was achieved by one in three patients (31.1%) in weeks 9–12.\n\nWe also had patients without any response to erenumab treatment. Eleven patients (24.4%) showed no change or worsening of MHD in weeks 9–12, in addition to the previous failure to BoNTA and all first-line treatment classes. Figure 2 shows response rates in weeks 9–12.\n\nFigure 2 The bee swarm plot shows mean monthly headache days during the 4-week baseline and in erenumab treatment at weeks 9–12 (n = 45).\n\nIn a descriptive analysis, patients who continued on erenumab 70 mg seemed to have higher response rates than patients who switched from 70 to 140 mg: −36.6% (95% CI −49.2−24.0) for the 70-mg group and −15.3% (CI −33.8–3.1) for the 140-mg group in weeks 9–12.\n\nOther parameters such as MMD, MDSH, and AMD showed significant improvement (Table 3). In particular, erenumab reduced days with the intake of a triptan by more than 50% during the observation period (baseline 10.7 TriD, 95% CI 9.1–12.3, −4.7 in weeks 9–12, 95% CI 4.6–7.7, p < 0.001). Patients with and without another concomitant prophylactic treatment (CCPT) did not differ in the reduction of MHD [−5.4, 95% CI −0.4–11.32 (weeks 9–12) for seven patients with CCPT, −4.5, 95% CI 2.6–6.5 for 38 patients without].\n\nTable 3 Headache characteristics during erenumab treatment vs. baseline (4 weeks before erenumab treatment).\n\n\tWeeks 1–4\tWeeks 5–8\tWeeks 9–12\t\nMHD (baseline)\t14.0 ± 8.3 (17.7 ± 6.8)\t13.4 ± 8.6 (18.7 ± 6.9)\t13.9 ± 8.5 (18.6 ± 6.8)\t\nReduction from baseline\t−3.7 ± 5.5\t−5.3 ± 5.4\t−4.7 ± 5.9\t\nN\t68\t60\t45\t\nP\t<0.001\t<0.001\t<0.001\t\nMMD (baseline)\t10.5 ± 6.4 (14.6 ± 5.3)\t10.4 ± 6.7 (15.3 ± 6.0)\t10.9 ± 6.4 (15.4 ± 5.0)\t\nReduction from baseline\t−4.0 ± 5.5\t−4.9 ± 4.4\t−4.5 ± 4.6\t\nN\t43\t38\t23\t\nP\t<0.001\t<0.001\t<0.001\t\nMDSH (baseline)\t3.4 ± 4.3 (6.7 ± 5.8)\t3.7 ± 4.7 (7.0 ± 6.3)\t3.3 ± 4.3 (7.6 ± 5.4)\t\nReduction from baseline\t−3.3 ± 4.4\t−3.3 ± 4.1\t−4.3 ± 4.7\t\nN\t29\t23\t13\t\nP\t0.004\t0.015\t0.09\t\nAMD (Baseline)\t7.0 ± 4.4 (11.9 ± 4.6)\t7.0 ± 4.3 (12.3 ± 5.7)\t6.5 ± 2.9 (12.8 ± 5.0)\t\nReduction from baseline\t−4.9 ± 4.0\t−5.3 ± 5.2\t−6.3 ± 4.8\t\nN\t43\t35\t22\t\nP\t<0.001\t<0.001\t<0.001\t\nTriD (Baseline)\t6.6 ± 5.7 (10.7 ± 5.9)\t5.1 ± 4.0 (10.3 ± 6.9)\t5.6 ± 2.8 (10.3 ± 6.2)\t\nReduction from baseline\t−4.1 ± 4.1\t−5.2 ± 6.1\t−4.7 ± 4.6\t\nN\t45\t39\t27\t\nP\t<0.001\t<0.001\t<0.001\t\nMHD, monthly headache days; MMD, monthly migraine days; MDSH. monthly days with severe headache; AMD, monthly days with acute medication use; TriD, monthly days with triptan use; n, patients in the respective category with available data for analysis; p, Bonferroni adjusted p-value for multiple (=15) comparisons. Data are reported as mean ± standard deviation.\n\nTolerability\nIn total, n = 52 (37.4%) patients reported side effects. The most common side effect was constipation (n = 26, 18.7%), followed by respiratory tract infections (n = 6, 4.3%), and itching at injection site (n = 5, 3.6%). Constipation was particularly common in patients with the parallel intake of tricyclic antidepressants: five out of 11 patients (45.1%) in this group reported constipation as a side effect.\n\nThe discontinuation rate due to side effects was 4.3% (n = 6) during the entire observation period. Patients recorded the following reasons for discontinuation: n = 3 worsening of migraine, n = 1 skin rash, n = 1 new asymptomatic ST depression in ECG, and n = 1 constipation.\n\nMore than 70% of patients (71.2%, n = 99) continued erenumab treatment after April 2019, 21.6% (n = 30) discontinued treatment due to insufficient response, and in further 2.9% (n = 4) information was missing.\n\nDiscussion\nIn this retrospective analysis, erenumab showed efficacy in CM patients who failed or had contraindications to five first-line migraine preventives and, in addition, BoNTA. Beginning with the first treatment cycle, erenumab led to a significant reduction in MHD in this difficult-to-treat cohort. Fifty percent of the patients reported a reduction in MHD of at least 30%, which is considered clinically meaningful (19). Migraine frequency reduction led to a reduced number of days with acute medication, in particular triptan, intake. The low discontinuation rate in this analysis indicates good tolerability of erenumab in this population.\n\nThis is the first real-world analysis, which assesses erenumab efficacy in CM patients with six prior frustrating treatment attempts (first-line oral medications plus BoNTA). Such patients have not been studied in any phase of the mAb developmental program, but reflect a substantial number of patients in headache centers. Therefore, analyses like ours help to understand the potential of this new medication class in the clinical context of the most refractory patients.\n\nPhases II and III studies for the CGRP and CGRP-receptor mAbs demonstrated efficacy of mAbs in patients who previously did not respond to other preventives. The number of treatment failures was limited to a maximum of two to four in CM trials, with some small differences between trials (11, 16, 20, 21). Findings from our real-world study also show positive results for erenumab in a more refractory patient population.\n\nIn the phase II study of erenumab in CM, 34.8% of patients had previously failed three preventive treatments (11). A post-hoc analysis in this particular subgroup revealed that 34.8% of the patients with erenumab 70 mg and 38.5% with erenumab 140 mg reached an at least 50% response in MMD vs. 15.3% in the placebo group (11). This is highly consistent with our findings, with over 30% of the patients achieving at least 50% response after 3 months of treatment. The LIBERTY trial focused specifically on patients who had failed two to four preventive treatments (20). Although this trial enrolled only patients with episodic migraine and a direct comparison with our analysis is not possible, responder rates were remarkably similar to our study population: in fact, three out of 10 patients on erenumab treatment reached at least 50% response (20).\n\nThe dosing of erenumab is still a matter of discussion (22). In the EM STRIVE trial, but not the CM trial, erenumab patients achieved a larger reduction of MMD with a dose of 140 mg rather than 70 mg at the time of the primary endpoint (10, 23). At the end of the open-label extension in both EM and CM, the 140-mg dose showed a numerically higher reduction of MMD than the 70-mg dose (24). In our headache centers, treatment initiation at the time of the analysis was done in line with the EMA approval of erenumab with 70 mg followed by an increase to 140 mg if the patient did not respond sufficiently. Therefore, it is not surprising that patients who were stable on 70 mg achieved higher response rates than those who switched to 140 mg as this population is more likely to be overall less responsive to erenumab. However, this analysis was purely descriptive. A dedicated outcome study is necessary to confirm this finding.\n\nIn randomized double-blind and open-label trials, erenumab demonstrates a good tolerability profile, and also, in our real-world study, only a few patients discontinued treatment due to adverse events. The most common side effect in our cohort was constipation (18.7%), which is considerably higher than in the STRIVE trial, in which about 3.5% of the patients reported constipation (23). Several factors may contribute to higher constipation rates in a real-world setting such as predisposition, co-medication with drugs that have an influence of gut mobility (e.g., antidepressants) or specific patient information before the initiation of erenumab therapy. In line, constipation rates were particularly high in patients with concomitant tricyclic antidepressant therapy, and treatment with erenumab in this patient population should be carefully evaluated.\n\nReal-world experience with erenumab is still limited. Initial reports in an Italian headache center included 65 patients with CM who had received at least one injection of erenumab (25). These patients had 5.4 ± 2.6 prior treatment failures; data on prior medication classes including BoNTA was not reported (25). In this study, eight patients had received at least two treatment cycles of erenumab by the time of publication. MMD decreased by 6.6 ± 4 at week 8 in this population, which corresponded to an outstanding 50% responder rate of 87.5% (25). We did not reproduce these findings in our sample, possibly due to population differences and a longer observation period. A placebo response is typically reduced with a longer treatment duration.\n\nThe first data from two Australian headache centers with 64 patients who had failed at least three previous preventive medications showed a >50% reduction in MHD in 30% of cases after 3 months of treatment (26). This is in line with our findings.\n\nIn a recently published observational trial of 89 Italian patients with episodic or chronic migraine, 61.8% of the patients reached a 30% response rate after the third treatment cycle with erenumab. In this cohort, only 11 patients (12.4%) had more than four previous treatment failures, which may lead to better response rates to erenumab than in our patient group. However, in a subgroup analysis of CM patients who previously failed BoNTA treatment, 56.8% achieved a 30% response, which is comparable to our results (27). The identification of clinical or laboratory parameters associated with a good treatment response could help us in the selection of patients for successful CGRP mAb therapy in the future (28).\n\nThe antinociceptive action of BoNTA is partially mediated by the inhibition of CGRP release from trigeminal nerve fibers (29, 30). Efficacy of erenumab in BoNTA non-responders indicates that the mechanisms of action do not fully overlap. One possible explanation is the abundance of erenumab in the entire circulation, while BoNTA has rather a local effect on CGRP release at the injection site (31).\n\nGerman treatment guidelines recommend efficacy evaluation of BoNTA after three treatment cycles (32). In our analysis, BoNTA non-responders had received more than four BoNTA treatments on average, which seems in contrast to the guideline recommendations. The following explanations may apply: patients had negative experience with oral preventatives and experienced some improvement related to pain intensity under BoNTA treatment with no or very few side effects. These patients usually stayed on BoNTA treatment until a switch to mAb treatment was possible. In some patients, the placebo response associated with BoNTA injections may have contributed to an initial treatment success. Placebo effects get lower over time. We know from previous literature that a diminished benefit after long-term treatment is possible, even if rare (33). Because the BoNTA treatment period was not the scope of this analysis, we did not collect headache days during this epoch. In the chart review, we detected higher discontinuation rates from BoNTA treatment due to side effects (11.5%) than in the PREEMPT trials (3.8%) or in real-world analyses (15, 33). Because this analysis focused on patients who failed BoNTA treatment due to safety or tolerability issues, we may have a bias toward patients with poor tolerability.\n\nThe main limitations of our study are the retrospective character and missing data points. Patients are requested to complete headache diaries before treatment initiation and during treatment with mAbs as part of our clinical routine. However, a number of patients fail to provide their calendars regularly, and therefore, data is lacking. As a consequence, analyses were limited to a comparison of individual time point vs. baseline using t-tests rather than analysis of variance over all timepoints. Owing to better data quality for headache days rather than migraine days only, we considered MHD as a primary endpoint and calculated response rates on the basis of MHD. Based on our clinical experience, in this cohort of patients with CM and without any other headache disorder, headache days mostly correspond to migraine days, and the decrease in MHD closely resembles the decrease in MMD. Analysis of response included only patients with complete data for MHD. Patients with missing data for any reasons, including previous treatment discontinuation, were excluded. Moreover, patients with a good treatment response may be inclined to fill their headache diary in a more accurate way. This might have caused a selection bias toward overrepresentation of patients with higher response rates.\n\nIn conclusion, this real-world analysis of erenumab complements clinical trial results and suggests that erenumab shows good efficacy and tolerability even in patients who failed all first-line prophylactic treatments plus BoNTA. Our analysis indicates efficacy of erenumab in a patient population for which no data from randomized placebo controlled trials exist.\n\nData Availability Statement\nThe datasets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\n\nAuthor Contributions\nBR and UR: study concept and design, drafting of the manuscript. BR, RK, AG, and UR: acquisition and collection of data, data analysis, and interpretation. JM, LO, LN, and AG: critical revision of the manuscript for important intellectual content. All authors: approval of the final version of the manuscript.\n\nConflict of Interest\nBR has received research funding and honoraria from Novartis Pharma, TEVA, Hormosan, and Pharm Allergan. RK declares no conflict of interest. JM has received honoraria from Novartis Pharma. LO declares no conflict of interest. LN has received honoraria from Novartis Pharma, Eli Lilly, Pharm Allergan, Desitin, Hormosan, and TEVA. AG has received honoraria from Novartis Pharma, Pharm Allergan, Desitin, Autonomic Technologies, Medtronic, Grnenthal, Mundipharma, MSD, TEVA, Hormosan, und Reckitt Benckiser. UR has received honoraria from Novartis Pharma, Amgen, Pharm Allergan, Autonomic Technologies, Co-Lucid, Eli Lilly, Medscape, StreaMedUp, and TEVA. BR, JM, LN, AG, and UR are also involved as investigators in clinical trials with monoclonal antibodies from Amgen, Alder, Eli Lilly, Novartis, and TEVA without personal remuneration.\n\nFunding. The research was supported by a personal grant of Novartis Pharma GmbH (project nr. MAMG334A_FVUST001).\n==== Refs\nReferences\n1. Hepp Z Dodick DW Varon SF Chia J Matthew N Gillard P . Persistence and switching patterns of oral migraine prophylactic medications among patients with chronic migraine: a retrospective claims analysis\n. Cephalalgia . (2017 ) 37 :470 –85\n. 10.1177/0333102416678382 27837173 \n2. Hepp Z Dodick DW Varon SF Gillard P Hansen RN Devine EB . Adherence to oral migraine-preventive medications among patients with chronic migraine\n. Cephalalgia . (2014 ) 35 :478 –88\n. 10.1177/0333102414547138 25164920 \n3. Agostoni EC Barbanti P Calabresi P Colombo B Cortelli P Frediani F . Current and emerging evidence-based treatment options in chronic migraine: a narrative review\n. J Headache Pain . (2019 ) 20 :92 . 10.1186/s10194-019-1038-4 31470791 \n4. Martelletti P . Erenumab is effective in reducing migraine frequency and improving physical functioning\n. BMJ Evidence-Based Med . (2019 ) 24 :76 . 10.1136/bmjebm-2018-110937 30108057 \n5. Giamberardino MA Affaitati G Costantini R Cipollone F Martelletti P . Calcitonin gene-related peptide receptor as a novel target for the management of people with episodic migraine: current evidence and safety profile of erenumab\n. J Pain Res . (2017 ) 10 :2751 –60\n. 10.2147/JPR.S128143 29263689 \n6. Negro A Martelletti P . Patient selection for migraine preventive treatment with anti-CGRP(r) monoclonal antibodies\n. Exp Rev Neurotherapeut . (2019 ) 19 :769 –76\n. 10.1080/14737175.2019.1621749 31109209 \n7. Raffaelli B Mussetto V Israel H Neeb L Reuter U . Erenumab and galcanezumab in chronic migraine prevention: effects after treatment termination\n. J Headache Pain . (2019 ) 20 :66 . 10.1186/s10194-019-1018-8 31159727 \n8. Schwedt T Reuter U Tepper S Ashina M Kudrow D Broessner G . Early onset of efficacy with erenumab in patients with episodic and chronic migraine\n. J Headache Pain . (2018 ) 19 :92 . 10.1186/s10194-018-0923-6 30276500 \n9. European Medicines Agencies (EMA) \nAimovig–INN Erenumab. Summary of Product Characteristics . Available online at: https://www.ema.europa.eu/en/documents/product-information/aimovig-epar-product-information_en.pdf on (accessed February 17, 2020).\n10. Tepper S Ashina M Reuter U Brandes JL DoleŽil D Silberstein S . Safety and efficacy of erenumab for preventive treatment of chronic migraine: a randomised, double-blind, placebo-controlled phase 2 trial\n. Lancet Neurol . (2017 ) 16 :425 –34\n. 10.1016/S1474-4422(17)30083-2 28460892 \n11. Ashina M Tepper S Brandes JL Reuter U Boudreau G Dolezil D . Efficacy and safety of erenumab (AMG334) in chronic migraine patients with prior preventive treatment failure: a subgroup analysis of a randomized, double-blind, placebo-controlled study\n. Cephalalgia . (2018 ) 38 :1611 –21\n. 10.1177/0333102418788347 29984601 \n12. Sacco S Bendtsen L Ashina M Reuter U Terwindt G Mitsikostas DD . European headache federation guideline on the use of monoclonal antibodies acting on the calcitonin gene related peptide or its receptor for migraine prevention\n. J Headache Pain . (2019 ) 20 :6 . 10.1186/s10194-018-0955-y 30651064 \n13. American Headache Society \nThe American Headache Society position statement on integrating new migraine treatments into clinical practice\n. Headache . (2019 ) 59 :1 –18\n. 10.1111/head.13496 \n14. Gemeinsamer Bundesausschuss \nErenumab: Resolution and Justification . Available online at: https://www.g-ba.de/bewertungsverfahren/nutzenbewertung/411/#english (accessed February 17, 2020).\n15. Dodick DW Turkel CC DeGryse RE Aurora SK Silberstein SD Lipton RB . OnabotulinumtoxinA for treatment of chronic migraine: pooled results from the double-blind, randomized, placebo-controlled phases of the PREEMPT clinical program\n. Headache . (2010 ) 50 :921 –36\n. 10.1111/j.1526-4610.2010.01678.x 20487038 \n16. Ailani J Pearlman E Zhang Q Nagy AJ Schuh K Aurora SK . Positive response to Galcanezumab following treatment failure to OnabotulinumtoxinA in patients with migraine: post-hoc analyses of 3 randomized double-blind studies\n. Eur J Neurol . (2020 ) 27 :542 –9\n. 10.1111/ene.14102 31595600 \n17. Headache Classification Committee of the International Headache Society (IHS) \nThe International Classification of Headache Disorders\n. 3rd ed \nCephalalgia. \n38 :1 –211\n. 10.1177/0333102417738202 \n18. Diener HC Gaul C Kropp P \nTherapie der Migräneattacke und Prophylaxe der Migräne, S1-Leitlinie, 2018\n. in: Deutsche Gesellschaft für Neurologie (Hrsg.), Leitlinien für Diagnostik und Therapie in der Neurologie . Available online at: https://www.dgn.org/leitlinien (accessed February 17, 2020).\n19. Silberstein S Tfelt-Hansen P Dodick DW Limmroth V Lipton RB Pascual J . Guidelines for controlled trials of prophylactic treatment of chronic migraine in adults\n. Cephalalgia . (2008 ) 28 :484 –95\n. 10.1111/j.1468-2982.2008.01555.x 18294250 \n20. Reuter U Goadsby PJ Lanteri-Minet M Wen S Hours-Zesiger P Ferrari MD . Efficacy and tolerability of erenumab in patients with episodic migraine in whom two-to-four previous preventive treatments were unsuccessful: a randomised, double-blind, placebo-controlled, phase 3b study\n. Lancet . (2018 ) 392 :2280 –7\n. 10.1016/S0140-6736(18)32534-0 30360965 \n21. Ferrari MD Diener HC Ning X Galic M Cohen JM Yang R . Fremanezumab versus placebo for migraine prevention in patients with documented failure to up to four migraine preventive medication classes (FOCUS): a randomised, double-blind, placebo-controlled, phase 3b trial\n. Lancet . (2019 ) 394 :1030 –40\n. 10.1016/S0140-6736(19)31946-4 31427046 \n22. Ornello R Tiseo C Frattale I Perrotta G Marini C Pistoia F . The appropriate dosing of erenumab for migraine prevention after multiple preventive treatment failures: a critical appraisal\n. J Headache Pain . (2019 ) 20 :99 . 10.1186/s10194-019-1054-4 31666008 \n23. Goadsby PJ Reuter U Hallström Y Broessner G Bonner JH Zhang F . A controlled trial of Erenumab for episodic migraine\n. N Engl J Med . (2017 ) 377 :2123 –32\n. 10.1056/NEJMoa1705848 29171821 \n24. Tepper SJ Ashina M Reuter U Brandes JL DoleŽil D Silberstein SD . Long-term safety and efficacy of erenumab in patients with chronic migraine: results from a 52-week, open-label extension study\n. Cephalalgia . (2020 ) 40 :543 –53\n. 10.1177/0333102420912726 32216456 \n25. Barbanti P Aurilia C Egeo G Fofi L . Erenumab: from scientific evidence to clinical practice-the first Italian real-life data\n. Neurol Sci . (2019 ) 40 :177 –9\n. 10.1007/s10072-019-03839-x 30927136 \n26. Cheng S Jenkins B Hutton E \n074 Early australian experience with erenumab for chronic migraine\n. J Neurol Neurosurgery Psychiatry. (2019 ) 90 :A23 \n10.1136/jnnp-2019-anzan.62 \n27. Ornello R Casalena A Frattale I Gabriele A Affaitati G Giamberardino MA . Real-life data on the efficacy and safety of erenumab in the Abruzzo region, central Italy\n. J Headache Pain . (2020 ) 32 :9 . 10.1186/s10194-020-01102-9 32264820 \n28. Christensen CE Younis S Deen M Khan S Ghanizada H Ashina M . Migraine induction with calcitonin gene-related peptide in patients from erenumab trials\n. J Headache Pain . (2018 ) 19 :105 . 10.1186/s10194-018-0927-2 30409109 \n29. Aoki KR . Review of a proposed mechanism for the antinociceptive action of botulinum toxin type A\n. NeuroToxicology . (2005 ) 26 :785 –93\n. 10.1016/j.neuro.2005.01.017 16002144 \n30. Domínguez C Vieites-Prado A Pérez-Mato M Sobrino T Rodríguez-Osorio X López A . CGRP and PTX3 as predictors of efficacy of Onabotulinumtoxin type A in chronic migraine: an observational study\n. Headache . (2018 ) 58 :78 –87\n. 10.1111/head.13211 29131327 \n31. Durham PL Cady R . Insights into the mechanism of onabotulinumtoxinA in chronic migraine\n. Headache . (2011 ) 51 :1573 –77\n. 10.1111/j.1526-4610.2011.02022.x 22082429 \n32. Ruscheweyh R Förderreuther S Gaul C Gendolla A Holle-Lee D Jürgens T . Treatment of chronic migraine with botulinum neurotoxin A. Expert recommendations of the German Migraine and Headache Society\n. Der Nervenarzt . (2018 ) 89 :1355 –64\n. 10.1007/s00115-018-0534-0 29947936 \n33. Guerzoni S Pellesi L Baraldi C Cainazzo MM Negro A Martelletti P . Long-term treatment benefits and prolonged efficacy of OnabotulinumtoxinA in patients affected by chronic migraine and medication overuse headache over 3 years of therapy\n. Front Neurol . (2017 ) 8 :586 . 10.3389/fneur.2017.00586 \n29163347\n\n",
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"journal": "Frontiers in neurology",
"keywords": "calcitonin gene-related peptide; chronic migraine; erenumab; onabotulinumtoxinA; prevention",
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"title": "Erenumab in Chronic Migraine Patients Who Previously Failed Five First-Line Oral Prophylactics and OnabotulinumtoxinA: A Dual-Center Retrospective Observational Study.",
"title_normalized": "erenumab in chronic migraine patients who previously failed five first line oral prophylactics and onabotulinumtoxina a dual center retrospective observational study"
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"abstract": "Background. Biologic therapy to inhibit tumor necrosis factor-alpha (TNF- α ) is an effective, safe treatment for patients with inflammatory bowel disease (IBD). All TNF- α inhibitors have been associated with liver toxicity, but many of these cases have been reported in patients receiving therapy for rheumatologic disease. Herein we report the first single-center case series of TNF- α antagonist related liver injury in patients with IBD. Methods. A retrospective case series was performed at the Henry Ford Inflammatory Bowel Diseases Center. IRB approval was obtained. Results. 2 patients were treated with infliximab, whereas the 3rd patient was treated with adalimumab for IBD. All 3 patients had negative viral markers, normal autoimmune serologies, and normal biliary imaging studies. Liver biopsy was performed in all 3 patients, and evidence of portal inflammation was seen. Liver enzymes normalized after discontinuation of therapy in all patients, and no long term effects have been observed. One patient was successfully transitioned from infliximab to adalimumab without relapse of either IBD or liver injury. Conclusion. Liver injury secondary to TNF- α antagonist is an underrecognized, important clinical entity with potentially serious consequences. The mechanism of drug-induced injury is idiosyncratic. Larger cohort studies are needed to establish risk factors and injury patterns related to hepatotoxicity in these patients.",
"affiliations": "Inflammatory Bowel Disease Center, Henry Ford Health System, 39450 West Twelve Mile Roud, Novi, MI 48377, USA.;Inflammatory Bowel Disease Center, Henry Ford Health System, 39450 West Twelve Mile Roud, Novi, MI 48377, USA.",
"authors": "Parekh|Ravish|R|0000-0002-9602-4458;Kaur|Nirmal|N|0000-0002-8243-2071",
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"doi": "10.1155/2014/956463",
"fulltext": "\n==== Front\nCase Rep Gastrointest MedCase Rep Gastrointest MedCRIGMCase Reports in Gastrointestinal Medicine2090-65282090-6536Hindawi Publishing Corporation 10.1155/2014/956463Case ReportLiver Injury Secondary to Anti-TNF-Alpha Therapy in Inflammatory Bowel Disease: A Case Series and Review of the Literature http://orcid.org/0000-0002-9602-4458Parekh Ravish http://orcid.org/0000-0002-8243-2071Kaur Nirmal *Inflammatory Bowel Disease Center, Henry Ford Health System, 39450 West Twelve Mile Roud, Novi, MI 48377, USA*Nirmal Kaur: nkaur1@hfhs.orgAcademic Editors: T. Hirata, H. Kawaratani, M. Neri, and I. Siddique\n\n2014 19 1 2014 2014 95646324 10 2013 10 12 2013 Copyright © 2014 R. Parekh and N. Kaur.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Biologic therapy to inhibit tumor necrosis factor-alpha (TNF-α) is an effective, safe treatment for patients with inflammatory bowel disease (IBD). All TNF-α inhibitors have been associated with liver toxicity, but many of these cases have been reported in patients receiving therapy for rheumatologic disease. Herein we report the first single-center case series of TNF-α antagonist related liver injury in patients with IBD. Methods. A retrospective case series was performed at the Henry Ford Inflammatory Bowel Diseases Center. IRB approval was obtained. Results. 2 patients were treated with infliximab, whereas the 3rd patient was treated with adalimumab for IBD. All 3 patients had negative viral markers, normal autoimmune serologies, and normal biliary imaging studies. Liver biopsy was performed in all 3 patients, and evidence of portal inflammation was seen. Liver enzymes normalized after discontinuation of therapy in all patients, and no long term effects have been observed. One patient was successfully transitioned from infliximab to adalimumab without relapse of either IBD or liver injury. Conclusion. Liver injury secondary to TNF-α antagonist is an underrecognized, important clinical entity with potentially serious consequences. The mechanism of drug-induced injury is idiosyncratic. Larger cohort studies are needed to establish risk factors and injury patterns related to hepatotoxicity in these patients.\n==== Body\n1. Introduction\nBiologic therapy to inhibit tumor necrosis factor-alpha (TNF-α), a proinflammatory cytokine, has become a widely used, safe, and effective treatment for patients with inflammatory bowel disease (IBD) [1]. Since 2008, the number of patients treated with TNF-α antagonists has rapidly increased, and as of 2011 more than 1,500,000 people have been exposed to infliximab therapy [2]. However, the side effect profile of these medications is still being established. TNF-α antagonists have been associated with the reactivation of latent tuberculosis, reactivation of hepatitis B, demyelinating neurologic disease, and congestive heart failure, among other adverse effects [3]. Cases of TNF-α antagonist-induced liver toxicity have been reported, but mainly in patients receiving therapy for rheumatologic disease [4–8]. Little has been reported about anti-TNF-α related hepatotoxicity in patients with IBD [2, 4, 9–12]. Clinician awareness of the adverse effects of commonly used therapies is paramount for safe administration of treatment. Herein we report the first single-center case series of anti-TNF-α related liver injury in patients with IBD.\n\n2. Methods and Materials\nThe Henry Ford Health System Institutional Review Board approved this retrospective case series. All patients were seen at the Henry Ford Health System Inflammatory Bowel Disease Center in Novi, Michigan. Patient charts were reviewed and clinical information was extracted.\n\n3. Ethical Considerations\nSince this study required only chart review and no patient intervention, ethical considerations were minimal. Patient privacy was maintained with de-identification of all study documents.\n\n4. Results\nAll results are listed in Table 1.\n\n4.1. Subject 1\nA 49-year-old female with a 15-year history of ulcerative pancolitis was initially treated with 5-aminosalicylic acid (5-ASA) derivatives, with good control for 12 years. Due to an increase in symptoms as well as moderately severe colitis seen on endoscopy, infliximab was added at 5 milligrams per kilogram (mg/kg) at weeks 0, 2, 6, and then every 8 weeks. After 6 months, due to persistent symptoms as well as persistent endoscopic disease severity, the infliximab dose was escalated to 10 mg/kg every 8 weeks. Prior to infliximab initiation, liver function tests were normal. After 18 months of infliximab therapy, liver enzymes were found to be elevated on routine serologic check: alanine aminotransferase (ALT) elevated to 85; aspartame aminotransferase (AST) was 104, alkaline phosphatase (ALP) elevated to 518, and bilirubin remained normal. The patient remained asymptomatic, with no features of compromised hepatic function, both subjectively and objectively. Autoimmune liver panel, including antinuclear antibody (ANA), antismooth muscle antibody (ASMA), and anti-liver-kidney-mitochondrial antibody (anti-LKM), was negative. Serologic markers for Hepatitis A, B, and C were also negative, including Hepatitis A Immunoglobulin M (IgM), Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (cAb) IgM, Hepatitis C antibody (HCV Ab), and Hepatitis C RNA (HCV RNA). The patient underwent magnetic resonance cholangiopancreatography (MRCP), which showed no evidence of primary sclerosing cholangitis. She ultimately underwent a liver biopsy, which showed minimal chronic portal inflammation with lack of any autoimmune features or fibrosis. After three months of persistent liver enzyme abnormalities, infliximab was discontinued. Twenty weeks after discontinuation of infliximab, ALT normalized to 21 and AST trended down to 37 and ALP to 142. Despite our discussion of adalimumab therapy or colectomy, the patient elected to avoid all medication except oral mesalamine. She has remained minimally symptomatic, with minimal mucosal activity on follow-up colonoscopy at 6 months.\n\n4.2. Subject 2\nA 34-year-old female with a 9-year history of mild ulcerative pancolitis developed worsening disease both symptomatically as well as endoscopically. Therapy with infliximab 5 mg/kg, at standard induction dosing and maintenance every 8 weeks, was prescribed, with good symptomatic response. Prior to initiation of infliximab, liver enzymes were within the normal range. After 2 infusions, liver enzymes elevated: ALT was 173 and AST was 160. Following the 3rd infusion at week 6, the patient's liver enzymes elevated even further: ALT was 300 and AST was 259. Autoimmune serologies including ANA, ASMA, and anti-LKM antibody and viral hepatitis panel including hepatitis A IgM, HBsAg, HBcAb IgM, HCV Ab, and HCV RNA were all negative. Alpha-1-antitrypsin levels were also normal. MRCP was unrevealing. Liver biopsy demonstrated chronic periportal inflammation with presence of eosinophils and focal stage 1 fibrosis. No autoimmune features were seen. Given the extent and persistence of enzyme elevation, infliximab was discontinued after 3 infusions. Liver enzymes improved after discontinuation of infliximab. The patient was started on adalimumab therapy after 8 weeks of discontinuation of infliximab. Liver enzymes continued to improve even after discontinuation of infliximab and subsequent initiation of adalimumab. After 6 months of treatment with adalimumab, with concomitant ASA therapy, this patient has continued to be in clinical and endoscopic remission, with liver enzymes being in the normal range.\n\n4.3. Subject 3\nA 19-year-old female with a 7-year history of severe, fistulizing, ileocolonic, and perianal Crohn's disease was initially treated with ASA, azathioprine, and infliximab. Her disease was refractory to medical management and she underwent total colectomy and permanent end-ileostomy. Given the patient's young age of disease onset and severity of disease, therapy with adalimumab at standard induction dosing (160 mg at week 0, 80 mg at week 2, and 40 mg every other week thereafter) was initiated three months postoperatively to prevent postoperative recurrence of Crohn's disease [13]. Liver enzymes prior to initiation of adalimumab were normal. Four weeks after drug initiation, the patient was hospitalized with complaints of nausea, abdominal pain, and diarrhea. She was found to have elevated liver enzymes, with ALT 184 and AST 167 (Figure 1). Viral hepatitis panel including Hepatitis A Ab IgM, HBsAg, HBcAb IgM, HCV Ab, and HCV RNA was negative. Autoimmune workup with ANA, ASMA, AMA, and Anti LKM Ab was negative as well. MRCP showed an unremarkable biliary system. The patient underwent liver biopsy, which showed lobular and chronic portal inflammation with microgranulomas. The infiltrate included lymphocytes and plasma cells with rare eosinophils and neutrophils. Also, histologically, occasional lymphocytic infiltrates of the bile duct epithelium were seen, focally resembling a florid ductal lesion (Figures 2 and 3). Given the temporal relationship of liver injury to the initiation of adalimumab, as well as the degree of symptomatic involvement, adalimumab therapy was discontinued. After six weeks of drug discontinuation, liver enzymes normalized (Figure 1). This patient has not initiated any further therapy. At 6 months of follow-up, her disease has remained quiescent symptomatically. A discussion regarding azathioprine initiation with close liver monitoring is planned for her follow-up visit.\n\n5. Discussion\nOur study reports the largest, single-center case series of anti-TNF-α drug-induced liver injury in patients with IBD. A recent case series by Ghabril and colleagues [2] reported 6 cases of anti-TNF-α drug-induced liver injury from United States Drug Induced Liver Injury Network database, over 8 years, between 2003 and 2011. Our experience of three such cases, seen in one region, over the course of one year, suggests that the incidence of this adverse effect may be more prevalent than is currently recognized. Furthermore, because biologic agents have been utilized for rheumatologic conditions with much more frequency than that of IBD, much of the safety data pertaining to biologic therapy is published in the rheumatology literature. Clinician awareness of this adverse effect is likely lower amongst gastroenterologists.\n\nLiver injury secondary to TNF-α antagonist can present with either a hepatocellular pattern or an autoimmune pattern. Several reported cases of TNF-α antagonist related liver injury describe a predominantly hepatocellular pattern [2, 4, 5, 10, 14, 15]. Autoimmune injury with positive autoantibodies, including ANA, ASMA, and Anti-LKM antibody, along with classic histologic features of autoimmune hepatitis such as interface hepatitis, lymphoplasmacytic infiltrate, and bridging fibrosis has been reported as well [7–9, 12, 16–19]. In the case series reported by Ghabril and colleagues, patients with autoimmune features experienced longer latency times and higher peak ALT levels compared to those lacking autoimmune features [2]. Cholestatic hepatitis secondary to anti-TNF-α agents has been reported [2, 6, 10, 20] and in one case report, hepatic necrosis resulted in fulminant liver failure requiring urgent liver transplantation [11]. There has also been a case report of hepatocellular carcinoma in a patient treated with a TNF-α antagonist in combination with azathioprine [21]. In our series, all three patients experienced hepatocellular injury both biochemically as well as histologically, with negative autoimmune serologies. Our patients did exhibit microscopic features of hepatitis, without interface hepatitis or lymphoplasmacytic infiltration. This pattern of injury is more consistent with drug-induced injury rather than acute autoimmune hepatitis, as evidenced by histology as well as resolution after discontinuation of the offending agent. The hepatitis was not fatal and no serious injury was reported.\n\nWe initially postulated that the variation in injury pattern could be secondary to variables such as concomitant medications or dosage of medications. However, review of our cases and the existing literature showed no such relationship. Dosage of TNF-α antagonists did not correlate with liver injury in our case series. Amongst our patients, Subject 1 received therapy with high dose infliximab (10 mg/kg every 8 weeks) when hepatotoxicity was documented. However, Subjects 2 and 3 received standard doses of infliximab (5 mg/kg every 8 weeks) and standard induction dosing of adalimumab (160 mg at week 0, 80 mg at week 2, and 40 mg every other week thereafter), respectively, when liver injury was noticed. Review of previously reported cases revealed that the onset of hepatitis has been noticed with single administration of infliximab in one case [10], but after prolonged administration of the medication in other cases.\n\nLatency time to the development of liver toxicity was also variable. In our case series, Subject 1 developed liver toxicity after 18 months of infliximab, whereas toxicity developed within 3 months in Subjects 2 and 3. Hepatotoxicity was not related to any particular TNF-α antagonist, and patient age also varied among our three patients. The variability of histology, dosage, time to toxicity, and presence of concomitant medications, in our patients as well as in review of published cases, highlights the idiosyncratic nature of this drug-induced liver injury. As clinician awareness of this entity increases, and more cases are detected, hopefully distinct patterns of injury will be delineated so that early detection can take place and fulminant liver failure can be prevented [17, 22, 23].\n\nThe lack of cross-reactivity between the TNF-α-antagonist-related liver injury, as seen in multiple case reports [2, 4, 14, 15, 18, 19, 24, 25], is likely due to the difference in molecular structure of these agents. Since infliximab is a chimeric IgG1 monoclonal antibody and adalimumab is a fully humanized IgG1 monoclonal antibody and etanercept is a fusion of recombinant soluble TNF-a receptor type 2 with an Fc domain of human IgG1, antibody formation and immune-mediated reactions are more likely to develop against infliximab rather than the latter two molecules. This phenomenon is supported by the above-referenced case studies, in which patients with infliximab-induced hepatitis have successfully transitioned to therapy with etanercept and adalimumab. In our case series, Subject 2 experienced infliximab-induced hepatocellular injury, which resolved after discontinuation of the drug. Therapy was successfully transitioned to adalimumab with no evidence of hepatocellular injury on follow-up laboratory testing, and the patient's disease remained in clinical and endoscopic remission. Thus, in the setting of infliximab-related liver injury, transitioning to an alternate TNF-α antagonist is a reasonable therapeutic strategy.\n\nOne clear limitation of our study is the lack of formal causality assessments. However, given the thorough clinical evaluation pursued in each of the three patients, the strong temporal relationship between the drug and liver injury, the lack of other causal factors such as acetaminophen, alcohol, nonalcoholic fatty liver disease, or metabolic syndrome, and, most importantly, the resolution of injury after discontinuation of the offending agent, the authors determined that suspicion for drug-induced injury was sufficient. A second limitation of the study is the small number of patients. However, given the retrospective, observational nature of this study, we believe that our case series is indicative of a larger, underrecognized clinical entity.\n\nIn conclusion, TNF-α antagonist-related liver injury is an underrecognized, important clinical entity with potentially serious consequences, such as liver failure. The mechanism of drug-induced injury can be either hepatocellular or autoimmune, and injury can occur irrespective of dose, number of infusions or injections, or time. Given the increasing utilization of TNF-α antagonists, many more patients will be at risk for hepatotoxicity in the future. Larger cohort studies are needed to establish the risk factors and injury patterns related to hepatotoxicity in these patients. Currently, most IBD clinics do not utilize protocols to monitor liver function in patients receiving therapy with TNF-α antagonists, but perhaps this practice should be considered.\n\nDisclosure\nDr. Kaur has received honoraria from UCB Pharmaceuticals and previously served on the speaker's bureau for AbbVie Pharmaceuticals. Dr. Parekh has no relationships to disclose.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Graphic summary of biochemical liver injury with administration of adalimumab in Subject 3. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP).\n\nFigure 2 Liver biopsy showing portal inflammation in Subject 3 (hematoxylin and eosin stain, magnification ×200).\n\nFigure 3 Liver biopsy showing lymphocytic and plasma cell infiltrate in Subject 3 (hematoxylin and eosin stain, magnification ×400).\n\nTable 1 Patient\tPatient 1\tPatient 2\tPatient 3\t\nAge\t49\t34\t19\t\n\n\n\t\nSex\tFemale\tFemale\tFemale\t\n\n\n\t\nDisease\tUC\tUC\tCrohn's\t\n\n\n\t\nConcomitant drugs\tMesalamine, synthroid\tMesalamine, synthroid, sertraline\tNone\t\n\n\n\t\nTNF-α-antagonist\tInfliximab\tInfliximab\tAdalimumab\t\n\n\n\t\nTime to liver toxicity\t18 months\t3 months\t1 month\t\n\n\n\t\nPeak ALT\t104\t300\t184\t\n\n\n\t\nPeak AST\t85\t259\t167\t\n\n\n\t\nTotal bilirubin\t0.4\t0.4\t1.7\t\n\n\n\t\nDirect bilirubin\t0.1\t0.1\t1\t\n\n\n\t\nPeak ALP\t518\t77\t527\t\n\n\n\t\nAlbumin\t3.3\t4\t3.2\t\n\n\n\t\nINR\t1.07\t0.98\t1.14\t\n\n\n\t\nANA\tNegative\tNegative\tNegative\t\n\n\n\t\nAnti-LKM\tNegative\tNegative\tNegative\t\n\n\n\t\nASMA\tN/A\tNegative\tNegative\t\n\n\n\t\nHep A IgM\tNegative\tNegative\tNegative\t\n\n\n\t\nHep B sAg\tNegative\tNegative\tNegative\t\n\n\n\t\nHep B core IgM\tNegative\tNegative\tNegative\t\n\n\n\t\nHep C Ab\tNegative \tNegative \tNegative\t\n\n\n\t\nMRCP\tNormal biliary system\tNormal biliary system\tNormal biliary system\t\n\n\n\t\nLiver Biopsy\tChronic portal inflammation\tChronic portal inflammation\tLobular and chronic portal inflammation with microgranulomas\t\n\n\n\t\nOutcome\tInfliximab discontinued. Liver recovery in 8 weeks.\nIn clinical and endoscopic remission on ASA monotherapy\tSwitched to Adalimumab. \nLiver recovery in 8 weeks.\nIn clinical and endoscopic remission\tAdalimumab discontinued. Liver recovery in 6 weeks. \nIn clinical remission on no therapy\t\nUlcerative colitis (UC), Crohn's disease (CD), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), international normalized ratio (INR), antinuclear antibody (ANA), antismooth muscle antibody (ASMA), antiliver-kidney-mitochondrial antibody (anti-LKM), Hepatitis A immunoglobulin M (IgM), Hepatitis B surface antigen (HBsAg), Hepatitis B core antibody (cAb) IgM, Hepatitis C antibody (HCV Ab), and magnetic resonance cholangiopancreatography (MRCP).\n==== Refs\n1 Ford AC Sandborn WJ Khan KJ Hanauer SB Talley NJ Moayyedi P Efficacy of biological therapies in inflammatory bowel disease: systematic review and meta-analysis American Journal of Gastroenterology 2011 106 4 644 659 2-s2.0-79953801792 21407183 \n2 Ghabril M Bonkovsky HL Kum C Liver injury from tumor necrosis factor-alpha antagonists: analysis of thirty-four cases Clinical Gastroenterology and Hepatology 2013 11 5 558.e3 564.e3 23333219 \n3 Nielsen OH Ainsworth MA Tumor necrosis factor inhibitors for inflammatory bowel disease The New England Journal of Medicine 2013 369 8 754 762 23964937 \n4 Mancini S Amorotti E Vecchio S de Leon MP Roncucci L Infliximab-related hepatitis: discussion of a case and review of the literature Internal and Emergency Medicine 2010 5 3 193 200 2-s2.0-77953542643 20107930 \n5 Tobon GJ Cañas C Jaller J-J Restrepo J-C Anaya J-M Serious liver disease induced by infliximab Clinical Rheumatology 2007 26 4 578 581 2-s2.0-33847686821 16547695 \n6 Menghini VV Arora AS Infliximab-associated reversible cholestatic liver disease Mayo Clinic Proceedings 2001 76 1 84 86 2-s2.0-0035160406 11155419 \n7 Germano V Diamanti AP Baccano G Autoimmune hepatitis associated with infliximab in a patient with psoriatic arthritis Annals of the Rheumatic Diseases 2005 64 10 1519 1520 2-s2.0-27744471913 16162908 \n8 Ozorio G McGarity B Bak H Jordan AA Lau H Marshall C Autoimmune hepatitis following infliximab therapy for ankylosing spondylitis Medical Journal of Australia 2007 187 9 524 526 2-s2.0-38449123106 17979620 \n9 Doyle A Forbes G Kontorinis N Autoimmune hepatitis during infliximab therapy for Crohn’s disease: a case report Journal of Crohn’s and Colitis 2011 5 3 253 255 2-s2.0-79955980376 \n10 Ierardi E Della Valle N Nacchiero MC De Francesco V Stoppino G Panella C Onset of liver damage after a single administration of infliximab in a patient with refractory ulcerative colitis Clinical Drug Investigation 2006 26 11 673 676 2-s2.0-33750325782 17163303 \n11 Kinnunen U Färkkilä M Mäkisalo H A case report: ulcerative colitis, treatment with an antibody against tumor necrosis factor (infliximab), and subsequent liver necrosis Journal of Crohn’s and Colitis 2012 6 6 724 727 2-s2.0-84857467324 \n12 Subramaniam K Chitturi S Brown M Pavli P Infliximab-induced autoimmune hepatitis in Crohn’s disease treated with budesonide and mycophenolate Inflammatory Bowel Diseases 2011 17 11 e149 e150 2-s2.0-80054725710 21987301 \n13 Regueiro M Schraut W Baidoo L Infliximab prevents Crohn’s disease recurrence after ileal resection Gastroenterology 2009 136 2 441.e1 450.e1 2-s2.0-58649121974 19109962 \n14 Carlsen KM Riis L Madsen OR Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept Clinical Rheumatology 2009 28 8 1001 1003 2-s2.0-67849084977 19370307 \n15 Haennig A Bonnet D Thebault S Alric L Infliximab-induced acute hepatitis during Crohn’s disease therapy: absence of cross-toxicity with adalimumab Gastroenterologie Clinique et Biologique 2010 34 8-9 e7 e8 2-s2.0-77957017374 20189334 \n16 Adar T Mizrahi M Pappo O Scheiman-Elazary A Shibolet O Adalimumab-induced autoimmune hepatitis Journal of Clinical Gastroenterology 2010 44 1 e20 e22 2-s2.0-75149157116 19593165 \n17 Coffin CS Fraser HF Panaccione R Ghosh S Liver diseases associated with anti-tumor necrosis factor-alpha (TNF-α ) use for inflammatory bowel disease Inflammatory Bowel Diseases 2011 17 1 479 484 2-s2.0-78650140223 20848520 \n18 Cravo M Silva R Serrano M Autoimmune hepatitis induced by infliximab in a patient with crohn’s disease with no relapse after switching to adalimumab BioDrugs 2010 24 supplement 1 25 27 2-s2.0-78650431965 21175232 \n19 Goldfeld DA Verna EC Lefkowitch J Swaminath A Infliximab-induced autoimmune hepatitis with successful switch to adalimumab in a patient with Crohn’s disease: the index case Digestive Diseases and Sciences 2011 56 11 3386 3388 2-s2.0-82555194138 21597977 \n20 Administration, U.S.F.a.D Remicaide Label and Approval History 2009 \n21 Chen SC Cummings OW Hartley MP Filomena CA Cho WK Hepatocellular carcinoma occurring in a patient with Crohn’s disease treated with both azathioprine and infliximab Digestive Diseases and Sciences 2006 51 5 952 955 2-s2.0-33745862364 16670938 \n22 Davern T Drug Induced Liver Disease, 2007: Informa Healthcare, 2007 \n23 Khokhar OS Lewis JH Hepatotoxicity of agents used in the management of inflammatory bowel disease Digestive Diseases 2010 28 3 508 518 2-s2.0-77957882731 20926880 \n24 García Aparicio AM Rey JR Sanz AH Alvarez JS Successful treatment with etanercept in a patient with hepatotoxicity closely related to infliximab Clinical Rheumatology 2007 26 5 811 813 2-s2.0-34147109887 16550301 \n25 Massarotti M Marasini B Successful treatment with etanercept of a patient with psoriatic arthritis after adalimumab-related hepatotoxicity International Journal of Immunopathology and Pharmacology 2009 22 2 547 549 2-s2.0-67650457678 19505409\n\n",
"fulltext_license": "CC BY",
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"issue": "2014()",
"journal": "Case reports in gastrointestinal medicine",
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"medline_ta": "Case Rep Gastrointest Med",
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"title": "Liver Injury Secondary to Anti-TNF-Alpha Therapy in Inflammatory Bowel Disease: A Case Series and Review of the Literature.",
"title_normalized": "liver injury secondary to anti tnf alpha therapy in inflammatory bowel disease a case series and review of the literature"
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"abstract": "Pathologic complete response rate (pCR), the primary end point of the ACOSOG (American College of Surgeons Oncology Group) Z1041 (Alliance) trial, and disease-free survival (DFS) and overall survival (OS) in women with operable HER2-positive breast cancer are similar between treatment regimens.\n\n\n\nTo assess DFS and OS for patients treated with sequential vs concurrent anthracycline plus trastuzumab.\n\n\n\nPhase 3 randomized clinical trial conducted at 36 centers in the continental United States and Puerto Rico. Women 18 years or older with invasive operable HER2-positive breast cancer were enrolled from September 15, 2007, to December 15, 2011, and randomized to 1 of 2 treatment arms. The analysis data set was locked on October 15, 2017, and analysis was completed on December 15, 2017.\n\n\n\nPatients randomized to arm 1 received 500 mg/m2 of fluorouracil, 75 mg/m2 of epirubicin, and 500 mg/m2 of cyclophosphamide (FEC) every 3 weeks for 12 weeks followed by the combination of 80 mg/m2 of paclitaxel and 2 mg/kg (except initial dose of 4 mg/kg) of trastuzumab weekly for 12 weeks. Patients randomized to arm 2 received the same combination of paclitaxel with trastuzumab weekly for 12 weeks followed by FEC every 3 weeks with weekly trastuzumab for 12 weeks. Women with hormone receptor-positive disease received endocrine therapy, and radiotherapy was delivered at physician discretion.\n\n\n\nThe primary outcomes were DFS and OS and pCR in the breast and nodes.\n\n\n\nTwo hundred eighty-two women with HER2-positive breast cancer were enrolled in the trial, and 2 withdrew consent before treatment. Among the remaining 280 women, the median age was 50 years (range, 28-76 years), 232 (82.9%) were white, 29 (10.3%) were black, 8 (2.9%) were Asian, 4 (1.4%) were American Indian or Alaskan Native, and 7 (2.5%) did not report race/ethnicity. There were 22 disease events in arm 1 and 27 in arm 2. Disease-free survival rates did not differ with respect to treatment arm (stratified log-rank P = .96; stratified hazard ratio [HR] [arm 2 to arm 1], 1.02; 95% CI, 0.56-1.83). Overall survival did not differ with respect to treatment arm (stratified log-rank P = .73; stratified HR [arm 2 to arm 1], 1.17; 95% CI, 0.48-2.88).\n\n\n\nAcross a median follow-up of 5.1 years (range, 26 days to 6.2 years), pCR, DFS, and OS did not differ with respect to sequential or concurrent administration of FEC with trastuzumab.\n\n\n\nClinicalTrials.gov identifier: NCT00513292.",
"affiliations": "Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.;Department of Health Sciences Research, Alliance Statistics and Data Center, Mayo Clinic, Rochester, Minnesota.;Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston.;Department of Surgery, University of Texas Southwestern Medical Center, Dallas.;Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.;Department of Surgery, Mayo Clinic, Rochester, Minnesota.;Doctor's Hospital of Laredo, Laredo, Texas.;Department of Medical Oncology, University of New Mexico School of Medicine, Albuquerque.;Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.",
"authors": "Buzdar|Aman U|AU|;Suman|Vera J|VJ|;Meric-Bernstam|Funda|F|;Leitch|Ann Marilyn|AM|;Ellis|Matthew J|MJ|;Boughey|Judy C|JC|;Unzeitig|Gary W|GW|;Royce|Melanie E|ME|;Hunt|Kelly K|KK|",
"chemical_list": "D014408:Biomarkers, Tumor; D015251:Epirubicin; D003520:Cyclophosphamide; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; D000068878:Trastuzumab; D017239:Paclitaxel; D005472:Fluorouracil",
"country": "United States",
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"doi": "10.1001/jamaoncol.2018.3691",
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"issue": "5(1)",
"journal": "JAMA oncology",
"keywords": null,
"medline_ta": "JAMA Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D018450:Disease Progression; D004334:Drug Administration Schedule; D015251:Epirubicin; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D017239:Paclitaxel; D000077982:Progression-Free Survival; D011647:Puerto Rico; D018719:Receptor, ErbB-2; D012307:Risk Factors; D013997:Time Factors; D000068878:Trastuzumab; D014481:United States",
"nlm_unique_id": "101652861",
"other_id": null,
"pages": "45-50",
"pmc": null,
"pmid": "30193295",
"pubdate": "2019-01-01",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "16983592;25564897;25130998;20113825;26527775;24529560;21991949;22257523;16199160;15738535;25895646;21061075;26874901;29064904;28398846;11521719;28669449;28453704;28581356;27800032;24239210",
"title": "Disease-Free and Overall Survival Among Patients With Operable HER2-Positive Breast Cancer Treated With Sequential vs Concurrent Chemotherapy: The ACOSOG Z1041 (Alliance) Randomized Clinical Trial.",
"title_normalized": "disease free and overall survival among patients with operable her2 positive breast cancer treated with sequential vs concurrent chemotherapy the acosog z1041 alliance randomized clinical trial"
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"companynumb": "US-PFIZER INC-2020000014",
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"activesubstancename": "EPIRUBICIN HYDROCHLORIDE"
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"abstract": "<strong>BACKGROUND</strong> Nivolumab is a human IgG4 monoclonal antibody against human programmed cell death 1 (PD-1). It has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). Treatment with nivolumab is sometimes associated with immune-related adverse events (ir AEs) in patients. These specific ir AEs include pneumonitis, hypothyroidism, dermatitis, enterocolitis, hepatitis, and neuropathy. However, hematological toxicity is rare. <strong>CASE REPORT</strong> A 57-year-old man with lung adenocarcinoma, with brain and adrenal gland metastases, was therefore started on nivolumab therapy as third-line treatment. After administration of the second dose with nivolumab, grade 3 febrile neutropenia (FN) and grade 2 liver dysfunction developed in the patient. The patient was started to on intravenous antibiotics, granulocyte colony-stimulating factor (G-CSF), and corticosteroids. Neutrophil counts and liver function gradually improved, and corticosteroids were tapered over 6 weeks. However, the patient was re-treated with G-CSF because the neutrophil counts decreased again. <strong>CONCLUSIONS</strong> Care needs to be taken with such patients because neutropenia due to treatment with nivolumab can recur, as well as other ir AEs.",
"affiliations": "Department of Thoracic Medical Oncology, Oita Prefectural Hospital, Oita City, Oita, Japan.;Department of Thoracic Medical Oncology, Oita Prefectural Hospital, Oita City, Oita, Japan.;Department of Respiratory Medicine, Oita Prefectural Hospital, Oita City, Oita, Japan.;Department of Respiratory Medicine, Oita Prefectural Hospital, Oita City, Oita, Japan.;Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Yufu, Oita, Japan.",
"authors": "Hisamatsu|Yasushi|Y|;Morinaga|Ryotaro|R|;Watanabe|Erina|E|;Ohtani|Satoshi|S|;Shirao|Kuniaki|K|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D016179:Granulocyte Colony-Stimulating Factor; D000077594:Nivolumab; D011239:Prednisolone; D008775:Methylprednisolone",
"country": "United States",
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"doi": "10.12659/AJCR.920809",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3201827510.12659/AJCR.920809920809ArticlesFebrile Neutropenia in a Patient with Non-Small Cell Lung Cancer Treated with the Immune-Checkpoint Inhibitor Nivolumab Hisamatsu Yasushi ABCDEF1Morinaga Ryotaro A1Watanabe Erina A2Ohtani Satoshi A2Shirao Kuniaki AF3\n1 Department of Thoracic Medical Oncology, Oita Prefectural Hospital, Oita City, Oita, Japan\n2 Department of Respiratory Medicine, Oita Prefectural Hospital, Oita City, Oita, Japan\n3 Department of Medical Oncology and Hematology, Oita University Faculty of Medicine, Yufu, Oita, JapanCorresponding Author: Yasushi Hisamatsu, e-mail: hisamatu@oita-u.ac.jpAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: Kuniaki Shirao has received honoraria from Taiho Pharmaceutical Co., and Bristol-Myers Squibb Co.\n\nSource of support: Kuniaki Shirao has received research funding from Taiho Pharmaceutical Co., Bristol-Myers Squibb Co., Chugai Pharmaceutical Co., Pfizer, Inc., Ono Pharmaceutical Co., Daiichi Sankyo Co., Sanofi K.K., Kyowa Hakko Kirin Co., Astellas Pharma, Inc., Shionogi & Co., and Takeda Pharmaceutical Co.\n\n2020 04 2 2020 21 e920809-1 e920809-6 18 10 2019 03 12 2019 24 1 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 57-year-old\n\nFinal Diagnosis: Febrile neutropenia\n\nSymptoms: Fever\n\nMedication: Nivolumab\n\nClinical Procedure: Chemotherapy\n\nSpecialty: Oncology\n\nObjective:\nAdverse events of drug therapy\n\nBackground:\nNivolumab is a human IgG4 monoclonal antibody against human programmed cell death 1 (PD-1). It has demonstrated efficacy against metastatic non-small cell lung cancer (NSCLC). Treatment with nivolumab is sometimes associated with immune-related adverse events (ir AEs) in patients. These specific ir AEs include pneumonitis, hypothyroidism, dermatitis, enterocolitis, hepatitis, and neuropathy. However, hematological toxicity is rare.\n\nCase Report:\nA 57-year-old man with lung adenocarcinoma, with brain and adrenal gland metastases, was therefore started on nivolumab therapy as third-line treatment. After administration of the second dose with nivolumab, grade 3 febrile neutropenia (FN) and grade 2 liver dysfunction developed in the patient. The patient was started to on intravenous antibiotics, granulocyte colony-stimulating factor (G-CSF), and corticosteroids. Neutrophil counts and liver function gradually improved, and corticosteroids were tapered over 6 weeks. However, the patient was re-treated with G-CSF because the neutrophil counts decreased again.\n\nConclusions:\nCare needs to be taken with such patients because neutropenia due to treatment with nivolumab can recur, as well as other ir AEs.\n\nMeSH Keywords:\nAgranulocytosisCarcinoma, Non-Small-Cell LungFebrile Neutropenia\n==== Body\nBackground\nProgrammed cell death 1 (PD-1) is a transmembrane protein expressed on T cells, B cells, and NK cells. It is an inhibitory molecule that binds to the PD-1 ligand (PD-L1) and PD-L2. PD-L1 is expressed on the surface of multiple tissue types, including many tumor cells, as well as hematopoietic cells. The PD-1: PD-L1/2 interaction directly inhibits apoptosis of the tumor cell, promotes peripheral T effector cell exhaustion, and promotes conversion of T effector cells to Treg cells [1].\n\nNivolumab is a human IgG4 monoclonal antibody that binds and blocks PD-1 receptors on cancer cell membranes, which results in the release of cancer immune-tolerance. Immune-related adverse events (ir AEs) such as liver damage, dysfunction of internal secretion, enterocolitis, and skin reactions are reported as AEs of nivolumab [2], while hematotoxicity is rare. Here, we present a case of neutropenia showing a biphasic phenomenon in a patient with non-small cell carcinoma due to treatment with nivolumab is presented.\n\nCase Report\nA 57-year-old man was diagnosed with lung adenocarcinoma in February 201X. He had both brain and adrenal gland metastases. Molecular tests showed that the genes for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) were negative. The tumor proportion score was unknown. The patient had a smoking history and pulmonary emphysema.\n\nAfter cyberknife stereotactic radiosurgery for the brain metastasis, the patient received 2 courses each of cisplatin-pemetrexed chemotherapy and docetaxel therapy. The patient was administered docetaxel on May 6. With both treatments, severe myelosuppression and FN did not occur. However, computed tomography (CT) showed disease progression after 2 cycles of docetaxel therapy. The patient was therefore started on nivolumab therapy (3 mg/kg every 2 weeks) as the third-line treatment on June 1. The patient’s absolute neutrophil count (ANC) at that time was normal (6150/μL).\n\nThe first and second doses with nivolumab were well tolerated, and the patient did not complain of any potential AEs. At the time of the third dose with nivolumab, on day 29 after administration of the first dose with nivolumab, Common Terminology Criteria for Adverse Events (CTCAE) grade 1 liver dysfunction and asymptomatic grade 3 neutropenia (920/μL) were detected. Therefore, the treatment was discontinued. Before nivolumab administration, the patient had been taking famotidine from January 201X. Because it is one of the agents that can cause agranulocytosis, it was stopped and switched to rabeprazole.\n\nOn day 32 after the first dose with nivolumab (day 58 after the last dose with docetaxel), the patient developed grade 3 FN, with the following laboratory results: white blood cells (WBC) 1.71 g/L; ANC 980/μL; hemoglobin (Hb) 8.1 g/L; platelets (PLT) 21.2×104/μL; aspartate aminotransferase (AST) 166 IU/L; alanine aminotransferase (ALT) 169 IU/L; and C-reactive protein (CRP) 12.5 mg/L (Table 1). The patient’s temperature was 39.0°C.\n\nBecause it was thought that the neutrophil count was likely to decrease further, the patient was diagnosed with FN. The tumor was significantly reduced, and there was no appreciable source of infection on CT (Figure 1). After blood cultures were taken, the patient was started on intravenous antibiotics.\n\nOn July 7 (day 37), a bone marrow biopsy was performed because the ANC had decreased to 280/μL and Ferritin had increased to 1732 ng/ml. Malignant tumor infiltration to bone marrow was not present. The biopsy specimen showed agranulocytosis (Figure 2) and the bone marrow examination results are shown in Table 2. The mononuclear phagocyte system constitutes approximately 1.0%.\n\nAntineutrophil antibodies that induce neutropenia were not detected in the patient’s serum. On day 32, grade 2 liver dysfunction (ALT 166 IU/L; AST 169 IU/L) was also detected. The patient was started on treatment with granulocyte G-CSF for 4 days for neutropenia and prednisolone 0.5 mg/kg/day for liver dysfunction. With the withdrawal of nivolumab therapy and the administration of G-CSF, the neutrophils increased. However, on July 14 (day 44), methylprednisolone was administered at a dose of 2 mg/kg (125 mg/day) because the liver function test results worsened (ALT 191 IU/L; AST 307 IU/L). Liver function then gradually improved, and corticosteroids were tapered over 6 weeks.\n\nThe patient was re-treated with G-CSF because only the neutrophil counts decreased again (ANC 500/μL) on August 16 (day 77). ANC immediately normalized, and liver dysfunction did not recur (Figure 3). The patient was then diagnosed with widespread disease progression and received palliative treatment.\n\nDiscussion\nThe course of this patient demonstrates 2 important clinical points. FN due to nivolumab was present, along with the recurrence of neutropenia due to nivolumab. Treatment with nivolumab is sometimes associated with ir AEs in patients. These specific ir AEs include pneumonitis, hypothyroidism, dermatitis, enterocolitis, hepatitis, and neuropathy. However, hematological toxicity is rare. A recent study on immune-checkpoint inhibitors (ICIs)-related hematological toxicity reported that anemia and thrombocytopenia are the most common hematological toxicities [3]. The incidence of anemia, thrombocytopenia, and neutropenia was 9.8%, 2.8%, and 0.94%, respectively [4]. The rate of nivolumab-related neutropenia is 0–0.6% in NSCLC [5–7].\n\nAccording to the European Society of Medical Oncology (ESMO) guidelines, FN is defined as an oral temperature >38.5°C or 2 consecutive readings of >38.0°C for 2 h and an ANC <500/μL, or expected to fall below 500/μL. Therefore, the present patient was diagnosed with FN. In 11% of patients with hemato-logical malignancies and 5% of patients with solid tumors, FN results in death due to infectious complications [8].\n\nThere have been 3 reported cases of neutropenia or agranulocytosis with NSCLC treated with nivolumab. Tabchi et al. [9] reported severe agranulocytosis due to nivolumab therapy; the patient’s past medical history included ulcerative colitis and lumpectomy for breast cancer, and she had severe agranulocytosis and liver dysfunction after 2 courses of nivolumab therapy for NSCLC. Turgeman et al. [10] reported 2 cases of neutropenia due to nivolumab therapy; 1 patient had a past history of Crohn’s disease, and after 5 courses of nivolumab therapy, she had neutropenia and diarrhea due to a Crohn’s exacerbation. Another patient had a history of intermediate-grade follicular lymphoma that had been treated with rituximab. He had grade 4 neutropenia. None of these 3 cases was diagnosed with FN.\n\nThere are various causes of neutropenia in cancer patients. It may be associated with the cytotoxic effects of chemotherapy or radiotherapy, systemic infections, some concomitant drugs, and bone marrow metastases.\n\nOn day 15, CRP was elevated (14.1 mg/dl). Neither fever nor malaise was recognized as the symptom of virus infection, and the cause of the clear CRP increase was unknown.\n\nIn this case, the patient had no history of malignancy except for NSCLC and had no autoimmune disease. Bone scintigraphy was not performed, but the bone marrow examination showed no bone marrow infiltration of cancer. Therefore, it was not considered to be the cause of neutropenia. Neutropenia caused by systemic infections before the administration of nivolumab was ruled out. Prior to nivolumab administration, he started famotidine, loxoprofen, oxycodone, and magnesium oxide in January 201X, rabeprazole on June 29, and trimethoprim-sulfamethoxazole at a dose of 1 g on July 14 to November 2 for the prevention of Pneumocystis pneumonia. Except for famotidine, he continued to take the other drugs throughout the entire treatment for FN and hepatitis after the improvement of recurrent neutropenia on day 77. Therefore, the FN was likely caused by nivolumab or famotidine. Certainly, famotidine is one of the agents causing agranulocytosis [11]. However, most cases of severe neutropenia or agranulocytosis present within the first 60 days after beginning the offending drug [12,13]. It is difficult to conclude that the febrile neutropenia in the present case was caused by famotidine; therefore, the neutropenia was probably caused by nivolumab. There are 2 developmental mechanisms of agranulocytosis caused by some concomitant medications [14]. One is an immunologic mechanism that causes the production of the antineutrophil antibody. The other direct mechanism is thought to involve drugs or their metabolites binding to the intranuclear material of granulocytic series progenitor cells and intracytoplasmic protein. The latter mechanism is most likely, because antineutrophil antibodies were not detected in the present case.\n\nAfter G-CSF administration for recurrent neutropenia on August 16 (day 77), liver function had not deteriorated. Therefore, G-CSF was unlikely to be the cause of liver damage. Liver function deteriorated despite administration of prednisolone 0.5 mg/kg/day on July 14 (day 44), but improved after increasing the dose of methylprednisolone to 2 mg/kg (125 mg/day).\n\nDrug-induced neutropenia usually resolves within 1–3 weeks after cessation of the offending drug, whereas the present patient experienced recurrent only neutropenia without liver dysfunction on day 77 and was treated again with G-CSF. There are some reports that pneumonitis associated with ICIs recurred during drug withholding/corticosteroid therapy after initial clinical improvement [15,16]. Similarly, Naqash et al. reported isolated neutropenia associated with PD-1 antibody in a patient who relapsed [17]. Although the detailed mechanisms of this unusual phenomenon remain to be investigated, it may be that durable responses have been CD8+ linked to ICI-induced persistent T effector memory fraction against tumor cells [18]. The possible cross-reactivity of these T cells against normal cells after stopping treatment may be of the plausible mechanisms that have been suggested to contribute to this phenomenon [19]. Although there are reports of neutropenia due to anti-PD-1 antibody administration, it is important to show that neutropenia alone may recur when the patient has different ir AEs.\n\nConclusions\nA case of FN occurring in an NSCLC patient treated with nivolumab was described. One should be careful in such cases because the neutropenia due to nivolumab may recur, as well as other ir AEs.\n\nConflict of interests\n\nKuniaki Shirao has received honoraria from Taiho Pharmaceutical Co., and Bristol-Myers Squibb Co.\n\nFigure 1. CT images. Lung adenocarcinoma is present in the mediastinum from the left upper lobe before nivolumab treatment in May 201X (A). Hospitalization for FN on day 32 after administration of the first dose with nivolumab. The tumor is significantly reduced with no appreciable source of infection on CT (B).\n\nFigure 2. Bone marrow imaging. (A: ×100), (B: ×400). There is no malignant tumor invasion into the bone marrow. The specimen shows agranulocytosis.\n\nFigure 3. Timeline for white blood cell count (WBC), absolute neutrophil count (ANC), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels since nivolumab dosing.\n\nTable 1. Blood test results.\n\n\t5/27 (day −5*)\t6/15 (day 15*)\t6/29 (day 29*)\t7/2 (day 32*)\t7/7 (day 37*)\t7/9 (day 42*)\t\nWBC (/μl)\t8630\t4740\t1640\t1710\t760\t4440\t\nANC (/μl)\t6150\t3590\t920\t980\t280\t3500\t\nHb (g/dl)\t8.9\t8.1\t8.1\t7.2\t8.7\t8.0\t\nPlt (104/μl)\t29.1\t23.1\t21.2\t17.1\t21.3\t16.6\t\nCRP (mg/dl)\t5.3\t14.1\t7.4\t12.5\t6.48\t5.43\t\nAST (U/L)\t9\t14\t67\t166\t208\t178\t\nALT (U/L)\t6\t11\t69\t169\t213\t233\t\n* Days after administration of the first nivolumab dose. WBC – white blood cells; ANC – absolute neutrophil count; Hb – hemoglobin; Plt – platelets; CRP – C-reactive protein; AST – aspartate aminotransferase; ALT – alanine aminotransferase.\n\nTable 2. bone marrow examination.\n\nNCC (/mm3)\t3.3×104\t\nMgK (/mm3)\t47\t\nM/E ratio\t1.57\t\nTotal myeloid (%)\t55.4\t\n Blast\t1.6\t\n Promyelocyte\t6.0\t\n Myelocyte\t20.2\t\n Metamyelocyte\t13.2\t\n Stab cell\t7.8\t\n Seg\t3.8\t\n Eosinophil\t0.2\t\n Basophil\t0.6\t\n Monocyte\t2.0\t\nTotal erythroid (%)\t35.2\t\n Pro-erythroid\t0.2\t\n Mega\t3.6\t\n Macro\t0\t\n Normal\t31.4\t\nLymphocytes (%)\t4.8\t\nPlasma cell (%)\t3.6\t\nPhagocytes (%)\t1.0\t\nTumor cell invasion\t–\t\nNCC – nucleated cell; MgK – megakaryocyte; M/E ratio – myeloid erythroid ratio.\n==== Refs\nReferences:\n1. Francisco LM Salinas VH Brown KE PD-L1 regulates the development, maintenance, and function of induced regulatory T cells J Exp Med 2009 206 3015 29 20008522 \n2. Pennock GK Chow LQ The evolving role of immune checkpoint inhibitors in cancer treatment Oncologist 2015 20 812 22 26069281 \n3. Davis EJ Salem JE Young A Hematologic complications of immune checkpoint inhibitors Oncologist 2019 24 584 88 30819785 \n4. Petrelli F Ardito R Borgonovo K Haematological toxicities with immunotherapy in patients with cancer: A systematic review and meta-analysis Eur J Cancer 2018 103 7 16 30196108 \n5. Borghaei H Paz-Ares L Horn L Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer N Engl J Med 2015 373 1627 39 26412456 \n6. Brahmer J Reckamp KL Baas P Nivolumab versus docetaxel in advanced squamous-cell non-small-cell lung cancer N Engl J Med 2015 373 123 35 26028407 \n7. Carbone DP Reck M Paz-Ares L First-line nivolumab in Stage IV or recurrent non-small-cell lung cancer N Engl J Med 2017 376 2415 26 28636851 \n8. de Naurois J Novitzky-Basso I Gill MJ Management of febrile neutropenia: ESMO Clinical Practice Guidelines Ann Oncol 2010 21 Suppl, 5 v252 56 20555092 \n9. Tabchi S Weng X Blais NL Severe agranulocytosis in a patient with metastatic non-small-cell lung cancer treated with nivolumab Lung Cancer 2016 99 123 26 27565926 \n10. Turgeman I Wollner M Hassoun G Severe complicated neutropenia in two patients with metastatic non-small-cell lung cancer treated with nivolumab Anticancer Drugs 2017 28 811 14 28574922 \n11. Aymard JP Aymard B Netter P Haematological adverse effects of histamine H2-receptor antagonists Med Toxicol Adverse Drug Exp 1988 3 430 48 2905759 \n12. Andersohn F Konzen C Garbe E Systematic review: Agranulocytosis induced by nonchemotherapy drugs Ann Int Med 2007 146 657 65 17470834 \n13. Pontikoglou C Papadaki HA Idiosyncratic drug-induced agranulocytosis: The paradigm of deferiprone Hemoglobin 2010 34 291 304 20524819 \n14. Tesfa D Keisu M Palmblad J Idiosyncratic drug-induced agranulocytosis: Possible mechanisms and management Am J Hematol 2009 84 428 34 19459150 \n15. Naidoo J Wang X Woo KM Pneumonitis in patients treated with anti-programmed death-1/programmed death ligand 1 therapy J Clin Oncol 2017 35 709 17 27646942 \n16. Tanaka R Fujisawa Y Sae I Severe hepatitis arising from ipilimumab administration, following melanoma treatment with nivolumab Jpn J Clin Oncol 2017 47 175 78 28173241 \n17. Naqash AR Appah E Yang LV Isolated neutropenia as a rare but serious adverse event secondary to immune checkpoint inhibition J Immunother Cancer 2019 7 169 31277704 \n18. Ribas A Shin DS Zaretsky J PD-1 blockade expands intratumoral memory T cells Cancer Immunol Res 2016 4 194 203 26787823 \n19. Young A Quandt Z Bluestone JA The balancing act between cancer immunity and autoimmunity in response to immunotherapy Cancer Immunol Res 2018 6 1445 52 30510057\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000310:Adrenal Gland Neoplasms; D000074322:Antineoplastic Agents, Immunological; D001932:Brain Neoplasms; D002289:Carcinoma, Non-Small-Cell Lung; D064147:Febrile Neutropenia; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008107:Liver Diseases; D008175:Lung Neoplasms; D008297:Male; D008775:Methylprednisolone; D008875:Middle Aged; D000077594:Nivolumab; D011239:Prednisolone",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e920809",
"pmc": null,
"pmid": "32018275",
"pubdate": "2020-02-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "30819785;27565926;30196108;20524819;17470834;26412456;20555092;28173241;26069281;28574922;2905759;31277704;26787823;26028407;30510057;19459150;27646942;20008522;28636851",
"title": "Febrile Neutropenia in a Patient with Non-Small Cell Lung Cancer Treated with the Immune-Checkpoint Inhibitor Nivolumab.",
"title_normalized": "febrile neutropenia in a patient with non small cell lung cancer treated with the immune checkpoint inhibitor nivolumab"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-247394",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"druga... |
{
"abstract": "MEK inhibitors are an emerging therapy with increasing use in mitogen-activated protein kinase-driven central nervous system (CNS) tumors. There is limited data regarding efficacy and toxicity in pediatric patients. We report our clinical experience with trametinib-based therapy for the treatment of 14 consecutive pediatric patients with recurrent low-grade glioma (N=11) or high-grade CNS tumors (N=3) with MAP kinase pathway mutations. Patients received trametinib as monotherapy (N=9) or in combination (N=5) with another antineoplastic agent. Nine patients (64%) were progression free during treatment. Five patients showed a partial response, while 4 had stable disease. Two patients (14%) progressed on therapy. All partial responses were in patients with low-grade tumors. The remaining 3 patients were not evaluable due to toxicity limiting duration of therapy. Two of 3 patients with low-grade glioma with leptomeningeal dissemination showed radiographic treatment response. Five patients reported improved clinical symptoms while on trametinib. Adverse events on trametinib-based therapy included dermatologic, mouth sores, fever, gastrointestinal, infection, neutropenia, headache, and fatigue, and were more common in patients using combination therapy. Trametinib-based therapy demonstrated signals of efficacy in our single institutional cohort of pediatric patients with mitogen-activated protein kinase-driven CNS tumors. Our observations need to be confirmed in a clinical trial setting.",
"affiliations": "Department of Neurosciences, University of California and Rady Children's Hospital.;Department of Neurosciences, University of California and Rady Children's Hospital.;Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego and Rady Children's Hospital, San Diego, CA.;Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego and Rady Children's Hospital, San Diego, CA.;Department of Pediatrics, Division of Hematology-Oncology, University of California San Diego and Rady Children's Hospital, San Diego, CA.;Department of Neurosciences, University of California and Rady Children's Hospital.",
"authors": "Paul|Megan R|MR|;Pehlivan|Katherine C|KC|;Milburn|Mehrzad|M|;Yeh-Nayre|Lanipua|L|;Elster|Jennifer|J|;Crawford|John R|JR|",
"chemical_list": "D000970:Antineoplastic Agents; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001819",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "42(8)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D016543:Central Nervous System Neoplasms; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007223:Infant; D008297:Male; D011379:Prognosis; D011728:Pyridones; D011744:Pyrimidinones; D012189:Retrospective Studies",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e730-e737",
"pmc": null,
"pmid": "32398601",
"pubdate": "2020-11",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Trametinib-based Treatment of Pediatric CNS Tumors: A Single Institutional Experience.",
"title_normalized": "trametinib based treatment of pediatric cns tumors a single institutional experience"
} | [
{
"companynumb": "US-009507513-2102USA008207",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe aim of this study was to retrospectively investigate clinical outcomes by relative dose and dose intensity of docetaxel (DOC) as chemotherapy for Japanese patients with castration-resistant prostate cancer (CRPC).\n\n\nMETHODS\nA total of 145 CRPC patients who received more than 4 courses of DOC chemotherapy at 14 hospitals between 2005 and 2011 were enrolled. Patients were divided into two groups--those receiving a higher or lower dose (mg/m(2)) or dose intensity (mg/m(2)/week). Differences between the groups regarding treatment outcomes and adverse events (AEs) were determined. Additionally, prognostic factors predictive of cancer-specific survival (CSS) in these patients were identified by both univariate and multivariate analysis.\n\n\nRESULTS\nThe total patient group underwent a mean of 11.2 ± 7.4 DOC cycles, and the mean CSS after therapy was 15.6 ± 10.1 months. The higher-dose group had a better prostate-specific antigen (PSA) response than the lower-dose group. However, there was no significant difference between the groups in prognosis after DOC chemotherapy. Leukopenia and neutropenia were observed more frequently in the higher-dose group. Serum biomarkers (including PSA, lactate dehydrogenase and alkaline phosphatase), hemoglobin levels and presence of pain at initiation of chemotherapy, as well as the PSA nadir level on first-line hormone therapy, all were significant predictors of CSS.\n\n\nCONCLUSIONS\nIn the Japanese population, relatively low-dose DOC chemotherapy had no deleterious effect on the CSS of CRPC patients, and a lower incidence of AEs occurred, in spite of a diminished PSA response compared with those receiving a higher dose.",
"affiliations": "Department of Urology, Toho University Sakura Medical Center, 564-1 Shimoshizu, Sakura, Chiba, 285-8741, Japan, naoto.kamiya@med.toho-u.ac.jp.",
"authors": "Kamiya|Naoto|N|;Suzuki|Hiroyoshi|H|;Ueda|Takeshi|T|;Sato|Naohide|N|;Nakatsu|Hiroomi|H|;Mikami|Kazuo|K|;Sato|Nobuo|N|;Nomura|Kazushi|K|;Akakura|Koichiro|K|;Okano|Tatsuya|T|;Ooki|Takemasa|T|;Naya|Yukio|Y|;Ota|Sho|S|;Masai|Motoyuki|M|;Ichikawa|Tomohiko|T|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D017430:Prostate-Specific Antigen",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10147-012-0510-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-9625",
"issue": "19(1)",
"journal": "International journal of clinical oncology",
"keywords": null,
"medline_ta": "Int J Clin Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000077143:Docetaxel; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D017430:Prostate-Specific Antigen; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "9616295",
"other_id": null,
"pages": "157-64",
"pmc": null,
"pmid": "23299278",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "18182665;20807808;15661054;18813832;22068464;17960793;15470214;20008841;19667269;21782481;20888271;20206975;16234823;18946750;17965423;21615854;20481655;15470213;15151954;18417502;3334948;17975152;20587613;17761981;15738542;1671606;8546908;20005697",
"title": "Clinical outcomes by relative docetaxel dose and dose intensity as chemotherapy for Japanese patients with castration-resistant prostate cancer: a retrospective multi-institutional collaborative study.",
"title_normalized": "clinical outcomes by relative docetaxel dose and dose intensity as chemotherapy for japanese patients with castration resistant prostate cancer a retrospective multi institutional collaborative study"
} | [
{
"companynumb": "JP-PFIZER INC-2016411395",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "A 66-year-old Caucasian man was initially admitted with a metastatic small cell lung carcinoma, hyponatraemia and obstructive pneumonia. His transthoracic echocardiogram (TTE) was normal. Ten days after admission, he was diagnosed with a non-ST segment elevation myocardial infarction (MI). Both a repeated TTE and a transoesophageal echocardiogram identified thickened, myxomatous mitral valve leaflet tips with small, mobile masses identified as vegetations, and new, eccentric, severe mitral regurgitation. Subsequent cardiac catheterisation recorded thrombotic occlusion of the right coronary artery. Successful coronary thrombectomy was carried out, but the patient died. A diagnosis of non-bacterial thrombotic endocarditis leading to coronary embolisation and MI was made. The clinical course and treatment choices are discussed.",
"affiliations": "School of Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA kmgray@utmb.edu.;Division of Cardiology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA.;School of Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA.;Division of Cardiology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, Texas, USA.",
"authors": "Gray|Kelsey Margaret|KM|http://orcid.org/0000-0002-7926-5540;Nguyen|Bao|B|;Baker|Larissa|L|;Ahmad|Masood|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-239893",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(6)",
"journal": "BMJ case reports",
"keywords": "cancer - see oncology; cardiovascular medicine; cardiovascular system; interventional cardiology; valvar diseases",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D059905:Endocarditis, Non-Infective; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008943:Mitral Valve; D055752:Small Cell Lung Carcinoma; D017131:Thrombectomy",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34155006",
"pubdate": "2021-06-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Non-bacterial thrombotic endocarditis and coronary thrombectomy in a patient with metastatic small cell lung carcinoma.",
"title_normalized": "non bacterial thrombotic endocarditis and coronary thrombectomy in a patient with metastatic small cell lung carcinoma"
} | [
{
"companynumb": "US-MYLANLABS-2021M1048440",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRetinopathy of prematurity (ROP) is a vasoproliferative disorder of the developing retina and a significant cause of childhood blindness around the world. Vascular endothelial growth factor (VEGF) plays an important role in the neovascular phase of ROP, and treatment with an anti-VEGF agent is justified in select cases. Bevacizumab is the most commonly used anti-VEGF agent in ROP, but ranibizumab has a shorter half-life with the potential for decreased systemic toxicity. The purpose of this study is to report our experience with anti-VEGF agents for the treatment of ROP.\n\n\nMETHODS\nA retrospective chart review was performed on consecutive infants screened for ROP. Infants treated with peripheral retinal ablation, bevacizumab 0.625 mg/0.025 mL, or ranibizumab 0.25 mg/0.025 mL were specifically identified for review of their clinical outcomes. All treated infants had at least 6 months of follow-up with the treating team and were examined until total regression of ROP.\n\n\nRESULTS\nOne hundred and forty-two infants were screened over a two-year period. Six infants received anti-VEGF agents, with a mean gestational age of 23.48 weeks and mean birth weight of 620 g. Ten eyes from the six infants received anti-VEGF treatment. All ten eyes demonstrated initial regression of ROP. However, ROP reactivation occurred in 5/6 (83%) eyes treated with ranibizumab, on average 5.9 weeks after treatment; whereas none of the 4 eyes treated with bevacizumab experienced reactivation (P < 0.05). One infant who received a unilateral injection of ranibizumab demonstrated bilateral regression of ROP.\n\n\nCONCLUSIONS\nThe role of anti-VEGF treatment for ROP is still being evaluated. Although the shorter half-life of ranibizumab makes it an attractive option, reactivation of ROP is possible. Physicians and families should be aware of this to follow infants closely for an extended period of time.",
"affiliations": "Retina Division, Department of Ophthalmology, Jules Stein Eye Institute, David Geffen School of Medicine at UCLA, Los Angeles, California.",
"authors": "Wong|Ryan K|RK|;Hubschman|Sasha|S|;Tsui|Irena|I|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000069579:Ranibizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/IAE.0000000000000578",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0275-004X",
"issue": "35(4)",
"journal": "Retina (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Retina",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001724:Birth Weight; D005260:Female; D005500:Follow-Up Studies; D005865:Gestational Age; D006801:Humans; D007223:Infant; D058449:Intravitreal Injections; D017075:Laser Coagulation; D008297:Male; D000069579:Ranibizumab; D012008:Recurrence; D012178:Retinopathy of Prematurity; D012189:Retrospective Studies; D042461:Vascular Endothelial Growth Factor A; D014792:Visual Acuity",
"nlm_unique_id": "8309919",
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"title": "Reactivation of retinopathy of prematurity after ranibizumab treatment.",
"title_normalized": "reactivation of retinopathy of prematurity after ranibizumab treatment"
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"abstract": "BACKGROUND\nSarcopenia is known to be associated with poor clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL). There is no consensus concerning the optimal method to define sarcopenia in DLBCL.\n\n\nMETHODS\nWe retrospectively reviewed 193 DLBCL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Sarcopenia was classified by the region where the pretreatment skeletal muscle index (SMI) was measured.\n\n\nRESULTS\nBoth the sarcopenia-L3 and sarcopenia-pectoralis muscle (PM) groups had increased incidences of severe treatment-related toxicities and treatment discontinuation compared with the non-sarcopenia-L3 and non-sarcopenia-PM groups, respectively. The sarcopenia-L3 and non-sarcopenia-L3 groups had 5-year overall survival (OS) rates of 40.5% and 67.8% (p < 0.001), respectively. The sarcopenia-PM and non-sarcopenia-PM groups had 5-year OS rates of 35.9% and 69.0% (p < 0.001), respectively. When the sarcopenia-L3 alone and sarcopenia-PM alone groups were compared, there were no differences in baseline characteristics, treatment toxicity, or survival. In multivariate analysis, when compared with the non-sarcopenia-both group, OS was significantly worse in the sarcopenia-both group (HR, 2.480; 95% CI, 1.284 - 4.792; p = 0.007), but not in patients with either sarcopenia-L3 alone or sarcopenia-PM alone (p = 0.151).\n\n\nCONCLUSIONS\nL3- and PM-SMIs are equally useful to define sarcopenia, which is related to intolerance to R-CHOP therapy and to worse survival in patients with DLBCL. More prognostic information can be obtained when these two SMIs are combined to define sarcopenia.",
"affiliations": "Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Republic of Korea.;Department of Radiology, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Republic of Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Republic of Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Republic of Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Republic of Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Republic of Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Republic of Korea.;Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Republic of Korea.",
"authors": "Go|Se-Il|SI|;Park|Mi Jung|MJ|;Song|Haa-Na|HN|;Kim|Hoon-Gu|HG|;Kang|Myoung Hee|MH|;Kang|Jung Hun|JH|;Kim|Hye Ree|HR|;Lee|Gyeong-Won|GW|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
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"doi": "10.18632/oncotarget.16552",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 283885851655210.18632/oncotarget.16552Research PaperA comparison of pectoralis versus lumbar skeletal muscle indices for defining sarcopenia in diffuse large B-cell lymphoma - two are better than one Go Se-Il 1Park Mi Jung 2Song Haa-Na 3Kim Hoon-Gu 14Kang Myoung Hee 14Kang Jung Hun 34Kim Hye Ree 3Lee Gyeong-Won 341 Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Changwon Hospital, Gyeongsang National University College of Medicine, Changwon, Republic of Korea2 Department of Radiology, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Republic of Korea3 Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University College of Medicine, Jinju, Republic of Korea4 Institute of Health Science, Gyeongsang National University College of Medicine, Jinju, Republic of KoreaCorrespondence to:Gyeong-Won Lee,brightree24@gmail.com18 7 2017 24 3 2017 8 29 47007 47019 4 2 2017 28 2 2017 Copyright: © 2017 Go et al.2017This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Backgrounds\nSarcopenia is known to be associated with poor clinical outcome in patients with diffuse large B-cell lymphoma (DLBCL). There is no consensus concerning the optimal method to define sarcopenia in DLBCL.\n\nMethods\nWe retrospectively reviewed 193 DLBCL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Sarcopenia was classified by the region where the pretreatment skeletal muscle index (SMI) was measured.\n\nResults\nBoth the sarcopenia-L3 and sarcopenia-pectoralis muscle (PM) groups had increased incidences of severe treatment-related toxicities and treatment discontinuation compared with the non-sarcopenia-L3 and non-sarcopenia-PM groups, respectively. The sarcopenia-L3 and non-sarcopenia-L3 groups had 5-year overall survival (OS) rates of 40.5% and 67.8% (p < 0.001), respectively. The sarcopenia-PM and non-sarcopenia-PM groups had 5-year OS rates of 35.9% and 69.0% (p < 0.001), respectively. When the sarcopenia-L3 alone and sarcopenia-PM alone groups were compared, there were no differences in baseline characteristics, treatment toxicity, or survival. In multivariate analysis, when compared with the non-sarcopenia-both group, OS was significantly worse in the sarcopenia-both group (HR, 2.480; 95% CI, 1.284 – 4.792; p = 0.007), but not in patients with either sarcopenia-L3 alone or sarcopenia-PM alone (p = 0.151).\n\nConclusions\nL3- and PM-SMIs are equally useful to define sarcopenia, which is related to intolerance to R-CHOP therapy and to worse survival in patients with DLBCL. More prognostic information can be obtained when these two SMIs are combined to define sarcopenia.\n\nsarcopeniadiffuse large B-cell lymphomamuscledrug toxicityprognosis\n==== Body\nINTRODUCTION\nThe introduction of rituximab into front-line therapy has dramatically improved the clinical outcome of patients with diffuse large B-cell lymphoma (DLBCL). Compared with conventional chemotherapy, rituximab-based regimens such as R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) resulted in an increased complete response (CR) rate and prolonged survival, without a significant increase in toxicity, in patients with DLBCL [1–4]. However, it is debatable whether frail patients, who have an increased risk of treatment complications, benefit from R-CHOP therapy because pivotal randomized trials excluded these populations from the analysis [1, 2, 4]. Furthermore, DLBCL patients with significant comorbidities or poor performance status (PS) are intolerant to R-CHOP therapy and have poor prognosis, mainly due to treatment-related toxicities and frequent cessation of treatment [5–7]. Recent studies have suggested that alternative therapeutic strategies to the standard R-CHOP regimen, such as dose modification, reduction of chemotherapy cycles, and replacement of anthracycline with other agents, showed a favorable toxicity profile with acceptable survival rates in frail patients with DLBCL [8–12]. Therefore, clinical markers to identify patients who are intolerant to standard R-CHOP therapy need to be developed for individualized therapy in DLBCL patients.\n\nCancer cachexia is a multifactorial syndrome related to systemic inflammation and adverse outcomes in patients with cancer [13, 14]. Many studies have reported that inflammatory markers and other biomarkers for cancer cachexia can help to predict the prognosis and to improve the performance of prognostic indices in DLBCL [15–21]. Additionally, sarcopenia is known to be associated with an increased risk of treatment-related toxicity and a worse survival outcome in various solid tumors [22–26]. Unfavorable aspects of sarcopenia have also been evaluated in patients with DLBCL. In a French study of 82 elderly DLBCL patients treated with an R-CHOP or R-miniCHOP regimen, sarcopenic patients had a higher revised International Prognostic Index (R-IPI), more frequent discontinuation of treatment, and a higher risk of death than did non-sarcopenic patients [27]. In a Japanese study of 207 DLBCL patients who received R-CHOP or its derivative regimen, male – but not female – sarcopenic patients had worse progression-free survival (PFS) compared with non-sarcopenic patients [28]. These two previous studies used the L3 skeletal muscle index (L3-SMI), measured by computed tomography (CT), to determine sarcopenia. Recently, we demonstrated that sarcopenia, determined by pectoralis muscle SMI (PM-SMI), was also strongly associated with intolerance to treatment and with poor prognosis in DLBCL patients who were treated with the standard R-CHOP regimen [29]. In addition, we suggested that the addition of sarcopenic status to IPI components can improve the predictive power of IPI [29].\n\nIn this study, given the uncertainty about the optimal SMI to define clinically meaningful sarcopenia in DLBCL, we compared the characteristics and clinical outcome between sarcopenic patients determined by L3-SMI and those determined by PM-SMI who were treated with standard front-line R-CHOP therapy. Furthermore, the synergistic role of L3- and PM-SMIs as prognostic markers was also investigated.\n\nRESULTS\nPatient population and characteristics\nIn total, 193 patients were included in the final analysis. There were 116 patients in the non-sarcopenia-both group. Of the remaining 77 patients with some form of sarcopenia, 22, 30, and 25 patients were classified into the sarcopenia-both, sarcopenia-L3 alone, and sarcopenia-PM alone groups, respectively. When the sarcopenic status was dichotomized according to the type of SMI, 52 and 141 patients comprised the sarcopenia-L3 and non-sarcopenia-L3 groups, and 55 and 138 patients comprised the sarcopenia-PM and non-sarcopenia-PM groups, respectively. There were no differences in L3-SMI between non-sarcopenia-both and sarcopenia-PM alone groups (p = 0.132) and in PM-SMI between non-sarcopenia-both and sarcopenia-L3 alone groups (p = 0.293). Both L3- and PM-SMIs were significantly and weakly associated with BMI (R2 = 0.29, p < 0.001 and R2 = 0.04, p = 0.003, respectively; Figure 1).\n\nFigure 1 Correlation between body mass index and (A) L3-SMI and (B) PM-SMI. Abbreviations: L3-SMI = L3 skeletal muscle index, PM-SMI = pectoralis muscle skeletal muscle index.\n\nBaseline characteristics of patients are presented in Table 1. Compared with the non-sarcopenia-L3 group, the sarcopenia-L3 group was associated with old age, poor PS, B-symptoms, advanced Ann Arbor stage, higher IPI, R-IPI, and National Comprehensive Cancer Network-IPI (NCCN-IPI), and hypoalbuminemia. The sarcopenia-PM group also had the adverse clinical characteristics observed in the sarcopenia-L3 group, except PS and Ann Arbor stage. When the sarcopenia-L3 alone and sarcopenia-PM alone groups were directly compared, there were no differences in any of the baseline characteristics.\n\nTable 1 Patients’ characteristics and treatment response\n\tSarcopenia-both(n = 22)\tSarcopenia-L3/PM alone (n = 55)\tNon-sarcopenia-both(n = 116)\tP†\tP‡\tPtrend§\t\nL3 alone(n = 30)\tPM alone(n = 25)\t\nAge, years\t\t\t\t\t0.001\t0.017\t0.002\t\n Median\t68\t66\t65\t58.5\t\t\t\t\n Range\t47 – 81\t27 – 86\t24 – 76\t21 – 82\t\t\t\t\nSex\t\t\t\t\t0.113\t0.805\t0.243\t\n Male\t16 (72.7)\t19 (63.3)\t12 (48.0)\t65 (56.0)\t\t\t\t\n Female\t6 (27.3)\t11 (36.7)\t13 (52.0)\t51 (44.0)\t\t\t\t\nECOG PS\t\t\t\t\t< 0.001\t0.056\t0.001\t\n 0 – 1\t11 (50.0)\t17 (56.7)\t18 (72.0)\t94 (81.0)\t\t\t\t\n 2 – 3\t11 (50.0)\t13 (43.3)\t7 (28.0)\t22 (19.0)\t\t\t\t\nB-symptoms\t\t\t\t\t0.037\t0.003\t0.001\t\n Absent\t12 (54.5)\t24 (80.0)\t18 (72.0)\t99 (85.3)\t\t\t\t\n Present\t10 (45.5)\t6 (20.0)\t7 (28.0)\t17 (14.7)\t\t\t\t\nBulky disease\t\t\t\t\t0.141\t0.058\t0.034\t\n Non-bulky\t15 (68.2)\t25 (83.3)\t20 (80.0)\t101 (87.1)\t\t\t\t\n Bulky\t7 (31.8)\t5 (16.7)\t5 (20.0)\t15 (12.9)\t\t\t\t\nAnn Arbor stage\t\t\t\t\t0.015\t0.158\t0.015\t\n I – II\t5 (22.7)\t11 (36.7)\t12 (48.0)\t59 (50.9)\t\t\t\t\n III – IV\t17 (77.3)\t19 (63.3)\t13 (52.0)\t57 (49.1)\t\t\t\t\nExtranodal involvement\t\t\t\t\t0.012\t0.092\t0.008\t\n 0 – 1 site\t12 (54.5)\t17 (56.7)\t16 (64.0)\t89 (76.7)\t\t\t\t\n > 1 site\t10 (45.5)\t13 (43.3)\t9 (36.0)\t27 (23.3)\t\t\t\t\nLDH\t\t\t\t\t0.153\t0.454\t0.168\t\n Normal\t8 (36.4)\t10 (33.3)\t10 (40.0)\t55 (47.4)\t\t\t\t\n Elevated\t14 (63.6)\t20 (66.7)\t15 (60.0)\t61 (52.6)\t\t\t\t\nIPI\t\t\t\t\t0.003\t0.006\t< 0.001\t\n Low to low-intermediate\t6 (27.3)\t15 (50.0)\t13 (52.0)\t77 (66.4)\t\t\t\t\n High-intermediate to high\t16 (72.7)\t15 (50.0)\t12 (48.0)\t39 (33.6)\t\t\t\t\nR-IPI\t\t\t\t\t0.003\t0.014\t< 0.001\t\n Very good\t0 (0.0)\t2 (6.7)\t3 (12.0)\t25 (21.6)\t\t\t\t\n Good\t6 (27.3)\t13 (43.3)\t10 (40.0)\t52 (44.8)\t\t\t\t\n Poor\t16 (72.7)\t15 (50.0)\t12 (48.0)\t39 (33.6)\t\t\t\t\nNCCN-IPI\t\t\t\t\t0.011\t0.013\t0.002\t\n Low to low-intermediate\t5 (22.7)\t13 (43.3)\t11 (44.0)\t67 (57.8)\t\t\t\t\n High-intermediate to high\t17 (77.3)\t17 (56.7)\t14 (56.0)\t49 (42.2)\t\t\t\t\nAlbumin\t\t\t\t\t< 0.001\t< 0.001\t< 0.001\t\n Normal\t6 (27.3)\t18 (60.0)\t12 (48.0)\t94 (81.0)\t\t\t\t\n Hypoalbuminemia\t16 (72.7)\t12 (40.0)\t13 (52.0)\t22 (19.0)\t\t\t\t\nTreatment response\t\t\t\t\t0.006\t0.002\t< 0.001\t\n CR\t11 (50.0)\t20 (66.7)\t16 (64.0)\t99 (85.3)\t\t\t\t\n PR, NR/SD, or PD\t7 (31.8)\t9 (30.0)\t6 (24.0)\t12 (10.3)\t\t\t\t\n Not available*\t4 (18.2)\t1 (3.3)\t3 (12.0)\t5 (4.3)\t\t\t\t\nData are presented as number of patients (%) except age.\n\nThere were no statistical differences between sarcopenia-L3 alone and -PM alone groups (data not shown).\n\nAbbreviations: PM = pectoralis muscle, ECOG PS = Eastern Cooperative Oncology Group performance status, LDH = lactate dehydrogenase, IPI = International Prognostic Index, R-IPI = revised International Prognostic Index, NCCN-IPI = National Comprehensive Cancer Network International Prognostic Index, CR = complete response, PR = partial response, NR = no response, SD = stable disease, PD = progressive disease.\n\n*Information for treatment response was not available in 13 patients due to the following reasons: early discontinuation of treatment due to treatment toxicity after the first cycle of chemotherapy (6 patients); patient's own will to withdraw the treatment (5 patients); and loss of follow-up (2 patients).\n\n†Comparing sarcopenia-L3 (sarcopenia-both + sarcopenia-L3 alone) with non-sarcopenia-L3 (others).\n\n‡Comparing sarcopenia-PM (sarcopenia-both + sarcopenia-PM alone) with non-sarcopenia-PM (others).\n\n§Comparing sarcopenia-both with sarcopenia-L3/PM alone and non-sarcopenia-both.\n\nIt was found that the greater the sarcopenic status, the worse the clinical status of patients. Considering baseline characteristics such as age, PS, tumor stage, and prognostic indices, the sarcopenia-both group had the worst clinical features, while the sarcopenia-L3/PM alone group had intermediate clinical features and the non-sarcopenia-both group had the most favorable clinical features.\n\nTreatment-related toxicity and compliance\nComparisons of toxicity and compliance for R-CHOP therapy between groups are described in Table 2. Compared with the non-sarcopenia-L3 group, the sarcopenia-L3 group had more frequent grade 3 anemia (28.9% vs. 14.9%, p = 0.027), grade 3–4 (34.6% vs. 18.4%, p = 0.017) and grade 4 (23.1% vs. 10.6%, p = 0.027) thrombocytopenia, grade 4–5 non-hematologic toxicity (21.2% vs. 5.7%, p = 0.001), TRM (23.1% vs. 3.6%, p < 0.001), and treatment discontinuation (34.6% vs. 13.5%, p = 0.001). Similarly, the sarcopenia-PM group had more frequent grade 3 anemia (38.3% vs. 12.3%, p < 0.001), grade 3–4 (36.2% vs. 18.5%, p = 0.012) and grade 4 (23.4% vs. 11.0%, p = 0.032) thrombocytopenia, grade 4–5 non-hematologic toxicity (19.2% vs. 6.9%, p = 0.022), TRM (19.2% vs. 5.5%, p = 0.007), and treatment discontinuation (29.8% vs. 15.8%, p = 0.034), in addition to febrile neutropenia (grade 3–4, 48.9% vs. 28.1%, p = 0.008; grade 4–5, 23.4% vs. 9.6%, p = 0.014), compared to the non-sarcopenia-PM group. However, there were statistically no differences in treatment-related toxicity or treatment discontinuation between the sarcopenia-L3 alone and sarcopenia-PM alone groups.\n\nTable 2 Comparison of toxicity and compliance for R-CHOP therapy according to sarcopenic status\n\tSarcopenia-both(n = 22)\tSarcopenia-L3/PM alone (n = 55)\tNon-sarcopenia-both(n = 116)\tP†\tP‡\tPtrend§\t\nL3 alone(n = 30)\tPM alone(n = 25)\t\nGrade 3–5 hematologic toxicity\t\t\t\t\t\t\t\t\n Anemia (G3)\t9 (40.9)\t6 (20.0)\t9 (36.0)\t12 (10.3)\t0.027\t< 0.001\t< 0.001\t\n Neutropenia (G3–4)\t19 (86.4)\t25 (83.3)\t19 (76.0)\t99 (85.3)\t0.876\t0.508\t0.756\t\n Neutropenia (G4)\t19 (86.4)\t22 (73.3)\t18 (72.0)\t82 (70.7)\t0.271\t0.314\t0.184\t\n Thrombocytopenia (G3–4)\t11 (50.0)\t7 (23.3)\t6 (24.0)\t20 (17.2)\t0.017\t0.012\t0.002\t\n Thrombocytopenia (G4)\t7 (31.8)\t5 (16.7)\t4 (16.0)\t11 (9.5)\t0.027\t0.032\t0.006\t\n Febrile neutropenia (G3–5)\t13 (59.1)\t7 (23.3)\t10 (40.0)\t34 (29.3)\t0.342\t0.008\t0.025\t\n Febrile neutropenia (G4–5)\t6 (27.3)\t4 (13.3)\t5 (20.0)\t10 (8.6)\t0.115\t0.014\t0.011\t\nG3–5 non-hematologic toxicity\t10 (45.5)\t14 (46.7)\t10 (40.0)\t35 (30.2)\t0.067\t0.263\t0.062\t\nG4–5 non-hematologic toxicity\t7 (31.8)\t4 (13.3)\t2 (8.0)\t6 (5.2)\t0.001\t0.022\t< 0.001\t\nTreatment-related mortality\t7 (31.8)\t5 (16.7)\t2 (8.0)\t3 (2.6)\t< 0.001\t0.007\t< 0.001\t\nTreatment discontinuation*\t9 (40.9)\t9 (30.0)\t5 (20.0)\t14 (12.1)\t0.001\t0.034\t0.001\t\nData are presented as number of patients having an event (%).\n\nThere were no statistical differences between sarcopenia-L3 alone and -PM alone groups (data not shown).\n\n*Three patients discontinued the treatment after 3 cycles of R-CHOP due to early disease progression.\n\n†Comparing sarcopenia-L3 (sarcopenia-both + sarcopenia-L3 alone) with non-sarcopenia-L3 (others).\n\n‡Comparing sarcopenia-PM (sarcopenia-both + sarcopenia-PM alone) with non-sarcopenia-PM (others).\n\n§Comparing sarcopenia-both with sarcopenia-L3/PM alone and non-sarcopenia-both.\n\nThe sarcopenia-both group was extremely intolerant to R-CHOP therapy. The rates of grade 3 anemia (40.9%), grade 3–4 (50.0%) and grade 4 (31.8%) thrombocytopenia, grade 3–5 (59.1%) and grade 4–5 (27.3%) febrile neutropenia, grade 4–5 non-hematologic toxicity (31.8%), TRM (31.8%), and treatment discontinuation (40.9%) were highest in the sarcopenia-both group, followed by the sarcopenia-L3/PM alone group and the non-sarcopenia-both group.\n\nTreatment response\nData for treatment response were available for 180 of 193 patients (Table 1). In the analysis of all 193 patients, the CR rate was much lower in the sarcopenia-both group than in the sarcopenia-L3/PM alone group and in the non-sarcopenia-both group (50.0% vs. 65.5% vs. 85.3%, p < 0.001). When treatment response was assessed in 159 patients, excluding 34 patients who discontinued treatment due to reasons other than disease progression, the difference in the CR rate was still significant between the sarcopenia-both, sarcopenia-L3/PM alone, and non-sarcopenic groups, but the significance was lower (71.4% vs. 83.3% vs. 92.2%, p = 0.043). There was no difference in the CR rate between the sarcopenia-L3 alone and sarcopenia-PM alone groups (p = 0.511).\n\nSurvival\nThe median follow-up durations were 58.4 and 52.4 months in all patients and in survivors, respectively. The sarcopenia-L3 group had worse PFS (5-year PFS, 39.8% vs. 64.9%, p < 0.001; Figure 2A) and OS (5-year OS, 40.5% vs. 67.8%, p < 0.001; Figure 2B) than did the non-sarcopenia-L3 group. The sarcopenia-PM group also had longer PFS (5-year PFS, 35.5% vs. 66.0%, p < 0.001; Figure 2C) and OS (5-year OS, 35.9% vs. 69.0%, p < 0.001; Figure 2D), compared with the non-sarcopenia-PM group.\n\nFigure 2 Kaplan-Meier curves for (A and C) progression-free survival and (B and D) overall survival (OS) according to sarcopenic status determined by L3-SMI and by PM-SMI, respectively. Abbreviations: L3-SMI = L3 skeletal muscle index, PM-SMI = pectoralis muscle skeletal muscle index.\n\nWhen the sarcopenia-L3 alone and sarcopenia-PM alone groups were compared, there were no differences in PFS (p = 0.927; Figure 3A) or OS (p = 0.996; Figure 3B). Given the very similar survival curves of the sarcopenia-L3 alone and sarcopenia-PM alone groups, the sarcopenia-L3/PM alone group, which comprised these two groups, was used in further survival analyses. The sarcopenia-both group had the worst PFS (5-year PFS, 19.1% vs. 52.4% vs. 68.5%, p < 0.001; Figure 3C) and OS (5-year OS, 18.2% vs. 54.5% vs. 71.5%, p < 0.001; Figure 3D), followed by the sarcopenia L3/PM alone group and the non-sarcopenia-both group.\n\nFigure 3 Kaplan-Meier curves for (A and C) progression-free survival and (B and D) OS in three and four groups divided according to sarcopenic status, respectively. Abbreviations: PM = pectoralis muscle.\n\nIn multivariate analysis adjusted for B-symptoms, albumin status, and five factors of the IPI, having both types of sarcopenia (i.e., the sarcopenia-both group but not the sarcopenia-L3/PM alone group), was one of the independent factors for worse PFS (HR = 2.166; 95% CI: 1.146 – 4.095; p = 0.017) and OS (HR = 2.480; 95% CI: 1.284 – 4.792; p = 0.007), compared with the non-sarcopenia-both group (Table 3).\n\nTable 3 Univariate and multivariate analyses for PFS and OS\nFactor\tPFS\tOS\t\nUnivariate\tMultivariate\tUnivariate\tMultivariate\t\nHR\t95% CI\tp\tHR\t95% CI\tp\tHR\t95% CI\tp\tHR\t95% CI\tp\t\nAge, years\t\t\t\t\t\t\t\t\t\t\t\t\t\n ≤ 60\tRef.\t\t\tRef.\t\t\tRef.\t\t\tRef.\t\t\t\n > 60\t3.092\t1.878 – 5.089\t< 0.001\t1.826\t1.056 – 3.159\t0.031\t3.246\t1.925 – 5.475\t< 0.001\t1.962\t1.108 – 3.476\t0.021\t\nSex\t\t\t\t\t\t\t\t\t\t\t\t\t\n Male\tRef.\t\t\t\t\t\tRef.\t\t\t\t\t\t\n Female\t0.803\t0.514 – 1.256\t0.337\t\t\t\t0.802\t0.502 – 1.281\t0.355\t\t\t\t\nECOG PS\t\t\t\t\t\t\t\t\t\t\t\t\t\n 0 – 1\tRef.\t\t\tRef.\t\t\tRef.\t\t\tRef.\t\t\t\n 2 – 3\t3.525\t2.255 – 5.511\t< 0.001\t2.023\t1.205 – 3.396\t0.008\t3.883\t2.434 – 6.196\t< 0.001\t2.145\t1.248 – 3.687\t0.006\t\nB-symptoms\t\t\t\t\t\t\t\t\t\t\t\t\t\n Absent\tRef.\t\t\tRef.\t\t\tRef.\t\t\tRef.\t\t\t\n Present\t2.607\t1.639 – 4.149\t< 0.001\t1.241\t0.724 – 2.125\t0.432\t2.589\t1.596 – 4.199\t< 0.001\t1.175\t0.679 – 2.032\t0.565\t\nBulky disease\t\t\t\t\t\t\t\t\t\t\t\t\t\n Non-bulky\tRef.\t\t\t\t\t\tRef.\t\t\t\t\t\t\n Bulky\t0.744\t0.393 – 1.410\t0.365\t\t\t\t0.827\t0.435 – 1.574\t0.563\t\t\t\t\nAnn Arbor stage\t\t\t\t\t\t\t\t\t\t\t\t\t\n I – II\tRef.\t\t\tRef.\t\t\tRef.\t\t\tRef.\t\t\t\n III – IV\t3.905\t2.342 – 6.510\t< 0.001\t2.192\t1.125 – 4.272\t0.021\t3.665\t2.162 – 6.213\t< 0.001\t2.094\t1.041 – 4.212\t0.038\t\nExtranodal involvement\t\t\t\t\t\t\t\t\t\t\t\t\t\n 0 – 1 site\tRef.\t\t\tRef.\t\t\tRef.\t\t\tRef.\t\t\t\n > 1 site\t4.213\t2.690 – 6.599\t< 0.001\t1.816\t1.018 – 3.239\t0.043\t3.939\t2.465 – 6.295\t< 0.001\t1.715\t0.929 – 3.166\t0.084\t\nLDH\t\t\t\t\t\t\t\t\t\t\t\t\t\n Normal\tRef.\t\t\tRef.\t\t\tRef.\t\t\tRef.\t\t\t\n Elevated\t2.596\t1.596 – 4.221\t< 0.001\t1.454\t0.845 – 2.501\t0.176\t2.882\t1.720 – 4.829\t< 0.001\t1.702\t0.955 – 3.032\t0.071\t\nAlbumin\t\t\t\t\t\t\t\t\t\t\t\t\t\n Normal\tRef.\t\t\tRef.\t\t\tRef.\t\t\tRef.\t\t\t\n Hypoalbuminemia\t3.281\t2.119 – 5.082\t< 0.001\t1.345\t0.810 – 2.234\t0.252\t3.873\t2.445 – 6.134\t< 0.001\t1.526\t0.896 – 2.600\t0.120\t\nBMI\t\t\t\t\t\t\t\t\t\t\t\t\t\n Normal to obese\tRef.\t\t\t\t\t\tRef.\t\t\t\t\t\t\n Underweight\t1.553\t0.676 – 3.569\t0.300\t\t\t\t1.749\t0.759 – 4.033\t0.190\t\t\t\t\nSarcopenia status\t\t\t\t\t\t\t\t\t\t\t\t\t\n Non-sarcopenia-both\tRef.\t\t\tRef.\t\t\tRef.\t\t\tRef.\t\t\t\n Sarcopenia-L3/PM alone\t1.785\t1.080 – 2.951\t0.024\t1.401\t0.820 – 2.393\t0.218\t1.927\t1.134 – 3.275\t0.015\t1.512\t0.860 – 2.658\t0.151\t\n Sarcopenia-both\t4.836\t2.764 – 8.462\t< 0.001\t2.166\t1.146 – 4.095\t0.017\t5.808\t3.265 – 10.332\t< 0.001\t2.480\t1.284 – 4.792\t0.007\t\nAbbreviations: PFS = progression-free survival, OS = overall survival, HR = hazard ratio, CI = confidence interval, ECOG PS = Eastern Cooperative Oncology Group performance status, LDH = lactate dehydrogenase, BMI = body mass index, PM = pectoralis muscle.\n\nDISCUSSION\nCancer-associated cachexia consumes skeletal muscle in cancer patients through the complex mechanisms. An experimental study suggested that adipose triglyceride lipase leads to sarcopenia by causing complete loss of white adipose tissue [14]. Another study reported that IL-6 mediates sarcopenia in cancer-associated cachexia by activating FOXO3 and atrogin [30]. Previous clinical studies reported that sarcopenia leads to higher drug exposure, which results in an increased incidence of dose-limiting toxicities in patients with cancer [31–33]. Similarly, the present study showed that sarcopenia was related to severe treatment-related toxicities, frequent withdrawal from treatment with consequential poor response rate, and worse survival in patients with DLBCL. Sarcopenia was also associated with factors indicative of poor nutritional status such as hypoalbuminemia and low BMI. These findings were identical in the sarcopenia-L3 and sarcopenia-PM groups. Furthermore, there were no differences in any clinical outcome between the sarcopenia-L3 alone and sarcopenia-PM alone groups.\n\nAn international consensus for cancer cachexia proposes to use lumbar SMI determined by CT to define sarcopenia [13]. In fact, numerous studies have used L3-SMI to determine sarcopenia [24, 26–28, 33–36]. However, a recent study reported that the cross-sectional area of the pectoralis muscle determined by low-dose chest CT scan was significantly correlated with total body skeletal muscle mass, as measured by bioelectrical impedance analysis in healthy subjects [37]. The clinical importance of sarcopenia determined by the pectoralis muscle was assessed in respiratory tract disorders such as chronic obstructive pulmonary disease (COPD) [38] and small cell lung cancer (SCLC) [25]. COPD patients with lower pectoralis muscle area had more severe airflow obstruction, worse exercise capacity, and poorer quality of life than those with higher pectoralis muscle area [38]. Male SCLC patients with sarcopenia determined by PM-SMI were likely to have more TRM, frequent early discontinuation of treatment, and poor prognosis compared with those without sarcopenia [25]. Taken together with these previous reports, the present study more strongly supports our previous finding [29] that sarcopenia determined by PM-SMI has an adverse impact in patients with DLBCL. There is another advantage in using the pectoralis muscle to determine sarcopenia in that it can be easily measured due to its anatomical simplicity [37, 38].\n\nIn subsequent analyses, we found that the extent of sarcopenia could be classified more specifically when both L3- and PM-SMIs were used together to determine sarcopenia. Over 30% and 40% of the patients who met the criteria for sarcopenia determined by both L3-SMI and PM-SMI experienced TRM and had early treatment discontinuation, respectively, in the present study. These patients had a 2.5 times higher risk of death in multivariate analysis adjusted for well-known prognostic factors, compared to patients who met neither the criteria for sarcopenia determined by L3-SMI nor those determined by PM-SMI. In contrast, patients who met only one of the criteria showed features intermediate between the sarcopenia-both and non-sarcopenia-both groups in terms of treatment-related toxicity and compliance with treatment. Furthermore, their survival and level of SMIs which did not meet the criteria for sarcopenia (e.g. L3-SMI in sarcopenia-PM alone group) was statistically not different with those of non-sarcopenia-both group. These findings suggest that PM-SMI is not only an alternative to L3-SMI but also has a complementary role to L3-SMI in determining sarcopenia. Several previous studies also proposed prognostic models that combine sarcopenia and other clinical factors relevant to cachexia. When a score combining sarcopenia and hypoalbuminemia replaced sarcopenia alone as a prognostic factor in DLBCL, HR for OS increased from 2.07 (sarcopenia alone) to 3.53 (higher score) [27]. Another study performed in the same cohort showed that sarcopenia and adipopenia can be integrated to predict the prognosis more accurately, when compared to the use of sarcopenia alone [39]. In metastatic renal cell cancer, sarcopenic patients with lower BMI experienced more dose-limiting toxicities from sunitinib therapy [26]. All of these findings imply that a more comprehensive approach is needed to identify cachectic patients, instead of identifying them using only sarcopenia determined by L3-SMI alone. In addition, given that chest and abdominal CT are routinely used in the initial assessment of patients with DLBCL, our approach using both L3 -and PM-SMIs to determine sarcopenic status is easily applicable in clinical practice.\n\nThere is a debate regarding whether sarcopenia is directly associated with poor response to anticancer therapy. Sarcopenia results in a higher plasma concentration of anticancer drugs [31, 32], which may be related to better response to treatment [40]. A higher rate of pathologic CR was reported in sarcopenic patients compared with non-sarcopenic patients who were treated with neoadjuvant chemotherapy for breast cancer [41]. However, early discontinuation of treatment owing to severe toxicity may limit the efficacy of anticancer therapy in patients with sarcopenia [40]. In patients who received neoadjuvant chemotherapy for esophageal cancer, the presence of sarcopenia did not affect the rate of pathological chemotherapy response [42]. In SCLC, objective response rate was not different between sarcopenic and non-sarcopenic patients if patients who experienced early discontinuation of treatment before first response evaluation were excluded from the analysis [25]. In the present study, treatment response became worse according to the degree of sarcopenia. However, the difference in treatment response became less marked, with borderline significance after patients who discontinued treatment due to potential treatment toxicity or non-compliance were excluded from the analysis. Therefore, we suggest that intensive supportive care may be necessary to maximize and maintain the efficacy of anticancer therapy in sarcopenic patients.\n\nThe main limitation of the present study was its retrospective nature. This makes the results rather difficult to interpret because of potentially inaccurate data collection, selection bias between groups, and missing of clinically important information such as the cell-of-origin subtype. Although the relationship between the sarcopenic status and the cell-of-origin has still not been confirmed, a previous report showed that there was no association between these two factors in patients with DLBCL [27]. Another limitation is a small sample size, which may limit the generalizability of findings. Therefore, the results observed in the present study should be validated in prospective studies to overcome the problems described above.\n\nIn conclusion, we demonstrated that both L3- and PM-SMIs can be equally used to define sarcopenia, which is associated with intolerance to R-CHOP therapy and poor prognosis in DLBCL patients. The use of only one muscle index may not be enough to define sarcopenia. Also, we expect that, when these two muscle indices are considered together to assess sarcopenic status, treatment in DLBCL patients can be more individualized.\n\nMATERIALS AND METHODS\nPatients\nWe retrospectively reviewed all consecutive DLBCL patients who were treated with the standard front-line R-CHOP regimen between January 2004 and October 2015 at Gyeongsang National University Hospital (GNUH). Among them, patients whose baseline CT chest and abdomen scans were available were included in this study. Exclusion criteria were as follows: 1) younger than 18 years of age, 2) front-line therapy other than the R-CHOP regimen, and 3) transformation from another type of lymphoma. This study was approved by the Institutional Review Board of GNUH.\n\nMuscle mass measurement\nCT scans were performed using a 64-detector CT (Brilliance-64; Philips Medical Systems, Best, The Netherlands) with a detector configuration of 64 × 0.625 mm, a tube voltage of 120 kVp, a fixed tube current of 200 mAs, a pitch of 0.923, a gantry rotation time of 0.5 s, and a smooth reconstruction (Philips “B”) filter. In the chest CT, the whole lung was scanned, from the lung apex to the diaphragm. In the abdominal CT, the whole abdomen was scanned, from the diaphragmatic dome to the pubic symphysis. The mass of the pectoralis muscle, including the pectoralis major and minor, and the muscle mass of the L3 region, including the abdominal wall, psoas, and paraspinal muscles, were measured by one radiologist with 8 years of experience.\n\nThe measurement method was as follows. First, reconstructed axial images with a 3-mm slice thickness and 3-mm interval were analyzed at the levels of the fourth thoracic and third lumbar vertebrae using CT histogram software (the “X section” analysis tool of Advantage Window 4.4; GE Healthcare). Second, the region of interest was placed as the outermost border of muscles using freehand manual drawing. Third, the area of these muscles ranging from -29 to 100 HU was calculated using CT histogram analysis. Then, the muscle mass was calculated as the cross-sectional area. In the case of the pectoralis muscle, the bilateral masses of the muscles were measured separately and the two values were averaged.\n\nDefinition of sarcopenia\nThe muscle mass area was divided by height, and the values were reported according to the region of measurement as L3-SMI and PM-SMI (cm2/m2). Sarcopenia was defined as an SMI less than the muscle region- and sex-specific-cut-off values suggested by Prado et al. [34] and by our previous study [29] (L3-SMI: male, 52.4 cm2/m2; female, 38.5 cm2/m2; and PM-SMI: male, 44 cm2/m2; female, 31 cm2/m2). In this study, sarcopenia and non-sarcopenia were categorized as follows:\n\nSarcopenia-L3 – sarcopenia indexed by L3-SMI, regardless of PM-SMI (the rest are non-sarcopenia-L3);\n\nSarcopenia-L3 alone – sarcopenia indexed by L3-SMI with a non-sarcopenic level of PM-SMI;\n\nSarcopenia-PM – sarcopenia indexed by PM-SMI, regardless of L3-SMI (the rest are non-sarcopenia-PM);\n\nSarcopenia-PM alone – sarcopenia indexed by PM-SMI with a non-sarcopenic level of L3-SMI;\n\nSarcopenia-both – both L3-and PM-SMIs at sarcopenic levels;\n\nSarcopenia-L3/PM alone – sarcopenia-L3 alone or sarcopenia-PM alone;\n\nNon-sarcopenia-both – neither L3-SMI nor PM-SMI at sarcopenic levels.\n\nClinical data\nClinical data of patients were independently collected using electronic medical record review by two physicians (S-I Go and G-W Lee). Any discordant data were carefully discussed among the investigators. Baseline demographics, components of IPI, and other clinical findings of DLBCL were reviewed. Hypoalbuminemia was defined as serum albumin < 3.5 g/dL and elevated lactate dehydrogenase (LDH) as serum LDH > 225 IU/L. Body mass index (BMI) was calculated by dividing the weight in kilograms by the height in square meters (kg/m2). Underweight was defined as BMI < 18.5 kg/m2 according to Asian standards [43]. Treatment response was evaluated in available cases based on the revised International Working Group response criteria [44]. Treatment-related toxicity was assessed using the National Cancer Institute Common Toxicity Criteria (ver. 4.0) [45]. Treatment-related mortality (TRM) was defined as mortality caused directly by treatment at any time or as mortality resulting from any cause other than lymphoma progression within 30 days of the last cycle of R-CHOP. Treatment discontinuation was defined as a minimum of six cycles of R-CHOP for localized or advanced disease – and three to four cycles of R-CHOP with involved-field radiotherapy for localized disease – not being able to be performed.\n\nStatistical analysis\nComparisons between two groups were performed using the chi-square or Fisher's exact test for categorical variables and the Mann-Whitney U-test for continuous variables, as appropriate. For ordinal data with three categories (sarcopenia-both, sarcopenia-L3/PM alone, and non-sarcopenia-both), the chi-square test for trend and Kruskal-Wallis test were performed for categorical and continuous variables, respectively. Correlations between continuous variables were tested by Pearson's correlation coefficient. The median follow-up times were calculated by the reverse Kaplan-Meier method [46]. Overall survival (OS) was defined as the time from the beginning of treatment to death from any cause or last follow-up. PFS was defined as the time from the beginning of treatment to first progression, death from any cause, or last follow-up. Kaplan-Meier curves for survival data were plotted and compared via the log-rank test. Cox regression was performed to calculate the hazard ratio (HR) for death and disease progression along with its 95% confidence interval (CI). Potentially significant variables (p < 0.10) on univariate analysis were included in multivariate analysis. A value of p < 0.05 was considered to be statistically significant. All statistical analyses were conducted using Stata software (ver. 14.0; Stata Corp., College Station, Texas).\n\nNo funding was received for the present study.\n\nCONFLICTS OF INTEREST\n\nThe authors declare no conflicts of interest.\n==== Refs\nREFERENCES\n1 Coiffier B Lepage E Briere J Herbrecht R Tilly H Bouabdallah R Morel P Van Den Neste E Salles G Gaulard P Reyes F Lederlin P Gisselbrecht C CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma N Engl J Med 2002 346 235 242 11807147 \n2 Pfreundschuh M Trumper L Osterborg A Pettengell R Trneny M Imrie K Ma D Gill D Walewski J Zinzani PL Stahel R Kvaloy S Shpilberg O CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) Group Lancet Oncol 2006 7 379 391 16648042 \n3 Pfreundschuh M Kuhnt E Trumper L Osterborg A 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Ropert S Delongchamps NB Zerbib M Goldwasser F Sarcopenia and body mass index predict sunitinib-induced early dose-limiting toxicities in renal cancer patients Br J Cancer 2013 108 1034 1041 23462722 \n27 Lanic H Kraut-Tauzia J Modzelewski R Clatot F Mareschal S Picquenot JM Stamatoullas A Lepretre S Tilly H Jardin F Sarcopenia is an independent prognostic factor in elderly patients with diffuse large B-cell lymphoma treated with immunochemotherapy Leuk Lymphoma 2014 55 817 823 23781925 \n28 Nakamura N Hara T Shibata Y Matsumoto T Nakamura H Ninomiya S Kito Y Kitagawa J Kanemura N Goto N Shiraki M Miyazaki T Takeuchi T Sarcopenia is an independent prognostic factor in male patients with diffuse large B-cell lymphoma Ann Hematol 2015 94 2043 2053 26385388 \n29 Go SI Park MJ Song HN Kim HG Kang MH Lee HR Kim Y Kim RB Lee SI Lee GW Prognostic impact of sarcopenia in patients with diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone J Cachexia Sarcopenia Muscle 2016 7 567 576 27104110 \n30 Puppa MJ Gao S Narsale AA Carson JA Skeletal muscle glycoprotein 130's role in Lewis lung carcinoma-induced cachexia FASEB J 2014 28 998 1009 24145720 \n31 Prado CM Lima IS Baracos VE Bies RR McCargar LJ Reiman T Mackey JR Kuzma M Damaraju VL Sawyer MB An exploratory study of body composition as a determinant of epirubicin pharmacokinetics and toxicity Cancer Chemother Pharmacol 2011 67 93 101 20204364 \n32 Mir O Coriat R Blanchet B Durand JP Boudou-Rouquette P Michels J Ropert S Vidal M Pol S Chaussade S Goldwasser F Sarcopenia predicts early dose-limiting toxicities and pharmacokinetics of sorafenib in patients with hepatocellular carcinoma PLoS One 2012 7 e37563 22666367 \n33 Sjoblom B Gronberg BH Benth JS Baracos VE Flotten O Hjermstad MJ Aass N Jordhoy M Low muscle mass is associated with chemotherapy-induced haematological toxicity in advanced non-small cell lung cancer Lung Cancer 2015 90 85 91 26198373 \n34 Prado CM Lieffers JR McCargar LJ Reiman T Sawyer MB Martin L Baracos VE Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study Lancet Oncol 2008 9 629 635 18539529 \n35 Psutka SP Carrasco A Schmit GD Moynagh MR Boorjian SA Frank I Stewart SB Thapa P Tarrell RF Cheville JC Tollefson MK Sarcopenia in patients with bladder cancer undergoing radical cystectomy: impact on cancer-specific and all-cause mortality Cancer 2014 120 2910 2918 24840856 \n36 Antoun S Baracos VE Birdsell L Escudier B Sawyer MB Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma Ann Oncol 2010 21 1594 1598 20089558 \n37 Kim YS Kim EY Kang SM Ahn HK Kim HS Single cross-sectional area of pectoralis muscle by computed tomography - correlation with bioelectrical impedance based skeletal muscle mass in healthy subjects Clin Physiol Funct Imaging 2015 10.1111/cpf.12333 \n38 McDonald ML Diaz AA Ross JC San Jose Estepar R Zhou L Regan EA Eckbo E Muralidhar N Come CE Cho MH Hersh CP Lange C Wouters E Quantitative computed tomography measures of pectoralis muscle area and disease severity in chronic obstructive pulmonary disease. A cross-sectional study Ann Am Thorac Soc 2014 11 326 334 24558953 \n39 Camus V Lanic H Kraut J Modzelewski R Clatot F Picquenot JM Contentin N Lenain P Groza L Lemasle E Fronville C Cardinael N Fontoura ML Prognostic impact of fat tissue loss and cachexia assessed by computed tomography scan in elderly patients with diffuse large B-cell lymphoma treated with immunochemotherapy Eur J Haematol 2014 93 9 18 \n40 Baracos V Kazemi-Bajestani SM Clinical outcomes related to muscle mass in humans with cancer and catabolic illnesses Int J Biochem Cell Biol 2013 45 2302 2308 23819995 \n41 Del Fabbro E Parsons H Warneke CL Pulivarthi K Litton JK Dev R Palla SL Brewster A Bruera E The relationship between body composition and response to neoadjuvant chemotherapy in women with operable breast cancer Oncologist 2012 17 1240 1245 22903527 \n42 Yip C Goh V Davies A Gossage J Mitchell-Hay R Hynes O Maisey N Ross P Gaya A Landau DB Cook GJ Griffin N Mason R Assessment of sarcopenia and changes in body composition after neoadjuvant chemotherapy and associations with clinical outcomes in oesophageal cancer Eur Radiol 2014 24 998 1005 24535076 \n43 Consultation WHOE Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies Lancet 2004 363 157 163 14726171 \n44 Cheson BD Pfistner B Juweid ME Gascoyne RD Specht L Horning SJ Coiffier B Fisher RI Hagenbeek A Zucca E Rosen ST Stroobants S Lister TA Revised response criteria for malignant lymphoma J Clin Oncol 2007 25 579 586 17242396 \n45 Common Terminology Criteria for Adverse Events (CTCAE), v4.0 In. \n46 Schemper M Smith TL A note on quantifying follow-up in studies of failure time Control Clin Trials 1996 17 343 346 8889347\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(29)",
"journal": "Oncotarget",
"keywords": "diffuse large B-cell lymphoma; drug toxicity; muscle; prognosis; sarcopenia",
"medline_ta": "Oncotarget",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D064131:Back Muscles; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008161:Lumbosacral Region; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D010369:Pectoralis Muscles; D011241:Prednisone; D012189:Retrospective Studies; D000069283:Rituximab; D055948:Sarcopenia; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "47007-47019",
"pmc": null,
"pmid": "28388585",
"pubdate": "2017-07-18",
"publication_types": "D016428:Journal Article",
"references": "24520908;26656519;21680814;25236324;24535076;22903527;17242396;22666367;20223728;23517562;24754632;23530101;23819995;28076864;27104110;8889347;23462722;26385388;24558953;22526364;19351764;20960528;24220559;24840856;21940214;21296615;26644520;18539529;14726171;22215473;20089558;20204364;26251897;24145720;24874478;26546456;11807147;26668097;27764838;23781925;19887488;26198373;16648042;18226581;25288018",
"title": "A comparison of pectoralis versus lumbar skeletal muscle indices for defining sarcopenia in diffuse large B-cell lymphoma - two are better than one.",
"title_normalized": "a comparison of pectoralis versus lumbar skeletal muscle indices for defining sarcopenia in diffuse large b cell lymphoma two are better than one"
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"abstract": "2 different strains of Nocardia were isolated from a lung mass in a post kidney-pancreas transplant patient through convex endobronchial ultrasound transbronchial needle aspiration (EBUS-TNBA). TBNA cultures (16S rRNA gene-targeted PCR sequencing) subsequently grew Nocardia beijingensis and Nocardia arthritidis.",
"affiliations": "University of Cincinnati, Pulmonary, Critical Care and Sleep Division, Department of Internal Medicine, Cincinnati, OH, United States.;University of Cincinnati, Pulmonary, Critical Care and Sleep Division, Department of Internal Medicine, Cincinnati, OH, United States.;University of Cincinnati, Pulmonary, Critical Care and Sleep Division, Department of Internal Medicine, Cincinnati, OH, United States.",
"authors": "Aragaki-Nakahodo|Alejandro|A|;Benzaquen|Sadia|S|;Kirschner|Michelle|M|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(14)00008-210.1016/j.rmcr.2013.11.001Case ReportCoinfection by Nocardia beijingensis and Nocardia arthritidis in an immunocompromised patient diagnosed by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA)☆ Aragaki-Nakahodo Alejandro aragakao@ucmail.uc.edualex_aragaki@yahoo.com∗Benzaquen Sadia benzaqsa@ucmail.uc.eduKirschner Michelle kirschml@ucmail.uc.eduUniversity of Cincinnati, Pulmonary, Critical Care and Sleep Division, Department of Internal Medicine, Cincinnati, OH, United States∗ Corresponding author. University of Cincinnati, Pulmonary, Critical Care and Sleep Division, 231 Albert Sabin Way, MSB Room 6053, ML 0564, Cincinnati, OH 45267, United States. Tel.: +1 513 558 0597; fax: +1 513 558 4858. aragakao@ucmail.uc.edualex_aragaki@yahoo.com15 3 2014 2014 15 3 2014 12 22 23 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).2 different strains of Nocardia were isolated from a lung mass in a post kidney-pancreas transplant patient through convex endobronchial ultrasound transbronchial needle aspiration (EBUS-TNBA). TBNA cultures (16S rRNA gene-targeted PCR sequencing) subsequently grew Nocardia beijingensis and Nocardia arthritidis.\n\nKeywords\nNocardia beijingensisNocardia arthritidisEndobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA)Transplant patient\n==== Body\nCase presentation\nA 50 year-old immunosuppressed Caucasian female presented to her primary care physician's office with a dry cough. Her past medical history was significant for simultaneous kidney and pancreas transplant in May 2010 for type I diabetes mellitus and end-stage renal disease on hemodialysis. She was placed on tacrolimus, prednisone, and mycophenolate mofetil for immunosuppression. Her post-transplant course was unremarkable except for an episode of acute calculous cholecystitis in October 2010 which was treated with intravenous antibiotics for 6 weeks and then a laparoscoptic cholecystectomy.\n\nShe developed a nonproductive cough in late March 2011 and was treated with amoxicillin-clavulanate 875 mg twice a day, for a total of 14 days. She denied any fever, chills or hemoptysis. Her cough resolved at day 4 of treatment. A follow-up chest X-ray (CXR) revealed a 3 cm rounded mass in the right upper lobe medially which was new when compared to a prior from October 2010. A computed tomography (CT) of the chest from April 5th showed a 2.6 by 1.5 cm irregularly shaped, medially located mass in the right upper lobe (RUL) medially which corresponded to the abnormality on the CXR. (Picture 1) The CT scan of the chest also showed a noncalcified 10 mm by 6 mm nodule in the right lower lobe along with multiple calcified nodules in both lungs along with calcified adenopathy.\n\nDue to the high probability of an infectious etiology and the central location of the mass, it was decided to obtain the sample via bronchoscopy. Convex endobronchial ultrasound (EBUS) bronchoscopy was used to locate a retrotracheal necrotic mass 1 cm superior to the carina and multiple transbronchial needle aspiration (TBNA) passes were performed with a 21 gauge needle. In addition, an electromagnetic navigation bronchoscopy was performed but not completed due to lack of definite airway into the lung mass, but transbronchial biopsies, bronchial brushings and a bronchioalveolar lavage were performed in the apical segment of the right upper lobe. Cytology and cultures for acid fast bacilli (AFB), bacteria, fungal, actinomycosis and nocardia were sent from the right retrotracheal site and the apical segment of the right upper lobe. Results from the EBUS-TBNA of the retrotracheal nodule showed slender branching organisms morphologically consistent with filamentous bacteria which were AFB negative (Picture 2). This later was confirmed to be Nocardia beijingensis and Nocardia arthritidis by 16S rRNA gene-targeted PCR sequencing. The patient was placed on high dose sulfamethoxazole/trimethoprim for 6 months, while her immunosuppressive therapy was reduced. Patient remained asymptomatic on follow-up appointments. Unfortunately, due to insurance issues, a follow-up imaging study could not be completed.\n\nDiscussion\nNocardia is a ubiquitous Gram positive aerobic actinomycetes that usually affects immunocompromised patients. Nocardiosis is mainly an opportunistic infection, but can also affect immunocompetent hosts [1]. Inoculation occurs via inhalation. The Nocardia genus includes a variety of species that are important pathogens in humans. The most common species causing human infection is the Nocardia asteroides complex, which includes N. asteroides sensus stricto type VI, Nocardia farcinica, Nocardia nova and recently Nocardia abscessus. Other pathogens include Nocardia brasiliensis, Nocardia pseudobrasiliensis, Nocardia otitidiscaviarium and Nocardia transvalensis\n[2,3].\n\nPulmonary nocardiosis is an infrequent but severe infection that can present as an acute, subacute or chronic suppurative disease, mimicking a lung abscess or carcinoma. Pulmonary nocardiosis is difficult to diagnose based on clinical and radiological findings [4]. As such, microbiological diagnosis is mandatory from lung specimens: sputum, pleural fluid, pleural biopsy, bronchioalveolar lavage (BAL), protected brushings and even abscess puncture sampling has been described [3,4].\n\nRecent publications regarding nocardiosis have described the emergence of new species. N. beijingensis was first isolated back in 2001 [5]. The first report of human infection was made by Kageyama et al. [6] back in 2004. Since then, a few other reports of N. beijingensis infection have been published [7–10]. On the other hand, N. arthritidis was also described as a human pathogen back in 2004. In this paper, the authors establish that N. beijingensis and N. arthritidis are closely related [11]. No other single report of N. arthritidis has been published.\n\nGiven the paucity of symptoms in this patient and the central location of the pulmonary nodule, bronchoscopy was advised as the preferred diagnostic test. Based on the CT of the chest and the high paratracheal location, EBUS-TBNA was favored over conventional TBNA. Through real time ultrasound evaluation, EBUS-TBNA of the retrotracheal nodule with a 21-gauge needle established coinfection of N. beijingensis and N. arthritidis. As described in the literature [12], this patient was treated with sulfamethoxazole-trimethoprim with good clinical response.\n\nNumerous publications establish EBUS-TBNA as a useful tool for lung cancer staging through lymph node biopsies [13–15]. But more recently, EBUS-TBNA has been useful for diagnosing benign disease such as sarcoidosis, tuberculosis, histoplasmosis, blastomycosis and nocardiosis [16,17]. As described by Fujikura et al. [16], EBUS-TBNA proved its diagnostic value for this patient in a safe manner.\n\nTo our knowledge, this is the second case report of nocardiosis diagnosed by EBUS-TBNA, and the first one to demonstrate coinfection with N. beijingensis and N. arthritidis.\n\n☆ Institution work was performed: University of Cincinnati Medical Center.\n\nPicture 1 CT of t he chest with right upper lobe mass.\n\nPicture 2 Gomori methenamine silver (GMS) stain with Nocardia beijingensis and Nocardia arthritidis.\n==== Refs\nReferences\n1 Arduino R.C. Johnson P.C. Miranda B.G. Nocardiosis in renal transplant recipients undergoing immunosuppression with cyclosporine Clin Infect Dis 16 1993 505 512 8513056 \n2 Corti M.E. Villafane-Fioti M.F. Nocardiosis: a review Int J Infect Dis 7 2003 243 250 14656414 \n3 Martinez-Tomas R. Menende-Villanueva R. Reyes-Calzada S. M Santos-Durantez Valles-Tarazona J.M. Modesto-Alapont M. Pulmonary nocardiosis: risk factors and outcomes Respirology 12 2007 394 400 17539844 \n4 Menendez R. Cordero P.J. Santos M. Gobernado M. Marco V. Pulmonary infection with Nocardia species: a report of 10 cases and review Eur Respir J 10 1997 1542 1546 9230244 \n5 Wang L. Zhang Y. Lu Z. Shi Y. Liu Z. Maldonado L. Nocardia beijingensis sp. nov., a novel isolate from soil Int J Syst Evol Microbiol 51 2001 1783 1788 11594609 \n6 Kageyama A. Poonwan N. Yazawa K. Nocardia beijingensis is a pathogenic bacterium to humans: the first infectious cases in Thailand and Japan Mycopathologia 157 2004 155 161 15119850 \n7 Chu R.W.P. Lung D. Wong S.N. Pulmonary abscess caused by Nocardia beijingensis : the second report of human infection Pediatr Infect Dis J 27 6 2008 572 573 18434931 \n8 Ogawa T. Kasahara K. Yonekawa S. Nakagawa C. Maeda K. Konishi M. Nocardia beijingensis pulmonary infection successfully treated with intravenous beta-lactam antibiotics and oral minocycline J Infect Chemother 17 2011 706 709 21409529 \n9 Martinaud C. Verdonk C. Bousquet A. Macnab C. Vaylet F. Soler C. Isolation of Nocardia beijingensis from a pulmonary abscess reveals human immunodeficiency virus infection J Clin Microbiol 49 7 2011 2748 2750 21593265 \n10 Ohmori S. Kobayashi M. Yaguchi T. Nakamura M. Primary cutaneous nocardiosis caused by Nocardia beijingensis in an immunocompromised patient with chemotherapy for advanced prostate cancer J Dermatol 39 8 2012 740 741 22077499 \n11 Kageyama A. Torikoe K. Iwamoto M. Masuyama J. Shibuya Y. Okazaki H. Nocardia arthritidis sp. nov., a new pathogen isolated from a patient with rheumatoid arthritis in Japan J Clin Microbiol 42 6 2004 2366 2371 15184406 \n12 Valerio-Minero M. Marin M. Cercenado E. Rabadan P.M. Bouza E. Munoz P. Nocardiosis at the turn of the century Medicine 88 4 2009 250 261 19593231 \n13 Yasufuku K. Chiyo M. Koh E. Moriya Y. Iyoda A. Sekine Y. Endobronchial ultrasound guided transbronchial needle aspiration for staging of lung cancer Lung Cancer 50 2005 347 354 16171897 \n14 Yasufuku, K. Nakajima, T. Motoori K. Sekine Y. Shibuya K. Hiroshima K. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer Chest 130 2006 710 718 16963667 \n15 Herth F.J. Eberhardt R. Vilmann P. Krasnik M. Ernst A. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes Thorax 61 2006 795 798 16738038 \n16 Fujikara Y. Kouzaki Y. Ohta S. Hara Y. Mikita K. Maeda T. A case of Nocardia asteroides infection in a patient with HIV/AIDS diagnosed by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) Intern Med 51 2012 1413 1417 22687853 \n17 Von Bartheld M.B. Dekkers O.M. Szlubowski A. Eberhardt R. Herth F.J. in ‘t Veen J.C. Endosonography vs conventional bronchoscopy for the diagnosis of sarcoidosis. The GRANULOMA randomized clinical trial J Am Med Assoc 309 2013 2457 2464\n\n",
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"issue": "12()",
"journal": "Respiratory medicine case reports",
"keywords": "Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA); Nocardia arthritidis; Nocardia beijingensis; Transplant patient",
"medline_ta": "Respir Med Case Rep",
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"pages": "22-3",
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"pmid": "26029531",
"pubdate": "2014",
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"title": "Coinfection by Nocardia beijingensis and Nocardia arthritidis in an immunocompromised patient diagnosed by endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA).",
"title_normalized": "coinfection by nocardia beijingensis and nocardia arthritidis in an immunocompromised patient diagnosed by endobronchial ultrasound guided transbronchial needle aspiration ebus tbna"
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"abstract": "Pentazocine is a commonly used synthetic opioid analgesic for moderate to severe pain secondary to various conditions. Complications of parenteral opioid abuse including localized ulcerations, abscess, indurations, and sclerosis are well-documented. We present a rare case of drug abuse due to pentazocine (Fortwin) in a 32-year-old female, who had severe myogenic contractures of her knee joints.",
"affiliations": "Department of Physical Medicine and Rehabilitation, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Physical Medicine and Rehabilitation, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Physical Medicine and Rehabilitation, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Physical Medicine and Rehabilitation, King George Medical University, Lucknow, Uttar Pradesh, India.;Department of Pharmacology, GSVM. Medical College, Kanpur, Uttar Pradesh, India.;Department of Pulmonary Medicine, King George Medical University, Lucknow, Uttar Pradesh, India.",
"authors": "Kumar|Dileep|D|;Gupta|Anil|A|;Sharma|V P|VP|;Yadav|Ganesh|G|;Singh|Arpita|A|;Verma|Ajay Kumar|AK|",
"chemical_list": "D000701:Analgesics, Opioid; D010423:Pentazocine",
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"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-47-45110.4103/0253-7613.161276Drug WatchPentazocine-induced contractures: Dilemma in management Kumar Dileep Gupta Anil Sharma V. P. Yadav Ganesh Singh Arpita 1Verma Ajay Kumar 2Department of Physical Medicine and Rehabilitation, King George Medical University, Lucknow, Uttar Pradesh, India1 Department of Pharmacology, GSVM. Medical College, Kanpur, Uttar Pradesh, India2 Department of Pulmonary Medicine, King George Medical University, Lucknow, Uttar Pradesh, IndiaCorrespondence to: Dr. Ganesh Yadav, E-mail: ganeshyadav4u@yahoo.co.inJul-Aug 2015 47 4 451 453 05 11 2014 19 2 2015 05 6 2015 Copyright: © Indian Journal of Pharmacology2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Pentazocine is a commonly used synthetic opioid analgesic for moderate to severe pain secondary to various conditions. Complications of parenteral opioid abuse including localized ulcerations, abscess, indurations, and sclerosis are well-documented. We present a rare case of drug abuse due to pentazocine (Fortwin) in a 32-year-old female, who had severe myogenic contractures of her knee joints.\n\nKEY WORDS\nContracturesmyopathypentazocinepentazocine abuse\n==== Body\nIntroduction\nMyopathy has frequently been associated with repeated intramuscular injections of narcotic analgesics such as pentazocine, butarphanol, propoxyphene, heroin, piritramide, methadone, and meperidine. Pentazocine is a commonly used synthetic narcotic analgesic for moderate to severe pain secondary to various conditions. The side-effects and complications of its use could be tense woody skin fibrosis, punched out irregular skin ulceration, abnormal skin pigmentation,[12] symmetrical fibrous myopathy, bilateral deep vein thrombosis,[3] and contractures.[4] Fibrosis has been reported in the muscles at the site of injection as well as in noninjected muscles.[5] Myogenic contractures can be due to trauma, inflammation, degenerative changes, ischemia, and spasticity. There are few reports of myopathy following chronic pentazocine administration. Myogenic contracture due to parenteral narcotic abuse is a rare entity. We present a case of pentazocine dependence with myopathy as a complication and discuss the associated issues.\n\nCase Report\nA 32-year-old female patient presented with the complaints of inability to stand erect and walking in equinus both sides along with stiffness of knees and ankles in our outpatient facility. She was nondiabetic and normotensive. She gave the history of chronic abuse of self-administered injection pentazocine (up to two ampoules [60 mg]/day intramuscularly) over a period of 2 years. She was apparently well 8 years back, when she developed pain in abdomen. Pain was acute in onset and colicky in nature. It was too severe to be reduced by oral medications, so she was advised pentazocine injections intramuscularly by a local physician for relief of pain. She took the unsupervised injections intramuscularly over anterior thigh and calf on both sides. Gradually she developed stiffness at both knee and ankle joints followed by contractures.\n\nOn general examination, her cardiopulmonary and neurological examination showed no abnormality except stiffness of both knee and ankle joints. On local examination of both lower limbs, tone of musculature gave feeling of abnormal woody hardness with shining skin over thigh and calf muscles. Multiple small healed abscesses scars were seen. Active and passive movement restriction was observed in both knees and ankles. Her feet were in equinus; more severe on right side and few degrees (10–15°) of dorsiflexion was seen on either side but unable to come to neutral position. She was unable to squat and sit cross-legged. There was 60° flexion contracture at right knee joint and 80° at left knee joint. Tendoachillis was tight on both sides. Both hips showed secondary flexion deformities [Figure 1].\n\nFigure 1 Flexion contracture of both hip, knee, and ankle (front view)\n\nHer routine blood investigations were within normal limits with hemoglobin-11 g/dL, total leukocyte count-5600/cmm, differential leukocyte count: Neutrophils-56%, lymphocytes-40%, eosinophils-2%, monocytes-2%, erythrocyte sedimentation rate (Wintrobe's method)-22 mm in 1st h, serum calcium-8.6 mg/dL, serum phosphorus-2.9 mg/dL, serum alkaline phosphatase-158 international unit, blood sugar (random)-132 mg %, blood urea-24 mg/dL, serum creatine-0.5 mg/dL, serum creatine phosphokinase (CPK)-70 IU. Elisa test for HIV, hepatitis C and hepatitis B surface antigen, all were found negative. Electromyographic (EMG) of bilateral gastrocnemius, tibialis anterior and vastus medialis revealed normal EMG pattern. High resolution sonography with color flow imaging and extended field of view imaging was done for evaluation of both thighs with direct contact scanning technique with 10 and 12 MHz transducers. Both thigh muscles were well visualized. The muscles were echogenic in texture but normal muscle bundle appearance was lost. The pinnate fiber was lost. It involved the diffuse muscle in anterolateral compartment. No evidence of any mass or calcification was seen. The findings were suggestive of echogenic pattern of the thigh muscle with loss of normal muscle texture and suggestive of diffuse fibrosis.\n\nArteriovenous color Doppler study of both lower limbs was normal. Skiagram of both knees (anterior-posterior and lateral) showed normal articular cartilage, without any erosions or calcification [Figure 2].\n\nFigure 2 X-ray radiographs of both knee joints antero-posterior and lateral views showing normal appearance of the knee joints\n\nThese clinical findings suggested the diagnosis of pentazocine (fortwin) abuse leading to generalized muscle fibrosis and flexion contractures of both hip and knee joints. Patient came to us for correction of flexion deformities in both knee joints. Patient was advised gradual passive stretching of hamstrings, skin traction, ankle mobilization exercises, gait training with a walking stick. While she was advised exercises, she was also advised to attend de-addiction program. Her family was counseled to provide her long term good care, support and help in her rehabilitation process. The surgical intervention was another option for her for which she had not consented presently. Meanwhile she is now not dependent on pentazocine and she was put on skeletal traction on both lower limbs. Right limb contracture decreased significantly but left limb contracture was static after 8 weeks of skeletal traction.\n\nThese type of contracture resistant to conservative means are candidates for surgical interventions. However neither the patient has given consent for surgical intervention nor we are sure for surgical outcome in case of severe skin and muscle fibrosis as we could not find much supporting literature.\n\nDiscussion\nFibrous myopathy has been described in association with the repeated intramuscular injections of narcotic analgesics. Clinical presentation vary case to case depending on site, amount and duration of drug use. Pentazocine-induced myofibrosis mainly involves muscles around hip and shoulder joints following long-standing pentazocine abuse. Many authors have tried to study the exact pathogenesis of cutaneous complications of pentazocine and suggested that pentazocine is most soluble in acidic conditions and may get precipitated in the slightly alkaline pH of extracellular fluid, which then initiates a chronic inflammatory response. Differential diagnoses of myogenic contractures include hereditary myopathies, Ankylosing spondylitis, Stiffman syndrome, Myositis ossificans, arthrogryposis, and parathyroid disease. Ankylosing spondylitis was ruled out as there was no involvement of the vertebral column. Stiff-man syndrome presents with spasms and cramps, and usual presentation is after middle age. The possibility of myositis ossificans was unlikely, as there was no new bone formation. Normal serum calcium and phosphate levels excluded hypoparathyroidism. Pentazocine-induced calcific myofibrosis was a strong possibility in view of the history of pentazocine abuse, calcified muscles, and the clinical presentation. According to WHO-Uppsala Monitoring Centre causality categories[6] and Naranjo ADR probability scale,[7] the association of pentazocin as the causal drug for this ADR is “Probable/likely” and may consist of stopping injections and considering the addition of corticosteroids and/or penicillamine.[8] If chronic intramuscular injection cannot be avoided, close serial monitoring of the muscles being injected should be done periodically and whenever hardening of muscle tissue, loss of muscle strength or range of motion, muscle tenderness or pain, or increasing functional disability is noted, prompt review of the drug and delivery system should be performed, and an alternative pain control intervention should be started.\n\nIn the present case, both knee joints were having no joint pathology as evident by normal skiagram. Normal CPK value and normal EMG pattern ruled out any ongoing muscle destruction pathology as reported in few studies. Schlicher et al.,[9] reported that pentazocine injection precipitates in extracellular tissue resulting in inflammation. Palestine et al.,[2] had observed fibrosis endarteritis, vascular thrombosis, granulomatous inflammation, and fat necrosis in histopathological studies in muscles after repeated use of pentazocine parenteraly. There is no known threshold for the amount of drug, number of injections or frequency of injections that could possibly be related to fibrous replacement of muscle tissue, neither it is clear whether the condition is reversible in any time frame. It is a common practice to use pentazocine (Fortwin) for management of severe chronic pain and slowly the individual becomes an addict. Good number of studies are presently available to demonstrate the long term use of pentazocine and its ill-effects leading to sclerotic ulcers, myopathy, and contractures. In such cases, de-addiction therapy, counseling and treatment of contractures should be started as early as possible to save each joint. In every case of contracture, may be locally or generalized we must take proper history for a potential drug abuse.\n\nPrescription drug abuse is a major health problem across the globe. Various other drugs, such as analgesics, cough syrups, vitamin preparations, and laxatives among others, are being used by individuals for reasons other than the medical indication. The availability of these drugs over the counter precludes the requirement of a prescription to procure them. With free over-the-counter access to these drugs in India and many developing countries, awareness of this complication is important so that unwanted side-effects can be avoided. Moreover, in cases such as that reported here, the drugs are initially prescribed for a medical indication and subsequent use by the patient continues without the advice of a physician.\n\nConclusions\nThe abuse of prescription opioids, such as pentazocine, is being increasingly reported across globe including India. Clinicians should be careful about the abuse potential of these compounds and cautious when dealing with individuals with a history of substance abuse and/or dependence. This would help in preventing such drug abuse and its complications and whenever problem is suspected intervention for deaddiction, corrective exercises and management of contracture should be instituted.\n\n\nFinancial Support and Sponsorship\nNil.\n\nConflicts of Interest\nThere are no conflicts of interest.\n==== Refs\n1 Schiff BL Kern AB Unusual cutaneous manifestations of pentazocine addiction JAMA 1977 238 1542 3 578228 \n2 Palestine RF Millns JL Spigel GT Schroeter AL Skin manifestations of pentazocine abuse J Am Acad Dermatol 1980 2 47 55 7354151 \n3 Padilla RS Becker LE Hoffman H Long G Cutaneous and venous complications of pentazocine abuse Arch Dermatol 1979 115 975 7 464626 \n4 Das CP Thussu A Prabhakar S Banerjee AK Pentazocine-induced fibromyositis and contracture Postgrad Med J 1999 75 361 2 10435175 \n5 Goyal V Chawla JM Balhara YP Shukla G Singh S Behari M Calcific myofibrosis due to pentazocine abuse: A case report J Med Case Rep 2008 2 160 18485231 \n6 The Use of the WHO–UMC System for Standardised Case Causality Assessment Last accessed on 2015 Feb 21 Available from:\nhttp://www.who-umc.org/Graphics/24734.pdf \n7 Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508 \n8 Weber M Diener HC Voit T Neuen-Jacob E Focal myopathy induced by chronic heroin injection is reversible Muscle Nerve 2000 23 274 7 10639623 \n9 Schlicher JE Zuehlke RL Lynch PJ Local changes at the site of pentazocine injection Arch Dermatol 1971 104 90 1 5120170\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "47(4)",
"journal": "Indian journal of pharmacology",
"keywords": "Contractures; myopathy; pentazocine; pentazocine abuse",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D003286:Contracture; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D009293:Opioid-Related Disorders; D010423:Pentazocine",
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"pages": "451-3",
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"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18485231;7354151;464626;10435175;5120170;7249508;10639623;578228",
"title": "Pentazocine-induced contractures: Dilemma in management.",
"title_normalized": "pentazocine induced contractures dilemma in management"
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"abstract": "Venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary embolism (PE). In this article, we present a case of a patient with an acute DVT who was treated with a therapeutic heparin drip, then developed syncope while in the hospital and found to have massive bilateral PEs. This case aims to arouse the medical staff's awareness of the VTE diagnosis even if the patient is fully anticoagulated. We review the indications for DVT hospitalization, heparin infusion monitoring, risk factors for developing PE from DVT, mechanisms of developing PE from DVT while on therapeutic anticoagulation, and signs and treatment of massive PE.",
"affiliations": "Hospital Medicine Department, Logan Regional Medical Center, Logan, WV, USA.",
"authors": "Hajouli|Said|S|0000-0002-6444-2751",
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"doi": "10.1177/2324709620914787",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620914787\n10.1177_2324709620914787\nCase Report\nMassive Fatal Pulmonary Embolism While on Therapeutic Heparin Drip\nhttps://orcid.org/0000-0002-6444-2751Hajouli Said MD1 1 Hospital Medicine Department, Logan Regional Medical Center, Logan, WV, USA\nSaid Hajouli, MD, 20 Hospital Dr, Logan, WV 25601, USA. Email: dr.SaidHajouli@gmail.com\n25 3 2020 \nJan-Dec 2020 \n8 232470962091478712 11 2019 22 2 2020 25 2 2020 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Venous thromboembolism (VTE) includes deep venous thrombosis (DVT) and pulmonary embolism (PE). In this article, we present a case of a patient with an acute DVT who was treated with a therapeutic heparin drip, then developed syncope while in the hospital and found to have massive bilateral PEs. This case aims to arouse the medical staff’s awareness of the VTE diagnosis even if the patient is fully anticoagulated. We review the indications for DVT hospitalization, heparin infusion monitoring, risk factors for developing PE from DVT, mechanisms of developing PE from DVT while on therapeutic anticoagulation, and signs and treatment of massive PE.\n\npulmonary embolismvenous thrombosisheparin dripanticoagulationfatal PEmassive PEcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nVenous thromboembolism (VTE) is an important cause of cardiovascular disability and death. The yearly incidence of VTE in the United States is 1 to 2 per 1000.1 It affects 300 000 to 600 000 individuals in the United States every year.1 The mortality rate at 28 days, after the first VTE diagnosis, is 9.4% in deep venous thrombosis (DVT) and 15.1% in pulmonary embolism PE.2 PE is a major source of morbidity and mortality that causes 300 000 deaths annually in the United States.3 Massive PE is defined by obstruction of >50% of the cross-sectional area of the pulmonary arterial tree causing severe and acute right ventricular (RV) overload and cardiopulmonary failure. Seventy percent of patients who die of a PE die within the first hour of symptoms onset.4 Anticoagulation is the main treatment for VTE. Anticoagulation and thrombolysis are the standard treatments for acute massive PE.\n\nCase Presentation\nA 46-year-old Caucasian male with a history of hypertension, obesity, hyperlipidemia, and left renal cell adenocarcinoma (RCC) a few years ago status post partial nephrectomy and was in remission, presented to the emergency room (ER) with a 10-day history of severe right lower extremity (LE) pain, redness, and swelling. No history of recent travel, trauma, immobilization, or surgery. No history of DVT in the past. He was not compliant with his medications that included Lisinopril and atorvastatin. His physical examination showed swelling of the right LE with erythema, edema, tenderness, and positive Homans’ sign. Dorsalis pedis and posterior tibial arteries pulses were +3 bilaterally. No cyanosis or blanching of the lower extremities. The rest of the physical examination was unremarkable. His basic laboratory workup including complete blood count, prothrombin time, partial thromboplastin time (PTT), international normalized ratio (INR), and the comprehensive metabolic panel was normal (Table 1). His LE venous Doppler showed acute DVT from the proximal right superficial femoral vein through the popliteal vein and involving the calf veins. The patient was given analgesics orally, but his pain did not subside so he was started on intravenous (IV) analgesics. The patient was admitted to the telemetry floor after he was started on a heparin drip with a bolus for full anticoagulation. Hypercoagulable state workups were sent. With his history of RCC, the patient had a computed tomography (CT) of the chest and abdomen/pelvis with IV contrast to rule out any masses/cancers as an underlying possible provoked cause of his acute DVT, but all came back negative. No incidental PE was seen in the CT chest (Figure 1). The patient was thought to have a high-risk DVT due to its extension, so the plan was to treat him with parenteral anticoagulation for 5 to 7 days and then switch to direct oral anticoagulation (DOAC). On day 5, the patient had an episode of syncope for 2 minutes when he was standing up from his bed. His vitals at that time were the following: blood pressure 121/67 mm Hg, heart rate 95 beats per minute, respiratory rate 16 breaths per minute, and oxygen saturation (SaO2) 96% on room air. Orthostatic vitals were negative. His electrocardiography (EKG) and telemetry did not show any arrhythmia. It was thought that the patient had a vasovagal reflex syncope. The patient was continued on heparin drip with an activated PTT (aPTT) 1.5 times the control all the time (Table 2). In a few minutes after his syncopal episode, the patient became hypoxic, tachypneic, and tachycardic. His repeated blood pressure was 128/75 mm Hg. His chest X-ray showed clear lungs. His repeated EKG showed sinus tachycardia with a heart rate of 101 beats per minute. His Wells score was 10.5, which is high risk for PE, so STAT CT-PE was done and showed bilateral large pulmonary emboli in both main pulmonary arteries extending into the upper and lower pulmonary arteries bilaterally with right ventricle appearing more prominent than the left suggesting right heart strain (Figures 2 and 3). STAT bedside echocardiogram showed severely enlarged RV with severely reduced RV systolic function and a large mobile mass in the right atrium (RA) suspected of a thrombus (Figures 4 and 5). A few minutes later, he was unresponsive and did not have a pulse. Advanced Cardiac Life Support (ACLS) was started per protocol for pulseless electrical activity (PEA) arrest. Tissue plasminogen activator infusion was administered per protocol. One hundred minutes after the ACLS, the patient remained pulseless and could not achieve a return of spontaneous circulation (ROSC) so the code was called out and the patient was pronounced dead. His hypercoagulable workup showed high factor II DNA analysis consistent with a single G20210A mutation (heterozygote) in factor II (prothrombin) gene. Factor V Leiden DNA was measured by allele-specific polymerase chain reaction and was high, which was consistent with a single R506Q mutation (heterozygote) in factor V gene.\n\nTable 1. Laboratory results on admission.\n\nWBC\t10.4\t\nHemoglobin\t15.9\t\nHematocrit\t48.2\t\nPlatelet\t294\t\nINR\t1\t\nPT\t10.4\t\nPTT\t26.8\t\nAbbreviations: WBC, white blood cell; INR, international normalized ratio; PT, prothrombin time; PTT, partial thromboplastin time.\n\nFigure 1. Computed tomography scan of chest with contrast. No pulmonary embolism.\n\nTable 2. aPTT monitoring.\n\nDay of Hospitalization\taPTT Level (Normal Range 24.5-31.5)\t\n1 (every 6 hours)\t59.5\t49.5\t50.6\t\n2\t72\t\t\t\n3\t49.8\t\t\t\n4\t50.4\t\t\t\n5\t50.7\t\t\t\nAbbreviation: aPTT, activated partial thromboplastin time.\n\nFigure 2. Computed tomography pulmonary embolism (CTPE) showing left pulmonary artery PE.\n\nFigure 3. Computed tomography pulmonary embolism (CTPE) showing right pulmonary artery PE.\n\nFigure 4. Echocardiogram showing right ventricular dilatation and hypokinesis.\n\nFigure 5. Echocardiogram showing thrombus in the right atrium.\n\nDiscussion\nVenous thromboembolism is the third most common cardiovascular cause of death in the United States after heart attacks and strokes.5 It can be treated in an inpatient or in an outpatient setting. PE is usually treated in an inpatient setting with an average hospital stay of 6 days.6 The safety of treating PE at home is uncertain as acute PE is associated with higher short-term mortality than acute DVT. Because of limited evidence, the American College of Chest Physicians (ACCP) gives a grade 2B recommendation as for early discharge of low-risk PE patients if PE Severity Index (PESI score) <85, and none of any of the following: hypoxia, hypotension (systolic blood pressure <100 mm Hg), intense symptoms, thrombocytopenia with platelet count <70 000/mm3, recent bleeding, PE even with anticoagulation, or profound renal or liver dysfunction.7\n\nOutpatient treatment of LEDVT does not increase the risk of complications or mortality when compared with inpatient treatment. There is a grade 1B recommendation from the 2012 ACCP guidelines for outpatient treatment of LEDVT whose home circumstances are adequate.7 However, there are some criteria that help determine which patient should be treated as inpatient, and the presence of one of them indicates the possible need for hospitalization8:\n\nMassive DVT: 5% of symptomatic LEDVT can progress into the iliofemoral veins or even into the inferior vena cava and cause massive DVT. Massive DVT will lead to swelling of the whole leg, severe symptoms, acrocyanosis, and acute limb ischemia if not treated appropriately. Hospitalization of these patients is recommended for parenteral analgesia and to consider thrombolytic agents, or for extended duration of parenteral anticoagulation (like unfractionated heparin [UFH] or low-molecular-weight heparin [LMWH] for 10-14 days).\n\nHigh risk of bleeding: 5% to 10% of newly diagnosed DVT patients are at high risk of bleeding when they start anticoagulation therapy and they should be monitored closely.2 Those include recent (within 1 week) surgery or trauma, thrombocytopenia (platelet count <100 × 106/L), coagulopathy, bleeding within the past 4 weeks (like from a peptic ulcer), active bleeding, or advanced cancer with intracerebral or intrahepatic metastases as metastases to these sites are usually highly vascular.\n\nConcurrent symptomatic PE: It is estimated that 10% of symptomatic LEDVT patients have also symptomatic PE at the time of DVT diagnosis and those patients require hospitalization.9\n\nInpatient treatment for acute LEDVT is also recommended for patients with severe pain that requires IV analgesics or patients with severe comorbidities (eg, advanced malignancies). Patients whose home environment is not appropriate are also treated as inpatients such as no phone access, no strong family support, unable to return to the hospital quickly if worsening, or any issues that impede the outpatient follow-ups and anticoagulation monitoring (such as psychological, cognitive, or physical impairments).\n\nThis patient was hospitalized as he required IV analgesics, was not compliant, and thought to have a high-risk DVT even he did not have a massive DVT.\n\nThe primary goal of VTE treatment is to reduce morbidity, mortality, clot propagation, and prevent recurrent thrombosis. Anticoagulation is the cornerstone of VTE treatment. DOAC is the preferred treatment for non–high-risk VTE.10 Parenteral anticoagulants like LMWH or UFH are recommended in the initial acute phase of high-risk VTE (first 7 days in which the inflammatory process is at its highest) and continued for at least 5 days.7,11 Heparin (continuous infusion or subcutaneous) was the standard of care for VTE treatment (grade 1A) until LMWH production. Heparin has multiple advantages such as short-acting time, inexpensive cost, rapid onset, and reversibility.12 It is the preferred treatment for hemodynamically unstable PE or iliofemoral DVT as those patients may require advanced therapies and interruption of their anticoagulation. Heparin interacts with antithrombin III and inhibits thrombin formation that leads to the prevention of fibrinogen conversion to fibrin, which prevents thrombosis. There is no optimal approach to monitor heparin therapy. The 2 available methods to monitor heparin are anti-Xa and aPTT. The aPTT is less expensive, more familiar to clinicians, and more available when compared with anti-Xa, and it is the most used method by medical providers to monitor heparin therapy. However, there are pre-analytic and analytic problems that may occur and may affect both aPTT and anti-Xa results such as inappropriate sample collection, transport, processing, storage, reagents used, and coagulometer used. There are also biological factors that may affect the aPTT but have less impact on the anti-Xa levels such as high levels of factor VIII or elevated fibrinogen.13-16 Anti-Xa is inaccurate in the setting of elevated total bilirubin levels to >6.6 mg/dL, elevated triglycerides to >360 mg/dL, and recent use of LMWH or fondaparinux (especially with renal dysfunction).17,18 Anti-Xa level does not require frequent monitoring tests or dose adjustment compared with aPTT.18 There are no sizeable VTE studies that looked into the outcomes of patients monitored with anti-Xa while on heparin treatment. The use of anti-Xa to monitor heparin therapy is recommended in the case of heparin resistance or prolonged baseline aPTT.19 The risks of recurrent VTE and thrombus extension were lower when aPTT was preserved between 1.5 and 2.5 times the control.20,21 These data produced the guidelines recommendations to keep the aPTT levels between 1.5 and 2.5 times the control as a therapeutic range.\n\nAnticoagulation does not dissolve an existing thrombus but stabilizes it, prevents its extension, and decreases (but does not eliminate) the risk of embolization and recurrent thrombosis. Forty percent of symptomatic DVT patients have silent PE at the time of diagnosis.22 Our patient did not have PE at the time of his DVT diagnosis according to his first CT chest with IV contrast. There are no specific comorbidities or VTE risk factors that can increase the likelihood of developing PE in DVT patients. In a study of 141 PE patients,23 the overall prevalence rate of concomitant DVT was 45.4% and 39% had proximal DVT. There were no statistically significant differences between the 2 groups (PE without DVT vs PE with concomitant DVT) in terms of VTE risk factors and comorbidities. In another study that had 114 patients with DVT,24 the prevalence of PE was 52.6%. They divided patients into 2 groups and compared the risk factor for each group: group I had DVT patients without PE and group II had DVT patients with PE.24 The only risk factor that reached statistical significance in this study was infection (more in group II, with a P value of .005), and they concluded that infection was linked to an increased risk of PE development in patients with LEDVT.25 However, this study had a small sample size of 114 patients only. Acute infection is a known factor to increase the risk of PE and DVT.26\n\nPulmonary embolism while on therapeutic anticoagulation is uncommon and possesses a challenge diagnosis and management.24 The 2 possible mechanisms in which the PE may occur even with therapeutic anticoagulation are clot propagation (emboli break off from an existing DVT to the blood circulation and then to the pulmonary arteries) or breakthrough PE (new thrombus formation in the pulmonary system).\n\nThe occurrence of PE as an extension of DVT is infrequent in patients treated well with anticoagulation. The topical propagation of DVT is common and could be part of the natural history of VTE as a prolonged inflammatory and remodeling process. In randomized controlled trials that included serial screening imaging studies (venous duplex or venography) after DVT diagnosis, the risk of asymptomatic topical DVT propagation in the first 10 days of therapy was 4.7% and 1.1% in UFH and LMWH, respectively,27 and these may reach up to 30% to 38% in some other studies (most of these cases had subtherapeutic anticoagulation).28,29 The risk of symptomatic topical DVT propagation is 0.3% and 0.6% for UFH and LMWH, respectively.28 The data for asymptomatic and symptomatic PE propagation are less known, and the reliable estimates of developing fatal PE from acute DVT are nonexistent. In one study that had patients presented with DVT and were treated with heparin for 5 to 10 days and then oral anticoagulation, the risk of fatal PE was low at 0.4%.30\n\nThe risk of the breakthrough event, when anticoagulation is managed well, is 2 per 100 patient-years for oral anticoagulation,31,32 and it may warrant cancer screening as a possible underlying cause. The breakthrough rate while on warfarin was 1.2% in Kaiser Performance ER patients in a study that excluded patients with VTE in the previous 30 days,33 31% had active cancer and 42% had at least one subtherapeutic INR 14 days before the ER visit. The incidence was 6.1% with therapeutic INR in an Australian study in 2013.34 This risk was 4% in the first 15 days of treatment with UHF or LMWH.35,36 In a prospective study that had 50 VTE patients (DVT, PE, or inferior vena cava thrombosis) treated with heparin drip and followed with repeated imaging at day 15, PE occurred in 2 patients (4%), one of them had subtherapeutic anticoagulation and died (2%).36 Fatal PE rate was 0.07% during treatment with warfarin or DOAC.32\n\nThe most common causes of the breakthrough PE are subtherapeutic anticoagulation (incorrect dose, drug interaction, or poor adherence) or underlying disease that can cause hypercoagulability such as active cancer,37 vasculitis (Behcet disease),38 myeloproliferative neoplasms,39 heparin-induced thrombocytopenia,40 vascular malformation,41 antiphospholipid antibody syndrome,42 and JAK2 V617F mutation.31,43\n\nIn our patient, inadequate anticoagulation was less likely as his aPTT was 1.5 times the control all the time (Table 2), which should significantly decrease the risk of recurrent thrombosis and prevent extension.20,21 Heparin resistance was also less likely as the patient did not require high doses of heparin to keep his aPTT at goal. Heparin-induced thrombocytopenia was excluded because of normal platelets 1 hour before the PEA arrest. His anticardiolipin antibodies and anti-B2-GPI antibodies were negative, which should make antiphospholipid antibody syndrome less likely too. He had a remote history of RCC but did not have active cancer at the time of presentation, and his CT scan of abdomen/pelvis did not show any masses. He did not have any signs or symptoms of vasculitis. His BCR-ABL and JAk2 mutations were negative, and his laboratory workup did not show increased red blood cell volume or thrombocytosis, which should rule out myeloproliferative neoplasms. The patient had both single G20210A mutation in the factor II gene and a single R506Q mutation in factor V gene, which increases the risk of recurrent thrombosis but the interval from the first DVT to recurrence is few years, not few days.44 In his case, we think that heparin failed to stabilize the thrombus in his LE and caused thrombus to break off from his LE into the bloodstream to RA and pulmonary system to cause massive fatal PE, which is not very common and would not be expected while on anticoagulation.\n\nSymptoms of PE are nonspecific, and it can be difficult to diagnosis PE and even more difficult in patients on therapeutic anticoagulation. Syncope can be the presenting symptom of PE in 0.06% to 0.55% ER patients and 0.15% to 2.1% in hospitalized syncope patients,45 which may reach up to 6%.46 Massive PE is characterized by systemic hypotension and cardiogenic shock. Systemic hypotension is described as a systolic arterial pressure <90 mm Hg or a drop in systolic arterial pressure of at least 40 mm Hg for at least 15 minutes.47 Shock is defined by tissue hypoperfusion that leads to encephalopathy, decreased urine output, hypoxia, or cool and clammy limbs. Massive PE may be a challenging diagnosis if it arises in patients who have not been sick lately. The physical examination will show systemic hypotension, altered mental status, tachycardia, tachypnea, cyanosis, jugular vein distension, a parasternal heave, a tricuspid valve regurgitation murmur, and an accentuated P2. EKG may show sinus tachycardia, S1Q3T3 pattern, or T-wave inversions in V1 to V4, but ECG may be completely normal. Bedside echocardiogram must be done when a massive PE is suspected to confirm the RV dysfunction/dilatation and exclude other etiologies that can cause the same symptoms such as cardiac tamponade. Contrast-enhanced chest CT angiography is the gold standard for the diagnosis of PE.48 Fibrinolysis is the treatment of choice for the massive PE if no contraindication.11,49,50 It rapidly lyses the thrombus and improves the RV functioning. Treatment also includes volume expansion, vasopressors, and inotropes if needed. Massive PE may cause acute occlusion of the RV outflow that can lead to acute circulatory collapse and death. Most death takes place within a few hours after the onset of symptoms. The mortality rate in massive PE is 15.2% if arterial hypotension and 24.5% if cardiogenic shock.47 If PE causes cardiac arrest, the mortality rate will be high and thrombolysis should be attempted to achieve ROSC and probably better outcomes. However, even with thrombolysis in cardiac arrest related PE, the mortality rate is 90%.51\n\nOther treatments of the massive PE if contraindications for thrombolysis exist include catheter thrombectomy and surgical embolectomy. The 2012 ACCP guidelines give grade 2C recommendations for catheter-assisted thrombus removal and surgical embolectomy and only if contraindications to thrombolysis exist and if surgical expertise and resources are available.7\n\nThe ACCP 2012 and 2016 guidelines recommend anticoagulation alone for the treatment of most acute DVTs. Other acute DVT treatments are thrombolysis (systemic or catheter-directed) and/or thrombectomy (surgical or catheter-directed), which are indicated only in patients with acute limb threat (phlegmasia cerulea dolens), massive iliofemoral DVT, or in which anticoagulation has failed. Those treatments are indicated only if patients have good functional status, low bleeding risk, fresh clot (<14 days old), and life expectancy >1 year.11,12 This is because the mortality rate and the risk of recurrent thrombosis are not changed with these interventions comparing with anticoagulation alone. Inferior vena cava filter is indicated only when anticoagulation is contraindicated (active bleeding).52 Our patient did not meet any of these criteria, and his acute DVT was treated according to the current guidelines with anticoagulation alone.\n\nConclusion\nVenous thromboembolism is still a possible diagnosis even if the patient is on full anticoagulation. PE is an important differential diagnosis of syncope. Keeping this in mind helps make an early diagnosis of a potentially fatal VTE and that may save patients’ lives. In this patient, his PE was diagnosed early and was treated with thrombolysis according to the current guidelines but he ended up in a PEA arrest and death, so more research may be required in the future to determine the risk factors for developing fatal PE from DVT while on anticoagulation and that can produce more guidelines to treat these patients and prevent their death.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases.\n\nInformed Consent: Informed consent for patient information to be published in this article was not obtained because our institution does not require informed consent for individual case reports.\n\nORCID iD: Said Hajouli \nhttps://orcid.org/0000-0002-6444-2751\n==== Refs\nReferences\n1 \nBeckman MG Hooper WC Critchley SE Ortel TL. \nVenous thromboembolism: a public health concern\n. Am J Prev Med . 2010 ;38 (4 suppl ):S495 -S501\n. doi:10.1016/j.amepre.2009.12.017 20331949 \n2 \nCushman M Tsai A Heckbert SR , et al\nIncidence rates, case fatality, and recurrence rates of deep vein thrombosis and pulmonary embolus: the Longitudinal Investigation of Thromboembolism Etiology (LITE)\n. Thromb Haemost . 2001 ;86 (suppl 1 ):OC2349 .\n3 \nTapson VF. \nAcute pulmonary embolism\n. N Engl J Med . 2008 ;358 :1037 -1052\n.18322285 \n4 \nHsieh PC Wang SS Ko WJ Han YY Chu SH. \nSuccessful resuscitation of acute massive pulmonary embolism with extracorporeal membrane oxygenation and open embolectomy\n. Ann Thorac Surg . 2001 ;72 :266 -267\n.11465197 \n5 \nTagalakis V Patenaude V Kahn SR Suissa S. \nIncidence of and mortality from venous thromboembolism in a real-world population: the Q-VTE study cohort\n. Am J Med . 2013 ;126 :832.e13-e21.\n6 \nAujesky D Stone RA Kim S Crick EJ Fine MJ. \nLength of hospital stay and postdischarge mortality in patients with pulmonary embolism: a statewide perspective\n. Arch Intern Med . 2008 ;168 :706 -712\n. doi:10.1001/archinte.168.7.706 18413552 \n7 \nKearon C Akl EA Comerota AJ , et al\nAntithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines\n. Chest . 2012 ;141 (2 suppl ):e419S -e496S\n. doi:10.1378/chest.11-2301 22315268 \n8 \nDouketis JD. \nTreatment of deep vein thrombosis: what factors determine appropriate treatment?\n\nCan Fam Physician . 2005 ;51 :217 -223\n.15751565 \n9 \nDouketis JD Foster GA Crowther MA Prins MH Ginsberg JS. \nClinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy\n. Arch Intern Med . 2000 ;160 :3431 -3436\n.11112236 \n10 \nKearon C Akl EA Ornelas J , et al\nAntithrombotic therapy for VTE disease: CHEST Guideline and Expert Panel Report\n. Chest . 2016 ;149 :315 -352\n.26867832 \n11 \nKearon C Kahn SR Agnelli G Goldhaber S Raskob GE Comerota AJ. \nAntithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)\n. Chest . 2008 ;133 (6 suppl ):454S -545S\n. doi:10.1378/chest.08-0658 18574272 \n12 \nGarcia DA Baglin TP Weitz JI Samama MM. \nParenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines\n. Chest . 2012 ;141 (2 suppl ):e24S -e43S\n. doi:10.1378/chest.11-2291 22315264 \n13 \nLevine MN Hirsh J Gent M , et al\nA randomized trial comparing activated thromboplastin time with heparin assay in patients with acute venous thromboembolism requiring large daily doses of heparin\n. Arch Intern Med . 1994 ;154 :49 -56\n.8267489 \n14 \nUprichard J Manning RA Laffan MA. \nMonitoring heparin anticoagulation in the acute phase response\n. Br J Haematol . 2010 ;149 :613 -619\n. doi:10.1111/j.1365-2141.2010.08129.x 20230412 \n15 \nEikelboom JW Hirsh J. \nMonitoring unfractionated heparin with the aPTT: time for a fresh look\n. Thromb Haemost . 2006 ;96 :547 -552\n.17080209 \n16 \nCuker A Raby A Moffat KA Flynn G Crowther MA. \nInterlaboratory variation in heparin monitoring: lessons from the Quality Management Program of Ontario coagulation surveys\n. Thromb Haemost . 2010 ;104 :837 -844\n. doi:10.1160/TH10-02-0099 20664895 \n17 \nFaust AC Kanyer D Wittkowsky AK. \nManaging transitions from oral factor Xa inhibitors to unfractionated heparin infusions\n. Am J Health Syst Pharm . 2016 ;73 :2037 -2041\n.27919873 \n18 \nRosborough TK. \nMonitoring unfractionated heparin therapy with antifactor Xa activity results in fewer monitoring tests and dosage changes than monitoring with the activated partial thromboplastin time\n. Pharmacotherapy . 1999 ;19 :760 -766\n.10391423 \n19 \nSmythe MA Priziola J Dobesh PP Wirth D Cuker A Wittkowsky AK. \nGuidance for the practical management of the heparin anticoagulants in the treatment of venous thromboembolism\n. J Thromb Thrombolysis . 2016 ;41 :165 -186\n. doi:10.1007/s11239-015-1315-2 26780745 \n20 \nBasu D Gallus A Hirsh J Cade J. \nA prospective study of the value of monitoring heparin treatment with the activated partial thromboplastin time\n. N Engl J Med . 1972 ;287 :324 -327\n.5041701 \n21 \nChiu HM Hirsh J Yung WL Regoeczi E Gent M. \nRelationship between the anticoagulant and antithrombotic effects of heparin in experimental venous thrombosis\n. Blood . 1977 ;49 :171 -184\n.831872 \n22 \nMeignan M Rosso J Gauthier H , et al\nSystematic lung scans reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis\n. Arch Intern Med . 2000 ;160 :159 -164\n. doi:10.1001/archinte.160.2.159 10647753 \n23 \nLee JS Moon T Kim TH , et al\nDeep vein thrombosis in patients with pulmonary embolism: prevalence, clinical significance and outcome\n. Vasc Specialist Int . 2016 ;32 :166 -174\n. doi:10.5758/vsi.2016.32.4.166 28042556 \n24 \nHerrera S Comerota AJ. \nEmbolization during treatment of deep venous thrombosis: incidence, importance, and prevention\n. Tech Vasc Interv Radiol . 2011 ;14 :58 -64\n. doi:10.1053/j.tvir.2011.01.002 21550507 \n25 \nPaik B Joh JH Park HC. \nAnatomic and clinical risk factors for pulmonary embolism in patients with deep venous thrombosis of the lower extremity\n. Ann Surg Treat Res . 2017 ;92 :365 -369\n. doi:10.4174/astr.2017.92.5.365 28480183 \n26 \nSmeeth L Cook C Thomas S Hall AJ Hubbard R Vallance P. \nRisk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting\n. Lancet . 2006 ;367 :1075 -1079\n. doi:10.1016/S0140-6736(06)68474-2 16581406 \n27 \nPrandoni P Lensing AW Buller HR , et al\nComparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis\n. Lancet . 1992 ;339 :441 -445\n.1346817 \n28 \nMeissner MH Caps MT Bergelin RO Manzo RA Strandness DE Jr. \nPropagation, rethrombosis and new thrombus formation after acute deep venous thrombosis\n. J Vasc Surg . 1995 ;22 :558 -567\n.7494356 \n29 \nKrupski WC Bass A Dilley RB Bernstein EF Otis SM. \nPropagation of deep venous thrombosis identified by duplex ultrasonography\n. J Vasc Surg . 1990 ;12 :467 -475\n.2214041 \n30 \nDouketis JD Kearon C Bates S Duku EK Ginsberg JS. \nRisk of fatal pulmonary embolism in patients with treated venous thromboembolism\n. JAMA . 1998 ;279 :458 -462\n.9466640 \n31 \nSchulman S. \nHow I treat recurrent venous thromboembolism in patients receiving anticoagulant therapy\n. Blood . 2017 ;129 :3285 -3293\n. doi:10.1182/blood-2017-03-742304 28483766 \n32 \nvan der Hulle T Kooiman J den Exter PL , et al\nEffectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis\n. J Thromb Haemost . 2014 ;12 :320 -328\n.24330006 \n33 \nLiu MY Ballard DW Huang J , et al\nAcute pulmonary embolism in emergency department patients despite therapeutic anticoagulation\n. West J Emerg Med . 2018 ;19 :510 -516\n.29760849 \n34 \nMoutzouris JP Ng AC Chow V Chung T Curnow J Kritharides L. \nAcute pulmonary embolism during warfarin therapy and long-term risk of recurrent fatal pulmonary embolism\n. Thromb Haemost . 2013 ;110 :523 -533\n.23740364 \n35 \nWells PS Anderson DR Rodger MA , et al\nA randomized trial comparing two low-molecular-weight heparins for the outpatient treatment of deep vein thrombosis and pulmonary embolism\n. Arch Intern Med . 2005 ;165 :733 -738\n.15824291 \n36 \nGirard P Mathieu M Simonneau G , et al\nRecurrence of pulmonary embolism during anticoagulant treatment: a prospective study\n. Thorax . 1987 ;42 :481 -486\n.3438891 \n37 \nLee AYY Kamphuisen PW Meyer G , et al\nTinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial\n. JAMA . 2015 ;314 :677 -686\n. doi:10.1001/jama.2015.9243 26284719 \n38 \nSpringer J Villa-Forte A. \nThrombosis in vasculitis\n. Curr Opin Rheumatol . 2013 ;25 :19 -25\n.23143223 \n39 \nDe Stefano V Ruggeri M Cervantes F , et al\nHigh rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists\n. Leukemia . 2016 ;30 :2032 -2038\n.27113812 \n40 \nLinkins LA Dans AL Moores LK , et al\nTreatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines\n. Chest . 2012 ;141 (2 suppl ):e495S -e530S\n.22315270 \n41 \nGoldenberg NA Branchford B Wang M Ray C JrDurham JD Manco-Johnson MJ. \nPercutaneous mechanical and pharmacomechanical thrombolysis for occlusive deep vein thrombosis of the proximal limb in adolescent subjects: findings from an institution-based prospective inception cohort study of pediatric venous thromboembolism\n. J Vasc Interv Radiol . 2011 ;22 :121 -132\n.21216157 \n42 \nFinazzi G Marchioli R Brancaccio V , et al\nA randomized clinical trial of high-intensity warfarin vs. conventional antithrombotic therapy for the prevention of recurrent thrombosis in patients with the antiphospholipid syndrome (WAPS)\n. J Thromb Haemost . 2005 ;3 :848 -853\n.15869575 \n43 \nIanotto JC Chauveau A Mottier D , et al\nJAK2V617F and calreticulin mutations in recurrent venous thromboembolism: results from the EDITH prospective cohort\n. Ann Hematol . 2017 ;96 :383 -386\n. doi:10.1007/s00277-016-2853-1 27766390 \n44 \nDe Stefano V Martinelli I Mannucci PM , et al\nThe risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation\n. N Engl J Med . 1999 ;341 :801 -806\n.10477778 \n45 \nCostantino G Ruwald MH Quinn J , et al\nPrevalence of pulmonary embolism in patients with syncope\n. JAMA Intern Med . 2018 ;178 :356 -362\n.29379959 \n46 \nAmmar H Ohri C Hajouli S , et al\nPrevalence and predictors of pulmonary embolism in hospitalized patients with syncope\n. South Med J . 2019 ;112 :421 -427\n. doi:0.14423/SMJ.000000000000100931375838 \n47 \nKasper W Konstantinides S Geibel A , et al\nManagement strategies and determinants of outcome in acute major pulmonary embolism: results of a multicenter registry\n. J Am Coll Cardiol . 1997 ;30 :1165 -1171\n.9350909 \n48 \nKonstantinides SV Torbicki A Agnelli G , et al\n2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism\n. Eur Heart J . 2014 ;35 :3033-3069, 3069a-3069k. doi:10.1093/eurheartj/ehu283 \n49 \nBüller HR Agnelli G Hull RD Hyers TM Prins MH Raskob GE. \nAntithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy\n. Chest . 2004 ;126 (3 suppl ):401S -428S\n.15383479 \n50 \nWan S Quinlan DJ Agnelli G Eikelboom JW. \nThrombolysis compared with heparin for the initial treatment of pulmonary embolism: a meta-analysis of the randomized controlled trials\n. Circulation . 2004 ;110 :744 -749\n.15262836 \n51 \nKürkciyan I Meron G Sterz F , et al\nPulmonary embolism as a cause of cardiac arrest: presentation and outcome\n. Arch Intern Med . 2000 ;160 :1529 -1535\n.10826469 \n52 \nWhite RH Brunson A Romano PS Li Z Wun T. \nOutcomes after vena cava filter use in noncancer patients with acute venous thromboembolism: a population-based study\n. Circulation . 2016 ;133 :2018 -2029\n. doi:10.1161/CIRCULATIONAHA.115.020338 27048765\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "anticoagulation; fatal PE; heparin drip; massive PE; pulmonary embolism; venous thrombosis",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000925:Anticoagulants; D017809:Fatal Outcome; D006493:Heparin; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism; D012307:Risk Factors; D013575:Syncope; D014057:Tomography, X-Ray Computed; D020246:Venous Thrombosis",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709620914787",
"pmc": null,
"pmid": "32208868",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11465197;15824291;9350909;20331949;31375838;23740364;26284719;18322285;8267489;24330006;28480183;1346817;26867832;25173341;26780745;10391423;7494356;29760849;20230412;21216157;23143223;10647753;3438891;22315264;23830539;15262836;27113812;16581406;27919873;27048765;18574272;9466640;10826469;28483766;22315268;28042556;17080209;15383479;11112236;10477778;20664895;18413552;21550507;831872;15869575;29379959;5041701;27766390;22315270;2214041;15751565",
"title": "Massive Fatal Pulmonary Embolism While on Therapeutic Heparin Drip.",
"title_normalized": "massive fatal pulmonary embolism while on therapeutic heparin drip"
} | [
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"companynumb": "US-MYLANLABS-2020M1067992",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
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"drugadditional": null,
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{
"abstract": "Introduction. Carbapenem-resistant Enterobacteriaceae (CRE) are an urgent threat in the USA and are associated with adverse clinical and economic outcomes. Several studies have evaluated risk factors for acquiring CRE versus carbapenem-susceptible Enterobacteriaceae, identifying antibiotic use and length of hospital stay as major players. However, no studies have compared risk factors for CRE colonization versus infection.Hypothesis/Gap Statement. Patients with CRE infection will have different risk factors and worse clinical outcomes than patients with CRE colonization.Aim. To assess clinical outcomes in patients with CRE infection versus CRE colonization.Methodology. A retrospective cohort of adult patients admitted between 1 June 2013 and 31 July 2018 with the first positive CRE culture from any source was performed. Patients were divided into two groups: CRE infection versus CRE colonization. Data collected included demographics, comorbidities, past antimicrobial usage and clinical outcomes (length of stay, in-hospital mortality). The primary outcome was infection-related length of stay. Data analysis was performed utilizing SPSS with a two-sided P value of less than 0.05 considered statistically significant.Results. A total of 56 patients were included (32 with infection; 24 with colonization). Baseline characteristics were similar between both groups. Infected patients were more likely to have higher actual body weight compared to colonized patients (P=0.03). CRE-infected patients had a longer infection-related hospital stay [12 days (5-20) and 7.5 days (1-13), respectively; P=0.08], but in-hospital mortality was similar between infected and colonized patients (37.5 and 29.2 %, respectively; P=0.30). Patients with infection were more likely to have previous exposure to levofloxacin (P=0.02) and trimethoprim/sulfamethoxazole (P=0.03) for a median of 9 days compared to those with colonization. The most common source of CRE in infected patients was the blood compared to respiratory sources in colonized patients.Conclusion. CRE infection as opposed to colonization was more common in patients with previous exposure to levofloxacin and trimethoprim/sulfamethoxazole and those with higher actual body weight.",
"affiliations": "Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 North State Street, Jackson, MS, USA.;Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 North State Street, Jackson, MS, USA.;Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 North State Street, Jackson, MS, USA.;Department of Pharmacy Practice, University of Mississippi School of Pharmacy, 2500 North State Street, Jackson, MS, USA.",
"authors": "Barber|Katie E|KE|;Wagner|Jamie L|JL|;Larry|Rachel C|RC|;Stover|Kayla R|KR|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015780:Carbapenems; D064704:Levofloxacin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "England",
"delete": false,
"doi": "10.1099/jmm.0.001286",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-2615",
"issue": "70(2)",
"journal": "Journal of medical microbiology",
"keywords": "CRE; Enterobacteriaceae; obesity",
"medline_ta": "J Med Microbiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D000073182:Carbapenem-Resistant Enterobacteriaceae; D015780:Carbapenems; D016022:Case-Control Studies; D024881:Drug Resistance, Bacterial; D004756:Enterobacteriaceae Infections; D005260:Female; D006801:Humans; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "0224131",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33263511",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": "28749714;31138574;23838221;25103492;31573026;25008195;28415969;30488368;28971864;29876368;24602945;31024972;27590417;27124716;31074254",
"title": "Frequency of and risk factors for carbapenem-resistant Enterobacteriaceae.",
"title_normalized": "frequency of and risk factors for carbapenem resistant enterobacteriaceae"
} | [
{
"companynumb": "US-JNJFOC-20201223034",
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"occurcountry": "US",
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"activesubstancename": "LEVOFLOXACIN"
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"drugadditional": "3",
... |
{
"abstract": "A 70-year-old end-stage renal disease patient was admitted for refractory hypoglycemia secondary to drug-drug interaction between clarithromycin and glipizide. We discussed the mechanism of antimicrobial and sulfonylurea interactions as well as the importance of understanding these interactions in the primary care setting to reduce medication-related hospitalizations.",
"affiliations": "Internal Medicine, Singapore General Hospital, Singapore, SGP.;Internal Medicine, Singapore General Hospital, SingHealth, Singapore, SGP.;Internal Medicine, Singapore General Hospital, Singapore, SGP.",
"authors": "Ruan|Xu Cong|XC|;Tan|Poh Yong|PY|;Tan|Yuyang|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.4800",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.4800Endocrinology/Diabetes/MetabolismInternal MedicineClarithromycin and Glipizide Drug-drug Interaction Leading to Refractory Hypoglycemia Muacevic Alexander Adler John R Ruan Xu Cong 1Tan Poh Yong 2Tan Yuyang 1\n1 \nInternal Medicine, Singapore General Hospital, Singapore, SGP \n2 \nInternal Medicine, Singapore General Hospital, SingHealth, Singapore, SGP \nXu Cong Ruan ruanxucong@gmail.com2 6 2019 6 2019 11 6 e480011 1 2019 1 6 2019 Copyright © 2019, Ruan et al.2019Ruan et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/14006-clarithromycin-and-glipizide-drug-drug-interaction-leading-to-refractory-hypoglycemiaA 70-year-old end-stage renal disease patient was admitted for refractory hypoglycemia secondary to drug-drug interaction between clarithromycin and glipizide. We discussed the mechanism of antimicrobial and sulfonylurea interactions as well as the importance of understanding these interactions in the primary care setting to reduce medication-related hospitalizations.\n\ndiabetesdrug interactionshypoglycemiaThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nHypoglycemia is a common problem faced by many patients with diabetes mellitus, especially when they are treated with glucose-lowering medication. Causes of hypoglycemia include drugs, sepsis, organ failure, insulinoma, prescribing/dispensing errors and post bariatric surgery [1]. Refractory hypoglycemia is defined as capillary blood glucose (CBG) persistently less than 80 mg/dL despite initial management with dextrose 50%. Prolonged hypoglycemia can increase neuronal cell death and this is especially prominent in high risk individuals such as those who are elderly, with chronic kidney disease, and suffer from polypharmacy [2]. We present a case of a patient who had refractory hypoglycemia attributed to antimicrobial and sulfonylurea interaction on background of end-stage renal disease on hemodialysis.\n\nCase presentation\nA 70-year-old Chinese female was admitted to a tertiary hospital for nonspecific symptoms of non-vertiginous dizziness with lethargy for two days. She has a history of diabetes of more than 20 years with recent tight glycemic control (HbA1c 5.4%). She also has end-stage renal failure on hemodialysis three times a week (eGFR < 15 ml/min). Her other past medical history includes hypertension, ischemic heart disease and metastatic breast cancer on exemestane, with complete response. Her medications include aspirin 100 mg OM, amlodipine 10 mg OM, losartan 75 mg OM, exemestane 25 mg OM, atorvastatin 40 mg ON, ferrous fumarate 200 mg BD, omeprazole 20 mg OM, cholecalciferol 1000 units OM, recormon 4000 units thrice a week, iron injection 100 mg every fortnight and calcium carbonate 1.25 g pre-lunch and pre-dinner. Her CBG measured at home was 70-90 mg/dL in the month prior to admission, despite taking regular meals. She has no hypoglycemia symptoms at baseline.\n\nOne week prior to admission, she visited her family physician for cough and fever lasting for a week, and was prescribed a course of clarithromycin for five days. There was no chest radiograph performed during this visit. Her last dose of clarithromycin was a day prior to admission.\n\nOn the day of admission, in view of her symptoms of dizziness and lethargy, she checked her CBG and noted that it was 50 mg/dL, which did not improve despite her taking additional meals and dextrose drinks. Beyond lethargy and giddiness, she did not have any other symptoms suggestive of neuroglycopenia. During her inpatient stay, her CBG was trended (Figure 1) and she was persistently hypoglycemic despite 11 boluses of 40 ml 50% dextrose, five intravenous boluses of 1 mg glucagon and a maintenance 10% dextrose drip. C-peptide was 23 UG/L (0.78-5.19 UG/L) and insulin level 34.5 mU/L (1.0-30.0 mU/L). This suggested increased insulin secretion from glipizide ingestion. We referred the patient to the endocrinology team. Their impression was that the refractory hypoglycemia was attributed to glipizide and clarithromycin drug-drug interaction in a renally impaired patient. Interestingly, her CBG improved to 120 mg/dL after hemodialysis, which likely assisted in removing serum glipizide. In view of her tight CBG control, glipizide was discontinued and she was placed on linagliptin, which was less likely to cause hypoglycemia.\n\nFigure 1 CBG trend of patient during inpatient stay and with illustrations of interventions provided, dextrose 50% 40 ml (blue arrows) and glucagon 1 mg (orange arrows).\nCBG: Capillary blood glucose\n\nDiscussion\nThis case illustrates how an elderly patient with end-stage renal failure on glucose-lowering medication can be predisposed to severe refractory hypoglycemia. In view of her advanced age, she may not illustrate early symptoms of hypoglycemia. In addition, her body was also less able to exert counter-regulatory response to hypoglycemia. In view of her renal impairment, there was progressive reduction in her insulin requirements through decreased renal clearance, degradation of insulin in peripheral tissues and renal gluconeogenesis [3]. Therefore, when her glucose-lowering medication was not titrated accordingly, it might account for the progressive decrease in her CBG trend prior to admission.\n\nThe main adverse effect of sulfonylurea is hypoglycaemia, which can be aggravated through the addition of hepatic cytochrome P450 inhibitors, such as antimicrobial agents [4,5]. In fact, it is estimated that 12.3% of all hypoglycemic events in patient prescribed sulfonylureas are associated with antimicrobial use, especially fluoroquinolones, macrolides, sulfamethoxazole-trimethoprim and azoles (Table 1) [4].\n\nTable 1 Common antimicrobial interactions with sulfonylurea leading to hypoglycemia.\nDrug\tPharmacodynamic Mechanism\tPharmacokinetic Mechanism\t\nDistribution\tMetabolism\t\nMacrolides, e.g., clarithromycin\t-\tMacrolides displace sulfonylurea from its protein bound state, leading to increased serum-free levels causing hypoglycemia\tMacrolides are P-glycoprotein inhibitors reducing the efflux of sulfonylurea from enterocytes, leading to increased serum levels precipitating hypoglycemia\t\nAzoles, e.g., fluconazole, voriconazole\t-\t-\tAzoles inhibit CYP2C9, therefore increasing serum sulfonylurea levels\t\nFluoroquinolones, e.g., moxifloxacin, ciprofloxacin, levofloxacin\tFluoroquinolones augment sulfonylurea in its inhibition of ATP K+ channels in pancreatic B-cells leading to earlier depolarization initiating insulin secretion\t-\t-\t\nSulfamethoxazole-trimethoprim\t-\t-\tSulfamethoxazole-trimethoprim inhibit CYP2C9, therefore increasing serum sulfonylurea levels\t\nThere are multiple postulations to explain this interaction. In addition to affecting hepatic metabolism, these agents also influence the distribution and elimination of sulfonylureas. Sulfonylureas are 90-99% protein bound, whereas macrolides such as clarithromycin are 40-70% protein bound [6]. The addition of macrolides can lead to the displacement of glipizide, leading to increased free serum glipizide in the body which exacerbates hypoglycemia. In addition, macrolides are P-glycoprotein inhibitors and may reduce the removal of sulfonylureas from the systemic circulation [4]. Lilja et al. illustrated that serum glibenclamide levels in volunteers were elevated by 24% after taking clarithromycin [7].\n\nMacrolides are well known CYP3A4 inhibitors. Unfortunately, glipizide is mostly cleared by CYP2C9. The inhibition of CYP3A4 by macrolides has minimum effect on the increase in serum glipizide levels [6].\n\nFor antifungals such as fluconazole and voriconazole, as well as sulfamethoxazole-trimethoprim, they are known to be CYP2C9 inhibitors. Since sulfonylureas are cleared by CYP2C9, their serum concentrations increase with the concomitant use of these medication, leading to hypoglycemia from the excessive release of insulin [5,8].\n\nFluoroquinolones, on the other hand, augments the pharmacodynamics action of sulfonylurea through inhibiting adenosine triphosphate-potassium channels (ATP-K+) in pancreatic B-cells, thereby leading to earlier depolarization, increasing insulin release causing hypoglycemia [9].\n\nFor our patient, her hypoglycemia was persistent despite multiple boluses of high concentration dextrose and intravenous glucagon. Glucagon was employed to counter hypoglycemia as it simulates glycogenolysis in the liver [10]. It is used as a salvage therapy for those with severe refractory hypoglycemia not responding to intravenous dextrose boluses.\n\nInteresting, while our patient did not respond to conventional therapy, her CBG improved immediately after dialysis. While we understand that glipizide is non-dialyzable when protein bound, it is likely that the clearance of unbound glipizide was made possible through the dialysis semipermeable membrane in view of its smaller molecular size [11].\n\nIn retrospect, for patients with renal impairment who illustrates symptoms of upper respiratory tract infection, it is prudent to delineate if her infection is viral or bacterial in origin to minimize the over-prescription antimicrobial agents. If indeed she does have pneumonia secondary to bacterial infection, a combination of amoxicillin/clavulanic acid with doxycycline would have been preferred to reduce the chance of drug-drug interactions.\n\nConclusions\nDrug-drug interactions and overtly tight glycemic control often lead to hypoglycemia in patients with diabetes mellitus. Hospitalization from hypoglycemia is associated with poor outcomes, especially in older patients, leading to death and neuroglycopenia. It is important to prevent polypharmacy in these individuals to reduce hospital admission rates. Interventions to enhance physicians’ knowledge of potential drug-drug interactions and judicious use of antimicrobials in this group of patients will facilitate care and reduce readmissions. It is also important to assess the glycemic control in individual patients based on their age and comorbidities such as liver and renal function to decide on the level of CBG control that is most appropriate.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n\nWe would like to thank Singapore General Hospital for providing us with the resources to make this case report possible.\n==== Refs\nReferences\n1 The treatment of hyperinsulinemic hypoglycaemia in adults: an update J Endocrinol Invest Davi MV Pia A Guarnotta V Pizza G Colao A Faggiano A 9 20 40 2017 27624297 \n2 Current practice of hypoglycemia management in the ED Am J Emerg Med Bilhimer MH Treu CN Acquisto NM 87 91 35 2017 27832978 \n3 Hypoglycemia Am J Med Morales J Schneider D 17 24 127 2014 \n4 Anti-infectives and the risk of severe hypoglycemia in users of glipizide or glyburide Clin Pharm Therap Schelleman H Bilker WB Brensinger CM Wan F Hennessy S 214 222 88 2010 \n5 Hypoglycemia after antimicrobial drug prescription for older patients using sulfonylureas JAMA Intern Med Parekh TM Raji M Lin YL Tan A Kuo YF Goodwin JS 1605 1612 174 2014 25179404 \n6 Severe hypoglycemia from clarithromycin-sulfonylurea drug interaction Diabetes Care Bussing R Gende A 1659 1661 25 2002 http://care.diabetesjournals.org/content/25/9/1659.2.long \n7 Effects of clarithromycin and grapefruit juice on the pharmacokinetics of glibenclamide Brit J Clin Pharm Lilja JJ Niemi M Fredrikson H Neuvonen PJ 732 740 63 2007 \n8 Unintentional sulfonylurea toxicity due to a drug-drug interaction: a case report BMC Res Notes Gunaratne K Austin E Wu PE 331 11 2018 29784014 \n9 Recurrent episodes of hypoglycemia induced by moxifloxacin Indian J Pharmacol Singal DK Mittal A Prakash A 301 302 45 2013 23833380 \n10 Glucagon--Early breakthroughs and recent discoveries Peptides Ahren B 74 81 67 2015 25814364 \n11 Glucose-lowering drugs in patients with chronic kidney disease: a narrative review on pharmacokinetic properties Nephrol Dial Transplant Arnouts P Bolignano D Nistor I Bilo H Gnudi L Heaf J Biesen Wv 1284 1300 29 2014 24322578\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(6)",
"journal": "Cureus",
"keywords": "diabetes; drug interactions; hypoglycemia",
"medline_ta": "Cureus",
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"title": "Clarithromycin and Glipizide Drug-drug Interaction Leading to Refractory Hypoglycemia.",
"title_normalized": "clarithromycin and glipizide drug drug interaction leading to refractory hypoglycemia"
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"abstract": "Bordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.",
"affiliations": "Internal Medicine/Infectious Disease, Newark Beth Israel Medical Center, Newark, USA.;Internal Medicine/Infectious Disease, Newark Beth Israel Medical Center, Newark, USA.",
"authors": "Nagarakanti|Sandhya|S|;Bishburg|Eliahu|E|",
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"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.13113\nInfectious Disease\nCoinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient\nMuacevic Alexander\nAdler John R\nNagarakanti Sandhya 1\nBishburg Eliahu 1\n1 Internal Medicine/Infectious Disease, Newark Beth Israel Medical Center, Newark, USA\nSandhya Nagarakanti sandhya.nagarakanti@rwjbh.org\n3 2 2021\n2 2021\n13 2 e131133 2 2021\nCopyright © 2021, Nagarakanti et al.\n2021\nNagarakanti et al.\nThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/44268-coinfection-of-severe-acute-respiratory-syndrome-coronavirus-2-sars-cov-2-and-bordetella-bronchiseptica-pneumonia-in-a-renal-transplant-patient\nBordetella species cause respiratory infections in both humans and animals. Bordetella bronchiseptica (B. bronchiseptica) infection is an uncommon pathogen in humans. The clinical spectrum of infections with SARS-CoV-2 includes viral pneumonia of variable severity, with some patients developing acute respiratory distress syndrome (ARDS), requiring mechanical ventilation support. Transplant patients with coronavirus disease (COVID-19) infection have high mortality. Bacterial coinfection, including pneumonia, have been described in patients with COVID-19. We present a renal transplant patient with COVID-19 pneumonia who developed B. bronchiseptica superinfection and had a rapid clinical and radiological response to azithromycin treatment.\n\nbordetella\ncovid-19\nmacrolide\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nBordetella species respiratory infections are well known in both humans and animals. The most prevalent Bordetella subspecies in humans is Bordetella pertussis (B. pertussis), while in animals it is Bordetella bronchiseptica (B. bronchiseptica) [1]. B. bronchiseptica is a zoonotic organism, rarely described as the cause of infection in humans [2]. In humans, infections range from simple upper respiratory tract infection to severe sepsis [2]. Few cases have been described in transplant recipients. We present a renal transplant patient with coronavirus disease (COVID-19) pneumonia who developed a superinfection with B. bronchiseptica. To our knowledge, this is the first case of pneumonia with this organism reported in association with COVID-19.\n\nCase presentation\n\nA 48-year-old male patient was admitted with shortness of breath, fever, generalized malaise and worsening productive cough starting a week prior to admission. The patient’s past medical history was significant for chronic obstructive pulmonary disease, history of renal transplant in 2001, hypertension, diabetes mellitus, obesity, gout, and obstructive sleep apnea. His past surgical history was significant for amputation of the left fourth and fifth toes, and right nephrectomy in 2019. His immunosuppressive regimen consisted of mycophenolate mofetil 500 mg twice daily and prednisone 5 mg per day. He denied any exposure to pets.\n\nOn physical examination, the patient's weight was 123 kg with a BMI of 34.4, temperature 99.2 °F, blood pressure 116/56 mm/hg, heart rate 91 beats/minute. Oxygen (O2) saturation was 60% in room air. He was alert and oriented on arrival. Cardiac exam revealed regular heart sounds without murmurs. On lung exam, there were bibasilar crackles. The rest of his physical exam was normal.\n\nWhite blood cell count was 7.7x10^3/µL ( 4-10.5^3/µL), 29% lymphocytes. Creatinine was 6.6 mg/dL (0.5-1.2 mg/dL) with a glomerular filtration rate (GFR) of 11 mL/min/1.73 m2 and serum glucose 151 mg/dL (range 65-109 mg/dL). His COVID-19 reverse transcription polymerase chain reaction (RT-PCR) test from nasopharyngeal swab was positive. Chest X-ray showed bilateral diffuse consolidations.\n\nThe patient was initially placed on a 100% non-rebreathing mask and later on a high flow O2 nasal cannula. The patient remained hypoxemic and developed respiratory failure. He was intubated and required mechanical ventilator support. The patient was also initiated on continuous renal replacement therapy. He was started on intravenous ceftriaxone 1 gm and oral azithromycin as well as a course of hydroxychloroquine 400 mg twice daily followed by 400 mg once daily. In addition, he was given intravenous methylprednisolone 100 mg daily. The patient completed five days of treatment of intravenous ceftriaxone and oral azithromycin with an improvement of radiologic findings. After a week, the patient started developing fevers up to 103 °F. Chest X-ray showed an increase in lung infiltrates (Figure 1).\n\nFigure 1 Chest X-ray showing bilateral infiltrates\n\nIntravenous cefepime 1 gm loading followed by 500 mg next day was given. The patient remained intubated, seemed to be clinically deteriorating, and continued to be febrile, and therefore, intravenous azithromycin 500 mg was given. The sputum sample sent 12 days after intubation grew B. bronchiseptica; blood cultures remained negative. The patient became afebrile and was extubated within 24 hours after starting intravenous azithromycin. Intravenous cefepime was stopped and intravenous piperacillin/tazobactam 2.25 gm every eight hours was started and the patient continued with intravenous azithromycin. The organism was resistant to cefepime, intermediately sensitive to ceftazidime, and sensitive to levofloxacin, trimethoprim-sulfamethoxazole, tigecycline, gentamicin, tobramycin, meropenem, and piperacillin/tazobactam. Due to the rapid response to azithromycin leading to extubation, a decision was made to discontinue piperacillin/tazobactam and to continue with azithromycin. The patient continued to improve clinically and remained afebrile. Treatment continued with intravenous azithromycin for a total of 10 days. Chest X-ray two weeks post-discharge showed pulmonary vascular congestion, left lung atelectasis, and resolution of his lung infiltrates (Figure 2). Two months after discharge, the patient was doing well clinically but required intermittent renal replacement therapy.\n\nFigure 2 Chest X-ray showing improvement in infiltrates after treatment with azithromycin\n\nDiscussion\n\nNine different subspecies of Bordetella have been identified. B. pertussis and B. parapertussis are most commonly associated with human infections. Clinically, human infections consist of upper respiratory tract infection, pneumonia, endocarditis, peritonitis, meningitis, and bacteremia [2].\n\nB. bronchiseptica is known to cause upper respiratory tract infections in dogs, cats, rabbits, swine, and guinea pigs. The organism is the causative agent of kennel cough in dogs and atrophic rhinitis in swine. B. bronchiseptica possesses genes similar to B. pertussis, suggesting a close relationship between them. The organism can cause serious infection in immunocompromised patients such as HIV-infected patients [3], acute leukemia [4], bone marrow transplant [5], and other malignancies. Patients infected with this organism often report contact with animals prior to the development of infection [6,7]. \n\nIn the recent pandemic of COVID-19, patients with underlying diabetes mellitus, obesity, and immunocompromised patients are at an increased risk of developing severe disease. Patients with a history of solid organ transplantation on immunosuppression have been described with significantly higher mortality [8]. The spectrum of clinical disease with COVID-19 varies from a mild respiratory illness to fulminant pneumonia with ARDS requiring mechanical ventilation. Some patients present with a clinical picture as well as radiological appearance similar to bacterial or atypical pneumonia. In hospitalized patients, it is sometimes difficult to distinguish between SARS-CoV-2 pneumonia and hospital or ventilator-associated pneumonia. Many of these patients are therefore started on antibiotic treatment and are worked up for bacterial or atypical pneumonia. In a recent review, Rawson et al. [9] reviewed the current literature on evidence of bacterial/fungal coinfection in hospitalized COVID-19 patients. They found 62/806 (8%) coinfection with bacterial/fungal organisms. Zhou et al. [8] reported a 15% (28/191) secondary bacterial infection, of which 27 patients died. Reports on atypical organisms infecting COVID-19 patients are lacking, and to our knowledge, there is no report of Bordetella pneumonia associated with COVID-19.\n\nOur patient had various risk factors for complicated SARS-CoV-2 infection [10]: he was obese, had diabetes mellitus, hypertension, history of renal transplantation, and was treated with immunosuppressants. Radiographic findings in COVID-19-associated pneumonia include bilateral, multifocal lung lesions, ground-glass opacities, consolidation, and pleural thickening [11]. Similar radiologic findings have been noted in B. bronchiseptica-associated pneumonia [3]. Infections with B. bronchiseptica in renal transplant patients have been uncommonly described. In one case, a patient with a history of renal transplant had bacteremia with B. bronchiseptica three weeks after undergoing a pancreas transplant who had exposure to dogs [12].\n\nIt is plausible to assume that our patient had an initial SARS-CoV-2 viral pneumonia, resulting in respiratory failure. B. bronchiseptica was cultured 12 days into his clinical course.\n\nB. bronchiseptica infections in animals are usually treated with doxycycline, quinolones, or macrolides. Infections in humans have been treated with an anti-pseudomonal penicillins, quinolones, aminoglycosides, tetracycline, trimethoprim-sulfamethoxazole, or carbapenems [13]. Response to macrolides has been reported to be variable [14]. The frequency of macrolide resistance among Bordetella isolates in animals is low. In vitro experiments show that resistance to erythromycin develops quickly but that the organisms that developed resistance were unable to colonize mice, suggesting that the drugs may be effective in vivo [14].\n\nMacrolides have not been the drugs of choice for treatment of B. bronchiseptica in humans, but it appears that susceptibility for this organism in vitro does not always predict clinical response [15]. It is therefore possible that this class of drugs may be effective in clinical settings, as happened in our case.\n\nConclusions\n\nBacterial coinfection or superinfections should be considered in patients hospitalized with COVID-19-associated pneumonia when the clinical status deteriorates after initial improvement. Severe infection with rare bacterial organisms, especially in transplant recipients, is a concern. An accurate microbiological diagnosis is essential so that patient can be treated appropriately. Clinical response may not coincide with microbiologic in vitro susceptibility results.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Molecular pathogenesis, epidemiology, and clinical manifestations of respiratory infections due to Bordetella pertussis and other Bordetella subspecies Clin Microbiol Rev Mattoo S Cherry JD 326 382 18 2005 15831828\n2 Human infections associated with Bordetella bronchiseptica Clin Microbiol Rev Woolfrey BF Moody JA 243 255 4 1991 1889042\n3 Bordetella bronchiseptica infection in human immunodeficiency virus-infected patients Clin Infect Dis Dworkin MS Sullivan PS Buskin SE Harrington RD Olliffe J MacArthur RD Lopez CE 1095 1099 28 1999 10452641\n4 An unusual cause of cough and dyspnea in an immunocompromised patient Chest Berkowitz DM Bechara RI Wolfenden LL 1599 1602 131 2007 17494814\n5 Hospital-acquired Bordetella bronchiseptica infection following hematopoietic stem cell transplantation J Clin Microbiol Huebner ES Christman B Dummer S Tang YW Goodman S 2581 2583 44 2006 16825386\n6 Bordetella bronchiseptica in the immunosuppressed population - a case series and review Mediterr J Hematol Infect Dis Yacoub AT Katayama M Tran J Zadikany R Kandula M Greene J 2014031 6 2014\n7 Bordetella bronchiseptica pneumonia in a patient with lung cancer; a case report of a rare infection BMC Infect Dis Monti M Diano D Allegrini F 644 17 2017 28946850\n8 Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan China: a retrospective cohort study Lancet Zhou F Yu T Du R 1 9 6736 2020\n9 Bacterial and fungal co-Infection in individuals with Coronavirus: a rapid review to support COVID-19 antimicrobial prescribing Clin Infect Dis Rawson T.M Moore LS Zhu N 0 1062 395 2020\n10 Risk factors of severe cases with COVID- 19: a meta-analysis Epidemiol Infect Ou M Zhu J Ji P 0 148 2020\n11 Imaging and clinical features of patients with 2019 novel coronavirus SARS-CoV-2 Eur J Nucl Med Mol Imaging Xu X Yu C Qu J 1275 1280 47 2020 32107577\n12 Bordetella bronchiseptica in a kidney-pancreas transplant recipient after dog vaccination J Kidney Youssefi N Chobanian M 120 2 2016\n13 Antimicrobial susceptibility of Bordetella avium and Bordetella bronchiseptica isolates Antimicrob Agents Chemother Mortensen JE Brumbach A Shryock TR 771 772 33 1989 2751288\n14 Development of macrolide resistance in Bordetella bronchiseptica is associated with the loss of virulence J Antimicrob Chemother Dewan KK Skarlupka AL Rivera I 2797 2805 73 2018 30107601\n15 Manual of Clininal Microbiology, Eleventh Edition Manual Jorgensen JH Pfaller MA Carroll KC Funke G Landry ML Richter SR Warnock DW Washington, DC ASM Books 12 2015 https://www.asmscience.org/content/book/10.1128/9781555817381\n\n",
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"title": "Coinfection of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Bordetella bronchiseptica Pneumonia in a Renal Transplant Patient.",
"title_normalized": "coinfection of severe acute respiratory syndrome coronavirus 2 sars cov 2 and bordetella bronchiseptica pneumonia in a renal transplant patient"
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"abstract": "A 57-year-old man came to the Emergency Department because of painful oral ulcers and skin lesions. He used methotrexate because of psoriasis, but he stopped using folic acid. Laboratory tests showed signs of dehydration and pancytopenia. We made the diagnosis 'methotrexate-intoxication'.",
"affiliations": "Radboudumc, afd. Maag-, Darm-, en Leverziekten, Nijmegen.",
"authors": "van Erp-van der Steen|Hanneke|H|;van Kouwen|Mariette C A|MC|",
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"mesh_terms": "D003937:Diagnosis, Differential; D005494:Folic Acid Deficiency; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D010198:Pancytopenia; D011565:Psoriasis",
"nlm_unique_id": "0400770",
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"title": "A man with multiple mucosal lesions and pancytopenia.",
"title_normalized": "a man with multiple mucosal lesions and pancytopenia"
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"abstract": "OBJECTIVE\nWe studied the safety and efficacy of multimodal thromboprophylaxis in patients with a history of venous thromboembolism (VTE) who undergo total hip arthroplasty (THA) within the first 120 postoperative days, and the mortality during the first year. Multimodal prophylaxis includes discontinuation of procoagulant medications, VTE risk stratification, regional anaesthesia, an intravenous bolus of unfractionated heparin prior to femoral preparation, rapid mobilization, the use of pneumatic compression devices, and chemoprophylaxis tailored to the patient's risk of VTE.\n\n\nMETHODS\nBetween 2004 to 2018, 257 patients with a proven history of VTE underwent 277 primary elective THA procedures by two surgeons at a single institution. The patients had a history of deep vein thrombosis (DVT) (186, 67%), pulmonary embolism (PE) (43, 15.5%), or both (48, 17.5%). Chemoprophylaxis included aspirin (38 patients), anticoagulation (215 patients), or a combination of aspirin and anticoagulation (24 patients). A total of 50 patients (18%) had a vena cava filter in situ at the time of surgery. Patients were followed for 120 days to record complications, and for one year to record mortality.\n\n\nRESULTS\nPostoperative VTE was diagnosed in seven patients (2.5%): DVT in five, and PE with and without DVT in one patient each. After hospitalization, three patients required readmiss-ion for evacuation of a haematoma, one for wound drainage, and one for monitoring of an elevated international normalized ratio (INR). Seven patients died (2.5%). One patient died five months postoperatively of a PE during open thrombectomy. She had discontinued anticoagulation. One patient died of a haemorrhagic stroke while receiving Coumadin. PE or bleeding was not suspected in the remaining five fatalities.\n\n\nCONCLUSIONS\nMultimodal prophylaxis is safe and effective in patients with a history of VTE. Postoperative anticoagulation should be prudent as very few patients developed VTE (2.5%) or died of suspected or confirmed PE. Mortality during the first year was mostly unrelated to either VTE or bleeding. Cite this article: Bone Joint J 2020;102-B(7 Supple B):71-77.",
"affiliations": "Department of Orthopaedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College of Cornell University, New York, New York, USA.;Department of Orthopaedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College of Cornell University, New York, New York, USA.;Department of Biomechanics, Hospital for Special Surgery, Weill Cornell Medical College of Cornell University, New York, New York, USA.;Department of Anesthesiology, Hospital for Special Surgery, Weill Cornell Medical College of Cornell University, New York, New York, USA.;Department of Anesthesiology, Hospital for Special Surgery, Weill Cornell Medical College of Cornell University, New York, New York, USA.;Department of Anesthesiology, Hospital for Special Surgery, Weill Cornell Medical College of Cornell University, New York, New York, USA.;Department of Orthopaedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College of Cornell University, New York, New York, USA.",
"authors": "Gonzalez Della Valle|Alejandro|A|;Shanaghan|Kate A|KA|;Nguyen|Joseph|J|;Liu|Jiabin|J|;Memtsoudis|Stavros|S|;Sharrock|Nigel E|NE|;Salvati|Eduardo A|EA|",
"chemical_list": "D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin; D006493:Heparin; D000069552:Rivaroxaban; D001241:Aspirin",
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"medline_ta": "Bone Joint J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000765:Anesthesia, Conduction; D000925:Anticoagulants; D019644:Arthroplasty, Replacement, Hip; D001241:Aspirin; D018890:Chemoprevention; D004434:Early Ambulation; D017558:Elective Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D006493:Heparin; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D048228:Intermittent Pneumatic Compression Devices; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011183:Postoperative Complications; D012189:Retrospective Studies; D012307:Risk Factors; D000069552:Rivaroxaban; D054556:Venous Thromboembolism; D014859:Warfarin",
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"title": "Multimodal prophylaxis in patients with a history of venous thromboembolism undergoing primary elective hip arthroplasty.",
"title_normalized": "multimodal prophylaxis in patients with a history of venous thromboembolism undergoing primary elective hip arthroplasty"
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"abstract": "Hyponatremia (serum Na levels of <135 mEq/L) is the most common electrolyte imbalance encountered in clinical practice, affecting up to 15-28% of hospitalized patients. This case report refers to a middle-aged man with severe hyponatremia due to Syndrome of Inappropriate Antidiuretic Hormone Secretion related to four possible etiological factors: glossopharyngeal squamous cell carcinoma, cisplatin treatment, right basal pneumonia with Pseudomonas aeruginosa, and the treatment with Levofloxacin. This case report discusses a rare complication of common conditions and of a common treatment. To our knowledge this is the first case of hyponatremia related to Levofloxacin and the second related to fluoroquinolones.",
"affiliations": "Department of Internal Medicine, University of Medicine and Pharmacy, Cluj-Napoca, Romania; 1st Medical Clinic, County Emergency Hospital, Cluj-Napoca, Romania.;Department of Internal Medicine, University of Medicine and Pharmacy, Cluj-Napoca, Romania; 1st Medical Clinic, County Emergency Hospital, Cluj-Napoca, Romania.",
"authors": "Mocan|Mihaela|M|0000-0001-5906-8024;Blaga|Sorin Nicu|SN|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2016/5434230Case ReportSevere Hyponatremia due to Levofloxacin Treatment for Pseudomonas aeruginosa Community-Acquired Pneumonia in a Patient with Oropharyngeal Cancer http://orcid.org/0000-0001-5906-8024Mocan Mihaela \n1\n\n2\n\n*\nBlaga Sorin Nicu \n1\n\n2\n1Department of Internal Medicine, University of Medicine and Pharmacy, Cluj-Napoca, Romania21st Medical Clinic, County Emergency Hospital, Cluj-Napoca, Romania*Mihaela Mocan: mihaela.mocan@gmail.comAcademic Editor: Florian Thalhammer\n\n2016 25 10 2016 2016 543423016 8 2016 5 10 2016 Copyright © 2016 M. Mocan and S. N. Blaga.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hyponatremia (serum Na levels of <135 mEq/L) is the most common electrolyte imbalance encountered in clinical practice, affecting up to 15–28% of hospitalized patients. This case report refers to a middle-aged man with severe hyponatremia due to Syndrome of Inappropriate Antidiuretic Hormone Secretion related to four possible etiological factors: glossopharyngeal squamous cell carcinoma, cisplatin treatment, right basal pneumonia with Pseudomonas aeruginosa, and the treatment with Levofloxacin. This case report discusses a rare complication of common conditions and of a common treatment. To our knowledge this is the first case of hyponatremia related to Levofloxacin and the second related to fluoroquinolones.\n==== Body\n1. Introduction\nHyponatremia (serum Na levels of <135 mEq/L) is the most common electrolyte imbalance encountered in clinical practice, affecting up to 15–28% of hospitalized patients. Both moderate and especially severe hyponatremia (Na <125 mEq/L) found in newly admitted hospital patients are linked with a significantly elevated in-hospital mortality of 28% compared to 9% in-hospital mortality in normonatremic, matched controls [1].\n\nDespite the frequency of this condition, the etiologic diagnosis and the management of hyponatremia are neither easy nor optimal [2]. This may be attributable to the diversity of underlying disease states associated with the condition and, until the last few years, a lack of targeted treatments.\n\n2. Case Presentation\nA 59-year-old male was brought in to the emergency department of Emergency County Hospital of Cluj-Napoca presenting with dizziness, psychomotor agitation, delirium with visual and auditory hallucinations, and temporal and spatial disorientation. The patient was known for chronic tobacco use (40 cigarettes/day) and heavy alcohol consumption.\n\nHistory taking revealed that his symptoms had started 1 month previously when he was hospitalized in the Pneumology Unit suffering from right chest pain, dyspnea, fatigue, productive cough, 38°C fever, and shaking chills. He was diagnosed with Pseudomonas aeruginosa right basal pneumonia based upon findings on physical examination and paraclinical explorations (chest CT scan, blood cultures, bronchoscopy with cytology, and aspirate cultures). Consequently, antibiotic treatment was initiated, at first, ceftriaxone 2 g/day (7 days long), but as there were no clinical signs of resolution, the treatment was switched to amikacin and colistin, for the following 10 days. On admission to our service he was still on antibiotic treatment for pneumonia, that time with Levofloxacin 500 mg per day, which had been started 4 days previously.\n\nHis medical history included a glossopharyngeal squamous cell carcinoma cT3N3Mx treated with combined chemotherapy (docetaxel, cisplatin, and capecitabine) and radiation therapy.\n\nThe clinical examination, at the admission time, revealed an overweight patient (BMI = 27 kg/m2) with warm and moist skin and psychomotor agitation. Cerebral CT scan was performed in the Emergency Room and it did not show any focal masses or other pathological findings that could explain the acute onset of the neurologic manifestations.\n\nThe lab exams (Table 1) showed a low serum sodium concentration of 114 mEq/L indicating severe hyponatremia, with correspondingly low serum osmolality of 233.9 mOsm/kg, normal creatinine, urea, and uric acid. His urinary Na was high 40 mEq/L and his central venous pressure was normal (5 cmH2O). Given the severity of the hyponatremia a treatment with hypertonic saline 3% was started in the Emergency Room and his existing Levofloxacin treatment was stopped. He was admitted to the Internal Medicine Department for surveillance. During the following 24 h the patient serum Na rose to 120 mEq/L (6 mEq/L). Hypertonic saline treatment was stopped and replaced with fluid restriction (800 mL/day), as the patient did not meet the exclusion criteria for applying this treatment (mentioned above). Within the next 72 h serum Na increased to 131 mEq/L and his symptoms subsided. Adrenal insufficiency and severe hypothyroidism were excluded through laboratory tests. Therefore, the etiology of euvolemic hypotonic hyponatremia diagnosed in our patients was likely to be Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) fulfilling both essential and supplemental criteria for the diagnosis [3].\n\nLooking back into his past medical file, as shown in Figure 1, we discovered that our patient had been hyponatremic ever since diagnosed with neck cancer. After chemotherapy the Na levels decreased slowly by 10 mEq/L, the patient being asymptomatic. During the acute episode of pneumonia and Levofloxacin treatment, hyponatremia suddenly aggravated and the patient became symptomatic. The mild fluid restriction (maximum 1500 mL/day), normal Na intake, and the avoidance of any medication that could affect sodium levels allowed the maintenance of Na concentration close to physiological limit, for more than 6 month after discharge (Figure 1).\n\n3. Discussions\nIn our case, we identified at least 4 possible causes of SIADH and hyponatremia:Glossopharyngeal squamous cell carcinoma\n\nCisplatin treatment\n\nRight basal pneumonia with Pseudomonas aeruginosa\n\n\nThe treatment with Levofloxacin\n\nEach of these etiological factors will be discussed separately beneath.\n\nHyponatremia is common in malignant solid tumors (up to 25% of all patients) either as part of the underlying disease or due to drug side effects [4]. SIADH has been reported in >3% of patients with head and neck cancer, most often in patients with lesions in the oral cavity and less frequently in those with lesions in the larynx, nasopharynx, hypopharynx, or other sites [5], frequently due to ectopic secretion of antidiuretic hormone (ADH). Treatment of lung cancer with chemotherapeutic agents such as platinum derivatives or vinca alkaloids may lead to hyponatremia. The development of hyponatremia, during cisplatin therapy, bears special mention for our case. Cisplatin stimulates ADH secretion to cause SIADH, but it can also directly damage renal tubules to interfere with sodium reabsorption, which in rare cases may lead to hyponatremia via salt wasting nephropathy [4].\n\nBesides malignancies, SIADH may be caused by a variety of other conditions, including CNS disorders, pulmonary disorders (e.g., tuberculosis, pneumonia, and acute respiratory failure), HIV infection, prolonged strenuous exercise, and drugs [3].\n\nA recent German study reported a high incidence of hyponatremia (31.8%) among patients with community-acquired pneumonia [6]. The degree of hyponatremia severity seemed to correlate with the patients' comorbidities (such as chronic heart failure, chronic renal disease, diabetes mellitus, and malignancies), higher severity of pneumonia, and higher inflammatory biomarkers. However, the association of these comorbidities with sodium levels was weak and disappeared after inclusion in a multivariate model. The relationship of hyponatremia and higher pneumonia severity probably reflects the presence of hypovolemia, severe sepsis, and subsequent activation of vasopressin and natriuretic peptides secretion [6]. The decrease in the ability to reduce urine osmolality and excrete water loads and the increasing levels of ADH in the absence of antibiotic treatment [7] might be incriminated in pneumonia-induced hyponatremia.\n\nAs for the antibiotic treatment, it seems that Levofloxacin could be a cause for SIADH. There is no data in the literature regarding hyponatremia to Levofloxacin, but there are case series presentations of quinolones' side effect. Fluoroquinolones have the potential to cause SIADH. The likely mechanism of hyponatremia is that quinolones cross the blood-brain barrier and stimulate the γ-aminobutyric acid and N-methyl-D-aspartate receptors, which leads to the synthesis and release of antidiuretic hormone [8, 9]. An objective causality assessment using the Naranjo scale could have been useful to demonstrate the link between Levofloxacin use and hyponatremia.\n\nFinally, the link between alcohol ingestion and hyponatremia is worth mentioning. Hyponatremia may be one of the laboratory signs of chronic alcohol abuse (up to 17% of the alcoholics), along with frequent presentation to ER department for recurrent unexplained falls, poorly controlled hypertension, and/or gastrointestinal symptoms [10]. The mechanisms for hyponatremia in alcoholics include hypovolemia, pseudohyponatremia due to alcohol-induced hypertriglyceridemia, beer potomania syndrome, and rarely SIADH or cerebral salt wasting. In our case, heteroanamnesis revealed the stop of alcohol ingestion 1 year prior to presentation, so chronic alcoholism was not considered as a cause of hyponatremia [10, 11]. However, a CNS disorder associated with alcohol consumption (Wernicke encephalopathy or Korsakoff dementia) was initially suspected to be the cause of the delirium at presentation, so high-dose thiamine was administered intravenously for 5 days.\n\nApart from the fact that persistent hyponatremia may affect the patients' quality of life, it seems to be a negative prognostic marker for overall survival. Large studies including patients with malignant disease demonstrate that serum Na level <130 mEq/L is independently associated with a 2–2.5-fold greater risk for in-hospital mortality [12].\n\n4. Conclusions\nIn summary, we presented a case of hyponatremia of multifactorial etiology that was promptly investigated and corrected. To our knowledge this is the first case of hyponatremia related to Levofloxacin and the second related to fluoroquinolones. The patients' outcome at six months was a good one, bearing in mind the comorbidities.\n\nCompeting Interests\nThe authors declare that there are no competing interests regarding the publication of this paper.\n\nAuthors' Contributions\nMihaela Mocan acquired data, conceived and wrote the paper, and reviewed literature; Sorin Nicu Blaga reviewed literature and made critical revisions of the paper.\n\nFigure 1 Evolution of serum Na levels since the diagnosis and treatment (03/01/2013) of glossopharyngeal squamous cell carcinoma until six months after discharge from Internal Medicine Department (03/16/2014). The moment of hospital admission is marked with the red arrow (10/23/2013).\n\nTable 1 Laboratory results at admission and in evolution.\n\nAnalysis\tAt admission\tDuring hospitalization \n\n\tAt discharge\tNormal range\t\nSodium (mEq/L)\t\n114\n\t\n131\n\t\n133\n\t135–145\t\nSodium deficiency (mEq)\t\n284.4\n\t—\t—\t—\t\nPotassium (mEq/L)\t3.8\t4.1\t4\t3.5–5.1\t\nChloride (mEq/L)\t98\t102\t104\t96–106\t\nUrea (mg/dL)\t24\t30\t25\t15–45\t\nCreatinine (mg/dL)\t0.58\t0.72\t0.80\t0.57–1.12\t\nUric acid (mg/dL)\t2.9\t3\t3.5\t2.6–7\t\nOsmolality (mOsm/kg)\t233\t—\t285\t285–295\t\nGlycemia (mg/dL)\t89\t90\t85\t70–110\t\nTSH (mIU/mL)\t3.15\t—\t—\t0.7–4.2\t\nCortisol (nmol/L)\t327\t—\t—\t171–536\t\nTotal protein (g/L)\t6.5\t—\t—\t6.4–8.3\t\nWBC (×103/mm3)\t4.7\t—\t5\t4–10.5\t\nHemoglobin (g/dL)\nHematocrit (%)\nPlatelet (×103/mm3)\t8.3\n24.1\n344\t—\n—\n—\t8.5\n25\n350\t11.5–15.5\n36–48\n150–400\t\n\n\n\t\nUrine chemistry\t \t \t \t \t\n Osmolality (mOsm/kg)\t116\t450\t800\t500–800\t\n Na (mEq/L)\t40\t60\t130\t40–220\t\n K (mEq/L)\t25\t56\t60\t20–125\t\n Density\t1025\t1030\t1031\t1015–1025\t\nVolume status: PVC (cmH2O)\t5\t—\t—\t —\t\nNa deficiency = [120-Naseric (mEq/L)] × G (kg) × 0.6.\n==== Refs\n1 Mannesse C. K. Vondeling A. M. van Marum R. J. van Solinge W. W. Egberts T. C. G. Jansen P. A. F. Prevalence of hyponatremia on geriatric wards compared to other settings over four decades: a systematic review Ageing Research Reviews 2013 12 1 165 173 10.1016/j.arr.2012.04.006 2-s2.0-84867473223 22588025 \n2 Clayton J. A. Le Jeune I. R. Hall I. P. Severe hyponatraemia in medical in-patients: aetiology, assessment and outcome Quarterly Journal of Medicine 2006 99 8 505 511 10.1093/qjmed/hcl071 2-s2.0-33748101587 \n3 Spasovski G. Vanholder R. Allolio B. Clinical practice guideline on diagnosis and treatment of hyponatraemia European Journal of Endocrinology 2014 170 3 G1 G47 10.1530/eje-13-1020 2-s2.0-84896285517 24569125 \n4 Castillo J. J. Vincent M. Justice E. Diagnosis and management of hyponatremia in cancer patients Oncologist 2012 17 6 756 765 10.1634/theoncologist.2011-0400 2-s2.0-84862846656 22618570 \n5 Ferlito A. Rinaldo A. Devaney K. O. Syndrome of inappropriate antidiuretic hormone secretion associated with head and neck cancers: review of the literature Annals of Otology, Rhinology and Laryngology 1997 106 10 878 883 10.1177/000348949710601014 2-s2.0-0031253104 \n6 Krüger S. Ewig S. Giersdorf S. Dysnatremia, vasopressin, atrial natriuretic peptide and mortality in patients with community-acquired pneumonia: Results from the german competence network CAPNETZ Respiratory Medicine 2014 108 11 1696 1705 10.1016/j.rmed.2014.09.014 2-s2.0-84922580333 25306251 \n7 Dreyfuss D. Leviel F. Paillard M. Rahmani J. Coste F. Acute infectious pneumonia is accompanied by a latent vasopressin-dependent impairment of renal water excretion American Review of Respiratory Disease 1988 138 3 583 589 10.1164/ajrccm/138.3.583 2-s2.0-0023710435 3059874 \n8 Babar S. M. SIADH associated with ciprofloxacin Annals of Pharmacotherapy 2013 47 10 1359 1363 10.1177/1060028013502457 2-s2.0-84888069935 24259701 \n9 Müssig K. Schnauder G. Mörike K. Severe and symptomatic hyponatraemia after moxifloxacin intake Netherlands Journal of Medicine 2009 67 5 p. 197 2-s2.0-66449110359 19581673 \n10 Liamis G. L. Milionis H. J. Rizos E. C. Siamopoulos K. C. Elisaf M. S. Mechanisms of hyponatraemia in alcohol patients Alcohol and Alcoholism 2000 35 6 612 616 10.1093/alcalc/35.6.612 2-s2.0-0033662298 11093969 \n11 Pallavi R. An unsuspected cause of hyponatremia: beer potomania Journal of the American Geriatrics Society 2015 63 8 1714 1715 10.1111/jgs.13582 2-s2.0-84939489667 26289702 \n12 Doshi S. M. Shah P. Lei X. Lahoti A. Salahudeen A. K. Hyponatremia in hospitalized cancer patients and its impact on clinical outcomes American Journal of Kidney Diseases 2012 59 2 222 228 10.1053/j.ajkd.2011.08.029 2-s2.0-84855826118 22001181\n\n",
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"title": "Severe Hyponatremia due to Levofloxacin Treatment for Pseudomonas aeruginosa Community-Acquired Pneumonia in a Patient with Oropharyngeal Cancer.",
"title_normalized": "severe hyponatremia due to levofloxacin treatment for pseudomonas aeruginosa community acquired pneumonia in a patient with oropharyngeal cancer"
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"abstract": "OBJECTIVE\nTo report results from a long-term prospective study of safety of haloperidol treatment and prevalence of haloperidol-related dyskinesias.\n\n\nMETHODS\nSubjects were children with autism requiring pharmacotherapy for target symptoms. After baseline assessments, children received haloperidol treatment; responders requiring further treatment were considered for enrollment into the present study. Six-month haloperidol treatment periods were followed by a 4-week placebo period. The procedure was repeated if further haloperidol treatment was required. At specified times children were evaluated by using multiple instruments.\n\n\nRESULTS\nBetween 1979 and 1994, 118 children aged 2.3 to 8.2 years participated in the study. The mean dose of haloperidol was 1.75 mg/day. Mainly withdrawal dyskinesias (WD) developed in 40 (33.9%) children; 20 had more than one dyskinetic episode. A subgroup that remained significantly longer in the study and had a significantly higher cumulative dose of haloperidol evidenced a significantly higher incidence of WD. Occurrence rates of tardive dyskinesia (TD) and multiple episodes of TD/WD were higher among girls.\n\n\nCONCLUSIONS\nFemale gender and pre- and perinatal complications may be involved in susceptibility to dyskinesias; greater cumulative haloperidol dose and/or longer exposure to haloperidol may increase the risk.",
"affiliations": "New York University School of Medicine.",
"authors": "Campbell|M|M|;Armenteros|J L|JL|;Malone|R P|RP|;Adams|P B|PB|;Eisenberg|Z W|ZW|;Overall|J E|JE|",
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"mesh_terms": "D014150:Antipsychotic Agents; D001321:Autistic Disorder; D002648:Child; D002675:Child, Preschool; D004409:Dyskinesia, Drug-Induced; D005260:Female; D006220:Haloperidol; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D011446:Prospective Studies",
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"title": "Neuroleptic-related dyskinesias in autistic children: a prospective, longitudinal study.",
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"abstract": "Defects in DNA Recombination due to mutations in RAG1/2 or DCLRE1C result in combined immunodeficiency (CID) with a range of disease severity. We present the clinical, immunologic and molecular characteristics of 21 patients with defects in RAG1, RAG2 or DCLRE1C, who accounted for 24% of combined immune deficiency cases in the Kuwait National Primary Immunodeficiency Disorders Registry. The distribution of the patients was as follow: 8 with RAG1 deficiency, 6 with RAG2 deficiency and 7 with DCLRE1C deficiency. Nine patients presented with SCID, 6 with OS, 2 with leaky SCID and 4 with CID and granuloma and/or autoimmunity (CID-G/AI). Eight patients [(7 SCID and 1 OS) (38%)] received hematopoietic stem cell transplant (HSCT). The median age of HSCT was 11.5months and the median time from diagnosis to HSCT was 6months. Fifty percent of the transplanted patients are alive while only 23% of the untransplanted ones are alive.",
"affiliations": "Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait; Allergy & Clinical Immunology Unit, Pediatric Department, Al-Sabah Hospital, Kuwait. Electronic address: walherz@hsc.edu.kw.;Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, United States.;Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, United States.;Laboratory of Host Defences, DIR, NIAID, NIH, DHHS, Bethesda, MD, United States.;Division of Immunology, Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, United States.",
"authors": "Al-Herz|Waleed|W|;Massaad|Michel J|MJ|;Chou|Janet|J|;Notarangelo|Luigi D|LD|;Geha|Raif S|RS|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C064658:RAG-1 protein; C426344:DCLRE1C protein, human; D004720:Endonucleases",
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"keywords": "Artemis; Combined immunodeficiency; DCLRE1C; DNA recombination; Rag; SCID",
"medline_ta": "Clin Immunol",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D001327:Autoimmune Diseases; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D000076610:Genetic Profile; D006099:Granuloma; D018380:Hematopoietic Stem Cell Transplantation; D018398:Homeodomain Proteins; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007153:Immunologic Deficiency Syndromes; D007155:Immunologic Factors; D007223:Infant; D007730:Kuwait; D008297:Male; D009687:Nuclear Proteins; D016511:Severe Combined Immunodeficiency; D060152:V(D)J Recombination",
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"pubdate": "2018-02",
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"references": "24230999;16960852;19953608;25707801;10777560;22277203;25075835;24290292;12406895;18223550;25138334;24144642;25512557;15025726;24290284;24481607;14610491;26996199;21478889;21624848;12055248;25875249;8861910;12200379;24985406;21732012;19451168;26248333;25917813;26457731;23818196;11313270;20673987;19912631",
"title": "DNA recombination defects in Kuwait: Clinical, immunologic and genetic profile.",
"title_normalized": "dna recombination defects in kuwait clinical immunologic and genetic profile"
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"abstract": "Graft-versus-host disease has been reported to occur rarely in syngeneic hematopoietic stem cell transplant recipients. Clinical and histological changes consistent with graft-versus-host disease have been reported to occur in this patient population. We report a case of a 46-year-old Caucasian male with diffuse large B-cell lymphoma in complete remission who underwent a syngeneic hematopoietic stem cell transplant. He was diagnosed with grade III acute skin and gastrointestinal graft-versus-host disease requiring high-dose corticosteroids and immunosuppressive therapy and resulting in a complete response. Syngeneic graft-versus-host disease is an anomaly that needs to be considered as a differential diagnosis of patients experiencing dermatitis, gastroenteritis, or hepatitis after an identical twin hematopoietic stem cell transplant.",
"affiliations": "1 Department of Pharmacy, The Mount Sinai Hospital, New York, NY, USA.;1 Department of Pharmacy, The Mount Sinai Hospital, New York, NY, USA.;1 Department of Pharmacy, The Mount Sinai Hospital, New York, NY, USA.;2 Department of Medicine, Division of Hematology and Medical Oncology, The Mount Sinai Hospital, New York, NY, USA.;2 Department of Medicine, Division of Hematology and Medical Oncology, The Mount Sinai Hospital, New York, NY, USA.;2 Department of Medicine, Division of Hematology and Medical Oncology, The Mount Sinai Hospital, New York, NY, USA.;2 Department of Medicine, Division of Hematology and Medical Oncology, The Mount Sinai Hospital, New York, NY, USA.",
"authors": "Patel|Sweta U|SU|;Yum|Kendra|K|;Kim|Sara|S|;Isola|Luis M|LM|;Scigliano|Eileen|E|;Jakubowski|Rita|R|;Park|Doyun|D|",
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"issue": "25(7)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Syngeneic; autologous; graft versus host disease; graft-versus-host disease prophylaxis",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D012074:Remission Induction",
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"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of syngeneic graft-versus-host disease.",
"title_normalized": "a case of syngeneic graft versus host disease"
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... |
{
"abstract": "BACKGROUND\nPhiladelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subtype of pediatric leukemia with high risk factors and poor outcome. There are few reports of its prevalence in Latin America.\n\n\nOBJECTIVE\nThis study evaluated the frequency and clinical and biological characteristics of Ph-like ALL in a pediatric cancer center in Colombia.\n\n\nMETHODS\nThe Ph-like genetic profile was analyzed by a low-density array (LDA). Samples from patients with Ph-like ALL were analyzed by fluorescent in situ hybridization for cytokine receptor like factor 2 (CRLF2) and ABL proto-oncogene 1, non-receptor tyrosine kinase (ABL1) rearrangements. Copy number variations were assessed by multiplex ligation probe amplification.\n\n\nRESULTS\nData from 121 patients were analyzed. Fifteen patients (12.4%) had Ph-like ALL, and these patients had significantly higher leukocyte counts at diagnosis and higher levels of minimal residual disease on days 15 and 33 of induction than patients without the Ph-like subtype. There were no significant differences in sex, age, or response to prednisone at day 8 between the two groups. CRLF2 rearrangements were identified in eight patients, and ABL1 rearrangements were identified in two patients. Other genetic alterations alone or in combination were identified in 77% of patients, including deletions in cyclin dependent kinase inhibitor 2 A/B (46.2%), IKAROS family zinc finger 1 (38.3%), and paired box 5 (30.8%).\n\n\nCONCLUSIONS\nPh-like ALL had a 12.4% prevalence in our cohort of patients with pediatric ALL. The identification of this group of patients has importance for risk stratification and future targeted therapy.",
"affiliations": "Pediatric Hematology/Oncology Unit, HOMI Fundación Hospital Pediátrico la Misericordia, Bogotá, Colombia.;Servicios Médicos Yunis Turbay y Cía S.A.S. Instituto de Genética, Bogotá, Colombia.;Pediatric Hematology/Oncology Unit, HOMI Fundación Hospital Pediátrico la Misericordia, Bogotá, Colombia.;Pediatric Hematology/Oncology Unit, HOMI Fundación Hospital Pediátrico la Misericordia, Bogotá, Colombia.;Pediatric Hematology/Oncology Unit, HOMI Fundación Hospital Pediátrico la Misericordia, Bogotá, Colombia.;Grupo Oncohematología Pediátrica, Universidad Nacional de Colombia, Bogotá, Colombia.;Pediatric Pathology Unit, HOMI Fundación Hospital Pediatrico la Misericordia, Bogotá, Colombia.;Pediatric Pathology Unit, HOMI Fundación Hospital Pediatrico la Misericordia, Bogotá, Colombia.;Servicios Médicos Yunis Turbay y Cía S.A.S. Instituto de Genética, Bogotá, Colombia.;Pediatric Hematology/Oncology Unit, HOMI Fundación Hospital Pediátrico la Misericordia, Bogotá, Colombia.;Grupo Oncohematología Pediátrica, Universidad Nacional de Colombia, Bogotá, Colombia.;Pediatric Hematology/Oncology Unit, HOMI Fundación Hospital Pediátrico la Misericordia, Bogotá, Colombia.;Servicios Médicos Yunis Turbay y Cía S.A.S. Instituto de Genética, Bogotá, Colombia.",
"authors": "Linares Ballesteros|Adriana|A|;Yunis|Luz Karime|LK|;García|Johnny|J|;Aponte|Nelson|N|;Flechas|Jessica|J|;Martinez|Cindy|C|https://orcid.org/0000-0003-1756-6812;Uribe|Gloria|G|;Quintero|Edna|E|;Díaz|Angela|A|;Pardo|Carlos|C|;Sarmiento|Isabel Cristina|IC|;Contreras|Agustin|A|;Yunis|Juan Jose|JJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/cnr2.1587",
"fulltext": "\n==== Front\nCancer Rep (Hoboken)\nCancer Rep (Hoboken)\n10.1002/(ISSN)2573-8348\nCNR2\nCancer Reports\n2573-8348\nJohn Wiley and Sons Inc. Hoboken\n\n34787376\n10.1002/cnr2.1587\nCNR21587\nClinical Research Article\nClinical Research Articles\nPhiladelphia‐like acute lymphoblastic leukemia: Characterization in a pediatric cohort in a referral center in Colombia\nLinares Ballesteros et al.\nLinares Ballesteros Adriana 1 2 talinaresb@unal.edu.co\n\nYunis Luz Karime 3 4\nGarcía Johnny 1\nAponte Nelson 1\nFlechas Jessica 1 2\nMartinez Cindy https://orcid.org/0000-0003-1756-6812\n2\nUribe Gloria 5\nQuintero Edna 5\nDíaz Angela 3\nPardo Carlos 1 2\nSarmiento Isabel Cristina 2\nContreras Agustin 1\nYunis Juan Jose 3 4 6\n1 Pediatric Hematology/Oncology Unit HOMI Fundación Hospital Pediátrico la Misericordia Bogotá Colombia\n2 Grupo Oncohematología Pediátrica Universidad Nacional de Colombia Bogotá Colombia\n3 Servicios Médicos Yunis Turbay y Cía S.A.S. Instituto de Genética Bogotá Colombia\n4 Grupo de Patología Molecular Universidad Nacional de Colombia Bogotá Colombia\n5 Pediatric Pathology Unit HOMI Fundación Hospital Pediatrico la Misericordia Bogotá Colombia\n6 Departamento de Patología, Facultad de Medicina e Instituto de Genética Universidad Nacional de Colombia Bogotá Colombia\n* Correspondence\nAdriana Linares Ballesteros, Pediatric Hematology/Oncology Unit, HOMI Fundación Hospital Pediátrico la Misericordia, Bogotá, Colombia.\nEmail: talinaresb@unal.edu.co\n\n17 11 2021\n5 2022\n5 5 10.1002/cnr2.v5.5 e158725 9 2021\n08 7 2021\n25 10 2021\n© 2021 The Authors. Cancer Reports published by Wiley Periodicals LLC.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nBackground\n\nPhiladelphia‐like (Ph‐like) acute lymphoblastic leukemia (ALL) is a subtype of pediatric leukemia with high risk factors and poor outcome. There are few reports of its prevalence in Latin America.\n\nAim\n\nThis study evaluated the frequency and clinical and biological characteristics of Ph‐like ALL in a pediatric cancer center in Colombia.\n\nMethods\n\nThe Ph‐like genetic profile was analyzed by a low‐density array (LDA). Samples from patients with Ph‐like ALL were analyzed by fluorescent in situ hybridization for cytokine receptor like factor 2 (CRLF2) and ABL proto‐oncogene 1, non‐receptor tyrosine kinase (ABL1) rearrangements. Copy number variations were assessed by multiplex ligation probe amplification.\n\nResults\n\nData from 121 patients were analyzed. Fifteen patients (12.4%) had Ph‐like ALL, and these patients had significantly higher leukocyte counts at diagnosis and higher levels of minimal residual disease on days 15 and 33 of induction than patients without the Ph‐like subtype. There were no significant differences in sex, age, or response to prednisone at day 8 between the two groups. CRLF2 rearrangements were identified in eight patients, and ABL1 rearrangements were identified in two patients. Other genetic alterations alone or in combination were identified in 77% of patients, including deletions in cyclin dependent kinase inhibitor 2 A/B (46.2%), IKAROS family zinc finger 1 (38.3%), and paired box 5 (30.8%).\n\nConclusions\n\nPh‐like ALL had a 12.4% prevalence in our cohort of patients with pediatric ALL. The identification of this group of patients has importance for risk stratification and future targeted therapy.\n\nacute lymphoblastic leukemia\nCDKN2A/B\nchildren\nColombia\nCRLF2\nETV6\nHispanic\nIKZF1\nPAX5\nPh‐like\nHOMI Fundación Hospital Pediátrico la Misericordia64342 Ministerio de Ciencias, Tecnología e Innovación (Minciencias)Servicios Médicos Yunis Turbay y Cia source-schema-version-number2.0\ncover-dateMay 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.6 mode:remove_FC converted:22.05.2022\nLinares Ballesteros A , Yunis LK , García J , et al. Philadelphia‐like acute lymphoblastic leukemia: Characterization in a pediatric cohort in a referral center in Colombia. Cancer Reports. 2022;5 (5 ):e1587. doi:10.1002/cnr2.1587\n\nAdriana Linares and Luz Karime Yunis contributed equally as first authors.\n\nFunding information HOMI Fundación Hospital Pediátrico la Misericordia, Grant/Award Number: 64342; Ministerio de Ciencias, Tecnología e Innovación (Minciencias); Servicios Médicos Yunis Turbay y Cia\n==== Body\npmc1 INTRODUCTION\n\nAcute lymphoblastic leukemia (ALL) is the most common pediatric neoplasm, in developed countries, long‐term survival close to 85% has been achieved with treatment strategies based on disease‐risk stratification. 1 , 2 Genetic alterations confer distinctive biological and clinical behaviors, which influence the response to treatment and are considered in the risk classification of modern protocols.\n\nMore than a decade ago, two academic groups, COG/St. Jude in the United States and DCOG in the Netherlands, simultaneously described a B‐ALL subtype with a gene expression profile similar to the one already recognized for BCR activator of RhoGEF and GTPase (BCR)‐ABL proto‐oncogene 1, non‐receptor tyrosine kinase (ABL1) but without the BCR‐ABL1 fusion protein, which is known as Philadelphia‐like (Ph‐like) or BCR‐ABL1‐like. 3 , 4 The Ph‐like subtype was recognized as a provisional entity in the last acute leukemia classification of the World Health Organization in 2016. 5 This subtype is characterized by multiple genetic alterations in cytokine receptors and kinase signaling pathways. More than 70 alterations have been described, including translocations, cryptic rearrangements, single nucleotide variants, and copy number variations (CNVs). 6 Alterations are also detected in the transcription factors involved in B lymphocyte development and maturation, including IKAROS family zinc finger 1 (IKZF1), EBF transcription factor 1 (EBF1), ETS variant transcription factor 6 (ETV6), ETS transcription factor ERG, transcription factor 3 (TCF3), and paired box 5 (PAX5), in 86% of the cases and with a frequency very similar to what is observed in Philadelphia‐positive B‐ALL cases. 7 However, there is currently no consensus on how to diagnose and characterize the Ph‐like expression profile in patients with B‐ALL. 6 , 8\n\nThe most frequent genetic alterations in patients with Ph‐like ALL are rearrangements of cytokine receptor like factor 2 (CRLF2), 9 which are strongly associated with adverse clinical and treatment response factors and a higher risk of relapse with conventional therapy. Such rearrangements are found more frequently in the Hispanic population 10 within cohorts of patients treated in North America. Unfortunately, there are little data on the frequency of Ph‐like B‐ALL in the Hispanic pediatric population outside the United States. 11\n\nThe aim of this study was to identify the frequency of Ph‐like B‐ALL and examine its genomic and clinical characteristics in a cohort of patients under 18 years of age from a referral center in Colombia.\n\n2 METHODS\n\nThis was a prospective, descriptive study, nested in a cohort of patients between 1 and 18 years of age with a confirmed diagnosis of B‐ALL from July 1, 2018 to August 1, 2020. Participants were selected at convenience from patients with a de novo confirmed diagnosis of B‐precursor ALL at the HOMI Fundación Hospital Pediátrico La Misericordia who received the ALL‐IC 2009 treatment protocol. Of 137 admitted patients, 10 were excluded due to lack of sample to perform Ph‐like expression profiling and 6 were excluded because they were BCR‐ABL1‐positive. Therefore, 121 patients were included in the analysis.\n\n2.1 Biopsy and bone marrow aspiration procedure\n\nOnce consent was obtained and information formats were reviewed and completed, a bone marrow aspirate sample was taken to process flow cytometry (FC) to identify recurrent translocations, including t(4; 11), t(12; 21), and t(9; 22). In addition, a sample was taken for DNA and RNA extraction, conventional and molecular cytogenetics tests, and CNV analysis by multiplex ligation probe amplification (MLPA). Samples in which recurrent translocations were not found underwent low density array (LDA) analysis for the Ph‐like expression profile. Those with a positive LDA test underwent fluorescence in situ hybridization (FISH) for CRLF2, ABL1, and ABL2.\n\n2.2 Immunophenotype analysis by FC\n\nThe Euroflow Screening Panel was used to analyze the immunophenotype of different maturation stages of neoplastic B cells in the bone marrow samples, with a combination of eight different fluorescent markers that allow the identification and phenotypic characterization of B lineage acute leukemias. 12\n\n2.3 DNA extraction\n\nDNA was extracted from 200 μl of bone marrow using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany) following the manufacturer's specifications. The DNA purity quantification and verification were performed using a NanoDrop 2000 spectrophotometer. The DNA obtained was stored at −20°C until use.\n\n2.4 RNA extraction\n\nRNA was isolated from bone marrow samples in EDTA using the Quick‐RNA MiniPrep Plus kit (ZYMO RESEARCH, Irvine, CA, USA) following the manufacturer's recommendations. The extracted RNA was converted into cDNA using the High‐Capacity cDNA Reverse Transcription kit (Applied Biosystems, San Francisco, CA, USA) following the manufacturer's recommendations. The DNA purity quantification and verification were assessed using a NanoDrop 2000. The RNA was stored at −80°C, and the cDNA was stored at −20°C until use.\n\n2.5 Cytogenetics\n\nCell culture was performed to obtain metaphases for the chromosomal study with G and Q bands according to standardized protocols. 13 Chromosome visualization was performed using GenASIs (Applied Spectral Imaging, Carlsbad, CA, USA). At least 25 metaphases per sample were analyzed, and the nomenclature was described according to the recommendations of the International System for Human Cytogenomic Nomenclature (ISCN) 2020.\n\n2.6 Fluorescence in situ hybridization\n\nFISH was performed to detect the following recurrent rearrangements: t(12; 21) (TEL‐AML1 [ETV6‐RUNX1] Translocation, Dual Fusion Probe, Cytocell, Cambridge, UK), t(4; 11) (MLL [KMT2A]/AFF1 Translocation, Dual Fusion Probe, Cytocell), and t(9; 22) (BCR‐ABL Translocation, Dual Fusion Probe, Cytocell). Likewise, in samples with an LDA‐positive Ph‐like expression profile, FISH was performed to assess CRLF2 (CRLF2 Breakapart FISH probe, Cytocell), ABL1 (ABL1 Breakapart FISH probe, Cytocell), and ABL2 (ABL2 Breakapart FISH probe, Cytocell) translocations. At least 100 nuclei per study were analyzed, and the interpretation was performed by two independent observers using GenASIs. The nomenclature was described according to the recommendations of the ISCN 2020.\n\n2.7 Multiplex ligation probe amplification\n\nAll patients underwent MLPA analysis to detect copy number alterations with the SALSA MLPA P335 ALL kit. The IKZF1 probe mix (MRC Holland, Amsterdam, The Netherlands), was used following the manufacturer's recommendations to detect CNVs of IKZF1, EBF1, CDKN2A/B, PAX5, ETV6, BTG anti‐proliferation factor 1 (BTG1), RB transcriptional corepressor 1 (RB1), and the PAR1 region.\n\n2.8 LDA expression profiling for Ph‐like ALL\n\nExpression analysis was performed using a TaqMan Gene Expression assay (Applied Biosystems), TaqMan® Gene Expression Master Mix, and TaqMan® probes on an ABI7500 Real‐Time PCR system (Applied Biosystems). The expressions of bone morphogenetic protein receptor type 1B (BMPR1B); adhesion G protein‐coupled receptor F1 (ADGRF1); CRLF2; mucin 4 cell surface associated (MUC4); neurexin 3 (NRXN3); carbonic anhydrase 6 (CA6); joining chain of multimeric IgA and IgM (JCHAIN); and spermatogenesis associated serine rich 2 like (SPATSL2) were assessed, 14 with some modifications, we used as a housekeeping gene glucose‐6‐phosphate dehydrogenase (G6PD), to normalize the data. Also, each sample was processed in triplicate, and the gene expression was obtained using the 2−ΔΔCt method. The LDA expression profile was considered positive when four or more genes (>0.5) had expression levels higher than loge10 > 2.3 compared to the control gene. Additionally, samples with individual overexpression of CRLF2 in the LDA profile were analyzed by CRLF2 FISH.\n\n2.9 Statistical analysis\n\nStatistical analyses of quantitative variables were carried out with measures of central tendency and dispersion, means and standard deviations, or medians and ranges, according to the distribution after analysis with normality tests (Kolmogorov–Smirnov or Shapiro–Wilk) to establish the behavior of the data as parametric or non‐parametric. Medians were compared using the Mann–Whitney U test for independent non‐parametric samples. Qualitative variables were analyzed with Pearson's Chi‐square test and Fisher's exact test. Statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) for Windows, version 25.0. A p < .05 was considered significant.\n\nFor bias control, all diagnosed children entered the study, thus minimizing selection bias. Validated techniques were used, as well as positive and negative controls that accompanied the processing of the samples. Information was double‐checked when entered into the database for quality control.\n\n3 RESULTS\n\nOne hundred and thirty‐seven patients were included in the study. Six patients with BCR‐ABL1 translocations were excluded, as were 10 patients in whom we were unable to perform LDA due to the poor quality of the RNA obtained. For the final analysis, 121 patients were included. In 15 patients (12.4%), a positive gene expression profile for Ph‐like B‐ALL was observed (the Ph‐like group). The non‐Ph‐like group comprised 94 patients with a negative LDA Ph‐like expression profile and 12 patients with recurrent translocations (n = 106).\n\nThe median age for the entire cohort was 5 years (range 1–17 years), with the Ph‐like group having a median age of 9 years (range 1–17 years) and the non‐Ph‐like group having a median age of 5 years (range 1–17 years). This difference was not statistically significant (p = .250). The median leukocyte counts at diagnosis in the Ph‐like and non‐Ph‐like groups were 62.8 × 109/L (range 12.9–447.2 × 109/L) and 7.08 × 109/L (range 0.5–345.1 × 109/L), respectively. This difference was statistically significant (p < .001). The most frequent genetic alteration found was hyperdiploidy (n = 43, 35.5%).\n\nTable 1 shows the biological and clinical characteristics of the patients according to the presence of the Ph‐like profile. More patients in the Ph‐like group had minimal residual disease (MRD) at day 15 and at day 33 (end of induction) than the non‐Ph‐like group (60 vs. 17.9%). Three patients in the Ph‐like group were originally considered to be high‐risk, considering the initial factors (age, leukocyte count, and prednisone response on day 8). With the MRD evaluation on days 15 and 33, five more patients were added to the high‐risk group at the end of induction. Two patients in each group received hematopoietic stem cell transplantation; three were alive at the end of the study period, and one patient in the Ph‐like group died after transplantation. One and six patients in the Ph‐like and non‐Ph‐like groups had an early relapse, all within 36 months of diagnosis.\n\nTABLE 1 Demographic data of the two groups of patients\n\nPatients characteristics\tPh‐like (+) n = 15\tPh‐like (−) n = 106\t\nGender (M:F)\t7/8\t55/51\t\nAge at diagnosis (years) ≥ 10 years\t4\t71\t\n<10 years\t11\t35\t\nWBC at diagnosis\t\t\t\n<20 x 109/L\t6\t79\t\n20 a 100 x 109/L\t3\t23\t\n>100 x 109/L\t6\t4\t\nCNS involvement\t2\t9\t\nDay 8 prednisone response\t\t\t\n<1000 blasts in peripheral blood\t12\t86\t\n>1000 blasts in peripheral blood\t3\t20\t\nDay 15 MRD\t\t\t\n<0,1%\t2\t30\t\n0.1–10%\t6\t53\t\n>10%\t7\t21\t\nDay 33 MRD\t\t\t\n<0.01%\t6\t78\t\n≥0.01%\t9\t19\t\nFailure at end of induction (>5% blasts morphological on bone marrow)\t2\t2\t\nRisk classification at end of induction\t\t\t\nStandard\t1\t14\t\nIntermediate\t6\t62\t\nHigh\t8\t30\t\nAbbreviations: CNS, central nervous system; MRD, minimal residual disease (measured by flow cytometry); WBC, white blood count.\n\nThe clinical data and treatment response of the Ph‐like group are shown in Table 2. The Phi‐like expression profile was identified in 15/121 patients (12.4%). CRLF2 rearrangements were identified in 8/15 patients (53.3%), 4 with IGH‐CRLF2 and 4 with P2RY8‐CRLF2, and ABL1 rearrangements were found in 2/15 patients (13.3%). The RAS signaling pathway was not evaluated. Half of the patients with CRLF2 rearrangements also harbored IKZF1 deletions. Other associated genetic alterations were analyzed by MLPA in 13 of the 15 patients in the Ph‐like group. Genetic alterations were detected in 10 of 13 patients (77%), either alone or in combination. The most common mutations were CDKN2A/B deletions (n = 6, 46.2%), IKZF1 deletions (n = 5, 38.3%), and PAX5 deletions (n = 4, 30.8%). Two patients had other alterations (15.4%). Three patients (23.1%) had no alterations. Of the 15 patients in the Ph‐like group, three had hyperdiploidy (two had rearrangements in CRLF2), and two had intrachromosomal amplification of chromosome 21 (iAMP21).\n\nTABLE 2 Clinical characteristics and initial treatment response of the 15 patients with Ph‐like ALL\n\nAge (years)\tGender\tWBC(x 109/L)\tPrednisone response at day 8 (good‐poor)\tCount blasts by FCM at day 15 (%)\tCount blasts by FCM at day 33 (%)\tCRLF2 rearrangements\tABL1 rearrangements\tCopy number variations\tRelapse Yes /No\tStatus dead /Alive\t\n3\tF\t9.44\tGood\t7.66\t0\tNegative\tNegative\tNo CNV\tNo\tAlive\t\n10\tF\t388\tPoor\t50.5\t2.04\tIGH‐CRLF2\tNegative\tIKZF1, CDKN2A/B, BTG1 DELETIONS\tNo\tDead\t\n11\tM\t151.1\tPoor\t61.1\t0\tIGH‐CRLF2\tNegative\tIKZKF1, RB1, PAX5 DELETIONS\tNo\tAlive\t\n9\tM\t447.2\tPoor\t86.59\t7.68\tNegative\tPositive\tIKZK1, CDKNDA/B, ETV6, BTG1 DELETIONS\tYes\tDead\t\n1\tM\t118.6\tGood\t10.7\t0.06\tP2RY8‐CRLF2\tNegative\tPAX5 DELETION\tNo\tAlive\t\n9\tM\t9.9\tGood\t7.96\t0.01\tP2RY8‐CRLF2\tNegative\tNot performed\tNo\tAlive\t\n9\tF\t9.2\tGood\t54.3\t3.44\tNegative\tPositive\tRB1 DELETION\tNo\tDead\t\n3\tF\t7.3\tGood\t0.07\t0.02\tP2RY8‐CRLF2\tNegative\tILR3A, P2RY8, CSF22RA DELETIONS\tNo\tAlive\t\n17\tM\t79.7\tGood\t4.76\t0\tIGH‐CRLF2\tNegative\tIKZF1, CDKN2A/B, PAX5, ETV6 DELETIONS\tNo\tAlive\t\n8\tM\t1.2\tGood\t0.96\t0\tP2RY8‐CRLF2\tNegative\tNo CNV\tNo\tAlive\t\n16\tF\t53.8\tGood\t0\t0\tNegative\tNegative\tCDKN2A/B DELETIONS\tNo\tAlive\t\n6\tM\t14.4\tGood\t7.46\t0.07\tNegative\tNegative\tNo CNV\tNo\tDead\t\n9\tF\t171.8\tGood\t79.44\t33.41\tNegative\tNegative\tNo CNV\tNo\tAlive\t\n9\tM\t255.9\tGood\t5.7\t0\tIGH‐CRLF2\tNegative\tIKZF1, CDKN2B DELETIONS\tNo\tAlive\t\n3\tF\t6.8\tGood\t15.25\t0.13\tNegative\tNegative\tJAK2, CDKN2A/B, PAX5 DELETIONS\tNo\tAlive\t\nAbbreviations: CNV, copy number variations; F, female; M, male.\n\nIn the non‐Ph‐like group, t(12; 21) translocation was identified in 11 patients, iAMP21 amplification in four patients, 12p deletion in four cases, t(1; 19) translocation in two patients, and t(4; 11) translocation in one patient. Sixty‐four patients had a diploid karyotype, 40 had hyperdiploidy, and two had a tetraploid karyotype. The cytogenetic and molecular findings of the Ph‐like and non‐Ph‐like groups are shown in Figure 1. MLPA studies were performed in 95 patients; 62 (65.3%) had CNVs (alone or in combination with other genetic abnormalities), 19 (20.0%) had CDKN2A/B deletions (20%), 8 (8.4%) had IKZK1 deletions, 9 (9.5%) had ETV6 deletions, and 6 (6.3%) had isolated deletion of PAX5.\n\nFIGURE 1 (A) Distribution of genetic alterations in pediatric patients with Ph‐like ALL. (B) Distribution of genetic alterations in pediatric patients without Ph‐like profile\n\nOverexpression of CRLF2 without a positive LDA for the Ph‐like expression profile was detected in six patients (5.7%) with negative FISH results for IGH‐CRLF2 and P2RY8‐CRLF2 rearrangements. The median age of these patients was 4 years (range 2–9 years), 5/6 patients had a leukocyte count less than 10 × 109/L, and none had a leukocyte count higher than 50 × 109/L. Five had hyperdiploidy, none had translocations associated with increased risk, such as t(4; 11) or t(12; 21), all had a good response to prednisone at day 8, and all had MRD ≤0.01 at day 33. Although one patient died on induction, no other patients experienced other adverse events, including recurrence, at the time of this evaluation.\n\nWhen comparing the group of patients with and without Ph‐like B‐ALL, differences were found in demographic and clinical variables (Table 3).\n\nTABLE 3 Association of demographic and clinical variables with Ph‐like B‐ALL and non‐Ph‐like B‐ALL\n\nVariable\tPh‐like\tNo Ph‐like\tOR\tIC 95%\tp\t\nGender (M:F)\t8/7\t55/51\t1.06\t0.36–3.13\t0.916\t\nLeukocytes at diagnosis >20 x 109/L\t9/15 (60%)\t27/106 (25%)\t4.38\t1.43–13.47\t0.009\t\nLeukocytes at diagnosis >50 x 109/L\t9/15 (60%)\t14/106\t18.37\t5.21–64.75\t<0.001\t\nLeukocytes at diagnosis >100 x 109/L\t6/15 (40%)\t4/106 (3,7%)\t17\t4.04–71.54\t<0.001\t\nDay 8 prednisone response\n\n>1000 absolute blasts\n\n\t3/15 (20%)\t20/106 (19%)\t1.07\t0.27–4.17\t0.575\t\nDay 15 MRD >1%\t12/15 (80%)\t50/104 (48%)\t6.75\t1.45–31.43\t0.005\t\nDay 15 MRD >10%\t7/15 (47%)\t21/104 (20%)\t3.45\t1.12–10.61\t0.032\t\nDay 33 MRD >0,01%\t9/15 (60%)\t17/97 (17%)\t6.15\t1.95–19.41\t0.002\t\nDay 33 Bone marrow morphologic remission\t13/15 (87%)\t95/97 (98%)\t7.3\t0.96–57.41\t0.086\t\nIKZF1 positive status\t5/13 (38%)\t8/95 (8,4%)\t6.79\t1.79–25.73\t0.009\t\nNote: Bold values represent a Ph‐like: philadelphia like, No Ph‐like: no philadelphia like, OR: odds ratio, CI 95%: confidence interval 95%, p < 0,002.\n\nAbbreviation: MRD, minimal residual disease measured by flow cytometry.\n\nThe follow‐up time of this cohort was 10–34 months. The mortality was similar between the groups (Ph‐like: 26% and non‐Ph‐like: 18.8%). Most of the deaths in both groups were treatment‐related, although one patient in each group died due to refractory relapse. At the time of this evaluation, six patients had relapsed in the non‐Ph‐like group, whereas no living patients in the Ph‐like group had relapsed.\n\n4 DISCUSSION\n\nIn this study, we examined the frequency of Ph‐like B‐ALL and assessed its genomic and clinical characteristics in a cohort of patients under 18 years of age from a referral center in Colombia. A Ph‐like profile frequency of 12.4% was found in our cohort. This frequency is similar to that reported by other authors (between 10 and 19%). 7 , 15 , 16 It is important to note that our patients are a Latino/Hispanic population outside of North America; there is very little published information on the frequency of this variant of ALL in children in Latin America. Perez‐Vera et al. published a summary reporting 53% of this subtype in two institutions in Mexico this is high compared with our findings, however their diagnostic methodology to consider a result positive was different from that used in this study. 11 The clinical characteristics found in the Ph‐like group were similar to those found in other studies in children, such as higher white blood cell counts 17 , 18 and a higher frequency of failure of remission at the end of induction. 17 , 18 , 19 No differences were found by sex, unlike the predominance in males found by other authors. 19\n\nMRD at the end of induction has become essential in many protocols to define risk and intensification of therapy; therefore, it is important to identify this subgroup of patients at an early point in treatment. In our study, a statistically significant difference was found in MRD at the end of induction between the Ph‐like and non‐Ph‐like groups (60 vs. 17% p = .002). Other authors have also reported this association in children with Ph‐like ALL. 18 , 19 In 20% of patients with Ph‐like ALL, the risk classification was modified to a higher classification when considering the MRD at the end of induction, but hematopoietic transplantation is not standard in our institutional protocol when patients have MRD positive at the end of induction, so patients with Ph‐like profile and MRD positive at the end of induction followed our protocol without transplantation in first remission .\n\nCRLF2 rearrangements were found in 53.3% of the patients with the Ph‐like gene expression profile, with the same proportion of patients having IGH‐CRLF2 and P2RY8‐CRLF2 rearrangements. These frequencies are variable in pediatric patients. There are reports of similar frequencies for both of these rearrangements, 18 although some authors report a predominance of the IGH‐CRLF2 rearrangement. Studies in adults with B‐ALL also report a higher frequency of CRLF2 rearrangements in patients with a Ph‐like expression profile. 20 Other genomic alterations, such as deletions of IKZF1, were observed in both groups, albeit less frequently. Deletions of IKZF1 were observed in 38.6% of patients in the Ph‐like group, which is similar to the findings of Roberts et al. 19 but lower than that reported in other pediatric cohorts (60–80%). 12 , 21 This result may be due to different sample sizes or patient populations, since some examined a selected high‐risk population. We found a small number of patients with CRLF2 overexpression without an LDA‐positive Ph‐like expression profile. These patients did not harbor CRLF2 rearrangements and did not have adverse prognostic factors, as has been described by other authors. 22 Hyperdiploidy in patients with Ph‐like ALL is not a consistent finding; Van Der Veer et al they did not find hyperdiploidy in a group of patients ALL Ph‐like. 23 On the other hand, Jain et al. that included 68% of Hispanic population living in United States, found hyperdiploidy in 20% of patients with Ph‐like profile, a similar proportion found in our study. 24 Related to iAMP21, this alteration could be found in patients with Ph‐like profile. Schwab and Harrison reported that near 60% of iAMP21‐ALL patients had mutations in genes within the RAS signaling pathway, this pathway is part of the Ph‐like phenotype. 25\n\nBoth groups had a similar proportion of high‐risk patients at the initial risk assessment (20 vs. 19%). In the Ph‐like group, the proportion of high‐risk patients increased to 53.5% at the end of induction, after taking the MRD into consideration. This finding is different from that of the study by Roberts et al, 19 which included all patients from a cohort of children with ALL, in which no patients in the Ph‐like group were initially categorized as high‐risk. However, at the end of induction, 27% of patients in the Ph‐like group switched to the high‐risk group due to MRD. Today MRD is part of risk classification of ALL protocols in children.\n\nDifficulties in diagnosing the Ph‐like expression profile persist, more than a decade after its identification. There is heterogeneity in the methods used to characterize the Ph‐like profile, and there is no consensus on the methodology used to identify this B‐ALL subtype. Other groups have reported difficulties in processing samples. The GIMEMA group analysis of samples from a cohort of adult ALL patients were retrospectively searched for the Ph‐like expression profile, and 16.2% of patients could not be analyzed due to RNA unavailability. 8 It should be address in the near future a consensus for the diagnosis of Ph‐like ALL.\n\nIdentifying this B‐ALL subtype may provide an opportunity to understand why some BCR‐ABL1‐negative patients without findings of poor prognosis have persistent MRD at the end of induction and require treatment intensification. The current diagnostic strategies are not uniform, and many may not be feasible in countries with limited resources. It is necessary to design straightforward methodologies that can be easily implemented to identify this subgroup of patients. 26\n\nThe best therapeutic strategy for this group of patients is still being examined, motivated by the impact of the revolutionary role of tyrosine kinase inhibitors such as imatinib in improving the outcomes of patients with Philadelphia‐positive B‐ALL. Several collaborative groups are currently conducting randomized clinical trials, whose results will be known over the next few years. 17 , 24 Among the questions to be resolved in this specific B‐ALL subtype is the possibility of using targeted therapy associated with conventional chemotherapy, which allows improving current results without increasing toxicity and eliminating the need for consolidation with HPT. 27\n\nIn conclusion, the frequency of the Ph‐like ALL subtype in our cohort (12.4%) was similar to that described in cohorts in North America. This subtype was associated with poor prognostic factors, as previously identified. Additionally, 77% of these patients had gene deletions, such as IKZF1 or CDKN2A/B. We should identify factors associated with a greater probability of having the Ph‐like expression profile in order to standardize methods to identify this B‐ALL variant in countries with limited resources. Identifying B‐ALL variants that require intensification of treatment, especially due to positive MRD at the end of induction, and which in the future may be susceptible to targeted therapies may improve the chances of cure for this subgroup of patients.\n\nCONFLICT OF INTEREST\n\nThe authors declare no conflict of interest.\n\nConceptualization, Funding Acquisition, Investigation, Resources, Supervision, Writing—Original Draft, Writing—Review and Editing, A.L.; Conceptualization, Investigation, Methodology, Resources, Validation, Writing – Original Draft, L.K.Y.; Investigation, Project Administration, Writing—Original Draft, Writing—Review And Editing, J.G.; Data Curation, Formal Analysis, Software, N.A.; Data Curation, Investigation, Supervision, J.F.; Data Curation, Investigation, Project Administration, Supervision, Validation, C.M.; Formal Analysis, Methodology, Resources, Writing—Review and Editing, G.U.; Formal Analysis, Methodology, Resources, Writing—Review and Editing, E.Q.; Methodology, Resources, Validation, A.D.; Formal Analysis, Investigation, Writing—Review and Editing, C.P.; Formal Analysis, Investigation, Writing—Review and Editing, I.S.; Conceptualization, Funding Acquisition, Project Administration, Supervision, Writing—Review and Editing, A.C.; Conceptualization, Formal Analysis, Methodology, Resources, Writing – Original Draft, Writing—Review and Editing, J.J.Y.\n\nETHICAL STATEMENT\n\nInformed consent was obtained from each patient or guardian. This protocol was approved by the institutional ethics committee of our institution (EC number 010 April 2019).\n\nACKNOWLEDGMENT\n\nAll genetic testing was performed at the Servicios Médicos Yunis Turbay y Cia SAS, Bogotá, D.C. Colombia.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 Schrappe M , Bleckmann K , Zimmermann M , et al. Reduced‐intensity delayed intensification in standard‐risk pediatric acute lymphoblastic leukemia defined by undetectable minimal residual disease: results of an international randomized trial (AIEOP‐BFM ALL 2000). J Clin Oncol. 2018;36 (3 ):244‐253.29148893\n2 Winick N , Martin PL , Devidas M , et al. Randomized assessment of delayed intensification and two methods for parenteral methotrexate delivery in childhood B‐ALL: Children's Oncology Group Studies P9904 and P9905. Leukemia. 2020;34 (4 ):1006‐1016.31728054\n3 Mullighan CG , Su X , Zhang J , et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360 (5 ):470‐480.19129520\n4 Den Boer ML , van Slegtenhorst M , De Menezes RX , et al. A subtype of childhood acute lymphoblastic leukaemia with poor treatment outcome: a genome‐wide classification study. Lancet Oncol. 2009;10 (2 ):125‐134.19138562\n5 Arber DA , Orazi A , Hasserjian R , et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016;127 (20 ):2391‐2405.27069254\n6 Iacobucci I , Roberts KG . Genetic alterations and therapeutic targeting of Philadelphia‐like acute lymphoblastic leukemia. Genes. 2021;12 :687. doi:10.3390/genes12050687 34062932\n7 Roberts KG , Li Y , Payne‐Turner D , et al. Targetable kinase‐activating lesions in Ph‐like acute lymphoblastic leukemia. N Engl J Med. 2014;371 (11 ):1005‐1015.25207766\n8 Chiaretti S , Messina M , Della Starza I , et al. Philadelphia‐like acute lymphoblastic leukemia is associated with minimal residual disease persistence and poor aoutcome. First report of the minimal residual‐disease oriented GIMEMA LAL1913. Haematologica. 2021;106 (6 ):1559‐1568.32467145\n9 Harvey RC , Mullighan CG , Chen I‐M , et al. Rearrangement of CRLF2 is associated with mutation of JAK kinases, alteration of IKZF1, Hispanic/Latino ethnicity, and a poor outcome in pediatric B‐progenitor acute lymphoblastic leukemia. Blood. 2010;115 (26 ):5312‐5321.20139093\n10 Cario G , Leoni V , Conter V , Baruchel A , Schrappe M , Biondi A . BCR‐ABL1‐like acute lymphoblastic leukemia in childhood and targeted therapy. Haematologica. 2020;105 (9 ):2200‐2204.33054045\n11 Perez‐Vera P , Moreno Lorenzana D , Juarez‐Velazquez MR , et al. High frequency of Ph‐like PCB‐ALL subtype in Mexican pediatric patients. Experience in two institutions. Blood. 2018;132 (suppl 1 ):4092.\n12 Van Dongen JJM , Lhermitte L , Bottcher S , et al. Euroflow antibody panels for standardized n‐dimensional flow cytometric immunophenotyping of normal, reactive and malignant leukocytes. Leukemia. 2012;26 :1908‐1975.22552007\n13 Arsham MS , Barch MJ , Lawce HJ . The AGT Cytogenetics Laboratory Manual. 4th ed. Wiley; 2017.\n14 Reshmi SC , Harvey RC , Roberts KG , et al. Targetable kinase gene fusions in high‐risk B‐ALL: a study from the Children's oncology group. Blood. 2017;129 (25 ):3352‐3361. doi:10.1182/blood-2016-12-758979 28408464\n15 Pui CH , Roberts KG , Yang JJ , Mullighan CG . Philadelphia chromosome‐like acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2017;17 (8 ):464‐470.28842136\n16 Khan M , Siddiqi R , Tran T . Philadelphia chromosome‐like acute lymphoblastic leukemia: a review of the genetic basis, clinical features, and therapeutic options. Semin Hematol. 2018;55 :235‐224.30502852\n17 Aldoss I , Advani A . Have any strategies in Ph‐like ALL been shown to be effective? Best Pract Res Clin Haematol. 2021;34 :101242.33762097\n18 Tasian SK , Loh ML , Hunger SP . Philadelphia chromosome–like acute lymphoblastic leukemia. Blood. 2017;130 (19 ):2064‐2072.28972016\n19 Roberts KG , Pei D , Campana D , et al. Outcomes of children with BCR‐ABL1‐like acute lymphoblastic leukemia treated with risk‐directed therapy based on the levels of minimal residual disease. J Clin Oncol. 2014;32 (27 ):3012‐3020.25049327\n20 Roberts KG , Gu Z , Payne‐Turner D , et al. High frequency and poor outcome of Philadelphia chromosome–like acute lymphoblastic leukemia in adults. J Clin Oncol. 2017;35 (4 ):394‐401.27870571\n21 Yadav V , Ganesan P , Veeramani R , Kumar D . Philadelphia‐like acute lymphoblastic leukemia. A systematic review. Clin Lymphoma Myeloma Leuk. 2021;1 :e57‐e65.\n22 Rasekh EO , Atef AM , Khalil M , Ebeid E , Madney Y , Hamdy N . Characterization of CRLF2 expression in pediatric B‐cell precursor acute lymphoblastic leukemia. Clin Lab. 2021;67 (1 ). doi:10.7754/Clin.Lab.2020.200414\n23 Van de Beer A , Waanders E , Pieters R , et al. Independent prognostic value of BCR‐ABL1‐like signature and IKZF1 deletion, but not high CRLF2 expression, in children with B‐cell precursor ALL. Blood. 2013;122 (15 ):2622‐2629.23974192\n24 Jain N , Jabbour EJ , McKay PZ , et al. Ruxolitinib or dasatinib in combination with chemotherapy for patients with relapsed/refractory Philadelphia (Ph)‐like acute lymphoblastic leukemia: a phase I‐II trial. Blood. 2017;130 (suppl 1 ):1322.\n25 Schwab C , Harrison CJ . Advances in B‐cell precursor acute lymphoblastic leukemia genomics. HemaSphere. 2018;2 :4.\n26 Konoplev S , Lu X , Konopleva M , et al. CRLF2‐positive B‐cell acute lymphoblastic leukemia in adult patients. Am J Clin Pathol. 2017;147 (4 ):357‐363.28340183\n27 Tasian SK , Assad A , Hunter DS , Du Y , Loh ML . A phase 2 study of Ruxolitinib with chemotherapy in children with Philadelphia chromosome‐like acute lymphoblastic leukemia (INCB18424‐269/ALL1521): dose‐finding results from part 1 safety phase. Blood. 2018;132 (suppl 1 ):555.30093383\n\n",
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"journal": "Cancer reports (Hoboken, N.J.)",
"keywords": "CDKN2A/B; CRLF2; Colombia; ETV6; Hispanic; IKZF1; PAX5; Ph-like; acute lymphoblastic leukemia; children",
"medline_ta": "Cancer Rep (Hoboken)",
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"pubdate": "2021-11-17",
"publication_types": "D016428:Journal Article",
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"title": "Philadelphia-like acute lymphoblastic leukemia: Characterization in a pediatric cohort in a referral center in Colombia.",
"title_normalized": "philadelphia like acute lymphoblastic leukemia characterization in a pediatric cohort in a referral center in colombia"
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"abstract": "Clozapine use is complicated by an increased risk of hematological adverse effects such as neutropenia and, rarely, eosinophilia.\n\n\n\nWe present the case of a 48-year-old man with treatment-resistant schizophrenia. On day 12 after clozapine initiation, he had a cough with a temperature of 39.8°C. On day 16, his leukocyte count had increased to 9320 cells/mm3 (neutrophils 7550 cells/mm3 and eosinophils 680 cells/mm3 ). We discontinued lithium because of neutrophilia and damage to renal function on day 20. His eosinophil count increased until day 29, reaching 6750 cells/mm3 . We suspected a drug-induced reaction and discontinued clozapine on day 30. His eosinophil count gradually decreased, reaching the normal range by day 40. However, his leukocyte and neutrophil counts also gradually decreased to below than the normal range by day 40. His leukocytes and neutrophil counts had recovered by day 55.\n\n\n\nWe concluded that this patient had clozapine-associated severe eosinophilia following lithium rebound neutropenia.",
"affiliations": "Department of Psychiatry, School of Medicine, Dokkyo Medical University, Tochigi, Japan.;Department of Psychiatry, School of Medicine, Dokkyo Medical University, Tochigi, Japan.;Department of Psychiatry, School of Medicine, Dokkyo Medical University, Tochigi, Japan.;Department of Psychiatry, School of Medicine, Dokkyo Medical University, Tochigi, Japan.;Department of Diagnostic and Generalist Medicine, School of Medicine, Dokkyo Medical University Hospital, Tochigi, Japan.;Department of Diagnostic and Generalist Medicine, School of Medicine, Dokkyo Medical University Hospital, Tochigi, Japan.;Department of Diagnostic and Generalist Medicine, School of Medicine, Dokkyo Medical University Hospital, Tochigi, Japan.;Department of Psychiatry, School of Medicine, Dokkyo Medical University, Tochigi, Japan.",
"authors": "Kikuchi|Kota|K|;Yasui-Furukori|Norio|N|0000-0002-4414-3770;Yokoyama|Saaya|S|;Hasegawa|Chie|C|;Kokubun|Atsuhiko|A|;Katsukura|Shinichi|S|;Shimizu|Taro|T|;Shimoda|Kazutaka|K|",
"chemical_list": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D016651:Lithium Carbonate; D003024:Clozapine",
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"doi": "10.1002/npr2.12143",
"fulltext": "\n==== Front\nNeuropsychopharmacol Rep\nNeuropsychopharmacol Rep\n10.1002/(ISSN)2574-173X\nNPR2\nNeuropsychopharmacology Reports\n2574-173X John Wiley and Sons Inc. Hoboken \n\n32951324\n10.1002/npr2.12143\nNPR212143\nCase Report\nCase Reports\nClozapine‐associated severe eosinophilia following lithium rebound neutropenia: A case report\nKIKUCHI et al.Kikuchi Kota \n1\n Yasui‐Furukori Norio https://orcid.org/0000-0002-4414-3770\n1\nfurukori@dokkyomed.ac.jp Yokoyama Saaya \n1\n\n2\n Hasegawa Chie \n1\n Kokubun Atsuhiko \n3\n Katsukura Shinichi \n3\n Shimizu Taro \n3\n Shimoda Kazutaka \n1\n \n1 \nDepartment of Psychiatry\nSchool of Medicine\nDokkyo Medical University\nTochigi\nJapan\n\n\n2 \nDepartment of Psychiatry\nOkamotodai Hospital\nTochigi\nJapan\n\n\n3 \nDepartment of Diagnostic and Generalist Medicine\nSchool of Medicine\nDokkyo Medical University Hospital\nTochigi\nJapan\n\n* Correspondence\n\nNorio Yasui‐Furukori, Department of Psychiatry, Dokkyo Medical University, School of Medicine, Mibu, Shimotsuga, Tochigi 321‐0293, Japan.\n\nEmail: furukori@dokkyomed.ac.jp\n\n19 9 2020 \n12 2020 \n40 4 10.1111/npr2.v40.4388 391\n22 7 2020 20 8 2020 24 8 2020 © 2020 The Authors. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of the Japanese Society of Neuropsycho Pharmacology.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nBackground\nClozapine use is complicated by an increased risk of hematological adverse effects such as neutropenia and, rarely, eosinophilia.\n\nCase presentation\nWe present the case of a 48‐year‐old man with treatment‐resistant schizophrenia. On day 12 after clozapine initiation, he had a cough with a temperature of 39.8°C. On day 16, his leukocyte count had increased to 9320 cells/mm3 (neutrophils 7550 cells/mm3 and eosinophils 680 cells/mm3). We discontinued lithium because of neutrophilia and damage to renal function on day 20. His eosinophil count increased until day 29, reaching 6750 cells/mm3. We suspected a drug‐induced reaction and discontinued clozapine on day 30. His eosinophil count gradually decreased, reaching the normal range by day 40. However, his leukocyte and neutrophil counts also gradually decreased to below than the normal range by day 40. His leukocytes and neutrophil counts had recovered by day 55.\n\nConclusion\nWe concluded that this patient had clozapine‐associated severe eosinophilia following lithium rebound neutropenia.\n\nThe eosinophil count increased reaching 6750 cells/mm3 with bronchitis and hepatitis during clozapine treatment. The leukocyte and neutrophil counts gradually decreased to below than the normal range by day 40 after discontinuation of lithium.\n\n\n\nclozapineeosinophilialithiumneutropenia source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.5 mode:remove_FC converted:08.12.2020\n\n\nKikuchi \nK \n, \nYasui‐Furukori \nN \n, \nYokoyama \nS \n, et al. Clozapine‐associated severe eosinophilia following lithium rebound neutropenia: A case report\n. Neuropsychopharmacol Rep . 2020 ;40 :388 –391\n. 10.1002/npr2.12143 \n32951324\n==== Body\n1 INTRODUCTION\nA recent network meta‐analysis suggested that clozapine is superior to other antipsychotics,\n1\n and several guidelines regarding pharmacotherapy for schizophrenia recommend clozapine as the best choice for treatment‐resistant schizophrenia.\n2\n, \n3\n However, its use is complicated by an increased risk of hematological adverse effects such as neutropenia\n4\n and, rarely, eosinophilia.\n5\n Eosinophilia develops as an immunologically mediated response in association with diverse processes, including allergic, neoplastic, and infectious diseases.\n6\n We present the case of a 48‐year‐old man with treatment‐resistant schizophrenia and clozapine‐associated severe eosinophilia and then neutropenia secondary to lithium discontinuation. Written consent for publication of the case report was provided by the patient.\n\n2 CASE REPORT\nA 48‐year‐old male patient had been diagnosed with schizophrenia according to the DSM‐5 19 years prior. He had received 6 sessions of electroconvulsive therapy and several medications, such as haloperidol and risperidone, but the response was poor response. He was started on clozapine treatment (initially 12.5 mg/day, increased by 12.5 or 25 mg/d every 6‐7 days) because the schizophrenia was treatment resistant and his Positive and Negative Syndrome Scale (PANSS) score was 110. At the time of clozapine initiation, he received haloperidol 3 mg/d, paliperidone 6 mg/d, and levomepromazine 25 mg/d, which decreased in a cross‐titration regimen. He also received lithium 400 mg/d because his white blood cell (WBC) count was lower than 4000 cells/mm3 before clozapine. On day 12, he presented with a cough and a temperature of 39.8°C. By day 16, his leukocyte count had increased to 9320 cells/mm3 (neutrophils 7550 cells/mm3 and eosinophils 680 cells/mm3). The antibiotic ceftriaxone was administered, but it was not effective. On day 19, he was transferred to our hospital for detailed investigations. His PANSS score was 70. His admission laboratory tests showed the following results: WBC 11 300 cells/mm3 (3300‐8600 cells/mm3), neutrophil count 8780 cells/mm3 (1790‐6340 cells/mm3), eosinophil count 1540 cells/mm3 (0‐520 cells/mm3), hemoglobin (Hgb) 11.9 (13.7‐16.8 g/dL), platelet count 350 K/μL (158‐348 K/μL), aspartate aminotransferase 21 U/L (13‐30 U/L), alanine aminotransferase 91 U/L (10‐42 U/L), alkaline phosphatase 466 U/L (106‐322 U/L), gamma‐glutamyl transpeptidase 139 U/L (19‐64 U/L), creatinine 3.32 mg/dL (0.65‐1.07 mg/dL), estimated glomerular filtration rate 17.2 ml/min/1.73 m2 (>60.0 ml/min/1.73 m2), and C‐reactive protein (CRP) 16.9 mg/L (0.0‐0.14 mg/L). At admission, his medications were as follows: haloperidol 3 mg/day, paliperidone 6 mg/day, levomepromazine 25 mg/day, and lithium 400 mg/day. Imaging on admission included a chest X‐ray, which showed no abnormal shadows. A chest CT showed slight bilateral pleural effusion and pericardial effusion. We discontinued lithium because of neutrophilia and damage to renal function on day 20. We also switched from ceftriaxone to piperacillin/tazobactam on day 20 due to liver damage. CRP and creatinine peaked on day 20 at 17.2 mg/L and 3.39 mg/dL, respectively. WBCs, neutrophils, aspartate aminotransferase, alanine aminotransferase, and gamma‐glutamyl transpeptidase peaked on day 22, at 14 600, 10 160 cells/mm3, 79, 623, and 235 U/L, respectively (Figure 1). However, the eosinophil count continued to increase until day 29, reaching 6750 cells/mm3. We suspected a drug‐induced reaction and lowered the clozapine dosage to 75 mg/day starting on day 25, finally discontinuing clozapine on day 30 and increased haloperidol to 6 mg/d because of the increasing tendency toward eosinophilia. After that, the eosinophil count gradually decreased to within the normal range by Day 40. However, the leukocyte and neutrophil counts also gradually decreased to within the normal ranges, dropping below the normal ranges by Day 40 (Figure 1). We monitored the patient for 10 consecutive days based on suggestions from the clozapine patient monitoring service (CPMS). His leukocyte and neutrophil counts recovered by Day 55. His psychotic symptoms deteriorated and his PANSS score increased to 95 in spite of haloperidol at 6 mg/d on day 50, and no improvement was observed with aripiprazole at 30 mg/d and brexpiprazole at 2 mg/d on day 80. Retrospective analysis of the drug‐induced lymphocyte stimulation test (DLST) was positive for clozapine.\n\nFigure 1 Clinical course of the patient including white blood cells, neutrophils, eosinophils, and body temperature during drug treatment. Upper and lower dotted lines indicate 3500 and 2000 cells/mm3, which is the lower limit for white blood cells and neutrophils, respectively, when clozapine is administered. The eosinophil count increased reaching 6750 cells/mm3 with bronchitis and hepatitis during clozapine treatment. The leukocyte and neutrophil counts gradually decreased to below than the normal range by day 40 after discontinuation of lithium\n\n3 DISCUSSION\nHere, we report the first case of clozapine‐associated severe eosinophilia and subsequent lithium discontinuation‐associated neutropenia. The patient also had bronchitis and hepatitis.\n\nClozapine eosinophilia has an incidence of 3% and mostly occurs in the first 2‐3 months after starting treatment. The largest study with 2,404 patients in Italy found an incidence of 2.2% based on the criteria of an eosinophil count greater than 400 cells/mm3.\n7\n The most recent studies reported that approximately one‐tenth (N = 33; 9.9%) of patients developed eosinophilia (absolute eosinophil count >600 cells/mm3).\n8\n In addition, cases of pancreatitis, hepatitis, colitis, nephritis, and myocarditis‐associated eosinophilia have been reported.\n9\n Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome) is an uncommon side effect of certain medications.\n6\n The incidence is 0.4 cases per 1,000,000 in the general population, and the mortality rate is as high as 10%. In cases in which eosinophilia is accompanied by the involvement of major organs,\n9\n, \n10\n clozapine should be discontinued immediately. Because a rash was not observed, our patient did not meet the DRESS criteria, although other symptoms developed in our patient.\n\nSeveral studies have suggested successful rechallenge after discontinuation of clozapine due to eosinophilia.\n11\n, \n12\n However, most cases included mild to moderate eosinophilia without organ damage. Our patient had severe eosinophilia with bronchitis and hepatitis, and he strongly refused a clozapine rechallenge.\n\nBased on the clinical course of neutropenia after clozapine and lithium discontinuation, it appears that the patient had not only clozapine rebound neutropenia but also lithium rebound neutropenia. Because the WBC count before the initiation of clozapine was lower than 4000 cells/mm3, which is the Japanese criteria for the initiation of clozapine, lithium was added,\n13\n and the WBC count increased to more than 4000 cells/mm3. Tomita et al reported that leukopenia and neutropenia appeared to develop in a patient owing to lithium discontinuation.\n14\n There has been no report suggesting the existence of clozapine discontinuation‐associated neutropenia, although there was one case of rebound insomnia reported after abrupt clozapine withdrawal.\n15\n Therefore, it is more likely that the lithium discontinuation was associated with the neutropenia in this case.\n\nCONFLICT OF INTEREST\nNorio Yasui‐Furukori has been a speaker for Otsuka Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharmaceutical Co., and MSD Co. Kazutaka Shimoda has received research support from Novartis Pharma KK, Dainippon Sumitomo Pharma Co., Astellas Pharma Inc, Meiji Seika Pharma Co., Ltd., Eisai Co., Ltd., Pfizer Inc, Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., and Takeda Pharmaceutical Co., Ltd., and honoraria from Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Janssen Pharmaceutical KK, Shionogi & Co., Ltd., Dainippon Sumitomo Pharma Co., Daiichi Sankyo Co., and Pfizer Inc The funders did not have any role in data collection or in the study design, analysis, decision to publish, or preparation of the manuscript. The remaining authors declare that they have no competing interests to report.\n\nAUTHOR CONTRIBUTIONS\nKK, NYF, SY, CH, AK, and SK were involved in the clinical investigations. NYF wrote the manuscript. TS, NYF, and KS were involved in the literature review and revisions. All authors read and approved the final manuscript.\n\nETHICS APPROVAL AND CONSENT TO PARTICIPATE\nThe ethics committee of the School of Medicine at Dokkyo Medical University determined that there was no need to review this case.\n\nCONSENT FOR PUBLICATION\nWritten informed consent was obtained from the parent for the publication of this case report.\n\nData Availability Statement\nData sharing is not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nREFERENCES\n1 \n\nSamara \nMT \n, \nDold \nM \n, \nGianatsi \nM \n, \nNikolakopoulou \nA \n, \nHelfer \nB \n, \nSalanti \nG \n, et al. Efficacy, acceptability, and tolerability of antipsychotics in treatment‐resistant schizophrenia: A Network Meta‐analysis\n. JAMA Psychiatry . 2016 ;73 :199 –210\n.26842482 \n2 \n\nKane \nJM \n, \nAgid \nO \n, \nBaldwin \nML \n, \nHowes \nO \n, \nLindenmayer \nJP \n, \nMarder \nS \n, et al. Clinical Guidance on the Identification and Management of Treatment‐Resistant Schizophrenia\n. J Clin Psychiatry . 2019 ;80 (2 ):18com12123.\n3 \n\nBarnes \nTR \n, \nDrake \nR \n, \nPaton \nC \n, \nCooper \nSJ \n, \nDeakin \nB \n, \nFerrier \nIN \n, et al. Evidence‐based guidelines for the pharmacological treatment of schizophrenia: Updated recommendations from the British Association for Psychopharmacology\n. J Psychopharmacol . 2020 ;34 :3 –78\n.31829775 \n4 \n\nMyles \nN \n, \nMyles \nH \n, \nXia \nS \n, \nLarge \nM \n, \nBird \nR \n, \nGalletly \nC \n, et al. A meta‐analysis of controlled studies comparing the association between clozapine and other antipsychotic medications and the development of neutropenia\n. Aust N Z J Psychiatry . 2019 ;53 :403 –12\n.30864459 \n5 \n\nde Filippis \nR \n, \nSoldevila‐Matías \nP \n, \nDe Fazio \nP \n, \nGuinart \nD \n, \nFuentes‐Durá \nI \n, \nRubio \nJM \n, et al. Clozapine‐related drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome: a systematic review\n. Exp Rev Clin Pharmacol . 2020 ;13 (8 ):875 –83\n.\n6 \n\nWatanabe \nH \n. Recent advances in drug‐induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms\n. J Immunol Res . 2018 ;2018 :5163129 .29744372 \n7 \n\nDeliliers \nGL \n. Blood dyscrasias in clozapine‐treated patients in Italy\n. Haematologica . 2000 ;85 :233 –7\n.10702809 \n8 \n\nGrover \nS \n, \nShouan \nA \n, \nChakrabarti \nS \n, \nAvasthi \nA \n. Haematological side effects associated with clozapine: A retrospective study from India\n. Asian J Psychiatr . 2020 ;48 :101906 .31865196 \n9 \n\nHo \nYC \n, \nLin \nHL \n. Continuation with clozapine after eosinophilia: A case report\n. Ann Gen Psychiatry . 2017 ;16 :46 .29259655 \n10 \n\nVerdoux \nH \n, \nQuiles \nC \n, \nde Leon \nJ \n. Clinical determinants of fever in clozapine users and implications for treatment management: a narrative review\n. Schizophr Res . 2019 ;211 :1 –9\n.31378552 \n11 \n\nMcArdle \nPA \n, \nSiskind \nDJ \n, \nKolur \nU \n, \nParker \nS \n, \nKorman \nN \n, \nPurushothaman \nS \n. Successful rechallenge with clozapine after treatment associated eosinophilia\n. Australas Psychiatry . 2016 ;24 :365 –7\n.27324147 \n12 \n\nLally \nJ \n, \nOʼConnor \nN \n, \nFullam \nS \n, \nCorcoran \nN \n, \nOʼReilly \nA \n, \nJordan \nJ \n, et al. Rechallenge following clozapine‐associated eosinophilia: a case report and literature review\n. J Clin Psychopharmacol . 2019 ;39 :504 –6\n.31335444 \n13 \n\nSporn \nA \n, \nGogtay \nN \n, \nOrtiz‐Aguayo \nR \n, \nAlfaro \nC \n, \nTossell \nJ \n, \nLenane \nM \n, et al. Clozapine‐induced neutropenia in children: management with lithium carbonate\n. J Child Adolesc Psychopharmacol . 2003 ;13 :401 –4\n.14642024 \n14 \n\nTomita \nT \n, \nGoto \nH \n, \nSumiya \nK \n, \nYoshida \nT \n, \nTanak \nK \n, \nKohda \nY \n. Efficacy of adenine in the treatment of leukopenia and neutropenia associated with an overdose of antipsychotics or discontinuation of lithium carbonate administration: three case studies\n. Clin Psychopharmacol Neurosci . 2016 ;14 :391 –5\n.27776394 \n15 \n\nStaedt \nJ \n, \nStoppe \nG \n, \nHajak \nG \n, \nRuther \nE \n. Rebound insomnia after abrupt clozapine withdrawal\n. Eur Arch Psychiatry Clin Neurosci . 1996 ;246 :79 –82\n.9063912\n\n",
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"journal": "Neuropsychopharmacology reports",
"keywords": "clozapine; eosinophilia; lithium; neutropenia",
"medline_ta": "Neuropsychopharmacol Rep",
"mesh_terms": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D003024:Clozapine; D004802:Eosinophilia; D006801:Humans; D016651:Lithium Carbonate; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D012559:Schizophrenia; D012720:Severity of Illness Index",
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"title": "Clozapine-associated severe eosinophilia following lithium rebound neutropenia: A case report.",
"title_normalized": "clozapine associated severe eosinophilia following lithium rebound neutropenia a case report"
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"abstract": "BACKGROUND\nBiopsy-based \"reversal hypothesis\" claimed conversion of miniaturized hair follicles into terminal ones for the improvement of male pattern hair loss (MPHL) with FDA-approved drugs.\n\n\nMETHODS\nMPHL volunteers (n = 13) completed a 24-month phototrichogram study. After 2 months no-treatment, panellists took finasteride 1mg daily for 2 years. Hair changes from the best responder would explain the nature of improved hair growth.\n\n\nRESULTS\nDue to the wide range of hair growth variables, no parameter was statistically significantly changed by finasteride in the group. Clinically there were 4 worse, 6 no change, 2 slightly and 1 moderately improved subject associated with turning telogen/empty terminal follicles into anagen after 12- and 24-month finasteride. From 113 miniaturized hair (diameters ≤ 30 µm) at baseline, 79 were still miniature hair after 2 years on finasteride. No hair were found at the remaining mapped sites except for 2 terminal hairs considered a probabilistic \"uncertainty.\"\n\n\nCONCLUSIONS\nModerate hair improvement resulted from increased productivity of deficient terminal follicles, but not yet irreversibly affected at baseline without implication of miniaturized hair follicles. The latter further regressed even with oral intake of finasteride. The data suggest the rejection of the \"reversal hypothesis\" unless proven otherwise with duly validated methods.",
"affiliations": "Skinterface and Brussels Hair Clinic, Brussels, Belgium.",
"authors": "Van Neste|Dominique|D|https://orcid.org/0000-0002-1613-7672",
"chemical_list": "D003879:Dermatologic Agents; D018120:Finasteride",
"country": "England",
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"doi": "10.1111/srt.12706",
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"issn_linking": "0909-752X",
"issue": "25(5)",
"journal": "Skin research and technology : official journal of International Society for Bioengineering and the Skin (ISBS) [and] International Society for Digital Imaging of Skin (ISDIS) [and] International Society for Skin Imaging (ISSI)",
"keywords": "FDA-approved drug; androgenetic alopecia; clinical trial; finasteride; hair growth; male pattern hair loss; miniaturized hair; reversal hypothesis; vellus hair follicle",
"medline_ta": "Skin Res Technol",
"mesh_terms": "D000328:Adult; D000505:Alopecia; D003879:Dermatologic Agents; D018120:Finasteride; D006197:Hair; D018859:Hair Follicle; D006801:Humans; D008297:Male; D012535:Scalp; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9504453",
"other_id": null,
"pages": "701-711",
"pmc": null,
"pmid": "31206839",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Viable terminal scalp hair follicles constitute a necessary and sufficient biological end-organ that conditions clinical efficacy of finasteride in males with male pattern hair loss without implying reversal of miniaturized follicles.",
"title_normalized": "viable terminal scalp hair follicles constitute a necessary and sufficient biological end organ that conditions clinical efficacy of finasteride in males with male pattern hair loss without implying reversal of miniaturized follicles"
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"abstract": "OBJECTIVE\nThe current study aims to investigate the neurodevelopment of premature infants after intravitreal injections of bevacizumab (IVB) for the treatment of retinopathy of prematurity (ROP) up to the age of 2 years.\n\n\nMETHODS\nThe study design was retrospective observational case series conducted at an institutional referral center. Infants with type 1 ROP were classified into 3 groups: laser only, IVB only, and a combination of IVB and laser treatment. Main Outcome Measures were neurodevelopmental outcomes of the patients after treatment were assessed by Bayley Scales for Infant Development.\n\n\nRESULTS\nSixty-one patients who finished the neurodevelopmental survey were included. No detrimental effects on neurodevelopment were found in IVB group compared with the patients who received laser treatment only. The patients in the IVB + laser group had a higher incidence of significant mental (p = 0.028) and psychomotor (p = 0.002) impairment at 24 months than the patients in the laser group. The odds ratio of having severe psychomotor defects in the IVB + laser group was 5.3 compared with the laser group (p = 0.041). The causal source for the differences that were detected remained unknown due to lack of randomization in the study and accompanying bias in patient selection.\n\n\nCONCLUSIONS\nTwo years after laser and/or intravitreal injections of bevacizumab for infants with retinopathy of prematurity, no difference on neurodevelopment for those who received only bevacizumab versus only laser treatment were found. Those infants who required rescue therapy with laser or bevacizumab injection after initial, unsuccessful treatment showed some detrimental, neurodevelopmental effects.",
"affiliations": "Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.;Division of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan.;Laboratory for Epidemiology, Department of Health Care Management, Chang Gung University, Taoyuan, Taiwan.;Laboratory for Epidemiology, Department of Health Care Management, Chang Gung University, Taoyuan, Taiwan.;Chang Gung University, College of Medicine, Taoyuan, Taiwan.;Chang Gung University, College of Medicine, Taoyuan, Taiwan.;Chang Gung University, College of Medicine, Taoyuan, Taiwan.",
"authors": "Lien|Reyin|R|;Yu|Mu-Hsien|MH|;Hsu|Kuang-Hung|KH|;Liao|Pei-Ju|PJ|;Chen|Yen-Po|YP|;Lai|Chi-Chun|CC|;Wu|Wei-Chi|WC|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0148019",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2681500010.1371/journal.pone.0148019PONE-D-15-37477Research ArticleEngineering and TechnologyEquipmentOptical EquipmentLasersMedicine and Health SciencesOphthalmologyRetinal DisordersRetinopathyRetinopathy of PrematurityPeople and PlacesPopulation GroupingsAge GroupsInfantsBiology and Life SciencesDevelopmental BiologyMorphogenesisNeurodevelopmentBiology and Life SciencesAnatomyOcular SystemOcular AnatomyRetinaMedicine and Health SciencesAnatomyOcular SystemOcular AnatomyRetinaPeople and PlacesPopulation GroupingsAge GroupsChildrenPeople and PlacesPopulation GroupingsFamiliesChildrenBiology and Life SciencesPhysiologyPhysiological ParametersBody WeightBirth WeightMedicine and Health SciencesPhysiologyPhysiological ParametersBody WeightBirth WeightMedicine and Health SciencesSurgical and Invasive Medical ProceduresNeurodevelopmental Outcomes in Infants with Retinopathy of Prematurity and Bevacizumab Treatment Neurodevelopment in ROP Patients with Bevacizumab TreatmentLien Reyin 12Yu Mu-Hsien 1Hsu Kuang-Hung 3Liao Pei-Ju 345Chen Yen-Po 26Lai Chi-Chun 26Wu Wei-Chi 26*1 \nDivision of Neonatology, Department of Pediatrics, Chang Gung Memorial Hospital, Taoyuan, Taiwan2 \nChang Gung University, College of Medicine, Taoyuan, Taiwan3 \nLaboratory for Epidemiology, Department of Health Care Management, Chang Gung University, Taoyuan, Taiwan4 \nDepartment of Health Care Administration, Oriental Institute of Technology, New Taipei City, Taiwan5 \nDepartment of Business Administration, National Taiwan University, Taipei, Taiwan6 \nDepartment of Ophthalmology, Chang Gung Memorial Hospital, Taoyuan, TaiwanHartnett Mary Elizabeth EditorUniversity of Utah (Salt Lake City), UNITED STATESCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: RL WCW. Performed the experiments: RL MHY KHH PJL YPC CCL WCW. Analyzed the data: KHH PJL. Contributed reagents/materials/analysis tools: KHH PJL. Wrote the paper: RL MHY KHH PJL YPC CCL WCW.\n\n* E-mail: weichi666@gmail.com27 1 2016 2016 11 1 e014801925 8 2015 12 1 2016 © 2016 Lien et al2016Lien et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Purpose\nThe current study aims to investigate the neurodevelopment of premature infants after intravitreal injections of bevacizumab (IVB) for the treatment of retinopathy of prematurity (ROP) up to the age of 2 years.\n\nMethods\nThe study design was retrospective observational case series conducted at an institutional referral center. Infants with type 1 ROP were classified into 3 groups: laser only, IVB only, and a combination of IVB and laser treatment. Main Outcome Measures were neurodevelopmental outcomes of the patients after treatment were assessed by Bayley Scales for Infant Development.\n\nResults\nSixty-one patients who finished the neurodevelopmental survey were included. No detrimental effects on neurodevelopment were found in IVB group compared with the patients who received laser treatment only. The patients in the IVB + laser group had a higher incidence of significant mental (p = 0.028) and psychomotor (p = 0.002) impairment at 24 months than the patients in the laser group. The odds ratio of having severe psychomotor defects in the IVB + laser group was 5.3 compared with the laser group (p = 0.041). The causal source for the differences that were detected remained unknown due to lack of randomization in the study and accompanying bias in patient selection.\n\nConclusions\nTwo years after laser and/or intravitreal injections of bevacizumab for infants with retinopathy of prematurity, no difference on neurodevelopment for those who received only bevacizumab versus only laser treatment were found. Those infants who required rescue therapy with laser or bevacizumab injection after initial, unsuccessful treatment showed some detrimental, neurodevelopmental effects.\n\nThis study was supported by grants from the Ministry of Science and Technology, Taipei, Taiwan (NSC101-2314-B-182A-055-MY3 and MOST104-2314-B-182A-100-MY2) and Chang Gung Memorial Hospital, Taoyuan, Taiwan (CMRPG3D0251 and CMRPG3D0522). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nRetinopathy of prematurity (ROP) is one of the primary causes of childhood blindness. In the later stages of ROP, neovascularization arises due to retinal immaturity, and this neovascularization leads to retinal traction and retinal detachment, which eventually affects vision. Neovascularization is mainly driven by vascular endothelial growth factor (VEGF) [1]. Currently, the recommended treatment for type 1 ROP as defined by the Early Treatment for Retinopathy of Prematurity Study is peripheral ablation by laser treatment [2]. Although laser treatment effectively halts the progression of stage 3 ROP to stage 4 ROP in 90% of patients [2], this treatment actually destroys large portions of the retina. A new treatment modality that is less traumatic to the retina is therefore urgently needed.\n\nBevacizumab (Avastin; Genetech Inc., San Francisco, CA) is a humanized anti-VEGF monoclonal antibody [3]. It is the first antiangiogenic agent for the treatment of metastatic colorectal cancer, and it has been used with good results in treating many retinopathies with VEGF up-regulation, including age-related macular degeneration [4,5], diabetic retinopathy [6–8], vitreous hemorrhage [9,10], neovascular glaucoma [11], and retinal vascular occlusion [12–14]. The VEGF level in the vitreous fluid has been shown to be highly elevated in ROP patients [15,16], suggesting the potential of intravitreal injections of bevacizumab (IVB) for the treatment of ROP.\n\nIVB has been shown to be very effective in treating ROP. However, the BEAT-ROP study is the only prospective randomized study to use bevacizumab for ROP [17]. The BEAT-ROP study showed a significant benefit of IVB for zone I but not zone II disease in infants with stage 3+ retinopathy of prematurity compared with conventional laser therapy; however, it did not address the issue of safety because a large patient population of 2800 infants, a number difficult to achieve clinically, would be needed to address this issue. It also did not address the issue of long-term recurrence. Therefore, there are currently no definite conclusions for how best to use bevacizumab for ROP patients [18].\n\nVEGF has been shown to play an important role in the neurodevelopment of newborn infants [19,20], and the impact of possible systemic VEGF suppression after IVB on the neurodevelopment of these patients is unknown. This study aimed to investigate the neurodevelopment of premature infants with severe ROP up to the age of 2 years after IVB. The outcomes were compared among the patients after laser treatment alone, IVB alone, and the combination of IVB and laser treatment.\n\nMaterials and Methods\nStudy Design\nThis was a retrospective study to assess neurodevelopment in extremely low birth weight (ELBW) infants after IVB or laser treatment for ROP. ELBW was defined as newborns with a birth weight of less than 1000 grams. The data were collected from Chang Gung Memorial Hospital in Taoyuan, Taiwan, and the study was approved by the Institutional Review Board of the Chang Gung Memorial Hospital, Taoyuan, Taiwan. If the patient had type 1 ROP as defined by the Early Treatment for Retinopathy of Prematurity Study [2], their parents or legal guardians were offered the choice of laser or IVB treatment after the benefits and risks of each had been thoroughly explained. The status of the off-label use of IVB for ROP treatment was also explained in detail. All parents consented to the treatments for their children with written document before the medical treatment provided to their children. During follow-up of their children, they signed additional consent for the participation of the study.\n\nPatient Enrollment\nPatients with type 1 ROP who were treated with laser or IVB treatment from December 2007 to December 2010 were followed and collected for data analysis. The indications for treatment were type 1 ROP as defined by the Early Treatment for Retinopathy of Prematurity Study: zone I, any stage ROP with plus disease; zone I, stage 3 ROP without plus disease; or zone II, stage 2 or 3 ROP with plus disease [2]. If there was a recurrence of ROP or a lack of treatment response following IVB, the patients were offered additional laser treatment to stop the progression of ROP. If there was a recurrence of ROP or a lack of treatment response after laser treatment, the patients were offered additional IVB to stop the progression of ROP. The patients who received IVB as the first line treatment and had a favorable response to IVB with regression of ROP were classified as the IVB group. The patients who received laser treatment as the first line treatment and had a favorable response to laser treatment with regression of ROP were classified as the laser group, and those who received combined IVB and laser treatment with final regression of ROP were classified as the IVB + laser group.\n\nThe inclusion criteria for the current study were patients: with type 1 ROP who had received either laser, IVB, or combined treatment, with regression of ROP following treatment; who had been followed up with neurodevelopmental assessments for 2 years; and whose parents had signed consent forms. Patients with major congenital anomalies, and those who lost to follow-up in the 2-year study period, were excluded from the study. Relevant clinical events including Apgar score, hemodynamically significant patent ductus arteriosus that required medical or surgical intervention, necrotizing enterocolitis, bronchopulmonary dysplasia, sepsis, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), the rate of inborn, use of antenatal steroids, number of days of ventilator used, respiratory dystress syndrome (RDS), and the postmenstrual age (PMA) of the first treatment were recorded.\n\nTreatment\nThe technique used for IVB was as previously described [21,22]. Briefly, the anesthesia involved an intravenous injection of midazolam (Dormicum, Cenexi SAS, Fontenay-sous-Bois, France) or fentanyl (Fentanyl-Fresenius, Bodene Limited, Port Elizabeth, South Africa) to sedate the infant before the IVB. Vital signs were monitored throughout the entire procedure. If the respiratory function of the infant was unstable, endotracheal intubation was performed to secure the airway. After the eyes had been prepared in a standard fashion using 5% povidone/iodine and topical antibiotics, 0.625 mg (0.025 ml) of bevacizumab was injected intravitreally via the pars plicata under intravenous sedation. The injection was performed initially with a 30-gauge needle directed perpendicularly to the globe, and then directed slightly toward the center of the eyeball after the needle passed the lens equator to prevent damaging the lens or retina. After the injection, retinal artery perfusion were checked, and the patients received topical antibiotics for 7 days.\n\nThe technique of laser treatment for ROP was as follows. Under intravenous sedation or general anesthesia, a diode laser with an indirect ophthalmoscopic delivery system (OcuLight® SLx; Iridex, Mountain View, CA) was used to deliver laser spots with a near confluent pattern, and the end point for laser burns was a grade II gray burn applied to the entire avascular retina from the ridge of extraretinal proliferation to the ora serrata [23].\n\nAfter the treatments, the patients were followed every 1 to 2 weeks until full vascularization of the retina was noted. Full vascularization was defined as vascularization as far as it would develop without an active fibrovascular component or clinically significant tractional elements [22].\n\nNeurodevelopmental Assessment\nNeurodevelopmental assessments were part of standard care and the data were obtained from medical records. Neurodevelopmental outcomes in the ROP patients after IVB or laser treatment were assessed by Bayley Scales for Infant Development (II) [24]. A certified child psychologist who had experienced with this assessment and was blinded to the patient’s prior treatment performed the evaluations for the patients. The assessments were performed in the patients at the corrected age of 6, 12, 18, and 24 months. Each period had relevant items on the assessments. The assessments consisted of 2 parts: mental development index (MDI) and psychomotor development index (PDI), and each item was scored by the specialist. Briefly, the MDI estimated cognitive capacity (e.g., receptive and productive language skills, problem solving, memory, and imitation), and the PDI estimated gross and fine motor skills. The mean score of the Bayley Scales was 100, and a score of less than 70 (2 standard deviations below the mean) indicated a significant developmental delay [25].\n\nStatistics\nContinuous variables were presented as the mean and standard deviation. The chi-square test was applied to examine associations between categorical variables in the study groups. The Shapiro-Wilk test was used to test the normality of the continuous variables in this study. An analysis of variance (ANOVA) was used to compare differences in numerical variables among the study groups, and the Kruskal-Wallis test was used for continuous variables with skew distribution. Scheffe’s post hoc test was used for post-hoc pairwise comparisons to identify the groups that were significantly different following ANOVA. Univariate analysis was performed to prescreen which time point of neuro-assessment appeared to have the maximal effect on poor neurodevelopmental outcomes among the study groups. Multiple logistic regression analysis was then performed for poor neurodevelopmental outcomes (MDI or PDI <70) among the study groups. The results were expressed as odds ratios (OR) after adjusting for sex, gestational age, and birth weight. When comparing cross-sectional neurodevelopmental outcomes among study groups, the missing data were excluded in the analyses.\n\nStatistical Analysis System software version 9.2 (SAS Institute Inc.Cary, NC) was used for all data analyses. A p value less than 0.05 was considered to indicate statistical significance in this study.\n\nResults\nA flow chart showing how the patients were enrolled and excluded from the study is presented in Fig 1. Sixty-one premature, ELBW patients who completed the neurodevelopmental assessments up to 2 years of age were included and entered into the final analysis. Among these patients, 33 received laser treatment only (laser group), 12 received IVB only (IVB group), and 16 received a combination of laser and IVB treatment (IVB + laser group). In the IVB + laser group, 9 patients (56%) received IVB first, but because of a lack of positive response or recurrence of ROP laser treatment was used as a salvage treatment. In the same group, 7 infants (44%) received laser treatment first, and then IVB was used as a salvage treatment due to a lack of treatment response or recurrent ROP. All of the patients except one in the laser group had bilateral ROP and therefore bilateral treatment. The mean number and range of surgical procedures were 1.4 ± 0.6 (range: 1 to 3), 1.1 ± 0.3 (range: 1 to 2), 2.6 ± 1.0 (range: 1 to 5) for laser group, IVB group, and IVB + laser group, respectively. All of the patients except 3 had regression of ROP after treatment. Two patients in the IVB + laser group and 1 patient in the laser group had progression to stage 4A ROP. After vitrectomy, the retinae of these 3 patients were attached. All of the patients in all of the groups had regression of ROP and an attached retina by the time of assessment. There were no differences in the gestational age at birth (p = 0.098), birth weight (p = 0.168), sex (p = 0.112), Apgar score at 1 minute after birth (p = 0.677), Apgar score at 5 minutes after birth (p = 0.778), the rate of hemodynamically significant patent ductus arteriosus (p = 0.772), the rate of necrotizing enterocolitis (p = 0.411), the rate of sepsis (p = 0.945), the rate of grade 1 or 2 IVH (p = 0.521), the rate of grade 3 or 4 IVH (p = 0.633), PVL (p = 0.239), the rate of inborn (0.801), use of antenatal steroids (0.484), number of days of ventilator used (p = 0.569) among the 3 study groups. The presence of zone 1 ROP was significantly higher in the IVB + laser group (p = 0.034). The rates of having zone 1 ROP were 15.2%, 25%, and 50% for the laser, IVB, and the IVB + laser groups, respectively. Bronchopulmonary dysplasia was present in all of the patients according to the definition of a previous paper,[26] and therefore the data were not entered into the statistical analysis. The demographics of the patients as well as the associated systemic risk factors are listed in Table 1.\n\n10.1371/journal.pone.0148019.g001Fig 1 Flow chart showing the inclusion and exclusion of the patients during the study period.\nIn total, 61 patients were enrolled and entered into the final analysis of the study.\n\n10.1371/journal.pone.0148019.t001Table 1 Demographics and the Systemic Risk Factors of the Patients Undergoing IVB, Laser, or Combined IVB and Laser Treatment.\n\tLaser (n = 33)\tIVB (n = 12)\tIVB+Laser (n = 16)\tp value\t\nGestational age, mean (SD), weeks\t25.6 (1.2)\t25.0 (1.2)\t24.8 (1.7)\t0.098 a\t\nBirth weight, mean (SD), g\t771.2 (91.2)\t749.6 (155.1)\t708.8 (92.5)\t0.168 a\t\nSex (M/F, n (%))\t15 (45.5)/18 (54.5)\t8 (66.7)/4 (33.3)\t12 (75)/4 (25)\t0.112 b\t\nApgar score, 1 min, median (range)\t4 (1, 8)\t4 (1, 7)\t4 (1, 7)\t0.836 a\t\nApgar score, 5 min, median (range)\t6 (3, 9)\t6 (1, 9)\t6 (3, 9)\t0.869 a\t\nPatent ductus arteriosus, n (%)\t13 (39.4)\t6 (50)\t6 (37.5)\t0.772 b\t\nNecrotizing enterocolitis, n (%)\t2 (6.1)\t0 (0)\t2 (12.5)\t0.411 b\t\nSepsis, n (%)\t15 (45.5)\t6 (50)\t7 (43.8)\t0.945 b\t\nIVH, grade 1 or 2, n (%)\t4 (12.1)\t2 (16.7)\t4 (25)\t0.521 b\t\nIVH, grade 3 or 4, n (%)\t5 (15.2)\t2 (16.7)\t1 (6.3)\t0.633 b\t\nPVL, n (%)\t0 (0)\t0 (0)\t1 (6.3)\t0.239 b\t\nPresence of zone 1 ROP, n (%)\t5 (15.2)\t3 (25)\t8 (50)\t0.034 b\t\nInborn, n (%)\t29 (87.9)\t10 (83.3)\t13 (81.3)\t0.811 b\t\nUse of antenatal steroids, n (%)\t23 (69.7)\t10 (83.3)\t10 (62.5)\t0.484 b\t\nNumber of ventilator used (days)\t88.9\t88.5\t95.2\t0.569 a\t\nRDS, n (%)\t33 (100)\t12 (100)\t16 (100)\t1.00 b\t\nPMA of first treatment, mean (SD), weeks\t35.3 (2.3)\t35.2 (2.9)\t33.7 (1.7)\t0.063 a\t\nAbbreviations: IVB intravitreal injection of bevacizumab, IVH intraventricular hemorrhage, PMA post menstrual age, PVL periventricular leukomalacia, RDS respiratory distress syndrome, ROP retinopathy of prematurity, SD standard deviation\n\na p values were calculated by Kruskal-Wallis test\n\nb p values were calculated by the chi-square test\n\nIn comparisons of the mean MDI scores, no significant differences were noted among the 3 treatment groups at 6 (p = 0.380), 12 (p = 0.793), and 18 (p = 0.100) months, however, significant differences were noted among the 3 groups at 24 (p = 0.028) months. In comparisons of the mean PDI scores, significant differences were noted among the 3 groups at 24 (p = 0.002) months. The scores were significantly different between the laser and the IVB + laser treatment groups based on the results of Scheffe’s post hoc test after multiple comparisons (Table 2).\n\n10.1371/journal.pone.0148019.t002Table 2 MDI and PDI Performed on Patients with Different Treatments up to 2 Years of Follow-up.\n\tTime\tN\tLaser\tIVB\tIVB+Laser\tp valuea\t\nMDI, mean (SD)\t6M\tN = 58\t95.0 (9.8)\t93.9 (6.1)\t90.3 (14.8)\t0.380\t\n\t12M\tN = 58\t88.6 (11.2)\t87.5 (9.0)\t86.5 (7.0)\t0.793\t\n\t18M\tN = 55\t90.0 (14.4)\t81.0 (12.9)\t81.3 (16.7)\t0.100\t\n\t24M\tN = 47\t95.7 (14.5)\t81.9 (18.6)\t82.3 (19.2)\t0.028 b\t\nPDI, mean (SD)\t6M\tN = 58\t84.7 (14.5)\t82.8 (13.3)\t82.3 (12.3)\t0.831\t\n\t12M\tN = 57\t78.5 (10.7)\t70.4 (9.5)\t72.0 (12.7)\t0.056\t\n\t18M\tN = 54\t88.3 (16.5)\t85.0 (14.8)\t84.0 (19.3)\t0.697\t\n\t24M\tN = 47\t98.0 (9.3)\t88.1 (19.7)\t79.6 (19.3)\t0.002 b\t\nAbbreviations: IVB intravitreal injection of bevacizumab, M months, MDI mental developmental index, PDI psychomotor developmental index, SD standard deviation\n\na p values were calculated by ANOVA\n\nb Scores were significantly different (p<0.05) between laser treatment and laser+IVB treatment based on the results of Scheffe’s post hoc test.\n\nPatients with Bayley Scales scores of less than 70 were considered to have significant developmental delays. There were no statistically significant differences in distributions of severe developmental delays in the MDI (MDI <70) among the 3treatment groups at 6 (p = 0.066), 12 (p = 0.450), 18 (p = 0.226), or 24 (p = 0.057) months (Fig 2). There were also no statistically significant differences in distributions of severe developmental delays in PDI (PDI <70) among the 3 treatment groups at 6 (p = 0.741), 12 (p = 0.087), and 18 (p = 0.760) months. However, the multiple-comparison analysis showed that the patients in the IVB + laser group had a higher risk for the occurrence of severe psychomotor impairment at 24 months compared to the patients in the laser group (p = 0.042) (Fig 3).\n\n10.1371/journal.pone.0148019.g002Fig 2 Comparison of significant mental developmental impairment in patients 2 years after various treatments for ROP.\nThere were no statistically significant differences in significant developmental delays in MDI (MDI <70) among the 3 treatment groups at 6 (p = 0.066), 12 (p = 0.450), 18 (p = 0.226), or 24 (p = 0.057) months.\n\n10.1371/journal.pone.0148019.g003Fig 3 Comparison of significant psychomotor developmental defects in patients 2 years after treatments for ROP.\nMultiple-comparison analysis showed that the patients in the IVB + laser group had a higher incidence of severe psychomotor defects (PDI <70) at 24 (p = 0.010) months than the patients in the laser group (*indicates a significant difference).\n\nUnivariate analysis was performed to prescreen which time regimen appeared to have the maximal effect on poor neurodevelopmental outcomes between the study groups. A maximal effect was found at 24 months on the MDI and 12 months on the PDI, and the data from those periods were then entered into multiple logistic regression analysis. The multiple logistic regression analysis of poor neurodevelopmental outcomes showed that the odds of having MDI <70 were 12.4 for the IVB group and 10.6 for the IVB + laser group compared with the laser treatment group. However, the analysis did not reach statistical significance (p = 0.084 and 0.075, respectively). The odds of having severe psychomotor developmental defects (PDI<70) were 4.7 for the IVB group and 5.3 for the IVB + laser group compared with the laser treatment group. The analysis did not reach statistical significance comparing the IVB group with the laser group (p = 0.075), however the analysis did reach statistical significance when comparing the laser + IVB group with the laser group (p = 0.041) (Table 3).\n\n10.1371/journal.pone.0148019.t003Table 3 Multiple Logistic Regression Analysis on Poor Neurodevelopmental Outcomes (MDI or PDI <70).\n\tMDI<70\tPDI<70\t\nTreatment\tOR a\t(95% CI)\tp b\tOR a\t(95% CI)\tp value b\t\nLaser\t1\t-\t-\t1\t-\t-\t\nIVB\t12.4\t(0.7, 214.8)\t0.084\t4.7\t(0.9, 25.9)\t0.075\t\nIVB + Laser\t10.6\t(0.8, 142.3)\t0.075\t5.3\t(1.1, 26.3)\t0.041\t\nAbbreviations:, CI confidence interval, IVB intravitreal injection of bevacizumab, MDI mental developmental index, OR odds ratio, PDI psychomotor developmental index\n\na Odds ratio was adjusted for sex, gestational age, and birth weight of the patients.\n\nb A maximal likelihood strategy, by which the data at the 24th month of MDI and the 12th month of PDI of the patients were selected and used to calculate the odds ratio of MDI or PDI <70.\n\nWe have compared the neurodevelopmental outcome between those infants treated with laser initially and then bevacizumab treatment compared to infants treated with bevacizumab treatment first and then laser. We did not find statistically significant difference between these 2 subgroups (data not shown). Also we did not find statistically significant difference in the ratio of severe neurodevelopmental defect between patients who had only one laser treatment and who had 2 laser treatments (data not shown).\n\nDiscussion\nOur results show that the patients in the IVB + laser group had a higher incidence of severe psychomotor developmental defects than the patients in the laser treatment alone group. The direct comparisons of MDI or PDI in the patients treated with laser treatment alone and IVB alone did not show significant differences in mental or psychomotor development up to 2 years of follow-up. Though there were no statistically significant differences found in the neurodevelopmental scores in the IVB group compared to laser group, there were certainly increased OR of abnormal MDI and PDI (at max effect) in the IVB group compared to the laser group (p values of 0.084 and 0.075, respectively). It is therefore a possible safety concern of using IVB on ROP patients and it is not known whether these effects will become more or less evident as we keep following up these patients. To the best of our knowledge, this paper is the first to evaluate the systemic development of children in children of Chinese decent after IVB with 2 years of longitudinal follow-up.\n\nThe cause of the worst neurodevelopmental outcome in the combined IVB and laser group remains to be investigated. The poorer outcome may be related to more surgical procedures being performed than in the other 2 groups of patients (1.4 ± 0.6, 1.1 ± 0.3, 2.6 ± 1.0 for laser group, IVB group, and IVB + laser group, respectively), and therefore a higher rate of sedation and anesthesia. In addition, a higher incidence of zone 1 ROP was noted in this group (15.2%, 25%, and 50% for the laser, IVB, and IVB + laser groups, respectively). Zone 1 ROP is usually associated with much worse outcomes compared with zone 2 ROP [2,17], and it is likely that patients with zone 1 ROP have a less mature organ system. A more immature avascular retina in zone 1 ROP may cause more anti-VEGF leakage into the systemic circulation. In addition, the destruction of the blood retina barrier by laser photocoagulation may result in a higher level of anti-VEGF leakage in the systemic circulation. Finally, the earlier the PMA at which the infants received treatment and retreatment was also a possible risk factor that could affect developmental outcome of these infants (Table 1). Infants in the IVB + laser group received the first treatment at approximately 1.5 weeks earlier that in the other treatment groups. The earlier treatment in the patients could be interpreted as these patients having worse eye diseases.\n\nRecent studies in both animals [27,28] and humans [29,30] have found evidence of systemic bevacizumab exposure after IVB. In an animal study, IVB at an early age could result in more systemic bevacizumab exposure [27]. Sato and associates [29] found that systemic VEGF levels in premature infants were depressed for at least 2 weeks after the administration of either 1 or 0.5 mg IVB in ROP patients. Our recent study [30] has further shown that VEGF levels in ROP infants were depressed for 8 weeks after IVB. VEGF plays an important role in neurogenesis in embryos and preterm newborns. In previous reports, blocking VEGF-A expression has been shown to impair brain vascularization [20] and lead to neuron apoptosis in the retina [31]. In addition, VEGF has been found to be lower in preterm pups compared to term pups, and this has been proposed to relate to the neurodevelopmental delay and reduced growth of the cerebral cortex in premature infants [19]. Since neurogenesis may continue in the third trimester [19], further inhibition of serum VEGF in preterm newborns may have long-term effects on the development of the central nervous system and other systems. However, more research is needed to verify these speculations because anti-VEGF treatments are usually used for once or short term in these ROP patients.\n\nThe assessment of neurodevelopment after IVB for ROP has been conducted by few studies. Martínez-Castellanos et al [32] did not show any neurodevelopmental impact 5 years after the use of IVB. Banker et al (Banker AS; Banker DA. Anatomical, functional, OCT and neurodevelomental analysis outcomes of Intravitreal Bevacizumab injection without laser for retinopathy of prematurity: 6 year follow-up. APAO, Hyderabad, India 2013) also did not find any signs of developmental delay in infants 6 years following the use of IVB. However, these studies and ours were limited by a small number of patients and a non-randomized study design. Other anti-VEGF agents with a shorter systemic half-life or reducing the current doses used for IVB may lessen the systemic impact for these premature babies. A prospective, randomized, large-scale study is warranted to elucidate the real impact of IVB on the neurodevelopment of these children.\n\nWe observed large changes in the severe developmental delay (MDI/PDI<70) during the study period. There are several possible explanations for these observations. First, the assessments were performed in the patients at the corrected ages of 6, 12, 18, and 24 months. Each period had relevant factors on the assessments that could have caused some variations. Second, the patients of these ages experience fast neurodevelopment, and therefore more neurodevelopmental changes were observed. Third, not all of the patients had the tests performed on them at each time point. These are possible explanations for the large changes in the severe developmental delay in these patients.\n\nThis study is limited by the small number of enrolled patients and the non-randomized design. Therefore, we cannot rule out the possibility of selection bias on treatment options, despite the fact that the baseline data among the treatment groups seemed to be similar. In addition, it is possible that that there is another risk factor that predisposes to both more severe ROP and abnormal neurodevelopment but we may not have yet identified. The study is retrospective in its design, and therefore potential counseling bias of the providers is present. Our institution is the largest medical center in Taiwan and one of the major referring centers for severe ROP. We could enroll sicker children and this could contribute to higher incidence of treatment-requiring ROP (Fig 1). The developmental outcomes as assessed by Bayley Scales for Infant Development (II) can only be used as a surrogate of the outcome measure, and may not be completely accurate [33]. The vision data of the patients were not available to correlate with the mental and psychomotor developmental data. However, all of the children had attached retinae with regression of ROP, and their vision was good enough to perform the tasks in the neurodevelopmental survey. The follow-up period of the current study is only 2 years, and during this period some fluctuations in neurodevelopment were noted as the systemic development was still not complete. Therefore, long-term neurodevelopmental data are even more important because they are closer to the final outcome when the development process has matured. Further studies with a randomized design and long-term follow-up and including more patients are needed to further explore the effect of IVB on ROP patients.\n\nConclusions\nOur results did not show any significant detrimental effects on the neurodevelopment of patients with ROP 2 years after IVB. Detrimental effects were found on the neurodevelopment of the patients who received combined IVB and laser treatment, presumably because they received more procedures and sedation, had earlier PMA for treatment, had more type 1 ROP with more immature retinae, or because destruction of the blood retina barrier after laser treatment caused more IVB leakage into the systemic circulation. However, this was not because these patients had a lower gestational age or birth weight or additional severe systemic comorbidities at baseline. More data are needed to objectively assess the effect of IVB on the neurodevelopment of premature babies.\n\nSupporting Information\nS1 File STROBE statement related to the study.\n(DOCX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 Alon T , Hemo I , Itin A , Pe'er J , Stone J , Keshet E (1995 ) Vascular endothelial growth factor acts as a survival factor for newly formed retinal vessels and has implications for retinopathy of prematurity . 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Am J Ophthalmol \n153 : 327 –333 . 10.1016/j.ajo.2011.07.005 \n21930258 \n30 Wu WC , Lien R , Liao PJ , Wang NK , Chen YP , Chao AN , et al (2015 ) Serum Levels of Vascular Endothelial Growth Factor and Related Factors After Intravitreous Bevacizumab Injection for Retinopathy of Prematurity . JAMA Ophthalmol \n133 :391 –397 . 10.1001/jamaophthalmol.2014.5373 \n25569026 \n31 Robinson GS , Ju M , Shih SC , Xu X , McMahon G , Caldwell RB , et al (2001 ) Nonvascular role for VEGF: VEGFR-1, 2 activity is critical for neural retinal development . FASEB J \n15 : 1215 –1217 . 11344092 \n32 Martinez-Castellanos MA , Schwartz S , Hernandez-Rojas ML , Kon-Jara VA , Garcia-Aguirre G , Guerrero-Naranjo JL , et al (2013 ) Long-term effect of antiangiogenic therapy for retinopathy of prematurity up to 5 years of follow-up . 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"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "11(1)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D000068258:Bevacizumab; D002657:Child Development; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D052577:Infant, Extremely Low Birth Weight; D007231:Infant, Newborn; D008607:Intellectual Disability; D058449:Intravitreal Injections; D053685:Laser Therapy; D011596:Psychomotor Disorders; D012178:Retinopathy of Prematurity",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0148019",
"pmc": null,
"pmid": "26815000",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15175435;7681737;20673589;14662586;11344092;18211942;1592003;18081904;10690834;22967867;17157590;20181842;17057542;19700197;17011869;19074916;16061586;17888083;19371954;19660736;21323540;16508426;21930258;19375689;7489357;25569026;17467524;18696094;23303921;16603955;11401896;17011951;23099498",
"title": "Neurodevelopmental Outcomes in Infants with Retinopathy of Prematurity and Bevacizumab Treatment.",
"title_normalized": "neurodevelopmental outcomes in infants with retinopathy of prematurity and bevacizumab treatment"
} | [
{
"companynumb": "TW-ROCHE-1706808",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
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"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND Tyrosine kinase inhibitors (TKIs) are currently an important targeted drug class in the treatment of chronic myeloid leukemia (CML). Imatinib was the first approved TKI for CML in 2001. Nilotinib is a second-generation TKI, approved in 2007; it inhibits BCR-ABL, PDGFR, and c-KIT, and is 30 times more potent than imatinib. Tyrosine kinase enzymes are expressed in multiple tissues and are involved in several signaling pathways; they have been shown to have several off-target side effects. CASE REPORT We report a case of an elderly male with CML and no history of gastrointestinal diseases, treated with nilotinib, and developed recurrent gastric polyps after three years of treatment. We excluded common causes of gastric polyps and therefore considered nilotinib as a probable cause of recurrent gastric polyps. CONCLUSIONS Recurrent gastric polyps could be a potential side effect of nilotinib treatment. Careful long-term monitoring of patients on TKI therapy is necessary and further long-term studies of TKI side effects are needed.",
"affiliations": "Department of Pharmacy, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.;Department of Hematology and Bone Marrow Transplantation (BMT), National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.;Department of Hematology and Bone Marrow Transplantation (BMT), National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.;Department of Hematology and Bone Marrow Transplantation (BMT), National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar.",
"authors": "Kassem|Nancy|N|;Ismail|Omar M|OM|;Elomri|Halima|H|;Yassin|Mohamad A|MA|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2870617910.12659/AJCR.903485903485ArticlesNilotinib Induced Recurrent Gastric Polyps: Case Report and Review of Literature Kassem Nancy ABEF1Ismail Omar M. ABE2Elomri Halima ADEF2Yassin Mohamad A. ADEF2\n1 Department of Pharmacy, National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, Qatar\n2 Department of Hematology and Bone Marrow Transplantation (BMT), National Center for Cancer Care and Research, Hamad Medical Corporation, Doha, QatarAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Nancy Kassem, e-mail: na-kassem@hotmail.com2017 14 7 2017 18 794 798 22 1 2017 24 4 2017 © Am J Case Rep, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 62\n\nFinal Diagnosis: Chronic myeloid leukemia\n\nSymptoms: Gastric polyps\n\nMedication: Nilotinib\n\nClinical Procedure: —\n\nSpecialty: Hematology\n\nObjective:\nUnusual or unexpected effect of treatment\n\nBackground:\nTyrosine kinase inhibitors (TKIs) are currently an important targeted drug class in the treatment of chronic myeloid leukemia (CML). Imatinib was the first approved TKI for CML in 2001. Nilotinib is a second-generation TKI, approved in 2007; it inhibits BCR-ABL, PDGFR, and c-KIT, and is 30 times more potent than imatinib. Tyrosine kinase enzymes are expressed in multiple tissues and are involved in several signaling pathways; they have been shown to have several off-target side effects.\n\nCase Report:\nWe report a case of an elderly male with CML and no history of gastrointestinal diseases, treated with nilotinib, and developed recurrent gastric polyps after three years of treatment. We excluded common causes of gastric polyps and therefore considered nilotinib as a probable cause of recurrent gastric polyps.\n\nConclusions:\nRecurrent gastric polyps could be a potential side effect of nilotinib treatment. Careful long-term monitoring of patients on TKI therapy is necessary and further long-term studies of TKI side effects are needed.\n\nMeSH Keywords\nAdenomatous PolypsBCR-ABL PositiveChronic Myelogenous LeukemiaDrug-Related Side Effects and Adverse ReactionsImatinibNilotinibTyrosine Kinase Inhibitors (TKI)\n==== Body\nBackground\nTyrosine kinase inhibitors (TKIs) are currently an important targeted drug class in the treatment of chronic myeloid leukemia (CML). Imatinib was the first approved TKI for CML, approved in 2001. Nilotinib is a second-generation TKI, which was approved in 2007; it inhibits BCR-ABL, PDGFR, and c-KIT, and is 30 times more potent than imatinib because of its increased ABL kinase selectivity and binding site affinity [1]. TKIs are expressed in multiple tissues and are involved in several signaling pathways, they were found to have several off-target side effects. The short-term side effects of TKIs are well known, but the long-term side effects, especially for the newer agents, have not yet been clearly identified [2,3].\n\nWe present a case of a patient with CML who developed recurrent gastric polyps after three years of nilotinib therapy as a second-line treatment. To the best of the authors’ knowledge, this is the first case of nilotinib-associated gastric polyps.\n\nCase Report\nA 62-year-old male known to have hypertension treated with irbesartan and amlodipine, diabetes mellitus type II treated with sitagliptin and metformin, dyslipidemia treated with simvastatin, and chronic phase CML treat with imatinib 400 mg PO daily as upfront therapy. After five years of imatinib treatment, the patient lost his molecular remission and treatment was shifted to the second-line TKI nilotinib at 400 mg BID. During the first month of this treatment, he developed toxicity to nilotinib: facial edema, skin rash, severe myalgia. In addition, his diabetes became uncontrolled, and so he was referred to an endocrinologist for diabetes control.\n\nAfter a few weeks, he improved spontaneously; CML monitoring showed major molecular response as per the European Leukemia Net (ELN) recommendations [4], and therefore treatment with nilotinib was continued.\n\nAfter three years of nilotinib therapy, during his regular follow-up, the patient’s CBC showed hemoglobin 10.1 g/dL (normal 13–17 g/dL) with MCV of 73.4 fL (normal 83–101 fL). Anemia workup revealed iron deficiency anemia. He was treated with oral iron for four months and showed clinical improvement.\n\nAs part of the anemia workup, his esophagogastroduodenoscopy (OGD) showed multiple gastric polyps that were removed; histopathology showed hyperplastic gastric polyps (Figure 1). A colonoscopy was performed and revealed normal results. The patient was started the proton pump inhibitor (PPI) rabeprazole.\n\nThe first recurrences of gastric polyps after a two month follow-up, as shown by OGD (Figure 2), were removed; histopathology showed: 1) focal foveolar hyperplasia and features in keeping with reflux; and 2) focal intestinal metaplasia. Further investigations were requested: gastrin level showed 55.2 pg/mL (normal range up to 115 pg/mL) and vitamin B12 at 192 pmol/L (normal 133–675 pmol/L).\n\nThe second recurrence of gastric polyps one year after the first recurrence were removed by OGD; histopathology showed: 1) fragmented gastric mucosa with lymphoplasmacytic infiltrate and large number of eosinophils; 2) ulceration and granulation tissue formation with attached acute inflammatory exudates noted; 3) negative for Helicobacter pylori; and 4) no intestinal metaplasia, dysplasia, or malignancy.\n\nThe third recurrence of gastric polyps, eight months from the second recurrence, OGD showed stomach cardiac hyperplastic polyps. A biopsy was taken, and histopathology showed diffuse intestinal metaplasia negative for H. pylori organisms or malignancy.\n\nThe typical differential diagnosis of gastric polyps includes familial adenomatous polyposis, Zollinger-Ellison syndrome, H. pylori, and pernicious anemia. In this case, an unrevealing family history, absence of previous gastrointestinal disease, normal gastrin, negative H. pylori, and normal vitamin B12 level made these differential diagnoses highly unlikely.\n\nThe patient’s gastric polyps were removed and the patient’s treatment with nilotinib has continued at the dosage in which the patient remained stable and in complete molecular remission. The treatment plan includes follow-up by a gastroenterologist and OGD every six to 12 months.\n\nDiscussion\nGastric polyps can be defined as luminal lesions that originate in the gastric epithelium or submucosa and protrude into the stomach lumen. Several subtypes of gastric polyps are recognized; fundic gland polyps (FGP), hyperplastic polyps, and adenomas are the most common benign polyps. However, some of these subtypes are considered to have malignant potential and to be precursors of early gastric cancer [5].\n\nThe malignant potential of gastric polyps has been correlated to their pathologic features. It has been reported in the literature that there is an association between gastric carcinomas and the presence of hyperplastic polyps. Around 1–20% of hyperplastic polyps have been reported to harbor foci of dysplasia [6–10].\n\nSeveral TKIs are approved for the treatment of CML; however, the safety of these drugs remains an important concern as they have several off-target side effects.\n\nIn our case, since differential diagnoses were excluded, and in the absence of a previous history of gastrointestinal disease, the possibility of drug-induced polyposis was raised and sub-sequently the patient’s medications were reviewed. He was receiving irbesartan and amlodipine for hypertension, sitagliptin and metformin for diabetes, simvastatin for dyslipidemia, nilotinib for CML, and rabeprazole then esomeprazole for gastritis.\n\nA literature review was conducted using PubMed and Medline from 2001 to 2016 using key words “Irbesartan, Amlodipine, Sitagliptin, Metformin, Simvastatin, Nilotinib, Imatinib, Tyrosine kinase inhibitor, Proton pump inhibitor, gastric polyp, hyperplastic polyp” to review the correlation between these medications and recurrence of gastric polyps. No reports for gastric polyps were found for irbesartan, amlodipine, sitagliptin, metformin, or simvastatin.\n\nSeveral reports and retrospective studies reported an association between PPIs and the development of FGP, with a mean interval of 32.5 months for polyp development [11–14]. In an observational study that included 599 patients undergoing endoscopy, long-term PPI use (defined as ≥ 5 years) was associated with an up to fourfold increase in the risk of FGP, while risk was not increased with short-term PPI therapy [11]. Other studies have not demonstrate a definitive link between long-term PPI and FGP [15–18]\n\nNo reported cases of nilotinib-associated gastric polyps were found in our literature review; however, there have been reports of secondary neoplasms associated with nilotinib and imatinib therapies. These secondary neoplasms included papilloma, gastric cancer, fibroma, thyroid neoplasms, pancreatic cancer, and gastrointestinal stromal tumors [19–31].\n\nTwo cases of gastric cancer were reported with nilotinib therapy in a post-marketing clinical use survey in Japan [26] and one case was reported in a global phase III multicenter trial [27].\n\nNilotinib was given as an upfront treatment (first-line treatment) in some cases and as a second-line treatment in other cases; the impact of the line of therapy on the occurrence of secondary neoplasms was not raised in literature and therefore remains uncertain.\n\nBased on the aforementioned literature review, the possibility of PPI-induced gastric polyps in our patient case was highly unlikely since our patient started PPI after the occurrence of gastric polyps, the first recurrence of polyps occurred after less than two months of PPI treatment; the second and third recurrences occurred after less than two years of therapy, which was not considered long-term therapy as suggested by the reviewed reports. Moreover, in the reported cases in the literature, PPI-induced polyps were mainly FGP; whereas in our case the polyps were hyperplastic.\n\nDespite the absence of reports supporting the association of nilotinib with gastric polyps, the possibility could not be excluded, as nilotinib is a relatively new drug and long-term side effects have not yet been extensively studied. In contrast, irbesartan, amlodipine, sitagliptin, metformin, and simvastatin are older drugs that have been studied in larger population and for a longer duration. Therefore, the absence of reports of this adverse event in the literature could exclude them from being the cause of gastric polyps, however, this does not rule out the possibility of occurrence of this condition as a result of simultaneous use of these drugs or PPI with nilotinib.\n\nFurthermore, reports of nilotinib-associated secondary neoplasm, especially gastric cancer, and the fact that hyperplastic polyps have malignant potential and are precursors of early gastric cancer [6–10] further supports the association of nilotinib with hyperplastic polyps.\n\nTo assess the probability of this adverse drug reaction, we used the Naranjo Adverse Drug Reaction Probability Scale (Table 1) [32]; the calculated score of 5 indicated that nilotinib was the probable cause for the development of recurrent gastric polyps in our patient.\n\nConclusions\nGastric polyps could be a probable side effect of nilotinib therapy. Considering the malignant potential of hyperplastic polyps and polyposis, in the era of TKIs, gastric polyps should be thought of as a potential premalignant condition. Careful long-term monitoring of patients on TKI therapy is necessary, and further long-term studies of side effects of TKIs are needed.\n\nConflict of interest\n\nNone declared.\n\nFigure 1. 2 cm stalked polyp in the greater curvature.\n\nFigure 2. Stomach with small cardiac hyperplastic polyp (same size as previous endoscopy).\n\nTable 1. Naranjo Adverse Drug Reaction Probability Scale: Items and score.\n\nQuestion\tYes\tNo\tDon’t know\tPatient’s Score\t\n1. Are there previous conclusive reports on this reaction?\t+1\t0\t0\t0\t\n2. Did the adverse event appear after the suspected drug was administered?\t+2\t− 1\t0\t+2\t\n3. Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was administered?\t+1\t0\t0\t0\t\n4. Did the adverse reaction reappear when the drug was re-administered?\t+2\t− 1\t0\t0\t\n5. Are there alternative causes (other than the drug) that could on their own have caused the reaction?\t− 1\t+2\t0\t+2\t\n6. Did the reaction reappear when a placebo was given?\t− 1\t+1\t0\t0\t\n7. Was the drug detected in the blood (or other fluids) in concentrations known to be toxic?\t+1\t0\t0\t0\t\n8. Was the reaction more severe when the dose was increased, or less severe when the dose was decreased?\t+1\t0\t0\t0\t\n9. Did the patient have a similar reaction to the same or similar drug in any previous exposure?\t+1\t0\t0\t0\t\n10. Was the adverse event confirmed by any objective evidence?\t+1\t0\t0\t+1\t\nScoring • >9 = definite ADR • 5–8 = probable ADR • 1–4 = possible ADR • 0 = doubtful ADR.\n\nNaranjo et. al. Clin Pharmacol Ther, 1981; 30(2): 239–45.\n==== Refs\nReferences:\n1. Weisberg E Manley PW Breitenstein W Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl Cancer Cell 2005 7 129 41 15710326 \n2. Druker BJ Guilhot F O’Brien SG Five-year follow-up for patients receiving imatinib for chronic myeloid leukemia N Engl J Med 2006 355 2408 17 17151364 \n3. Caldemeyer L Dugan M Edwards J Akard L Long-term side effects of tyrosine kinase inhibitors in chronic myeloid leukemia Curr Hematol Malig Rep 2016 11 2 71 79 26922746 \n4. Baccarani M Cortes J Pane F Chronic myeloid leukemia: An update of concepts and management recommendations of European LeukemiaNet J Clin Oncol 2009 27 35 6041 51 19884523 \n5. Park DY Lauwers GY Gastric polyps classification and management Arch Pathol Lab Med 2008 132 633 40 18384215 \n6. Dirschmid K Platz-Baudin C Stolte M Why is the hyperplastic polyp a marker for the precancerous condition of the gastric mucosa? Virchows Arch 2006 448 80 84 16189701 \n7. Dijkhuizen SM Entius MM Clement MJ Multiple hyperplastic polyps in the stomach: Evidence for clonality and neoplastic potential Gastroenterology 1997 112 2 561 66 9024310 \n8. Daibo M Itabashi M Hirota T Malignant transformation of gastric hyperplastic polyps Am J Gastroenterol 1987 82 10 1016 25 3661508 \n9. Orlowska J Jarosz D Pachlewski J Butruk E Malignant transformation of benign epithelial gastric polyps Am J Gastroenterol 1995 90 12 2152 59 8540506 \n10. Zea-Iriarte WL Sekine I Itsuno M Carcinoma in gastric hyperplastic polyps. A phenotypic study Dig Dis Sci 1996 41 2 377 86 8601386 \n11. Jalving M Koornstra JJ Wesseling J Increased risk of fundic gland polyps during long-term proton pump inhibitor therapy Aliment Pharmacol Ther 2006 24 9 1341 48 17059515 \n12. Zelter A Fernández JL Bilder C Fundic gland polyps and association with proton pump inhibitor intake: A prospective study in 1,780 endoscopies Dig Dis Sci 2011 56 6 1743 48 21127978 \n13. Freeman HJ Proton pump inhibitors and an emerging epidemic of gastric fundic gland polyposis World J Gastroenterol 2008 14 9 1318 20 18322941 \n14. El-Zimaity HM Jackson FW Graham DY Fundic gland polyps developing during omeprazole therapy Am J Gastroenterol 1997 92 10 1858 60 9382052 \n15. Declich P Ferrara A Galati F Do fundic gland polyps develop under long term omeprazole therapy? Am J Gastroenterol 1998 93 1393 \n16. Declich P Ambrosiani A Bellone S Fundic gland polyps under omeprazole treatment Am J Clin Pathol 1999 112 576 78 10510676 \n17. Vieth M Stolte M Fundic gland polyps are not induced by proton pump inhibitor therapy Am J Clin Pathol 2001 116 716 20 11710689 \n18. Klinkenberg-Knol E Nelis F Dent J Long term omeprazole treatment in resistant gastroesophageal reflux disease: Efficacy, safety and influence on gastric mucosa Gastroenterology 2000 118 661 69 10734017 \n19. Pilot PR Sablinska K Owen S Hatfield A Epidemiological analysis of second primary malignancies in more than 9500 patients treated with imatinib Leukemia 2006 20 148 49 16292349 \n20. Voglova J Muzik J Faber E Incidence of second malignancies during treatment of chronic myeloid leukemia with tyrosine kinase inhibitors in the Czech Republic and Slovakia Neoplasma 2011 58 256 62 21395367 \n21. Roy L Guilhot J Martineau G Unexpected occurrence of second malignancies in patients treated with interferon followed by imatinib mesylate for chronic myelogenous leukemia Leukemia 2005 19 1689 92 16015386 \n22. Verma D Kantarjian H Strom SS Malignancies occurring during therapy with tyrosine kinase inhibitors (TKIs) for chronic myeloid leukemia (CML) and other hematologic malignancies Blood 2011 118 4353 58 21846902 \n23. Gambacorti-Passerini C Antolini L Mahon FX Multicenter independent assessment of outcomes in chronic myeloid leukemia patients treated with imatinib J Natl Cancer Inst 2011 103 553 61 21422402 \n24. Duman BB Paydas S Disel U Secondary malignancy after imatinib therapy: Eight cases and review of the literature Leuk Lymphoma 2012 53 1706 8 22329351 \n25. Stein BL Chronic myeloid leukemia and risk of second malignancy in two eras of treatment Leuk Lymphoma 2012 53 1651 53 22360717 \n26. Novartis Pharmaceuticals Japan [Internet]. Prescribing information. Tokyo, Tasigna [updated June 2013; cited 1 January 2017]. Available from; http://product.novartis.co.jp/tas/ts/pms_tas_shibo_20130628.pdf [in Japanese] \n27. Kantarjian HM Hochhaus A Saglio G Nilotinib versus imatinib for the treatment of patients with newly diagnosed chronic phase, Philadelphia chromosome-positive, chronic myeloid leukaemia: 24-month minimum follow-up of the phase 3 randomised ENESTnd trial Lancet Oncol 2011 12 841 51 21856226 \n28. Novartis Pharmaceuticals US [Internet]. Prescribing Information. US, Gleevec [updated January 2015; cited 20 December 2016] Available from; http://pharma.us.novartis.com/product/pi/pdf/gleevec_tabs.pdf \n29. Kantarjian HM Giles FJ Bhalla KN Nilotinib is effective in patients with chronic myeloid leukemia in chronic phase after imatinib resistance or intolerance: 24-month follow-up results Blood 2011 117 1141 45 21098399 \n30. Sekiguchi Y Shimada A Matsuzawa M Occurrence of carcinoma of the pancreas following nilotinib therapy for chronic myeloid leukemia: Report of a case with review of the literature Turk J Haematol 2015 32 3 257 62 26376592 \n31. Shugo H Hodo Y Watanabe T Multiple gastrointestinal stromal tumors during nilotinib treatment for chronic myelogenous leukemia in a patient with neurofibromatosis type 1 Nihon Shokakibyo Gakkai Zasshi 2014 111 8 1579 86 25100347 \n32. Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508\n\n",
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"journal": "The American journal of case reports",
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"medline_ta": "Am J Case Rep",
"mesh_terms": "D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D011127:Polyps; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D012008:Recurrence; D013272:Stomach Diseases",
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"pubdate": "2017-07-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Nilotinib Induced Recurrent Gastric Polyps: Case Report and Review of Literature.",
"title_normalized": "nilotinib induced recurrent gastric polyps case report and review of literature"
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"abstract": "Baclofen is a γ-aminobutyric acid B (GABA-B) receptor agonist that is approved for spasticity. Recently, the off-label use of baclofen for alcohol use disorder (AUD) has increased. However, baclofen is known to induce a neuroadaptation process, which may be identified by the occurrence of a specific baclofen withdrawal syndrome (BWS), that is, confusion, agitation, seizures, and delirium. The same set of symptoms characterizes alcohol withdrawal syndrome (AWS), which could lead to mistaking BWS for AWS in some situations. We report the cases of 3 patients under a chronic baclofen treatment for AUD. The patients emergently presented with a clinical state of confusion that was initially diagnosed and treated as AWS, with limited effect of benzodiazepines. Retrospectively, using a validated algorithm for assessing drug-induced withdrawal, we determined that all of these clinical cases were consistent with BWS. Both AWS and BWS should be considered in the case of acute confusion or delirium occurring in patients treated with baclofen for AUD. Moreover, further research should investigate to what extent GABA-A and GABA-B induce shared or distinct neuroadaptation processes and withdrawal syndromes.",
"affiliations": "From the *PRES Nord de France, Univ Lille Nord de France; and Departmentsof †Psychiatry and Addiction Medicine, ‡Pharmacology and Pharmacovigilance, and §Resuscitation Care, CHU Lille, Lille, France.",
"authors": "Rolland|Benjamin|B|;Jaillette|Emmanuelle|E|;Carton|Louise|L|;Bence|Camille|C|;Deheul|Sylvie|S|;Saulnier|Fabienne|F|;Bordet|Régis|R|;Cottencin|Olivier|O|",
"chemical_list": "D058786:GABA-B Receptor Agonists; D001418:Baclofen",
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"issue": "34(1)",
"journal": "Journal of clinical psychopharmacology",
"keywords": null,
"medline_ta": "J Clin Psychopharmacol",
"mesh_terms": "D000328:Adult; D064829:Alcohol Abstinence; D000428:Alcohol Drinking; D000430:Alcohol Withdrawal Delirium; D000437:Alcoholism; D001418:Baclofen; D003221:Confusion; D003693:Delirium; D003937:Diagnosis, Differential; D058786:GABA-B Receptor Agonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D056687:Off-Label Use; D011237:Predictive Value of Tests; D012307:Risk Factors; D013375:Substance Withdrawal Syndrome",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Assessing alcohol versus baclofen withdrawal syndrome in patients treated with baclofen for alcohol use disorder.",
"title_normalized": "assessing alcohol versus baclofen withdrawal syndrome in patients treated with baclofen for alcohol use disorder"
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"abstract": "Erb-b2 receptor tyrosine kinase 2 gene (ERBB2) (also called HER2) has long been recognized as an oncogenic driver in some breast and gastroesophageal cancers in which amplification of this gene confers sensitivity to treatment with Erb-b2 receptor tyrosine kinase 2 (ERBB2)-directed agents. More recently, somatic mutations in ERBB2 have been reported in 1% to 2% of patients with lung adenocarcinoma. Previous case series have suggested clinical tumor responses using anti-ERBB2 small molecules and antibody therapies.\n\n\n\nHere we report the outcomes of nine patients with metastatic lung adenocarcinoma with ERBB2 mutations being treated with ERBB2-targeted therapies.\n\n\n\nFour of the nine patients had response to targeted therapies, with durations of response ranging from 3 to 10 months. We identified a de novo phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene (PIK3CA) mutation and ERBB2 copy number gain as potential resistance mechanisms.\n\n\n\nWe showed patients with ERBB2-mutated lung adenocarcinoma can respond to targeted therapies, and we identified potential resistance mechanisms upon progression to targeted therapies.",
"affiliations": "Division of Hematology and Oncology, Stanford Hospital and Clinics, Stanford, California.;Stanford Cancer Institute, Stanford University, Stanford, California.;Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, People's Republic of China.;Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California; Palo Alto Veterans Administration Health Care System, Palo Alto, California.;Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.;Stanford Cancer Institute, Stanford University, Stanford, California; Department of Radiation Oncology, Stanford University, Stanford, California.;Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California.;Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California. Electronic address: jwneal@stanford.edu.",
"authors": "Chuang|Jody C|JC|;Stehr|Henning|H|;Liang|Ying|Y|;Das|Millie|M|;Huang|Jane|J|;Diehn|Maximilian|M|;Wakelee|Heather A|HA|;Neal|Joel W|JW|",
"chemical_list": "D011799:Quinazolines; D043823:Taxoids; D008453:Maytansine; D000077143:Docetaxel; D000077716:Afatinib; D014747:Vinblastine; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D000068878:Trastuzumab; D017239:Paclitaxel; D000077235:Vinorelbine; D000080044:Ado-Trastuzumab Emtansine",
"country": "United States",
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"doi": "10.1016/j.jtho.2017.01.023",
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"issue": "12(5)",
"journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer",
"keywords": "Afatinib; ERBB2; HER2; Targeted therapy; Trastuzumab",
"medline_ta": "J Thorac Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D000077716:Afatinib; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D058534:Class I Phosphatidylinositol 3-Kinases; D000077143:Docetaxel; D019008:Drug Resistance, Neoplasm; D005260:Female; D018628:Gene Dosage; D018734:Genes, erbB-2; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008453:Maytansine; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D017239:Paclitaxel; D011799:Quinazolines; D012189:Retrospective Studies; D043823:Taxoids; D000068878:Trastuzumab; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "101274235",
"other_id": null,
"pages": "833-842",
"pmc": null,
"pmid": "28167203",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article",
"references": "25899785;27734950;24369725;27247954;15013588;26391018;22325357;27018799;24323026;27283993;27581375;22761469;15753357;16775247;24142049;17936563;25789838;27349506;23610105;23204226;14679114;26964772;15457249;24705333;26824988;26598547",
"title": "ERBB2-Mutated Metastatic Non-Small Cell Lung Cancer: Response and Resistance to Targeted Therapies.",
"title_normalized": "erbb2 mutated metastatic non small cell lung cancer response and resistance to targeted therapies"
} | [
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"abstract": "The aim of this study is to evaluate a cognitive-behavioral treatment for children and adolescents with tic disorder including habit reversal training (HRT) in a sample of children and adolescents (n = 27). Multiple outcome measures were used to assess the effects of the treatment on tic symptoms. In addition, impairment/subjective burden ratings and the self-efficacy to control tics were assessed. A within-subject design with two phases (8 weeks diagnostic; 16 sessions treatment) was analyzed using multilevel modeling (MLM). During the treatment phase, significant improvements in tic symptoms, impairment, and self-efficacy to control tics were found on most outcome measures. Treatment effects were found on the clinical rating of tic symptoms (Yale Global Tic Severity Scale [YGTSS]), the self-efficacy to control tics, and the video-observed motor tic frequency by comparing the improvements during treatment with the course of the outcome measures during the preceding diagnostic phase.",
"affiliations": "School of Child and Adolescent Cognitive Behavior Therapy (AKiP), University Hospital, Cologne, Germany.;School of Child and Adolescent Cognitive Behavior Therapy (AKiP), University Hospital, Cologne, Germany.;School of Child and Adolescent Cognitive Behavior Therapy (AKiP), University Hospital, Cologne, Germany.;School of Child and Adolescent Cognitive Behavior Therapy (AKiP), University Hospital, Cologne, Germany.;School of Child and Adolescent Cognitive Behavior Therapy (AKiP), University Hospital, Cologne, Germany.;School of Child and Adolescent Cognitive Behavior Therapy (AKiP), University Hospital, Cologne, Germany.",
"authors": "Viefhaus|Paula|P|;Feldhausen|Marion|M|;Görtz-Dorten|Anja|A|;Volk|Helene|H|;Döpfner|Manfred|M|;Woitecki|Katrin|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0145445518796203",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0145-4455",
"issue": "44(1)",
"journal": "Behavior modification",
"keywords": "Tourette’s disorder; children and adolescents; habit reversal training; tic disorder; treatment evaluation",
"medline_ta": "Behav Modif",
"mesh_terms": "D000293:Adolescent; D001521:Behavior Therapy; D002648:Child; D005260:Female; D006184:Habits; D006801:Humans; D008297:Male; D020377:Self Efficacy; D012720:Severity of Illness Index; D013981:Tic Disorders; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7803043",
"other_id": null,
"pages": "114-136",
"pmc": null,
"pmid": "30146896",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy of Habit Reversal Training in Children With Chronic Tic Disorders: A Within-Subject Analysis.",
"title_normalized": "efficacy of habit reversal training in children with chronic tic disorders a within subject analysis"
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"abstract": "Upfront KRAS and NRAS gene testing ('RAS') is the standard of care for metastatic colorectal cancer (mCRC), to guide first-line treatment. The presence of RAS mutation (MT) is a negative predictor for the efficacy of anti-EGFR antibodies and the use of cetuximab and panitumumab is restricted to RAS wild-type (WT) mCRC. Conversion from RAS WT to RAS MT mCRC after treatment with anti-EGFR antibodies is a known and well-described acquired resistance mechanism. The by far less frequent 'NeoRAS wild-type' phenomenon (reversion from RAS MT to RAS WT) has recently drawn attention. The proposed effect of chemotherapy on RAS status in mCRC patients is not fully understood. Because of the intriguing biological consequence of a RAS MT to RAS WT reversion, subsequent treatment of NeoRAS WT patients with anti-EGFR antibodies is increasingly being discussed. Here, we report three clinical cases of NeoRAS WT mCRC patients, which received standard-of-care regimens for RAS MT mCRC. Anti-EGFR antibodies were used in two out of three patients after progression of the disease. One of the patients had a long-term response. In line with our observations, NeoRAS WT phenomenon occurs in clinical practice. Retesting of RAS status during treatment should be discussed in patients with unusual long-term clinical courses of RAS MT mCRC to optimise treatment strategy and to evaluate the use of anti-EGFR antibodies.",
"affiliations": "Department of Hematology, Oncology, and Tumor Immunology, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany; Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany; Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of Hematology, Oncology, and Tumor Immunology, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany; Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Charité Comprehensive Cancer Center, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Institute of Pathology Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Hematology, Oncology, and Tumor Immunology, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Hematology, Oncology, and Tumor Immunology, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Hematology, Oncology, and Tumor Immunology, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Hematology, Oncology, and Tumor Immunology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Hematology, Oncology, and Tumor Immunology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Hematology, Oncology, and Tumor Immunology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Hematology, Oncology, and Tumor Immunology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Hematology, Oncology, and Tumor Immunology, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany.;Department of Hematology, Oncology, and Tumor Immunology, Campus Charité Mitte, Charité - Universitätsmedizin Berlin, Berlin, Germany; Department of Hematology, Oncology, and Tumor Immunology, Campus Virchow-Klinikum, Charité - Universitätsmedizin Berlin, Berlin, Germany. Electronic address: ivan.jelas@charite.de.",
"authors": "Osumi|Hiroki|H|;Vecchione|Loredana|L|;Keilholz|Ulrich|U|;Vollbrecht|Claudia|C|;Alig|Annabel H S|AHS|;von Einem|Jobst C|JC|;Stahler|Arndt|A|;Striefler|Jana K|JK|;Kurreck|Annika|A|;Kind|Andreas|A|;Modest|Dominik P|DP|;Stintzing|Sebastian|S|;Jelas|Ivan|I|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2021.05.010",
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"issn_linking": "0959-8049",
"issue": "153()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Cetuximab; Circulating tumour DNA; Liquid biopsy; Metastatic colorectal cancer; NeoRAS wild-type; Panitumumab; ctDNA",
"medline_ta": "Eur J Cancer",
"mesh_terms": null,
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "86-95",
"pmc": null,
"pmid": "34153718",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "NeoRAS wild-type in metastatic colorectal cancer: Myth or truth?-Case series and review of the literature.",
"title_normalized": "neoras wild type in metastatic colorectal cancer myth or truth case series and review of the literature"
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"abstract": "A case report of a 47-year-old woman with triple-negative breast cancer on a clinical trial called PRIMETIME (NCT02518958) who received the anti-PD-1 inhibitor nivolumab and the experimental anticancer agent RRx-001 is presented. Although initially diagnosed and treated for anti-PD-1-induced pneumonitis, clinical and radiological abnormalities triggered further investigation, leading to the diagnosis of pulmonary tumor thrombotic microangiopathy (PTTM). This example highlights the importance of exercising due diligence in determining immune-related adverse events and suggests that PD-1-induced pneumonitis should be a diagnosis of exclusion rather than a diagnosis by default. A case history and review of the literature are presented for PTTM, which we propose to define as a paraneoplastic syndrome.",
"affiliations": "Walter Reed National Military Medical Center, Bethesda, Md., USA.;Walter Reed National Military Medical Center, Bethesda, Md., USA.;EpicentRx, Mountain View, Calif., USA.;EpicentRx, Mountain View, Calif., USA.;Walter Reed National Military Medical Center, Bethesda, Md., USA.",
"authors": "Carter|Corey A|CA|;Browning|Robert|R|;Oronsky|Bryan T|BT|;Scicinski|Jan J|JJ|;Brzezniak|Christina|C|",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.1159/000443723",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000443723cro-0009-0068Published online: January, 2016The Case of a Zebra That Was Misdiagnosed as a Horse: Pulmonary Tumor Thrombotic Microangiopathy, a New Paraneoplastic Syndrome, Mimicking PD-1-Induced Pneumonitis Carter Corey A. aBrowning Robert aOronsky Bryan T. bScicinski Jan J. b*Brzezniak Christina aaWalter Reed National Military Medical Center, Bethesda, Md., USAbEpicentRx, Mountain View, Calif., USA*Jan J. Scicinski, EpicentRx, 800 W El Camino Real, Suite 180, Mountain View, CA 94040 (USA), E-Mail jscicinski@epicentrx.comJan-Apr 2016 27 1 2016 27 1 2016 9 1 68 75 Copyright © 2016 by S. Karger AG, Basel2016This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.A case report of a 47-year-old woman with triple-negative breast cancer on a clinical trial called PRIMETIME (NCT02518958) who received the anti-PD-1 inhibitor nivolumab and the experimental anticancer agent RRx-001 is presented. Although initially diagnosed and treated for anti-PD-1-induced pneumonitis, clinical and radiological abnormalities triggered further investigation, leading to the diagnosis of pulmonary tumor thrombotic microangiopathy (PTTM). This example highlights the importance of exercising due diligence in determining immune-related adverse events and suggests that PD-1-induced pneumonitis should be a diagnosis of exclusion rather than a diagnosis by default. A case history and review of the literature are presented for PTTM, which we propose to define as a paraneoplastic syndrome.\n\nKey Words\nPulmonary tumor thrombotic microangiopathyParaneoplastic syndromePD-1-induced pneumonitis\n==== Body\nIntroduction\nAccording to the well-known expression ‘When you hear hoofbeats, think of horses not zebras’, the art of medicine is based on soundness: the higher the pretest probability, the sounder the diagnosis. The problem with this medical aphorism is that it actively encourages the clinician to turn a deaf ear (and a blind eye) to the possibility of lesser known and, therefore, more easily overlooked disease states that mimic or ‘sound like’ the more expected ‘horse’ diagnosis. This report presents a case in point: a 47-year-old woman with triple-negative breast cancer on a clinical trial called PRIMETIME (NCT02518958) who received the anti-PD-1 inhibitor nivolumab and the experimental anticancer agent RRx-001 for 18 weeks; initially treated for pneumonitis, an ‘expected’ autoimmune complication of nivolumab, based on the development of dyspnea and CT abnormalities. The overall clinical picture, nevertheless, was atypical, which prompted the investigating team to aggressively pursue alternate possibilities, ultimately leading to the correct diagnosis: pulmonary tumor thrombotic microangiopathy or PTTM.\n\nThis example highlights the importance of exercising due diligence and not automatically jumping to conclusions with regard to the diagnosis of immune-related adverse events (irAEs) such as pneumonitis during treatment with PD-1 or CTLA-4 inhibitors. Analogous to another pulmonary medical aphorism, ‘all that wheezes is not asthma’, the differential diagnosis for breathlessness in the context of immune checkpoint inhibition is broader than only pneumonitis and should involve a systematic investigation for other etiologies, including the rare and rapidly progressive disorder PTTM. A case history and review of the literature are presented for PTTM, which we propose to define as a paraneoplastic syndrome (PNS). In addition, a potential treatment option based on its pathophysiology is discussed.\n\nThe goal of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1) pathway blockade, including nivolumab approved for the treatment of melanoma, squamous-cell lung cancer [1] and renal cell carcinoma [2], is to overcome the T-cell suppression mediated by these inhibitory receptors (fig. 1); a potential side effect of revving up the immune system to attack malignant tumors is the breaking of self-tolerance and the induction of irAEs [3], which include rash, colitis, hepatotoxicities, endocrinopathies, and interstitial pneumonitis [4].\n\nAs the most serious irAE, reportedly responsible for 5 total fatalities across the spectrum of nivolumab-treated patients [5], the incidence of pneumonitis increased from 3.4% on a melanoma trial to 6% on a NSCLC clinical trial, according to a recent Bristol Myers Squibb press release [6]; this increase in incidence should raise the suspicion that increased awareness of and, consequently, narrowed focus on pneumonitis by oncologists has resulted in erroneous overdiagnosis. The clinical manifestations of pneumonitis are protean and include fever, chills, malaise, cough, chest tightness, hypoxia, and dyspnea, while the nonspecific radiological characteristics [7] of ground glass opacities (i.e., lung opacities that do not obscure the associated vessels), consolidations (i.e., lung opacities that do obscure the associated vessels), and effusions also overlap with multiple other disease entities including acute respiratory distress syndrome, pneumonia, pulmonary embolism (PE), congestive heart failure, and the subject of this case report, PTTM.\n\nPTTM is a rare and possibly underdiagnosed [8] extrapulmonary sequella of metastatic cancer, specifically adenocarcinomas [9], formally described in 1990 by von Herbay et al. [10] that presents as acute cor pulmonale, a maladaptive response to pulmonary hypertension [11], resulting in dyspnea and hypoxemia as well as ground-glass opacity (or diffuse consolidation) and pulmonary edema on CT [12, 13]. The available literature on PTTM is sparse, existing mostly as case reports or small case series from Japan, with a lack of higher-order treatment studies. Adenocarcinomas, and gastric cancer in particular [14], have been linked with PTTM in these Japanese case reports, which is not surprising, given the high incidence rate of gastric cancer in Japan.\n\nThe etiologic mechanism of PTTM is related to the intravasation of circulating tumor cells in the pulmonary vasculature; these circulating tumor cells release a plethora of vascular remodeling factors [15] including vascular endothelial growth factor (VEGF), fibroblast growth factor, osteopontin [16], and platelet derived growth factor (PDGF) associated with abnormal endothelial proliferation, the local activation of the coagulation cascade, and the development of pulmonary hypertension from resultant stenosis of the pulmonary capillaries and arterioles (fig. 2).\n\nIn the absence of gold standard surgical biopsy, PTTM, which is only rarely diagnosed antemortem, due to a nearly uniform fatality rate [17], (almost all reported patients have died within 2 weeks of dyspnea onset), may be suspected in cancer patients ruled out for PE who develop acute or subacute right-sided heart failure, pulmonary hypertension, and abnormal coagulation parameters.\n\nOur nivolumab-treated patient with metastatic triple-negative breast cancer who is the subject of this case report recapitulated these clinical and laboratory abnormalities almost ‘to a T’, including, unfortunately, the time interval between onset of first symptoms and death. While the term ‘textbook example’ is not applicable in the context of PTTM, since no textbooks on it have been written (only case reports), this patient's clinical course and trajectory were indeed ‘textbook’ for PTTM, even though a default diagnosis of nivolumab-induced pneumonitis was initially made. However, in light of the atypical presentation, discussed below, and findings that did not quite ‘add up’, the team, suspecting that pneumonitis was a red herring, decided to trust their intuition, and pursued a further work-up, which ultimately led to the diagnosis of PTTM.\n\nCase Report\nA 47-year-old female with rapidly progressive refractory triple-negative metastatic breast cancer, metastatic to the lungs, was treated at Walter Reed on a clinical trial called PRIMETIME (NCT02518958) where she received the anti-PD-1 inhibitor nivolumab, 3 mg/kg, every other week in combination with weekly RRx-001, an experimental epi-immunologic agent. During her week 18 infusion on December 3, 2015, she developed fever (101°F, 38.3°C), headache, palpitations, and diaphoresis; the presence of fever prompted a sepsis work-up consisting of complete blood count, routine blood culture, urinalysis, and chest X-ray in the hospital to determine the source of the fever and rule out an infection.\n\nExamination revealed tachycardia to 124 bpm. A spiral CT scan was negative for PE. The remainder of the physical exam was unremarkable. ECG recordings revealed only sinus tachycardia. Septic work-up was negative. Glycemia was in the normal range (120 mg/dl). Her labs were otherwise significant only for anemia (hemoglobin 9.4 g/dl and hematocrit 30.6%) and a normal leukocyte count (5.8 × 103/μl) with a high percentage of segmented neutrophils on the differential (normal 43–73%) and no bandemia. As part of the work-up for sinus tachycardia, thyroid function tests were performed but thyroid-stimulating hormone (TSH) and free T4 were within normal limits.\n\nHer symptoms progressed to dyspnea and hypoxia the next day (on December 4, 2015) after administration of isotonic normal saline to restore volume. Chest CT, which had been clear on admission, revealed interlobular septal thickening, diffuse ground-glass attenuation, and bilateral effusions (fig. 3).\n\nA shortened list of differential diagnoses included atypical viral or bacterial pneumonia, cardiogenic pulmonary edema (since the patient had received doxorubicin in the past), and treatment-induced pneumonitis. On that basis, i.v. fluids were withheld, the patient was discontinued from the trial and combination treatment with broad-spectrum empiric antibiotics (vancomycin, Zosyn and levaquin) and 1 mg/kg prednisone was started. However, the antibiotics and corticosteroids were withdrawn a week later due to worsening dyspnea and hypoxia. A ventilation-perfusion scan was performed on December 14, 2015 and read as low probability for PE (no perfusion defects).\n\nTo identify the cause of the edema, a transthoracic echocardiography was ordered, which revealed a normal left ventricular ejection fraction with right ventricular dilatation and severely reduced right ventricular function secondary to pulmonary hypertension (a pressure >50 mm Hg is generally accepted as severe [18] and her estimated right ventricular systolic pressure exceeded 65 mm Hg). proBNP was also drawn; it was elevated at 3,226.0 pg/ml, indicative of heart failure (5–125 nl range). Cardiac troponins were not elevated.\n\nThe presence of acute cor pulmonale pointed away from pneumonitis and strongly suggested three rare possibilities: (1) occlusion of the pulmonary vessels from microscopic tumor emboli (also known as pulmonary tumor embolism), leading to pulmonary arterial hypertension (PAH); (2) PTTM, a related but even rarer pulmonary vasculopathy, associated with adenocarcinomas of the stomach, pancreas, breast, lung, and liver, in which minute tumor emboli in the peripheral pulmonary arteries damage the vascular endothelium, leading to accelerated coagulation [12] and PAH, and (3) pulmonary venous occlusive disease, the venous form of PAH [19, 20], due to fibrous occlusion of the post-capillary vessels, which may or may not be associated with an autoimmune process [10] (the association is only anecdotal). The pulmonary hypertension was managed with diuretics (furosemide 40 mg i.v.), bosentan 62.5 mg, and oxygen (2 liters by nasal cannula) as well as intravenous epoprostenol, norepinephrine, and dobutamine; however, no improvement was observed.\n\nSince a lung biopsy carried too much risk, the patient was catheterized; pulmonary artery catheter-derived blood samples were negative for the presence of tumor emboli. Blood was also drawn for the measurement of coagulation parameters, since PTTM is associated with coagulopathy. The results were as follows: elevated D-dimer (or serum fibrin degradation products) of 1.04 μg/ml (normal <0.5 μg/ml) and a prolonged prothrombin time of 16.5 s (normal 11–14 s). Platelets were never outside of the normal range. The partial thromboplastin time and thrombin time were both prolonged at 67.2 s (normal 25–35 s) and 48 s (normal 14–20 s), respectively, due to treatment with a heparin GTT for potential venous clots.\n\nIn the setting of adenocarcinoma, pulmonary hypertension, and a negative CT and ventilation-perfusion scan for PE, these coagulation abnormalities were highly suggestive of a PTTM diagnosis. PTTM is distinct from simple embolic obstruction because it is characterized by (1) the systemic activation of coagulation with the generation of intravascular fibrin and the consumption of procoagulants, leading to a disseminated intravascular coagulation-like picture, present in this case and (2) remodeling of the pulmonary vasculature [21] due to expression of VEGF and PDGF from embolic tumor cells (see fig. 2) [22].\n\nBased on the proposed involvement of VEGF and PDGF in the pathogenesis of PTTM, the primary investigator planned to treat the patient with sunitinib, which dually inhibits VEGF and PDGF pathways; however, before she could start on treatment, sadly the patient expired.\n\nConclusions\nThe observations in this case study strongly suggest that PD-1-induced pneumonitis should be a diagnosis of exclusion rather than a diagnosis by default, requiring a thorough work-up to rule out conditions that may mimic it, including PE, atypical pneumonia, pulmonary venous occlusive disease, congestive heart failure, and PTTM. In the case of this acutely dyspneic patient, who initially received a ‘pneumonitis by default’ diagnosis, PTTM was only identified when her shortness of breath deteriorated despite treatment with high dose steroids, alerting the principal investigator to the possibility of heart failure, which led to further investigation.\n\nThe treating oncologist must be alert to the development or presence of PNS, defined as a ‘pathology caused by tumor cells, which systematically produce a large amount of hormones, growth factors, cytokines and a variety of specific symptoms’ [23]. These include: Cushing syndrome, carcinoid syndrome, dermatomyositis-polymyositis, myasthenia gravis and syndrome of inappropriate antidiuretic hormone [24]. To this list, we would add PTTM, since its pathogenesis is related to the local release of mitogenic factors associated with vascular remodeling and coagulopathy. As a heretofore unrecognized PNS, PTTM requires background knowledge and a high index of clinical suspicion. In the absence of a biopsy, echocardiographic studies and coagulation tests are the diagnostic tests of choice.\n\nEven though the case under discussion was refractory to standard therapies and the patient died before sunitinib, the multitargeted tyrosine kinase selective for VEGF and PDGF receptors, could be started, it is reasonable to assume that early diagnosis and treatment would have resulted in a better outcome.\n\nStatement of Ethics\nThe patient described in this case report has given his informed consent as part of the PRIMETIME clinical study (NCT02518958). This study protocol has been approved by the Walter Reed National Military Medical Center Institutional Review Board.\n\nDisclosure Statement\nB.T.O. and J.J.S. are employees of EpicentRx, Inc. EpicentRx, Inc. provided funding for the study. The remaining authors declare that they have no competing interests.\n\nFig. 1 PD-1 is a cell-surface receptor of the CD28 superfamily that triggers inhibitory pathways to attenuate T-cell responses and promote immune suppression. The PD-1 antibody blocks the interaction between PD-1 and its ligands PD-L1 and PD-L2 (not shown).\n\nFig. 2 Proposed mechanism of PTTM. Microscopic tumor emboli due to disease progression release cytokines and growth factors (e.g., VEGF and PDGF) leading to coagulopathy and vascular remodeling. The latter is responsible for pulmonary hypertension. The involvement of VEGF and PDGF justifies or supports treatment with a tyrosine kinase inhibitor like sunitinib that inhibits VEGF and PDGF pathways.\n\nFig. 3 CT of the lungs demonstrates diffuse ground-glass attenuation, bilateral effusions, and scattered pulmonary nodules. The yellow arrows show prominent interlobular septal thickening.\n==== Refs\nReferences\n1 http://packageinserts.bms.com/pi/pi_opdivo.pdf (accessed December 28, 2015)\n2 Motzer RJ Escudier B McDermott DF Nivolumab versus everolimus in advanced renal-cell carcinoma N Engl J Med 2015 373 1803 1813 26406148 \n3 Di Giacomo AM Biagioli M Maio M The emerging toxicity profiles of anti-CTLA-4 antibodies across clinical indications Semin Oncol 2010 37 499 507 21074065 \n4 Weber JS Yang JC Atkins MB Disis ML Toxicities of immunotherapy for the practitioner J Clin Oncol 2015 33 2092 2099 25918278 \n5 Topalian SL Sznol M McDermott DF Survival, durable tumor remission, and long-term safety in patients with advanced melanoma receiving nivolumab J Clin Oncol 2014 32 1020 1030 24590637 \n6 http://news.bms.com/press-release/follow-data-two-pivotal-opdivo-nivolumab-trials-demonstrates-sustained-survival-result (accessed December 28, 2015)\n7 Nishino M Sholl LM Hodi FS Hatabu H Ramaiya NH Anti-PD-1-related pneumonitis during cancer immunotherapy N Engl J Med 2015 373 288 290 26176400 \n8 Godbole R Ghatol A Betancourt J Sacoolidge J Kamangar N Pulmonary tumor thrombotic microangiopathy: clinical, radiologic, and histologic correlation J Clin Imaging Sci 2015 5 44 26312142 \n9 Shih HM Lin CC Shiao YW Pulmonary tumor thrombotic microangiopathy Am J Emerg Med 2011 29 241.e3 241.e4 20825897 \n10 von Herbay A Illes A Waldherr R Otto HF Pulmonary tumor thrombotic microangiopathy with pulmonary hypertension Cancer 1990 66 587 592 2163747 \n11 Rabinovitch M Pathobiology of pulmonary hypertension Annu Rev Pathol 2007 2 369 399 18039104 \n12 Uruga H Fujii T Kurosaki A Hanada S Takaya H Miyamoto A Morokawa N Homma S Kishi K Pulmonary tumor thrombotic microangiopathy: a clinical analysis of 30 autopsy cases Intern Med 2013 52 1317 1323 23774540 \n13 Kitamura A Nishimura N Jinta T Suda R Yamano Y Ishikawa G Tomishima Y Hamaoka T Suzuki K Chohnabayashi N A case of pulmonary tumor thrombotic microangiopathy diagnosed by transbronchial lung biopsy and treated with chemotherapy and long-term oxygen and anticoagulation therapies Case Rep Pulmonol 2013 2013 259080 24069542 \n14 Chinen K Tokuda Y Fujiwara M Fujioka Y Pulmonary tumor thrombotic microangiopathy in patients with gastric carcinoma: an analysis of 6 autopsy cases and review of the literature Pathol Res Pract 2010 206 682 689 20554399 \n15 Chinen K Kazumoto T Ohkura Y Matsubara O Tsuchiya E Pulmonary tumor thrombotic microangiopathy caused by a gastric carcinoma expressing vascular endothelial growth factor and tissue factor Pathol Int 2005 55 27 31 15660700 \n16 Takahashi F Kumasaka T Nagaoka T Osteopontin expression in pulmonary tumor thrombotic microangiopathy caused by gastric carcinoma Pathol Int 2009 59 752 756 19788622 \n17 Sato Y Marutsuka K Asada Y Yamada M Setoguchi T Sumiyoshi A Pulmonary tumor thrombotic microangiopathy Pathol Int 1995 45 436 440 7581935 \n18 Berger M Haimowitz A Van Tosh A Berdoff RL Goldberg E Quantitative assessment of pulmonary hypertension in patients with tricuspid regurgitation using continuous wave Doppler ultrasound J Am Coll Cardiol 1985 6 359 365 4019921 \n19 Weisser K Wyler F Gloor F Pulmonary veno-occlusive disease Arch Dis Child 1967 42 322 327 6025375 \n20 Rosenthal A Vawter G Wagenvoort CA Intrapulmonary veno-occlusive disease Am J Cardiol 1973 31 78 83 4682413 \n21 Kumar N Price LC Montero MA Dimopoulos K Wells AU Wort SJ Pulmonary tumour thrombotic microangiopathy: unclassifiable pulmonary hypertension? Eur Respir J 2015 46 1214 1217 26206876 \n22 Demirag F Cakir E Yazici U Tastepe I Pulmonary tumor thrombotic microangiopathy from metastatic epithelioid angiosarcoma J Thorac Dis 2013 5 E107 E111 23825782 \n23 Cui T Hurtig M Elgue G Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors PLoS One 2010 5 e16010 21209860 \n24 Pelosof LC Gerber DE Paraneoplastic syndromes: an approach to diagnosis and treatment Mayo Clin Proc 2010 85 838 854 20810794\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "9(1)",
"journal": "Case reports in oncology",
"keywords": "PD-1-induced pneumonitis; Paraneoplastic syndrome; Pulmonary tumor thrombotic microangiopathy",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "68-75",
"pmc": null,
"pmid": "26933422",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "6025375;20825897;26176400;15660700;4682413;20554399;23774540;26406148;4019921;7581935;2163747;19788622;24590637;24069542;21074065;26206876;18039104;25918278;23825782;21209860;26312142;20810794",
"title": "The Case of a Zebra That Was Misdiagnosed as a Horse: Pulmonary Tumor Thrombotic Microangiopathy, a New Paraneoplastic Syndrome, Mimicking PD-1-Induced Pneumonitis.",
"title_normalized": "the case of a zebra that was misdiagnosed as a horse pulmonary tumor thrombotic microangiopathy a new paraneoplastic syndrome mimicking pd 1 induced pneumonitis"
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"abstract": "BACKGROUND The efficacy and safety of re-challenge with immune checkpoint inhibitors after immune-related adverse events have not been established. We report a case of successful re-administration of nivolumab in metastatic renal cell carcinoma after discontinuation due to immune-related adverse events. CASE REPORT Laparoscopic nephrectomy was performed on a 52-year-old man diagnosed with renal cell carcinoma pT1bN0M0. After surgery, left adrenal and lung metastases appeared. Nivolumab was administered as a sixth-line therapy, and he achieved a partial response, but interstitial pneumonia occurred. He was diagnosed with grade 2 immune-related adverse events, and nivolumab treatment was discontinued. Interstitial pneumonia was well controlled by steroids. He maintained a partial response for a long time, and the lung metastases disappeared 7 months after discontinuation. However, bilateral lung metastases reappeared 10 months after the discontinuation. We decided to re-administer nivolumab, while carefully monitoring the patient and fully explaining the risk of recurrence of immune-related adverse events. After 5 cycles of re-administration, computed tomography revealed a reduction in metastases without re-activation of interstitial pneumonia. He experienced a grade 1 fever the day after re-administration, but continued nivolumab therapy without other adverse events. After 7 cycles of re-administration, the lung metastases increased, and nivolumab treatment was terminated. Two months later, a grade 2 interstitial pneumonia recurred, but improved rapidly with oral steroids. CONCLUSIONS For patients who have discontinued immune checkpoint inhibitors due to immune-related adverse events, re-challenge of immune checkpoint inhibitors may be an option after explaining the risk of relapse of immune-related adverse events.",
"affiliations": "Department of Urology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Urology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Urology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Urology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Urology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.;Department of Urology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan.",
"authors": "Shibata|Yosuke|Y|;Noguchi|Go|G|;Suzuki|Takahisa|T|;Osaka|Kimito|K|;Umemoto|Susumu|S|;Kishida|Takeshi|T|",
"chemical_list": "D000077594:Nivolumab",
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"doi": "10.12659/AJCR.932924",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34358221\n10.12659/AJCR.932924\n932924\nArticles\nRe-Challenging with Nivolumab in Metastatic Renal Cell Carcinoma After Immune-Related Interstitial Pneumonia: A Case Report\nShibata Yosuke AEF\nNoguchi Go EF\nSuzuki Takahisa E\nOsaka Kimito E\nUmemoto Susumu E\nKishida Takeshi EF\nDepartment of Urology, Kanagawa Cancer Center, Yokohama, Kanagawa, Japan\nCorresponding Author: Yosuke Shibata, e-mail: y.shiba.329@gmail.com\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n2021\n06 8 2021\n22 e932924-1e932924-6\n28 4 2021\n16 6 2021\n23 6 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 52-year-old\n\nFinal Diagnosis: Renal cell carcinoma\n\nSymptoms: Cough\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: Urology\n\nObjective:\n\nUnusual clinical course\n\nBackground:\n\nThe efficacy and safety of re-challenge with immune checkpoint inhibitors after immune-related adverse events have not been established. We report a case of successful re-administration of nivolumab in metastatic renal cell carcinoma after discontinuation due to immune-related adverse events.\n\nCase Report:\n\nLaparoscopic nephrectomy was performed on a 52-year-old man diagnosed with renal cell carcinoma pT1b-N0M0. After surgery, left adrenal and lung metastases appeared. Nivolumab was administered as a sixth-line therapy, and he achieved a partial response, but interstitial pneumonia occurred. He was diagnosed with grade 2 immune-related adverse events, and nivolumab treatment was discontinued. Interstitial pneumonia was well controlled by steroids. He maintained a partial response for a long time, and the lung metastases disappeared 7 months after discontinuation. However, bilateral lung metastases reappeared 10 months after the discontinuation. We decided to re-administer nivolumab, while carefully monitoring the patient and fully explaining the risk of recurrence of immune-related adverse events. After 5 cycles of re-administration, computed tomography revealed a reduction in metastases without re-activation of interstitial pneumonia. He experienced a grade 1 fever the day after re-administration, but continued nivolumab therapy without other adverse events. After 7 cycles of re-administration, the lung metastases increased, and nivolumab treatment was terminated. Two months later, a grade 2 interstitial pneumonia recurred, but improved rapidly with oral steroids.\n\nConclusions:\n\nFor patients who have discontinued immune checkpoint inhibitors due to immune-related adverse events, re-challenge of immune checkpoint inhibitors may be an option after explaining the risk of relapse of immune-related adverse events.\n\nKeywords:\n\nCarcinoma, Renal Cell\nLung Diseases, Interstitial\nNivolumab\n==== Body\nBackground\n\nThe CheckMate-025 trial demonstrated the significance of nivolumab over everolimus for the treatment of advanced renal cell carcinoma (RCC) previously treated with antiangiogenic agents. The response rate for nivolumab was 23%, and the median duration of response was 18.2 months, indicating good results, but 9.6% had to discontinue nivolumab due to immune-related adverse events (irAEs) [1]. In the case of serious irAEs, permanent discontinuation of the immune checkpoint inhibitors (ICIs) is required; otherwise, the same ICI is often re-administered after the irAE has resolved. As there are no randomized trials examining ICI re-administration and there are only a few retrospective reports, the safety and efficacy of ICI re-administration after discontinuation due to irAEs remain unclear. We report the case of a patient with metastatic RCC who had a second response to re-administration of nivolumab after discontinuation due to interstitial pneumonia.\n\nCase Report\n\nA 52-year-old man underwent laparoscopic radical left nephrectomy for a 6.5-cm left renal mass. The pathological results indicated clear cell RCC, Fuhrman grade 4, and pT1bN0M0. The patient had no predisposing factors for RCC. Five years later, a left adrenal metastasis appeared.\n\nSince he did not wish to undergo adrenalectomy, he was treated with various targeted therapy agents (sorafenib, sunitinib, everolimus, axitinib, and pazopanib). However, lung metastases appeared, and the left adrenal metastasis developed 12 years after the surgery (Figure 1A). Nivolumab therapy was initiated as the sixth-line therapy.\n\nNivolumab (3 mg/kg) was administered every 2 weeks. After 3 cycles of administration, he presented with cough. Computed tomography (CT) revealed reticular interstitial shadows in both lungs on the right predominant side (Figure 2A). He was diagnosed with grade 2 interstitial pneumonia, and nivolumab therapy was discontinued. He was treated with steroidal pulse therapy, and the interstitial pneumonia improved quickly. After the pulse therapy, he was administered a down-titrated oral prednisolone dose. Steroid therapy was terminated after 14 months. At the time of diagnosis of interstitial pneumonia, both lung and adrenal metastases were reduced, as documented by CT. The patient achieved (Figure 1B) and maintained partial response (PR) after nivolumab discontinuation; lung metastases disappeared 7 months after discontinuation (Figure 1C). Ten months after nivolumab discontinuation, bilateral lung metastases reappeared, but the patient was not treated because of the risk of irAEs. After 23 months of nivolumab discontinuation, the lung metastases progressed, and his cough worsened (Figure 3A).\n\nWe decided to re-challenge with nivolumab and explained the risk of recurrence of interstitial pneumonia in the patient. After re-administration of nivolumab, the patient underwent a chest X-ray and had consultations with a respiratory physician every 2 weeks. The day after re-administration, he developed a grade 1 fever that subsided spontaneously without antibiotics. He continued nivolumab therapy without any other adverse events. After 5 cycles of re-administration, CT revealed a reduction in all metastases (Figure 3B), and the patient achieved PR again.\n\nHowever, after 7 cycles of treatment, the lung metastases increased again, and nivolumab treatment was terminated (Figure 3C). Two months after nivolumab discontinuation, a chest X-ray revealed consolidation. Subsequent CT showed a recurrence of grade 2 interstitial pneumonia with a contralateral left predominance (Figure 2B). We administered down-titrated oral prednisolone (1 mg/kg) that rapidly improved the interstitial pneumonia. Nine months after nivolumab discontinuation, there was no further evidence of interstitial pneumonia, and the patient was placed under observation and provided with the best supportive care.\n\nDiscussion\n\nIn the CheckMate-025 study, interstitial pneumonia was observed in 5.2% of the patients, of which 71.4% had grades 1–2, 28.6% had grades 3–4, and none had grade 5 [1]. According to the guidelines, re-administration of ICIs after grade 2 irAEs is allowed if the patient has improved to grade 1 or lower, but re-administration is not recommended for patients with grade 3 or higher [2–4].\n\nRecently, there have been retrospective reports of re-administration of ICIs for metastatic RCC. Abou Alaiwi et al analyzed 45 cases of metastatic RCC that were re-administered with ICIs after discontinuation due to irAEs and reported a response to ICI re-treatment in 23.1% of patients who did not respond to the initial ICI treatment [5]. IrAE recurrences were observed in 50% of cases, but no grade 4 and 5 irAEs were observed, and there was no correlation between the grades of the first irAE and the second irAE. Ravi et al reported 69 patients who received at least 2 separate lines of ICI for RCC [6]. PR was obtained in 37.5% of patients who were re-administered with other ICIs after discontinuation due to irAEs, which was higher than the 37% overall response rate of the initial ICI treatment. Patients who developed irAEs on the initial ICI treatment had a significantly higher risk of developing irAEs with ICI re-challenge than patients who did not (41% vs 20%). However, this rate was low compared to the 71% rate of developing irAEs with the initial ICI treatment. Grade 3 or higher irAEs were observed in 26% of patients treated with the initial ICI and in 16% of patients with ICI re-treatment.\n\nThe reasons for the low rate of irAEs after ICI re-administration include the possibility that irAE recurrence beyond the observation period may have been missed, and that the use of steroids or immunosuppressive agents during ICI re-administration may have affected irAE recurrence. In patients with melanoma, it has been reported that the recurrence rate of irAEs decreased after ICI re-treatment after anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) monotherapy, and that the history of anti-CTLA-4 treatment did not affect the recurrence rate of a grade 3 or higher irAEs with anti-programmed cell death 1 antibodies re-treatment [7,8]. The mechanism of irAE recurrence is not yet understood, although differences in the mechanism of action of ICIs may contribute to a lower rate of irAE recurrence in the re-administration of different ICIs, as reported for melanoma by Ravi et al [6].\n\nIn other carcinomas, factors involved in the effect of ICI re-challenge and irAE recurrences have been reported. Santini reported that patients who did not respond to the initial ICI treatment before irAEs showed improvement in progression-free survival and overall survival after ICI re-challenge [9]. He further reported that the factors contributing to irAE recurrence were (1) initial irAEs requiring hospitalization and (2) PR or complete response after the first ICI administration. Simonaggio also reported a shorter time to onset of the first irAE in patients with irAE recurrence than those with no recurrence (9 vs 15 weeks; P=0.04) [10].\n\nIn this case, the patient had a durable response after interruption of ICI treatment but then progressed and was re-treated with the same ICI, resulting in another response. There are few reports on the efficacy of re-challenging with the same ICI when patients progress after a durable response, as in this case. Reports of durable response in other carcinomas showed that many cases progressed within 2 years, and about 20% of patients responded to the same ICI [11].\n\nThese data suggest that an additional response and overall survival prolongation may be achieved with ICI re-challenge. Although there was no significant worsening of the grade or incidence of irAEs with ICI re-treatment compared with the initial ICI treatment, caution is required because there is no established follow-up method for early detection of irAE recurrence and there are no randomized data on the safety and efficacy of ICI re-challenge.\n\nConclusions\n\nICI re-challenge after irAE can be an option after patients are fully informed of the risk of irAE relapse. It is important to re-challenge ICIs cautiously in collaboration with other specialists.\n\nWe would like to thank Editage (www.editage.com) for English language editing.\n\nFigure 1. The CT scan shows left adrenal and lung metastases before initial nivolumab therapy (A), after 3 cycles of nivolumab therapy (B), and 7 months after nivolumab discontinuation (C).\n\nFigure 2. X-rays and CT when interstitial pneumonia appeared. (A) Interstitial pneumonia after 3 cycles of nivolumab treatment. (B) Recurrence of interstitial pneumonia after re-challenge with nivolumab.\n\nFigure 3. The CT scan shows left adrenal and lung metastases before re-challenge with nivolumab (A), PR after 5 cycles of re-administration (B), and enlarged after 7 cycles of re-administration (C).\n\nConflict of Interest\n\nNone.\n\nDeclaration of Figures Authenticity\n\nAll figures submitted have been created by the authors who confirm that the images are original with no duplication and have not been previously published in whole or in part.\n==== Refs\nReferences:\n\n1. Motzer RJ Escudier B George S Nivolumab versus everolimus in patients with advanced renal cell carcinoma: Updated results with long-term follow-up of the randomized, open-label, phase 3 CheckMate 025 trial Cancer 2020 126 18 4156 67 32673417\n2. Thompson JA Schneider BJ Brahmer J NCCN Guidelines Insights: Management of immunotherapy-related toxicities, Version 1.2020 J Natl Compr Canc Netw 2020 18 3 230 41 32135517\n3. Haanen J Carbonnel F Robert C Management of toxicities from im-munotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2017 28 Suppl.4 iv119 42 28881921\n4. Brahmer JR Drake CG Wollner I Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: Safety, clinical activity, pharmacodynamics, and immunologic correlates J Clin Oncol 2010 28 19 3167 75 20516446\n5. Abou Alaiwi S Xie W Nassar AH Safety and efficacy of restarting immune checkpoint inhibitors after clinically significant immune-related adverse events in metastatic renal cell carcinoma J Immunother Cancer 2020 8 1 e000144 32066646\n6. Ravi P Mantia C Su C Evaluation of the safety and efficacy of immunotherapy rechallenge in patients with renal cell carcinoma JAMA Oncol 2020 6 10 1606 10 32469396\n7. Abu-Sbeih H Ali FS Naqash AR Resumption of immune checkpoint inhibitor therapy after immune-mediated colitis J Clin Oncol 2019 37 30 2738 45 31163011\n8. Ribas A Puzanov I Dummer R Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial Lancet Oncol 2015 16 908 18 26115796\n9. Santini FC Rizvi H Plodkowski AJ Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC Cancer Immunol Res 2018 6 9 1093 99 29991499\n10. Simonaggio A Michot JM Voisin AL Evaluation of readministration of immune checkpoint inhibitors after immune-related adverse events in patients with cancer JAMA Oncol 2019 5 9 1310 17 31169866\n11. Borcoman E Kanjanapan Y Champiat S Novel patterns of response under immunotherapy Ann Oncol 2019 30 3 385 96 30657859\n\n",
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"mesh_terms": "D002292:Carcinoma, Renal Cell; D006801:Humans; D007680:Kidney Neoplasms; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000077594:Nivolumab",
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"pubdate": "2021-08-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Re-Challenging with Nivolumab in Metastatic Renal Cell Carcinoma After Immune-Related Interstitial Pneumonia: A Case Report.",
"title_normalized": "re challenging with nivolumab in metastatic renal cell carcinoma after immune related interstitial pneumonia a case report"
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"abstract": "BACKGROUND\nSurgical stress and pain are potential provoking factors for postoperative myasthenic crisis (POMC). We report the occurrence of early POMC and late deep vein thrombosis (DVT) in a man with myasthenia gravis (MG) undergoing thymectomy, addressing possible link between reversal of opioid overdose with naloxone and the triggering of POMC.\nA 71-year-old man with impaired renal function (ie, estimated glomerular filtration rate [egfr]: 49.1 mL/min/1.73 m) with diagnosis of MG made 2 months ago was scheduled for thymectomy. After uncomplicated surgery, he experienced opioid overdose that was treated with naloxone. Hyperlactatemia then developed with a concomitant episode of hypertension. Three hours after reversal, he suffered from myasthenic crisis presenting with respiratory failure and difficult weaning from mechanical ventilation.\n\n\nMETHODS\nStress-induced hyperlactatemia and subsequent myasthenic crisis INTERVENTIONS:: Pyridostigmine and immunosuppressive therapy with prednisolone were initiated. Hyperlactatemia subsided on postoperative day (POD) 5. Tracheal extubation was performed successfully on POD 6.\n\n\nRESULTS\nDuring the course of hospitalization, his eGFR (ie, 88.9 mL/min/1.73 m) was found to improve postoperatively. After discharge from hospital, he developed DVT in the left femoral and popliteal veins on POD 24 when he was readmitted for immediate treatment with low-molecular-weight heparin. He was discharged without sequelae on POD 31. There was no recurrence of myasthenic crisis or DVT at 3-month follow-up.\n\n\nCONCLUSIONS\nFollowing naloxone administration, hyperlactatemia may be an indicator of pain-related stress response, which is a potential provoking factor for myasthenic crisis. Additionally, patients with MG may have an increased risk of DVT possibly attributable to immune-mediated inflammation. These findings highlight the importance of perioperative avoidance of provoking factors including monitoring of stress-induced elevations in serum lactate concentration, close postoperative surveying for myasthenic crisis, and early recognition of possible thromboembolic complications in this patient population.",
"affiliations": "Department of Anesthesiology, Chi Mei Medical Center, Tainan.;Department of Anesthesiology, Chi Mei Medical Center, Tainan.;Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine.;Department of Emergency Medicine, E-Da Hospital.;Department of Anesthesiology, Chi Mei Medical Center, Tainan.;Department of Anesthesiology, Chi Mei Medical Center, Tainan.;Department of Anesthesiology, Chi Mei Medical Center, Tainan.;Department of Anesthesiology, Chi Mei Medical Center, Tainan.;Department of Anesthesiology, Chi Mei Medical Center, Tainan.;Department of Emergency Medicine, E-Da Hospital.;Department of Anesthesiology, Chi Mei Medical Center, Tainan.",
"authors": "Lin|Cheng-Yuan|CY|;Liu|Wei-Cheng|WC|;Chiang|Min-Hsien|MH|;Tsai|I-Ting|IT|;Chen|Jen-Yin|JY|;Cheng|Wan-Jung|WJ|;Ho|Chun-Ning|CN|;Liao|Shu-Wei|SW|;Chu|Chin-Chen|CC|;Sun|Cheuk-Kwan|CK|;Hung|Kuo-Chuan|KC|",
"chemical_list": "D000925:Anticoagulants; D002800:Cholinesterase Inhibitors; D006495:Heparin, Low-Molecular-Weight; D007166:Immunosuppressive Agents; D009292:Narcotic Antagonists; D009270:Naloxone; D011239:Prednisolone; D011729:Pyridostigmine Bromide",
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"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32282741\nMD-D-19-06865\n10.1097/MD.0000000000019781\n19781\n7100\nResearch Article\nClinical Case Report\nMyasthenic crisis and late deep vein thrombosis following thymectomy in a patient with myasthenia gravis\nA case reportLin Cheng-Yuan MDa Liu Wei-Cheng MDa Chiang Min-Hsien MDb Tsai I-Ting MDcd Chen Jen-Yin MD, PhDae Cheng Wan-Jung MDa Ho Chun-Ning MDa Liao Shu-Wei MDa Chu Chin-Chen MD, PhDa Sun Cheuk-Kwan MD, PhDcd∗ Hung Kuo-Chuan MDa∗ NA. \na Department of Anesthesiology, Chi Mei Medical Center, Tainan\n\nb Department of Anesthesiology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine\n\nc Department of Emergency Medicine, E-Da Hospital\n\nd College of Medicine, I-Shou University, Kaohsiung,\n\ne Department of the Senior Citizen Service Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan.\n∗ Correspondence: Kuo-Chuan Hung, Department of Anesthesiology, Chi Mei Medical Center, No.901, Chung-Hwa Road, Yung-Kung Dist, Tainan County 71004, Taiwan, R.O.C (e-mail: ed102605@gmail.com); Cheuk-Kwan Sun, Department of Emergency Medicine, E-Da Hospital Kaohsiung, College of Medicine, I-Shou University, Kaohsiung, Taiwan. (e-mail: lawrence.c.k.sun@gmail.com).\n4 2020 \n10 4 2020 \n99 15 e1978102 9 2019 17 1 2020 04 3 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nSurgical stress and pain are potential provoking factors for postoperative myasthenic crisis (POMC). We report the occurrence of early POMC and late deep vein thrombosis (DVT) in a man with myasthenia gravis (MG) undergoing thymectomy, addressing possible link between reversal of opioid overdose with naloxone and the triggering of POMC.\n\nPatient concerns:\nA 71-year-old man with impaired renal function (ie, estimated glomerular filtration rate [egfr]: 49.1 mL/min/1.73 m2) with diagnosis of MG made 2 months ago was scheduled for thymectomy. After uncomplicated surgery, he experienced opioid overdose that was treated with naloxone. Hyperlactatemia then developed with a concomitant episode of hypertension. Three hours after reversal, he suffered from myasthenic crisis presenting with respiratory failure and difficult weaning from mechanical ventilation.\n\nDiagnosis:\nStress-induced hyperlactatemia and subsequent myasthenic crisis\n\nInterventions:\nPyridostigmine and immunosuppressive therapy with prednisolone were initiated. Hyperlactatemia subsided on postoperative day (POD) 5. Tracheal extubation was performed successfully on POD 6.\n\nOutcomes:\nDuring the course of hospitalization, his eGFR (ie, 88.9 mL/min/1.73 m2) was found to improve postoperatively. After discharge from hospital, he developed DVT in the left femoral and popliteal veins on POD 24 when he was readmitted for immediate treatment with low-molecular-weight heparin. He was discharged without sequelae on POD 31. There was no recurrence of myasthenic crisis or DVT at 3-month follow-up.\n\nConclusions:\nFollowing naloxone administration, hyperlactatemia may be an indicator of pain-related stress response, which is a potential provoking factor for myasthenic crisis. Additionally, patients with MG may have an increased risk of DVT possibly attributable to immune-mediated inflammation. These findings highlight the importance of perioperative avoidance of provoking factors including monitoring of stress-induced elevations in serum lactate concentration, close postoperative surveying for myasthenic crisis, and early recognition of possible thromboembolic complications in this patient population.\n\nKeywords\ndeep vein thrombosishyperlactatemiamyasthenia gravismyasthenic crisisthymectomyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nMyasthenia gravis (MG), an autoimmune antibody-mediated disease that affects the neuromuscular junction, is characterized by fluctuating weakness of voluntary muscles, in particular the extraocular, bulbar, and proximal limb muscles.[1] It is considered to be a rare disease with an overall incidence rate of about 0.01 per 1,000 persons/yr in the United States.[1] Although thymectomy is the first-line therapy for thymomatous MG patients,23 various medications, surgical stress, and anesthetic agents may trigger postoperative myasthenic crisis (POMC) after this procedure.45 We reported the occurrence of POMC in a man who developed hyperlactatemia after naloxone administration for opioid overdose. During the course of hospitalization, his renal function was found to improve after thymectomy. He also developed late deep vein thrombosis (DVT) after discharge from hospital. The associations among MG, DVT, and renal pathology as well as the possible link between perioperative hyperlactatemia and POMC were also discussed. Written consent was obtained from the patient.\n\n2 Case presentation\nA 71-year-old man, non-smoker (height: 155 cm; weight: 59 kg), was scheduled to receive video-assisted thoracoscopic extended thymectomy with the diagnosis of MG. Two months previously, he developed symptoms of right ptosis and progressive swallowing difficulty. Based on a positive response to edrophonium and increased titers of autoantibodies to acetylcholine receptor (19.3 nmol/L; normal < 0.2 nmol/L), he was diagnosed as having MG with severity belonging to Osserman's classification IIb (ie, generalized moderate weakness and/or bulbar dysfunction).[6] Thoracic computed tomography demonstrated glandular hyperplasia of the thymus (Fig. 1A). The patient was started on prednisolone 20 mg daily and pyridostigmine 60 mg three times daily. His past history included hypertension without evidence of previous myasthenic crisis or thromboembolic events (eg, history of lower limb swelling). The results of electrocardiography, pulmonary function test [eg, vital capacity: 93%], echocardiography (eg, left ventricular ejection fraction: 85.1%), chest radiography (Fig. 1B), and laboratory studies (eg, coagulation test) were unremarkable. On the other hand, impaired renal function [i.e., serum creatinine: 1.42 mg/dL; eGFR: 49.1 mL/min/1.73 m2] was observed after admission.\n\nFigure 1 (A) Thymic hyperplasia on thoracic computed tomography (CT) (arrow); (B) Unremarkable finding on preoperative chest radiograph, indicating unlikely non-pulmonary origin of postoperative respiratory distress. CT = computed tomography.\n\nPreoperative physical examination of the patient showed clear consciousness without respiratory distress. Vital signs included a blood pressure of 187/103 mm Hg, heart rate of 82 beats/min, and respiratory rate of 14 breaths/minute. Under real-time neuromuscular monitoring with a train-of-four (TOF) monitor (TOF-watch SX, N.V. Organon, Oss, Netherlands), anesthesia was induced with propofol (130 mg) and rocuronium (0.85 mg/kg). Following successful tracheal intubation with a double-lumen tracheal tube (Broncho-Cath; Mallinckrodt, Athlone, Ireland), general anesthesia was maintained with sevoflurane, rocuronium (total dosage: 40 mg), and a continuous infusion of remifentanil. An 18-gauge peripheral intravenous line and an arterial line were introduced. The surgical time was 4 hours 15 minutes with an estimated blood loss of 100 mL. Upon completion of surgery, sugammadex 4 mg/kg was administered to reverse neuromuscular blockade, with a maximum TOF ratio of 0.93 following reversal. Additionally, intravenous morphine 8 mg was given for postoperative analgesia. After successful extubation in the operating room and resumption of spontaneous breathing, he was transferred to the post-anesthesia care unit (PACU) for further care.\n\nDuring the immediate postoperative period, the patient was hemodynamically stable without respiratory distress. Because of surgical pain with a numeric rating scale of 5 (scale of 0–10), intravenous morphine was titrated to a total dosage of 7 mg. Forty-five minutes later, respiratory distress with drowsiness was noted. Physical examination found pinpoint pupils with a TOF ratio of 0.9. Blood gas analysis demonstrated severe hypercapnia (arterial carbon dioxide pressure: 117.7 mm Hg) and acidosis (pH: 6.996, lactate levels: 3.3 mmol/L). On suspicion of morphine overdose, intravenous naloxone was administered twice (0.08 mg each time). After 20 minutes, the patient regained consciousness and normal respiratory pattern. Subsequent blood gas analysis demonstrated hyperlactatemia (lactate levels: 6.0 mmol/L) (Fig. 2) despite improvement in arterial carbon dioxide pressure and arterial oxygen pressure after naloxone administration. Taking into account the overall clinical improvement, he was transferred to ward with spontaneous breathing and stable hemodynamics after observation for 100 minutes following initial reversal of opioid overdose.\n\nFigure 2 Change in serum lactate concentration during perioperative period with important events marked on the timeline. ICU = intensive care unit, Intraop = intraoperative period, PACU = post-anesthesia care unit.\n\nHowever, one hour after being transferred to ward (ie, three hours after naloxone administration), he was found to exhibit consciousness loss, respiratory distress, and pinpoint pupils. Intravenous naloxone 0.4 mg was given, followed by endotracheal intubation and transfer to the intensive care unit for mechanical ventilatory support. Brain computed tomography showed no intracranial lesion. He regained consciousness two hours after naloxone administration in the intensive care unit without symptoms of opioid withdrawal (eg, pulmonary edema).[7] As weaning from mechanical ventilation was difficult on POD 3, a diagnosis of POMC was made.[1] Steroid therapy (prednisolone 40 mg twice daily) and pyridostigmine (60 mg 3 times a day) was initiated. The patient was extubated smoothly on POD 6 and was discharged from hospital on POD 12. The course of hyperlactatemia was shown in Figure 2. In addition, his eGFR increased from 49.1 mL/min/1.73 m2 at baseline to 88.9 ml/min/1.73m2 on POD 5. Pathological analysis of the specimen from thymectomy confirmed the diagnosis of type B2 thymoma according to the World Health Organization (WHO) classification.[8]\n\n\nThe patient was readmitted on POD 24 because of left thigh swelling. Ultrasonographic examination showed evidence of DVT involving the left femoral and popliteal veins. Anticoagulant therapy with low-molecular-weight heparin (ie, subcutaneous Clexane 60 mg every 12 hours) was implemented immediately after hospitalization, and he was discharged without sequelae on POD 31. During hospitalization, his eGFR was 86.5 mL/min/1.73m2. There was no recurrence of myasthenic crisis or DVT up to 3 months of follow-ups.\n\n3 Discussion\nOwing to the reduced number of functioning nicotinic acetylcholine receptors, even small amounts of nondepolarizing neuromuscular blocking agents can lead to profound neuromuscular blockade in patients with MG.[9] Reversal of neuromuscular blockade in patients with MG by sugammadex has been reported to result in rapid and complete recovery of neuromuscular function without signs of postoperative residual neuromuscular blockade.[9] In our patient with respiratory distress in the PACU, postoperative recurrence of neuromuscular blockade (ie, recurarization) was unlikely based on a TOF ratio of 0.9. The diagnosis of opioid overdose was made based on the typical clinical symptoms and signs (ie, pinpoint pupils, respiratory distress, drowsiness) as well as symptom improvement after naloxone administration. Since the serum half-life of naloxone is approximately 60 minutes,[7] surgical patients receiving naloxone for reversal of opioid overdose is recommended to be observed for 90 minutes.[7] Although our patient did not develop renarcosis in the PACU after observation for 100 minutes, it occurred about 3 hours after initial reversal. Patients with MG have been reported to demonstrate enhanced sensitivity to opioid,410 which may at least partially explain the delayed renarcosis after initial reversal in our patient.\n\nMG is a disease of young women and old men with an overall mortality rate of 2.2%.[1] Myasthenic crisis, which occurs in approximately 15% to 20% of MG patients within the first 2 years of the diagnosis[11] with a mortality rate of 4% to 4.47%,112 is characterized by respiratory failure requiring invasive or noninvasive mechanical ventilation.[1] Old age and respiratory failure requiring tracheal intubation were identified as predictors of mortality.[1] Of all patients with MG undergoing thymectomy, 10% to 11.5% may experience POMC and require intubation with a median duration of intubation up to 9 days (range: 2–28 days).1314 Several predisposing factors were identified for the occurrence of POMC, including preoperative bulbar symptoms, intraoperative blood loss >1000 mL, preoperative serum level of anti-acetylcholine receptor antibody >100 nmol/L,[14] and WHO histologic classification B2–B3 thymoma.[13] Accordingly, the risk factors for POMC in our patient included the presence of preoperative bulbar symptoms and WHO histologic thymoma grading of B2.\n\nA previous study developed a clinical score for the prediction of POMC after taking into account MG-associated compromise of respiratory function, disease duration, and extent of muscle involvement.[15] The clinical predictive score, which included vital capacity <80% (yes = 3, no = 0), disease duration <3 months (yes = 2, no = 0), and bulbar symptoms immediately before thymectomy (yes = 1, no = 0), yields a total score ranging from 0 to 6.[15] The probability of postoperative crisis was 0.9% and 25.9% for low (less than 3) and high (3 or more) score groups, respectively. According to this scoring system, the risk score of our patient was 3, indicating a high risk of myasthenia crisis.\n\nThe occurrence of respiratory failure 3 hours after opioid reversal could be attributed to the development of concomitant renarcosis and of POMC in our patient. As stress (ie, surgery) and pain are known potential triggers for POMC,510 we titrated the lowest effective dose of naloxone (ie, total dosage of 0.16 mg) to minimize the risk of opioid withdrawal. Despite the precautions taken, reversal of morphine-associated analgesia may cause pain-induced stress. Interestingly, we found the development of hyperlactatemia, which subsided on POD 5 (lactate levels: 2 mmol/L), after initial reversal (Fig. 2). Previous studies have shown that hyperlactatemia can result from a stress response because stress-induced sympathetic nervous activation and increase in metabolic rate may contribute to accelerated glycolysis and an altered energy utilization.1617 As there was no intraoperative hemodynamic instability to explain the possible development of ischemic hyperlactatemia, stress hyperlactatemia after initial reversal could be the diagnosis in our patient. Therefore, care should be taken when naloxone is used for opioid reversal in patients with MG undergoing thymectomy because the resulting stress, as reflected by an elevated serum lactate level, may trigger POMC. Nevertheless, the predictive value of hyperlactatemia for POMC in this patient population remains to be elucidated.\n\nDVT occurred in our patient on POD 24. In general, stasis of blood flow, hypercoagulable state, and vascular endothelial cell damage are the major factors that predispose to DVT (ie, “Virchow's triad”).[18] The risk factors for DVT have been reported to be setting-related (eg, major general surgery and trauma) and patient-related (eg, old age and malignancy).1920 In our patient, the predisposing factors for DVT included old age and recent surgery.1920 In addition, recent evidence suggests that immune-mediated diseases may play a role in DVT occurrence,2122 probably due to inflammation-induced activation of proinflammatory cytokines and adhesion molecules as well as elevation of clotting factor levels that contribute to the development of venous thromboembolism.2324 Indeed, a previous large-scale study demonstrated that there were increased risks of DVT in patients with immune-mediated diseases.[21] In concert with this finding, a case study proposed that MG-related endothelial injury may be responsible for the development of DVT and the life-threatening pulmonary embolism.[22] Our report may further support an increased risk of DVT in patients with immune-mediated diseases. Therefore, anticoagulation therapy and constant monitoring for venous thrombosis disease may be considered for patients with MG even after thymectomy because it may take up to 5 years postoperatively to achieve a stable remission of the symptoms and signs of MG.[25] Considering the risk of thromboembolism, pulmonary embolism[22] should be included on the list of differential diagnoses other than myasthenic crisis on encountering a patient with a known diagnosis of MG who presents with respiratory distress.\n\nAnother interesting finding in our patient was that his eGFR improved from 49.1 mL/min/1.73m2 at baseline to 88.9 mL/min/1.73m2 as soon as POD 5 and remained stable on POD 26 (86.5 mL/min/1.73 m2). Although the reasons remain unclear, MG is known to be associated with various immunological diseases including glomerulonephritis.2627 Additionally, the presence of thymoma may also be related to minimal change nephrotic syndrome.[28] An isolated case report also demonstrated improvement in renal function at a 4-month follow-up after thymectomy in a patient with concomitant MG and membranous nephropathy.[29] The authors[29] suggested a possible role of MG-mediated impairment of cellular immunity or the presence of anti- acetylcholine receptor autoantibodies antibodies in the pathogenesis of glomerulonephritis. Therefore, whether the prompt improvement in renal function shortly after surgery in our patient reflects a rectification of MG-associated anomalies in cellular and humoral immunity remains to be elucidated.\n\nA previous study reported that patients with POMC had a worse prognosis compared with that in those without,[30] highlighting the need for appropriate perioperative management for patients with MG to prevent the occurrence of POMC. In addition to avoiding the provoking factors (eg, β-blockers and nondepolarizing neuromuscular blocking agents),[5] various anesthetic approaches have been reported to impact on postoperative outcomes in MG patients.[31] For instance, patients receiving a combined anesthetic technique (ie, combined general and epidural analgesia) were found to have a lower incidence of postoperative ventilatory support than that in those undergoing balanced anesthesia after thymectomy.[31] Several uncontrolled randomized clinical trials suggested that preoperative intravenous immunoglobulin may be beneficial to patients scheduled for thymectomy to prevent POMC,3233 but this benefit was not found in another randomized control study.[34]\n\n\n4 Conclusion\nMyasthenic crisis and DVT are potential complications in patients with MG following thymectomy, underscoring the importance of avoiding intraoperative provoking factors and meticulous postoperative monitoring for early detection of myasthenic crisis to prevent life-threatening events as well as continual outpatient follow-up for possible thromboembolic complications. Hyperlactatemia may be a perioperative indicator of stress related to the triggering of myasthenic crisis.\n\nAuthor contributions\n\nConceptualization: Cheng-Yuan Lin, Min-Hsien Chiang, Jen-Yin Chen, Cheuk-Kwan Sun, Kuo-Chuan Hung.\n\n\nData curation: Wei-Cheng Liu, Wan-Jung Cheng.\n\n\nFormal analysis: I-Ting Tsai, Shao-Chun Wu, Kuo-Chuan Hung.\n\n\nInvestigation: Jen-Yin Chen, Chin-Chen Chu, Cheuk-Kwan Sun.\n\n\nMethodology: I-Ting Tsai, Shu-Wei Liao, Chin-Chen Chu.\n\n\nWriting – original draft: Cheng-Yuan Lin, Wei-Cheng Liu, Cheuk-Kwan Sun, Kuo-Chuan Hung.\n\n\nWriting – review and editing: Cheuk-Kwan Sun, Kuo-Chuan Hung.\n\nAbbreviations: DVT = deep vein thrombosis, eGFR = estimated glomerular filtration rate, MG = myasthenia gravis, PACU = post-anesthesia care unit, POD = postoperative day, POMC= postoperative myasthenic crisis, TOF = train-of-four, WHO = World Health Organization.\n\nHow to cite this article: Lin CY, Liu WC, Chiang MH, Tsai IT, Chen JY, Cheng WJ, Ho CN, Liao SW, Chu CC, Sun CK, Hung KC. Myasthenic crisis and late deep vein thrombosis following thymectomy in a patient with myasthenia gravis: a case report. Medicine. 2020;99:15(e19781).\n\nCYL and WCL signifies equal contribution to this work compared to the first author, ∗signifies equal contribution compared to the corresponding author\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] \nAlshekhlee A Miles J Katirji B \nIncidence and mortality rates of myasthenia gravis and myasthenic crisis in US hospitals\n. Neurology \n2009 ;72 :1548 –54\n.19414721 \n[2] \nYu L Zhang XJ Ma S \nThoracoscopic thymectomy for myasthenia gravis with and without thymoma: a single-center experience\n. Ann Thorac Surg \n2012 ;93 :240 –4\n.21978875 \n[3] \nWolfe GI Kaminski HJ Aban IB \nRandomized trial of thymectomy in myasthenia gravis\n. N Engl J Med \n2016 ;375 :511 –22\n.27509100 \n[4] \nAdams SL Mathews J Grammer LC \nDrugs that may exacerbate myasthenia gravis\n. Ann Emerg Med \n1984 ;13 :532 –8\n.6742556 \n[5] \nBershad E Feen E Suarez J \nMyasthenia gravis crisis\n. South Med J \n2008 ;101 :63 .18176295 \n[6] \nOsserman KE Genkins G \nStudies in myasthenia gravis: review of a twenty-year experience in over 1200 patients\n. Mt Sinai J Med \n1971 ;38 :497 –537\n.4941403 \n[7] \nRzasa Lynn R Galinkin J \nNaloxone dosage for opioid reversal: current evidence and clinical implications\n. Ther Adv Drug Saf \n2018 ;9 :63 –88\n.29318006 \n[8] \nDadmanesh F Sekihara T Rosai J \nHistologic typing of thymoma according to the new World Health Organization classification\n. Chest Surg Clin N Am \n2001 ;11 :407 –20\n.11413764 \n[9] \nde Boer HD Shields MO Booij LH \nReversal of neuromuscular blockade with sugammadex in patients with myasthenia gravis: a case series of 21 patients and review of the literature\n. Eur J Anaesthesiol \n2014 ;31 :715 –21\n.25192270 \n[10] \nOzcan J Balson IF Dennis AT \nNew diagnosis myasthenia gravis and preeclampsia in late pregnancy\n. BMJ Case Rep \n2015 ;2015 :bcr2014208323 .\n[11] \nBedlack RS Sanders DB \nOn the concept of myasthenic crisis\n. J Clin Neuromuscul Dis \n2002 ;4 :40 –2\n.19078687 \n[12] \nThomas CE Mayer SA Gungor Y \nMyasthenic crisis: clinical features, mortality, complications, and risk factors for prolonged intubation\n. Neurology \n1997 ;48 :1253 –60\n.9153452 \n[13] \nXue L Wang L Dong J \nRisk factors of myasthenic crisis after thymectomy for thymoma patients with myasthenia gravis\n. Eur J Cardiothorac Surg \n2017 ;52 :692 –7\n.29156018 \n[14] \nWatanabe A Watanabe T Obama T \nPrognostic factors for myasthenic crisis after transsternal thymectomy in patients with myasthenia gravis\n. J Thorac Cardiovasc Surg \n2004 ;127 :868 –76\n.15001919 \n[15] \nKanai T Uzawa A Sato Y \nA clinical predictive score for postoperative myasthenic crisis\n. Ann Neurol \n2017 ;82 :841 –9\n.29083502 \n[16] \nGarcia-Alvarez M Marik P Bellomo R \nStress hyperlactataemia: present understanding and controversy\n. Lancet Diabetes Endocrinol \n2014 ;2 :339 –47\n.24703052 \n[17] \nMizock BA \nSignificance of hyperlactatemia without acidosis during hypermetabolic stress\n. Crit Care Med \n1997 ;25 :1780 –1\n.9366754 \n[18] \nAnning S \nThe historical aspects of venous thrombosis\n. Med Hist \n1957 ;1 :28 –37\n.13399502 \n[19] \nMembers ATF Torbicki A Perrier A \nGuidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC)\n. Eur Heart J \n2008 ;29 :2276 –315\n.18757870 \n[20] \nAnderson FA JrSpencer FA \nRisk factors for venous thromboembolism\n. Circulation \n2003 ;107 :I9 –16\n.12814980 \n[21] \nRamagopalan SV Wotton CJ Handel AE \nRisk of venous thromboembolism in people admitted to hospital with selected immune-mediated diseases: record-linkage study\n. BMC Med \n2011 ;9 :1 .21219637 \n[22] \nLin S Wang Y Guan W \nPulmonary embolism caused by myasthenia gravis: a case report\n. Medicine (Baltimore) \n2018 ;97 :e13578 .30544480 \n[23] \nFox EA Kahn SR \nThe relationship between inflammation and venous thrombosis\n. Thromb Haemost \n2005 ;94 :362 –5\n.16113826 \n[24] \nLevi M van der Poll T Büller HR \nBidirectional relation between inflammation and coagulation\n. Circulation \n2004 ;109 :2698 –704\n.15184294 \n[25] \nChen Z Luo H Peng Y \nComparative clinical features and immune responses after extended thymectomy for myasthenia gravis in patients with atrophic versus hyperplastic thymus\n. Ann Thorac Surg \n2011 ;91 :212 –8\n.21172515 \n[26] \nTomida C Yamagata K Ishizu T \nA case of nephrotic syndrome associated with myasthenia gravis and malignant thymoma\n. Nihon Jinzo Gakkai Shi \n1999 ;41 :77 –82\n.10361423 \n[27] \nValli G Fogazzi GB Cappellari A \nGlomerulonephritis associated with myasthenia gravis\n. Am J Kidney Dis \n1998 ;31 :350 –5\n.9469510 \n[28] \nLong Q Wu P Jiang G \nMinimal change nephrotic syndrome associated with invasive thymoma: a case report with literature review\n. Clin Nephrol \n2014 ;81 :296 –301\n.23211340 \n[29] \nMatsuda M Miki J Tabata K-i \nMyasthenia gravis with membranous nephropathy, successfully treated with extended total thymectomy\n. Intern Med \n2000 ;39 :490 –4\n.10852171 \n[30] \nLi Y Wang H Chen P \nClinical outcome and predictive factors of postoperative myasthenic crisis in 173 thymomatous myasthenia gravis patients\n. Int J Neurosci \n2018 ;128 :103 –9\n.28803488 \n[31] \nChevalley C Spiliopoulos A de Perrot M \nPerioperative medical management and outcome following thymectomy for myasthenia gravis\n. Can J Anaesth \n2001 ;48 :446 –51\n.11394511 \n[32] \nHuang CS Hsu HS Kao KP \nIntravenous immunoglobulin in the preparation of thymectomy for myasthenia gravis\n. Acta Neurol Scand \n2003 ;108 :136 –8\n.12859292 \n[33] \nAlipour-Faz A Shojaei M Peyvandi H \nA comparison between IVIG and plasma exchange as preparations before thymectomy in myasthenia gravis patients\n. Acta Neurol Belg \n2017 ;117 :245 –9\n.27530310 \n[34] \nGamez J Salvadó M Carmona F \nIntravenous immunoglobulin to prevent myasthenic crisis after thymectomy and other procedures can be omitted in patients with well-controlled myasthenia gravis\n. Ther Adv Neurol Disord \n2019 ;12 :1756286419864497 .31360225\n\n",
"fulltext_license": "CC BY",
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"issue": "99(15)",
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"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D002800:Cholinesterase Inhibitors; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D065906:Hyperlactatemia; D006973:Hypertension; D007166:Immunosuppressive Agents; D008297:Male; D009157:Myasthenia Gravis; D009270:Naloxone; D009292:Narcotic Antagonists; D009293:Opioid-Related Disorders; D010359:Patient Readmission; D011183:Postoperative Complications; D011239:Prednisolone; D011729:Pyridostigmine Bromide; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency; D013934:Thymectomy; D016896:Treatment Outcome; D020246:Venous Thrombosis",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Myasthenic crisis and late deep vein thrombosis following thymectomy in a patient with myasthenia gravis: A case report.",
"title_normalized": "myasthenic crisis and late deep vein thrombosis following thymectomy in a patient with myasthenia gravis a case report"
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"abstract": "Expectant management and medical treatment of ectopic pregnancy either systemically or locally are reviewed. Because of the risks of tubal rupture, this nonsurgical management should be done with utmost care. To date, surgical removal of an ectopic pregnancy remains the method of choice and this can be safely done by laparoscopy. Alternate treatments should be carefully evaluated in clinical trials.",
"affiliations": "Department of Obstetrics and Gynecology, McGill University, Montreal, Quebec, Canada.",
"authors": "Tulandi|T|T|",
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"medline_ta": "Int J Gynaecol Obstet",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000284:Administration, Oral; D006063:Chorionic Gonadotropin; D003613:Danazol; D015232:Dinoprostone; D004359:Drug Therapy, Combination; D005260:Female; D005947:Glucose; D006801:Humans; D015552:Injections, Intralesional; D007273:Injections, Intramuscular; D010535:Laparoscopy; D008727:Methotrexate; D015735:Mifepristone; D011189:Potassium Chloride; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D014621:Vagina",
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"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Nonsurgical treatment of ectopic pregnancy.",
"title_normalized": "nonsurgical treatment of ectopic pregnancy"
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"abstract": "Elderly patients with stage III non-small-cell lung cancer (NSCLC) are frequently underrepresented in clinical trials that evaluate chemoradiotherapy, due to their poor functional status, coexisting illnesses and limited life expectancy. The Japan Clinical Oncology Group 0301 trial (JCOG0301) was the first study to demonstrate that thoracic radiation therapy (TRT) with daily low-dose carboplatin may improve the outcome of elderly patients with stage III NSCLC. However, the efficacy and safety profiles of chemoradiotherapy, including platinum doublets, have not been clearly determined in this patient population. We retrospectively assessed the efficacy and toxicity of weekly paclitaxel in combination with carboplatin and concurrent TRT in patients aged ≥75 years with previously untreated locally advanced NSCLC. Between February, 2004 and July, 2013, we collected the data of 20 patients treated with weekly paclitaxel and carboplatin for 6 weeks and concurrent TRT. The objective response rate was 90%, the disease control rate was 95%, the median progression-free survival was 8.63 months [95% confidence interval (CI): 5.7-16.7] and the median overall survival (OS) was 16.1 months (95% CI: 10.7-41.6). There were no grade 4 hematological or non-hematological toxicities and no reported treatment-related deaths. Therefore, platinum doublet therapy in combination with TRT did not provide a clinically significant survival benefit in our population of elderly patients with locally advanced NSCLC. However, the present study demonstrated the good feasibility and safety of this regimen. Further prospective clinical trials are required to evaluate the efficacy and safety of platinum doublet with TRT in elderly patients.",
"affiliations": "Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Department of Respiratory Medicine, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Division of Radiation Oncology, Institute of Biomedical Research and Innovation, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Division of Radiation Oncology, Institute of Biomedical Research and Innovation, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;;Department of Radiation Oncology, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe City Medical Center General Hospital, Kobe, Hyogo, Japan ;",
"authors": "Takeshita|Jumpei|J|;Masago|Katsuhiro|K|;Fujita|Shiro|S|;Hata|Akito|A|;Kaji|Reiko|R|;Kawamura|Takahisa|T|;Tamai|Koji|K|;Matsumoto|Takeshi|T|;Nagata|Kazuma|K|;Otsuka|Kyoko|K|;Nakagawa|Atsushi|A|;Otsuka|Kojiro|K|;Tomii|Keisuke|K|;Shintani|Takashi|T|;Takayama|Kenji|K|;Kokubo|Masaki|M|;Katakami|Nobuyuki|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2014.249",
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"issn_linking": "2049-9450",
"issue": "2(3)",
"journal": "Molecular and clinical oncology",
"keywords": "chemoradiotherapy; elderly patient; locally advanced non-small cell lung cancer; paclitaxel; platinum doublet",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "454-460",
"pmc": null,
"pmid": "24772317",
"pubdate": "2014-05",
"publication_types": "D016428:Journal Article",
"references": "19097774;22622008;10023700;10561343;1710541;15800308;16157935;15205196;10669675;16500915;11815975;23335087;20625120;7165009;17762336;22156624;10615079;10788684;16192578;8780630;21903745;12874270;11165402;12697878;16968876;18718891",
"title": "Weekly administration of paclitaxel and carboplatin with concurrent thoracic radiation in previously untreated elderly patients with locally advanced non-small-cell lung cancer: A case series of 20 patients.",
"title_normalized": "weekly administration of paclitaxel and carboplatin with concurrent thoracic radiation in previously untreated elderly patients with locally advanced non small cell lung cancer a case series of 20 patients"
} | [
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"companynumb": "JP-CIPLA LTD.-2016JP17242",
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"activesubstancename": "CARBOPLATIN"
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{
"abstract": "Pseudocellulitis has been previously described with the use of chemotherapy agent gemcitabine. This condition is thought to occur due to vascular toxicity and increased localized permeability of the skin capillaries. We report herein a case of recurrent pseudocellulitis due to gemcitabine in a patient with metastatic pancreatic cancer. We believe this condition is underreported and underrecognized. Furthermore, it may be misdiagnosed as cellulitis and inappropriately treated with systemic antibiotics. As the diagnosis is clinical and the condition is self-limited, referral to other specialists is usually not required. Awareness of gemcitabine-induced pseudocellulitis is important in order to reassure the patients, their families, and non-oncology providers and to avoid unnecessary (and often costly) diagnostic work-up.",
"affiliations": "Department of Hematology-Oncology, St. Francis Hospital and Medical Center, Hartford, CT, USA c_dasanu@yahoo.com.;Department of Internal Medicine, University of Connecticut Health Center, Farmington, CT, USA.",
"authors": "Dasanu|Constantin A|CA|;Bockorny|Bruno|B|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.1177/1078155214531610",
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"issn_linking": "1078-1552",
"issue": "21(5)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Pseudocellulitis; chemotherapy; gemcitabine; skin toxicity",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D002481:Cellulitis; D003841:Deoxycytidine; D006801:Humans; D008297:Male; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms; D012008:Recurrence",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "377-9",
"pmc": null,
"pmid": "24769519",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent pseudocellulitis due to gemcitabine: underrecognized and underreported?",
"title_normalized": "recurrent pseudocellulitis due to gemcitabine underrecognized and underreported"
} | [
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"companynumb": "US-CIPLA LTD.-2015US05481",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
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{
"abstract": "BACKGROUND\nIn the CALGB (Alliance) 100104 study, lenalidomide versus placebo after autologous stem-cell transplantation (ASCT) was investigated for patients with newly diagnosed myeloma. That study showed improved time to progression and overall survival and an increase in second primary malignancies for lenalidomide at a median follow-up of 34 months. Here we report an updated intention-to-treat analysis of CALGB (Alliance) 100104 at a median follow-up of 91 months.\n\n\nMETHODS\nPatients were eligible for this randomised, double-blind, placebo-controlled, phase 3 trial if they had symptomatic disease requiring treatment; had received, at most, two induction regimens; and had achieved stable disease or better in the first 100 days after ASCT. We randomly assigned patients to either lenalidomide or placebo groups using permuted block randomisation, with a fixed block size of six. Randomisation was stratified by three factors: normal or elevated β2 microglobulin concentration at registration (≤2·5 mg/L vs >2·5 mg/L), previous use or non-use of thalidomide during induction therapy, and previous use or non-use of lenalidomide during induction therapy. The starting dose was two capsules (10 mg) per day, escalated to three capsules (15 mg) per day after 3 months. The primary endpoint was time to progression (time of progressive disease or death from any cause), with intention-to-treat analysis. This study is registered with ClinicalTrials.gov, identifier NCT00114101. New patients are no longer being recruited, but some patients remain on treatment and in follow-up.\n\n\nRESULTS\nBetween April 14, 2005, and July 2, 2009, 460 patients were randomly assigned to receive either lenalidomide (n=231) or placebo (n=229). After three interim analyses, the study was unblinded at a median follow-up of 18 months, at which point 86 (67%) of 128 patients without progressive disease in the placebo group chose to cross over to the lenalidomide group. The median follow-up for the updated survival analysis, as of Oct 19, 2016, was 91 months (IQR 83·6-103·1). The median time to progression was 57·3 months (95% CI 44·2-73·3) for the lenalidomide group and 28·9 months (23·0-36·3) for the placebo group (hazard ratio 0·57, 95% CI 0·46-0·71; p<0·0001). The most common grade 3-4 adverse events were neutropenia (116 [50%] patients in the lenalidomide group and 41 [18%] patients in the placebo group) and thrombocytopenia (34 [15%] patients in the lenalidomide group and 12 [5%] patients in the placebo group). 18 (8%) haematological and 14 (6%) solid tumour second primary malignancies were diagnosed after randomisation and before disease progression in the lenalidomide group, compared with three (1%) haematological and nine (4%) solid tumour second primary malignancies in the placebo group. Three haematological and five solid tumour second primary malignancies in the placebo group were in the crossover subgroup.\n\n\nCONCLUSIONS\nDespite an increase in haematological adverse events and second primary malignancies, lenalidomide maintenance therapy after ASCT significantly improved time to progression and could be considered a standard of care.\n\n\nBACKGROUND\nThe National Cancer Institute.",
"affiliations": "University of Nebraska Medical Center, Omaha, NE, USA.;Alliance Statistics and Data Center, Duke University, Durham, NC, USA.;Dana-Farber/Partners CancerCare, Boston, MA, USA.;The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;University of Pennsylvania, Philadelphia, PA, USA.;University of Minnesota, Minneapolis, MN, USA.;Washington University School of Medicine, St Louis, MO, USA.;University of Florida Health, Gainesville, FL, USA.;University of Wisconsin, Madison, WI, USA.;Weill Medical College of Cornell University, New York, NY, USA.;State University of New York Upstate Medical University, Syracuse, NY, USA.;Mount Sinai School of Medicine, New York, NY, USA.;Oregon Health and Science University, Portland, OR, USA.;Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;University of California at San Francisco, San Francisco, CA, USA.;MD Anderson Cancer Center, Houston, TX, USA.;Wake Forest Baptist Medical Center, Winston-Salem, NC, USA.;University of Minnesota, Minneapolis, MN, USA.;Dana-Farber/Partners CancerCare, Boston, MA, USA.;Alliance for Clinical Trials in Oncology, Chicago, IL, USA; Loyola University, Chicago, IL, USA.;Alliance Statistics and Data Center, Duke University, Durham, NC, USA.;Alliance Statistics and Data Center, Duke University, Durham, NC, USA.;Alliance Statistics and Data Center, Duke University, Durham, NC, USA.;Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.;Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.;Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.;Medical College of Wisconsin, Milwaukee, WI, USA.;Medical College of Wisconsin, Milwaukee, WI, USA.;Medical College of Wisconsin, Milwaukee, WI, USA; Blood and Marrow Transplant Clinical Trials Network, Rockville, MD, USA.;UNC Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.;The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.;University of California at San Francisco, San Francisco, CA, USA.;Dana-Farber/Partners CancerCare, Boston, MA, USA.;Roswell Park Cancer Institute, Buffalo, NY, USA. Electronic address: philip.mccarthy@roswellpark.org.",
"authors": "Holstein|Sarah A|SA|;Jung|Sin-Ho|SH|;Richardson|Paul G|PG|;Hofmeister|Craig C|CC|;Hurd|David D|DD|;Hassoun|Hani|H|;Giralt|Sergio|S|;Stadtmauer|Edward A|EA|;Weisdorf|Daniel J|DJ|;Vij|Ravi|R|;Moreb|Jan S|JS|;Callander|Natalie S|NS|;van Besien|Koen|K|;Gentile|Teresa G|TG|;Isola|Luis|L|;Maziarz|Richard T|RT|;Bashey|Asad|A|;Landau|Heather|H|;Martin|Thomas|T|;Qazilbash|Muzaffar H|MH|;Rodriguez|Cesar|C|;McClune|Brian|B|;Schlossman|Robert L|RL|;Smith|Scott E|SE|;Hars|Vera|V|;Owzar|Kouros|K|;Jiang|Chen|C|;Boyd|Molly|M|;Schultz|Chelsea|C|;Wilson|Marcia|M|;Hari|Parameswaran|P|;Pasquini|Marcelo C|MC|;Horowitz|Mary M|MM|;Shea|Thomas C|TC|;Devine|Steven M|SM|;Linker|Charles|C|;Anderson|Kenneth C|KC|;McCarthy|Philip L|PL|",
"chemical_list": "D010919:Placebos; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1016/S2352-3026(17)30140-0",
"fulltext": "\n==== Front\n10164358443133Lancet HaematolLancet HaematolThe Lancet. Haematology2352-30262882661610.1016/S2352-3026(17)30140-0nihpa902679ArticleUpdated analysis of CALGB 100104 (Alliance): a randomised phase III study evaluating lenalidomide vs placebo maintenance after single autologous stem cell transplant for multiple myeloma Holstein Sarah A. MDUniversity of Nebraska Medical Center, Omaha, NEJung Sin-Ho PhD*Alliance Statistics and Data Center, Duke University, Durham, NCRichardson Paul G. MD*Dana-Farber/Partners CancerCare, Boston, MAHofmeister Craig C. MDThe Ohio State University Comprehensive Cancer Center, Columbus, OHHurd David D. MD*Wake Forest Baptist Medical Center, Winston-Salem, NCHassoun Hani MDMemorial Sloan Kettering Cancer Center, New York, NYGiralt Sergio MD*Memorial Sloan Kettering Cancer Center, New York, NYStadtmauer Edward A. MD*University of Pennsylvania, Philadelphia, PAWeisdorf Daniel J. MD*University of Minnesota, Minneapolis, MNVij Ravi MBBS*Washington University School of Medicine, St. Louis, MOMoreb Jan S. MD*UF Health, University of Florida, Gainesville, FLCallander Natalie S. MDUniversity of Wisconsin, Madison, WIvan Besien Koen MD*Weill Medical College of Cornell University, New York, NYGentile Teresa G. MDState University of New York Upstate Medical University, Syracuse, NYIsola Luis MD*Mount Sinai School of Medicine, New York, NYMaziarz Richard T MD*Oregon Health & Science University, Portland, ORBashey Asad MDBlood and Marrow Transplant Program at Northside Hospital, Atlanta, GALandau Heather MDMemorial Sloan Kettering Cancer Center, New York, NYMartin Thomas MD*University of California at San Francisco, San Francisco, CAQazilbash Muzaffar H MD*MD Anderson Cancer Center, Houston, TXRodriguez Cesar MDWake Forest Baptist Medical Center, Winston-Salem, NCMcClune Brian MDUniversity of Minnesota, Minneapolis, MNSchlossman Robert L. MDDana-Farber/Partners CancerCare, Boston, MASmith Scott E. MD*Alliance for Clinical Trials in Oncology, Chicago, ILLoyola University, Chicago, ILHars Vera MScAlliance Statistics and Data Center, Duke University, Durham, NCOwzar Kouros PhD*Alliance Statistics and Data Center, Duke University, Durham, NCJiang Chen PhDAlliance Statistics and Data Center, Duke University, Durham, NCBoyd Molly Alliance Statistics and Data Center, Mayo Clinic, Rochester, MNSchultz Chelsea BSAlliance Statistics and Data Center, Mayo Clinic, Rochester, MNWilson Marcia BSMAlliance Statistics and Data Center, Mayo Clinic, Rochester, MNHari Parameswaran MD*Medical College of Wisconsin, Milwaukee, WIPasquini Marcelo C. MDMedical College of Wisconsin, Milwaukee, WIHorowitz Mary M. MD*Medical College of Wisconsin, Milwaukee, WIBlood and Marrow Transplant Clinical Trials Network, Rockville, MDShea Thomas C. MD*UNC Lineberger Cancer Center, University of North Carolina, Chapel Hill, NCDevine Steven M. MD*The Ohio State University Comprehensive Cancer Center, Columbus, OHLinker Charles MD*University of California at San Francisco, San Francisco, CAAnderson Kenneth C. MD*Dana-Farber/Partners CancerCare, Boston, MAMcCarthy Philip L. MD*Roswell Park Cancer Institute, Buffalo, NYCorrespondence: Philip L. McCarthy, Roswell Park Cancer Institute, Carlton & Elm Streets, Buffalo, NY 14263, philip.mccarthy@roswellpark.org* denotes authors who are full professors\n\n29 11 2017 17 8 2017 9 2017 01 9 2018 4 9 e431 e442 This manuscript version is made available under the CC BY-NC-ND 4.0 license.Background\nCALGB 100104 (Alliance) studied lenalidomide vs. placebo following autologous stem cell transplant (ASCT) for newly diagnosed myeloma patients, demonstrating improved time to progression (TTP) and overall survival (OS), and an increase in second primary malignancies (SPM) for lenalidomide at 34-months median follow-up. Here we report an updated intent-to-treat analysis at 91-months median follow-up.\n\nMethods\nPatients were eligible if they had active myeloma, had received at most two induction regimens and had achieved stable disease or better in the first 100 days after ASCT. In this phase 3 study, 460 patients were randomised in a double-blind manner to either lenalidomide (n=231) or placebo (n=229) utilizing a permutated-block randomisation with fixed block size. Randomisation was stratified by three factors: normal or elevated β2-microglobulin level at registration (≤2·5 mg/L vs > 2·5 mg/L), prior use or nonuse of thalidomide during induction therapy, and prior use or nonuse of lenalidomide during induction therapy. The starting dose was 10 mg daily, escalated to 15 mg daily after three months. The primary endpoint was TTP (time of progressive disease or death from any cause) using intent-to-treat analysis. After three interim analyses, the study was unblinded at median follow-up of 18 months and 86/128 placebo patients without progressive disease chose to cross over to lenalidomide. This study is registered with ClinicalTrials.gov identifier NCT00114101; new patients are no longer being recruited, but some patients remain on treatment and in follow-up.\n\nFindings\nThe median TTP for lenalidomide is 57·3 months (95% CI 44·2–73·3) and 28·9 months (95% CI 23·0–36·3) for placebo (hazard ratio (HR): 0·57, 95% CI 0·46–0·71, p<0·0001). The TTP benefit with lenalidomide was observed regardless of whether patients were in a complete response at time of randomisation or whether they had received thalidomide or lenalidomide induction therapy. The most common grade 3–4 adverse events were neutropenia (116 (50%) of 231 patients in the lenalidomide arm and 37 (16%) of 229 patients in the placebo arm) and thrombocytopenia (34 patients (15%) in the lenalidomide arm and 11 patients (4·8%) in the placebo arm. Eighteen haematological (7·8%) and 14 solid tumour (6·1%) SPMs have been diagnosed following randomisation and prior to disease progression in the lenalidomide arm vs. three haematological (1·3%) and nine solid tumour (3·9%) SPMs in the placebo arm. Of the placebo SPMs, three haematological and five of nine solid tumour SPMs were in the crossover subgroup.\n\nInterpretation\nDespite an increase in haematological adverse events and SPMs, lenalidomide maintenance therapy following ASCT significantly improves TTP and can be considered a standard of care.\n==== Body\nIntroduction\nDespite improvements in survival of newly diagnosed myeloma patients as a consequence of induction therapy with novel agents followed by consolidation with high dose melphalan and autologous stem cell transplant (ASCT), the majority of patients will suffer disease relapse/progression. There has been significant interest in the role of maintenance therapy following ASCT in order to delay disease relapse/progression and prolong survival. A number of randomised studies evaluated maintenance therapy with thalidomide, the first generation immunomodulatory agent (IMiD), following ASCT. In aggregate, while a benefit for progression-free survival (PFS) was observed, a consistent overall survival benefit has not been demonstrated and prolonged therapy with thalidomide has been limited by this agent’s side effect profile.1 Lenalidomide, the second generation IMiD, has a more favourable side-effect profile and therefore has been studied in the context of post-ASCT maintenance therapy.\n\nCancer and Leukemia Group B (CALGB) 100104, in collaboration with the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) and the Eastern Cooperative Oncology Group (ECOG) randomised 460 patients to lenalidomide or placebo maintenance following ASCT. CALGB is now part of the Alliance for Clinical Trials in Oncology. Initial publication demonstrated that lenalidomide maintenance was associated with significantly longer time to disease progression (TTP) (median TTP of 46 months for the lenalidomide group and 27 months for the placebo group, p<0·0001) as well as a significant improvement in overall survival at median follow-up of 34 months.2 Eight percent of patients in the lenalidomide group developed second primary malignancies (SPMs) before disease progression compared with three percent in the placebo group. Three other large randomised studies (IFM 2005-02, GIMEMA RV-209, and Myeloma XI study) evaluated the role of lenalidomide maintenance following ASCT.3–5 While both the IFM 2005-02 and GIMEMA RV-209 studies reported significant improvements in PFS in the lenalidomide groups, there was no significant improvement in overall survival. The survival data for the Myeloma XI trial are not yet mature. SPM rates (excluding noninvasive skin cancers) of 7·5%3 and 2·8%4 were observed in the lenalidomide treatment groups of the IFM 2005-02 and GIMEMA RV-209 studies, respectively. A recent meta-analysis that included CALGB 100104, IFM 2005-02, and GIMEMA RV-209 found that lenalidomide maintenance significantly improves overall survival.6 Here we present an updated analysis of CALGB 100104 which provides long-term follow-up data with respect to TTP, overall survival and SPMs.\n\nMethods\nStudy design and patient selection\nAdults aged 18 to 70 years were enrolled across 47 centers in the United States. Patients were eligible if they had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, had symptomatic disease requiring treatment, had received no more than 12 months of any prior therapy, were within 12 months of initiation of induction therapy and had received at most two induction regimens. Patients were excluded if they had disease progression during induction therapy or if they had previously undergone a prior peripheral blood, bone marrow, or solid organ transplant. Patients with stable disease or better (marginal, partial, or complete response) in the first 100 days after ASCT were eligible. Additional details regarding inclusion and exclusion criteria can be found in the supplemental material. Each participant signed an IRB-approved, protocol-specific informed consent in accordance with federal and institutional guidelines.\n\nRandomisation and masking\nPatients were randomly assigned (1:1) in a double-blinded manner to initiate either lenalidomide or placebo between day 90 and day 100 after ASCT. Randomisation was stratified by three factors: normal or elevated β2-microglobulin level at registration (≤ 2·5 mg/L vs. > 2·5 mg/L), prior use or nonuse of thalidomide during induction therapy, and prior use or nonuse of lenalidomide during induction therapy. A permutated-block randomisation with a block size of six and equal allocation between two arms was utilized for each stratum. The study was unblinded on December 17, 2009 after the third interim analysis. A detailed description of the randomisation, unblinding, and interim analyses is included in the supplemental material. Of the 128 eligible patients without progressive disease in the placebo group, 86 chose to cross over and receive lenalidomide therapy.\n\nProcedures\nAll patients with stable disease or better were scheduled to start therapy between day 100–110 post-ASCT. All patients started on two capsules (10 mg of lenalidomide, or placebo) per oral daily. After three months, the dose could be escalated to three capsules (15 mg) daily. Response and progression were initially defined using the European Blood and Marrow Transplant Group7 and were subsequently changed to the International Myeloma Working Group (IMWG) criteria.8 Criteria for continued treatment were decided by the local centers. Dose modifications are detailed in the supplemental material. Disease progressions (see supplemental material for definition), deaths, responses at day 100, one-year, two-year, and three-year post-ASCT were determined at the treating center and centrally reviewed according to the IMWG criteria, with the exception that stringent CR (sCR) was not utilized as a response category as the majority of patients did not undergo free light chain testing. The central review was done in a blinded manner by four of the authors (SAH, PLM, SG, EAS).\n\nOutcomes\nThe primary endpoint was time to progression (TTP), defined as time to progressive disease or death from any cause after transplantation. Secondary objectives included overall survival (defined as the length of time from ASCT to death from any cause), assessment of complete response rate, and determination of feasibility of long-term administration of lenalidomide. The assessment of second primary malignancies was an exploratory objective not specified in the protocol.\n\nStatistical analysis\nFor sample size calculations, a total of n=462 patients were planned to be randomised over a period of 33 months. Accounting for a drop-out rate of 15%, this would require registering n=554 patients over this period. Under an equal allocation scheme (i.e., 231 patients per arm), a planned accrual period of 33 months and a follow-up period of 30 months, this design would have a power of at least 0·9 for the log-rank test to compare a median TTP of 2 years for the control arm and 2·8 years for the experimental arm (HR=1·4) with one-sided alpha = 0·05. The primary statistical analysis was conducted using the log-rank test and the secondary analysis was conducted using the Cox regression method. To assess the occurrence of second primary malignancies (SPM) reported post-randomisation, the non-protocol endpoint of event-free survival (EFS), defined as time of first event (SPM, progressive disease, or death) is considered. Interim analyses were planned on a semi-annual basis to coincide with the semi-annual meetings of the CALGB Data and Safety Monitoring Board (DSMB) starting from about 21 months. Superiority tests were conducted using a group sequential test design by Emerson and Fleming9 and futility tests were conducted to test if the HR of TTP between the two arms was <1·4 with one-sided alpha=0·05. The survival functions are estimated using the Kaplan-Meier estimator.10 The Cox score statistic is used to test discrepancy between survival distributions adjusting for baseline patient characteristics.11 Hazard ratios are estimated using a Cox model under the implicit assumption of proportional hazards. To assess cause-specific (progression, death, and SPM) risk, the cumulative incidence curves are estimated using Kaplan-Meier estimators12 and compared using the log-rank test proposed by Gray.13 All analyses are right censored and per protocol used ASCT as the reference date except the EFS analysis, which uses the randomisation date. The complete response rates at one year after transplant for the lenalidomide and placebo arms were compared by Chi-square testing. The difference in the most frequent grade 3 and higher at least possibly treatment-related adverse events proportion between independent patient groups is tested using Fisher’s test and estimated using a conditional maximum likelihood estimator of the odds ratio.14 The analyses were conducted by the Alliance Statistics and Data Center using the R Statistical Environment [R Development Core Team 2011] along with the survival and cmprsk extension packages and SAS © 9·4 TS Level 1M3 for Windows [SAS Institute, Cary, NC, USA]. A detailed description of the statistical considerations, including the design and analysis methods, has been provided in the supplemental material. All analyses were based on the study database frozen on October 19, 2016.\n\nRole of the funding source\nThe National Cancer Institute (NCI) sponsored the study. Lenalidomide and placebo were provided by Celgene (Summit, New Jersey, United States) to the NCI, which in turn provided the study drugs to the investigators. Celgene was not involved in the study design, conduct of the study, or in the analysis or reporting of the data. All authors had access to the data through the Alliance Statistics and Data Center, which collected the data.\n\nRESULTS\nFour hundred sixty patients, out of 568 enrolled patients, were randomised between April 14, 2005 and July 2, 2009: 231 to the lenalidomide group and 229 to the placebo group. As has been previously reported, patients were evenly distributed by age, sex, disease stage, β2-microglobulin level at registration (supplemental material).2 The disposition of the patients, including reasons for ineligibility, is shown in the CONSORT diagram (Figure 1 and supplemental material). The reasons for treatment discontinuation are summarised in the supplemental material.\n\nThe median follow-up for the updated survival analysis, as of October 19, 2016 was 91 months. One-hundred forty-six of the 231 patients in the lenalidomide group (63%) as compared with 176 of the 229 patients in the placebo group (77%) had progressive disease or had died (Figure 2A). The median TTP was 57·3 months (95% CI 44·2–73·3) in lenalidomide group and 28·9 months (95% CI 23·0–36·3) in the placebo group with a hazard ratio of 0·57 (95% CI 0·46 to 0·71; p<0·001). TTP analyses comparing Alliance (EMA) and FDA censoring rules are presented in the supplemental material. A total of 88 out of the 231 patients in the lenalidomide group have died (38%) compared with 120 out of 229 patients in the placebo group (52%) (Figure 2B). The median OS is 113·8 months (95% CI 100·4-not reached) in the lenalidomide group and is 84·1 months (95% CI 73·8–106·0) in the placebo group (hazard ratio 0·61; 95% CI, 0·46 to 0·80; p<0·0004). The rate of overall survival at five years is 76% (95% CI, 70% to 81%) among patients in the lenalidomide group and 64% (95% CI, 58% to 70%) among patients in the placebo group.\n\nThe median time to crossover to lenalidomide for those placebo patients who chose to crossover at time of study unblinding was 11 months (range 2·6–49·7 months). Similar hazard ratios for TTP and overall survival were observed when placebo patients crossing over within 6 months of randomisation (n=19) (TTP hazard ratio 0·58, 95% CI 0·47-0·72, p<0·0001; overall survival hazard ratio 0·61, 95% CI 0·47-0·81, p=0·0004) or within 12 months (n=46) (TTP hazard ratio 0·53, 95% CI 0·43-0·66, p<0·0001; overall survival hazard ratio 0·58, 95% CI 0·44-0·76, p<0·0001) of randomisation were included in the lenalidomide arm (supplemental material). The median time on treatment for the lenalidomide arm was 31·0 months (95% CI 24·8–35·8 months) and was 18·1 months (95% CI 17·1–22·6 months) for the placebo arm (p<0.0001). Within the placebo group, the median time on treatment for the crossover patients was 30·7 months (95% CI 27·1–37·4) and 14·5 months (95% CI 12·5–17·3) for those patients who did not crossover. Treatment-free intervals were not determined. The median dose for the time on treatment for the lenalidomide arm was 6.8 mg daily.\n\nFor those patients who experienced disease progression, the median survival time following progression was similar amongst the two treatment arms (42·6 months (95% CI 36·4–60·5) for lenalidomide and 39·2 months (95% CI 31·2–45·0) for placebo; hazard ratio 0·83 (95% CI 0·61 to 1·13, p=0.23)) (Figure 3). Similarly, no differences in survival time after progression were observed when placebo patients crossing over within six months of randomisation (hazard ratio 0·84; 95% CI 0·62-1·13, p=0.24) or within 12 months (hazard ratio 0·85; 95% CI 0·64 to 1·15, p=0.30) of randomisation were included in the lenalidomide group (supplemental material). Time to second objective disease progression (PFS2) could not be calculated as neither the date of second progression nor the start of third-line therapy was routinely collected from the sites.\n\nPatients were stratified based on prior lenalidomide or thalidomide therapy, beta-2 microglobulin level (elevated vs normal), and investigator-reported complete response status (complete response or no complete response) at time of randomisation. Figure 3 shows the forest plots comparing the relative influences of these stratification factors on TTP and overall survival. There was a benefit of lenalidomide maintenance for TTP across all stratification groups (Figure 4A). Patients who received lenalidomide induction and lenalidomide maintenance (n=84) had a median TTP of 71·6 months (95% CI 57·3–97·8) vs. 46·0 months (95% CI 37·2–73·1) (p=0·21) for those who received lenalidomide maintenance in the absence of prior lenalidomide induction (n=147) (supplemental material). There was a benefit of lenalidomide maintenance on overall survival regardless of whether patients received prior lenalidomide induction or not (Figure 4B). The median overall survival did not differ significantly for patients who received lenalidomide maintenance with prior lenalidomide induction (104·7 months, 95% CI 97·8-not reached) vs those who received lenalidomide maintenance without prior lenalidomide induction (113·8 months, 95% CI 90·5-not reached) (p=0·078) (supplemental material). For patients in the placebo arm, the presence or absence of lenalidomide induction did not impact median TTP or overall survival (supplemental material). The median TTP for patients in the placebo group who were not in complete response at time of randomisation (n=60) was 19.8 months (95% CI 14·6–36·8) vs 33.0 months (95% CI 23·6–40·6) for patients in complete response (n=153) (p=0·37) (supplemental material). For the lenalidomide arm, the median TTP for patients not in complete response at time of randomisation (n=86) was 37·2 months (95% CI 28·9–60·1) vs 66·7 months (95% CI 50·6–94·3) (n=128) (p=0·0018). The median overall survival for these groups were 90·6 months (95% CI 72·5-not reached) (placebo, non-complete response), 80·6 months (95% CI 68· 9-not reached) (placebo, complete response), 97·8 months (95% CI 75· 0-not reached) (lenalidomide, non-complete response) and not reached (95% CI 100· 4-not reached) (lenalidomide, complete response) (supplemental material).\n\nCentralized review was performed to assess response (per IMWG criteria) at time of randomisation as well as 1-, 2-, and 3-years post-ASCT (Table 1). Similar complete response rates were observed in the placebo and lenalidomide arms at 1 year (Chi-square testing of complete response/no-complete response vs lenalidomide/placebo, p-value pf 0·78). However, by year 3, the majority of patients who remained in complete response or VGPR were either in the lenalidomide arm or in the crossover arm. There were not reliable data regarding the numbers of patients in biochemical relapse at each time point.\n\nReported salvage therapies were reviewed and the confirmed initial salvage therapies were compiled (supplemental material). Of those patients with confirmed initial salvage regimens, more patients received lenalidomide or a lenalidomide-containing regimen at time of relapse in the placebo arm (73 out 104) than in the lenalidomide (32 out of 101) or crossover arms (18 out of 42). Thirty-five patients were reported to have received a second ASCT at some point, as well as seven who underwent allogeneic transplant and one patient who received a second ASCT and an allogeneic transplant from a haploidentical donor.\n\nGrade 3 and higher haematological and non-haematological adverse events that occurred after randomisation were previously reported for the lenalidomide and placebo arms.2 With longer follow-up, there have been a small number of additional adverse events reported (Table 2 and supplemental material). The adverse events in the placebo arm are now further categorized into the placebo crossover group and the non-crossover group. The majority of the haematologic adverse events in the placebo patients occurred in those who crossed over to receive lenalidomide. A total of three grade 5 adverse events occurred (two in the lenalidomide group and one in the placebo non-crossover group).\n\nThe SPMs that were diagnosed after the time of randomisation and before the time of myeloma progression and receipt of salvage therapy are shown in Table 3. To date, a total of 18 haematological (7·8%), 14 solid tumour (6·1%), and 11 (4·8%) noninvasive SPMs have been diagnosed in the lenalidomide arm vs. a total of three haematological (1·3%), nine solid tumour (3·9%), and six (2·6%) noninvasive SPMs in the placebo arm. Of the placebo arm SPMs, three of three haematological, five of nine solid tumour, and five of six noninvasive SPMs were in the crossover group. Of the twenty-one patients with haematological SPMs, nine received a thalidomide-containing induction regimen, six received a lenalidomide-containing regimen, and six contained an anthracycline-containing induction regimen (supplemental material). Details of the solid tumour SPMs are shown in the supplemental material. The majority of the solid tumour SPMs were reported within the first three years after randomisation, but with longer follow-up, haematological SPMs continue to develop (supplemental material). The median times to haematological or solid tumour SPMs were similar for both treatment groups: 60·8 months (95% CI 36·1-not reached) (placebo, haematological) vs 49·8 months (95% CI 35·7–83·5) (lenalidomide, haematological) (p=0·86), 27·0 months (95% CI 18·1-not reached) (placebo, solid tumour) vs 21·7 months (95% CI 16·6-not reached) (lenalidomide, solid tumour) (p=0·45) (supplemental material). SPMs were also reported after myeloma progression and initiation of salvage therapy, including one haematological, four solid tumour, and two noninvasive SPM in the lenalidomide arm, and five haematological, two solid tumour, and two noninvasive SPMs in the placebo arm (supplemental material). Of those placebo arm SPMs, one haematological and one noninvasive SPM occurred in the crossover subgroup. Finally, one haematological, seven solid tumour, and two noninvasive SPMs were reported in enrolled patients who were never randomised (supplemental material).\n\nThe cumulative incidence risks (CIR) of progressive disease, death, and SPM by treatment arm were analyzed. As shown in Figure 5, the CIR of progressive disease/death is higher for placebo compared with lenalidomide (p<0·0001) while the CIR of developing a SPM is higher for lenalidomide (p=0·0073) (Figure 5A). The CIR of death from any cause is higher with placebo than with lenalidomide (p<0.0001) (Figure 5B). The CIR of death from myeloma is higher in the placebo group (p<0·0001) while the CIR of death from SPM is higher in the lenalidomide group (p=0·031) (Figure 5C). The CIR curves for haematological vs solid tumour SPMs are shown in the supplemental material. To assess for the potential impact of crossover of placebo patients to lenalidomide on these risks, the CIR of progressive disease/death and SPM were assessed for the placebo patients who did not cross over and for the crossover patients (supplemental material). The risks of progressive disease, death, or SPM are not statistically significantly different between the lenalidomide and crossover arms. The median event-free survival (EFS; time to progressive disease, SPM, or death from any cause) for placebo was 27·0 months (95% CI 21·8–34·9) and 44·2 months (95% CI 37·3–56·1) for lenalidomide with a hazard ratio of 0·63 (95% CI 0·51-0·78) (p<0.0001) (supplemental material).\n\nDISCUSSION\nThis updated analysis of the phase 3 randomised trial evaluating lenalidomide vs placebo maintenance following ASCT demonstrates a persistent TTP and overall survival benefit for lenalidomide treatment. This benefit is maintained despite the crossover of a majority of eligible patients on the placebo arm to lenalidomide at the time of study unblinding. Survival after progression does not differ between the two treatment groups. The benefit derived from lenalidomide maintenance is independent of induction therapy as well as complete response status at time of randomisation. Lenalidomide maintenance is associated with an increased risk of haematological SPMs. This study, as well as a number of transplant and non-transplant randomised studies, have demonstrated benefit with prolonged lenalidomide therapy.3–5, 15, 16 A meta-analysis of the CALGB, IFM and GIMEMA studies found that lenalidomide maintenance significantly improves overall survival (median overall survival not yet reached for lenalidomide vs. 86 months for control (HR =0·74, log-rank p=0·001)), regardless of response achieved post-ASCT.6\n\nThe study most directly comparable to CALGB 100104 is the IFM 2005-02 trial, which also evaluated lenalidomide vs placebo maintenance therapy following ASCT. While a PFS benefit with lenalidomide was observed, there was no difference in overall survival between the study arms.3 There are multiple factors which may contribute to the difference in survival outcomes between the studies, including the types of induction regimens, consolidation therapy, numbers of transplants, the duration of lenalidomide maintenance and available salvage therapies. Overall, the IFM 2005-02 study population was exposed to more traditional chemotherapy while the CALGB 100104 study population was exposed to more novel agent-based therapy. The extent to which pre-transplant therapy determines response to subsequent salvage therapies remains to be determined. However, our analysis reveals that patients progressing on lenalidomide maintenance have a similar overall survival after progression as do placebo patients after progression (Figure 3), which suggests that prolonged lenalidomide maintenance does not confer disease resistance.\n\nThe optimal dose, schedule, and duration of lenalidomide maintenance continue to be topics of much discussion. The present study as well as the GIMEMA RV-209 and Myeloma XI studies involved lenalidomide maintenance therapy continued until progression while the IFM 2005-02 study discontinued lenalidomide maintenance after a median time of two years (range 1–3 years) due to concerns regarding SPM risk.3–5 The IFM 2009 study which assessed the timing of ASCT,17 incorporated one year of lenalidomide maintenance while the ongoing American study (DETERMINATION Trial) is identical in design except that maintenance is continued until progression. Future comparison of survival outcomes and toxicities, including the incidence of SPMs, between the IFM 2009 and DETERMINATION studies will provide important information regarding the impact of maintenance duration. The American and French studies (e.g., CALGB 100104, BMT CTN 0702, IFM 2005-02, and IFM 2009)2, 3, 17, 18 have utilized continuous dosing of lenalidomide while other European studies (e.g., Myeloma XI, GIMEMA RV-209, RV-MM-EMN-441, EMN02/HO95)4, 5, 19, 20 have utilized a 21/28 day schedule. In the absence of a prospective study comparing the two dosing schedules, it is difficult to conclude from the previously conducted studies whether one schedule is more optimal than the other from either a survival or toxicity perspective. However, it should be noted that the largest of the studies, CALGB 100104 and Myeloma XI, have found very similar median TTP/PFS durations for the lenalidomide arms (57·3 and 60 months respectively) despite the different dosing schedules. As ongoing and planned studies involving the addition of other agents to lenalidomide maintenance progress, it is likely that the optimal dosing, schedule and duration of lenalidomide maintenance will continue to evolve.\n\nCentral review of the response data (Table 1) revealed that, despite significant efforts by participating sites to provide follow-up data, there were missing data at later time points. These include bone marrow biopsies, 24-hour urine quantitations and incomplete serum and urine electrophoresis analyses. The independent review committee reviewed all available primary source data. Despite these limitations, this review assessment did reveal that surprisingly, there was little difference in the complete response/VGPR rate between the two arms at one year. However, the majority of patients in complete response/VGPR by year 3 were in either the lenalidomide arm or the crossover subgroup of the placebo arm.\n\nThis updated analysis of CALGB 100104 continues to show an increased risk of SPMs associated with lenalidomide maintenance therapy, although the risks of progressive disease and death due to myeloma were substantially higher than the risk of SPM in both cohorts. SPM risk is associated with multiple factors, including the underlying disease, age, and myeloma therapy. There were patients enrolled but never randomised who developed SPMs (supplemental material). This is consistent with the underlying SPM risk in this patient population. The risk of malignancy increases with advancing age and age-related clonal hematopoiesis is associated with increased risk of haematological malignancies.21, 22 Multiple studies have demonstrated that monoclonal gammopathy of undetermined significance and myeloma, even in the absence of therapy, are associated with increased risk of haematological malignancies, particularly MDS/AML.23–25 This finding implicates the presence of an intrinsic defect in the hematopoietic system in patients with plasma cell dyscrasias. An increased risk of solid tumours in myeloma patients has also been reported.26 There was not a predominant solid tumour SPM type found in the present study. With respect to lenalidomide, a meta-analysis of 3254 newly diagnosed patients treated on seven randomized phase 3 trials revealed that the cumulative 5-year incidence of all SPMs at 5 years was 6·9% in patients who received lenalidomide vs. 4·8% in those who did not (p=0·037).27 An increase in haematological malignancies (3·1% vs. 1·4%, p=0·029) but not solid tumours was observed.\n\nSince the time of first publication of CALGB 100104, four new solid tumour SPMs and ten new haematological SPMs were reported in the lenalidomide group. It appears that the risk of solid tumours may be primarily incurred during the first several years of lenalidomide therapy post-transplant, with haematological malignancies continuing to be diagnosed with later follow-up (Supplemental Figures 6–7). However, given the overall small number of SPMs, it is difficult to draw any definite conclusions regarding the temporal association between SPM type and lenalidomide exposure. Genetic analysis, particularly of the haematological SPMs, is needed to better determine the mechanisms by which lenalidomide contributes to the pathogenesis of SPMs. While MDS/AML has previously been associated with high-dose melphalan and myeloma therapy, the appearance of B-cell ALL SPMs has been somewhat unexpected. Further studies are needed to determine whether the effects of lenalidomide on IKZF1, a transcription factor which has been associated with B-cell ALL,28–30 contribute to the development of ALL as a SPM.\n\nIn conclusion, our study demonstrates that lenalidomide maintenance therapy post-ASCT confers significant TTP and overall survival benefit. The overall survival data, which shows a median overall survival of 9·5 years (from time of ASCT), provides a new benchmark for survival, particularly noteworthy as this study was conducted in an era where triplet regimens containing IMiD/PI were not routinely used. Cytogenetic and FISH testing of diagnostic samples was not available for the majority of patients, thus the impact of lenalidomide maintenance on different cytogenetic risk groups cannot be determined. Preliminary results of the Myeloma XI trial demonstrated benefit in high and low cytogenetic risk patients.5 This report demonstrates that patients in CR post-ASCT benefit from lenalidomide maintenance, however, the CR response was determined by numbers of bone marrow plasma cells and immunofixation testing. The newly revised IMWG criteria now include minimal residual disease assessment and multiple studies have demonstrated superior outcomes for patients who achieve MRD-negativity post-ASCT.31–33 Thus the extent to which lenalidomide maintenance improves survival outcomes for MRD-negative vs MRD-positive patients remains to be determined. One limitation of the study is that quality of life data were not prospectively collected. However, this study is amongst a growing number of studies demonstrating the feasibility of long-term maintenance therapy with lenalidomide. Lenalidomide maintenance until progression post-ASCT may be considered a standard of care and should form the backbone of future maintenance studies incorporating novel agents such as monoclonal antibodies or vaccine-based approaches.\n\nSupplementary Material\n1 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.\n\nClinicalTrials.gov Identifier: NCT00114101\n\nAuthor contributions:\n\nHolstein: Literature search, figures, data collection, data analysis, data interpretation, writing\n\nJung: data analysis, data interpretation, writing\n\nRichardson: data interpretation, writing\n\nHofmeister: data interpretation, writing\n\nHurd: data interpretation, writing\n\nHassoun: data interpretation, writing\n\nGiralt: data interpretation, writing\n\nStadtmauer: data interpretation, writing\n\nWeisdorf: data interpretation, writing\n\nVij: data interpretation, writing\n\nMoreb: data interpretation, writing\n\nCallander: data interpretation, writing\n\nvan Besien: data interpretation, writing\n\nGentile: data interpretation, writing\n\nIsola: data interpretation, writing\n\nMaziarz: data interpretation, writing\n\nBashey: data interpretation, writing\n\nLandau: data interpretation, writing\n\nMartin: data interpretation, writing\n\nQazilbash: data interpretation, writing\n\nRodriguez: data interpretation, writing\n\nMcClune: data interpretation, writing\n\nSchlossman: data interpretation, writing\n\nSmith: data interpretation\n\nHars: data analysis, data interpretation, figures, writing\n\nOwzar: study design, data interpretation, writing\n\nJiang: data analysis, data interpretation, figures, writing\n\nBoyd: data collection, data analysis\n\nSchultz: data collection, data analysis\n\nWilson: data collection, data analysis\n\nHari: data interpretation, writing\n\nPasquini: data interpretation, writing\n\nHorowitz: data interpretation, writing\n\nShea: study design, data interpretation, writing\n\nDevine: study design, data interpretation, writing\n\nLinker: study design, data interpretation, writing\n\nAnderson: study design, data interpretation, writing\n\nMcCarthy: Literature search, study design, data collection, data analysis, data interpretation, writing\n\nThe study team would like to thank the patients and families who participated in this study and the clinical teams who provided care for the patients. We wish to acknowledge the efforts of the research nurses, data coordinators, and investigators who participated in the data cleaning efforts. We would also like to acknowledge those members of the Alliance who assisted with the protocol development and amendments, including Michael Kelly, Destin Carlisle and Guadalupe Aquino. We would like to thank Michelle Maglio for administrative support. We thank John Postiglione for his efforts on this study. Finally, we wish to honor the memory of Dr. Dan Sargent who tragically died in 2016. Dr. Sargent was the head of the Alliance Statistics and Data Center and facilitated the publication of the first report of the CALGB 100104 study as well as the update. He provided sage advice throughout the analysis.\n\nDeclaration of interests:\n\nDr. Anderson reports personal fees from Celgene, Millennium Takeda, Gilead, Bristol Myers Squibb. Dr. Bashey has nothing to disclose. Ms Boyd has nothing to disclose. Dr. Callander has nothing to disclose. Dr. Devine has nothing to disclose. Dr. Gentile has nothing to disclose. Dr. Giralt reports research funding and personal fees from Celgene and Takeda, research funding from Sanofi, personal fees from Jazz and Amgen. Dr. Hari reports grants and personal fees from Celgene. Ms Hars has nothing to disclose. Dr. Hassoun reports grants from CALGB/Alliance during the conduct of the study and grants from Celgene. Dr. Hofmeister reports other support (local principal investigator for clinical trial using drug made by Celgene) from Celgene. Dr. Holstein reports personal fees from Celgene, Takeda and Amgen. She received travel support and honoraria for response adjudication of this study by the Alliance for Clinical Trials in Oncology. Dr. Horowitz has nothing to disclose. Dr. Hurd has nothing to disclose. Dr. Isola has nothing to disclose. Dr. Jiang has nothing to disclose. Dr. Jung has nothing to disclose. Dr. Landau reports grants from Celgene during the conduct of the study, personal fees from Spectrum Pharmaceuticals, Prothena, Janssen, and Takeda. Dr. Linker has nothing to disclose. Dr. Maziarz has nothing to disclose. Dr. McCarthy reports research support and personal fees from Celgene, and personal fees from Bristol Myers Squibb, Karyopharm, Gamida Cell, Janssen, Sanofi, and The Binding Site. He received travel support and honoraria for response adjudication of this study by the Alliance for Clinical Trials in Oncology. Dr. McClune has nothing to disclose. Dr. Moreb has nothing to disclose. Dr. Owzar has nothing to disclose. Dr. Pasquini reports personal fees from Atara Biotherapeutics, Pfizer, and Baxalta. Dr. Qazilbash has nothing to disclose. Dr. Richardson reports personal fees from Celgene. Dr. Rodriguez has nothing to disclose. Dr. Schlossman has nothing to disclose. Ms Schultz has nothing to disclose. Dr. Shea has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Stadtmauer reports personal fees from Celgene and Takeda. Dr. van Besien has nothing to disclose. Dr. Vij reports personal fees from Celgene, Bristol Myers Squibb, Janssen, AbbVie, Karyopharm and research support and personal fees from Amgen and Takeda. Dr. Weisdorf has nothing to disclose. Ms Wilson has nothing to disclose.\n\nFunding source: Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under Award Numbers U10CA031946, U10CA033601, U10CA180821 and U10CA180882 (to the Alliance for Clinical Trials in Oncology),U01HL069294, U10CA021115, , U10CA004457, U10CA007968, U10CA016450, U10CA021060, U10CA032291, U10CA047559, U10CA059518, U10CA077298, U10CA077440, U10CA077651, U10CA077658, U10CA138561, U10CA180791, U10CA180799, U10CA180833, U10CA180838, U10CA180850, U10CA180858, U10CA180866, and U10CA180867. Support for this study was provided in part by the Blood and Marrow Transplant Clinical Trials Network through grant #U10HL069294 from the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute. Support was also provided in part by the Eastern Cooperative Oncology Group (ECOG) supported by CA21115. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This study was also supported in part by Celgene Corporation.\n\nThe National Cancer Institute (NCI) sponsored the study.\n\nFigure 1 CONSORT flow diagram of patient disposition at the current data cut-off.\n\nFigure 2 Kaplan-Meier estimates of time to progression (A) and overall survival (B). ASCT denotes autologous stem cell transplant.\n\nFigure 3 Kaplan-Meier estimates of survival time following progression.\n\nFigure 4 Forest plot of time to progression (A) and overall survival (B). Hazard ratios from subgroup analyses are shown on a natural-log scale. The radii of the circles are proportional to the inverse of the square of the standard error.\n\nFigure 5 Cumulative incidence risk (CIR) of progressive disease, death, and second primary malignancies (SPMs) by treatment arm. A) The CIR of progressive disease or death from any cause is higher with placebo compared to lenalidomide (p<0·0001). The CIR of developing a SPM is higher with lenalidomide compared with placebo (p=0·0073). B) The CIR of death from any cause is higher with placebo compared with lenalidomide (p<0·0001). C) The CIR of death from myeloma is higher with placebo than with lenalidomide (p<0·0001) while the CIR of death from SPM is higher with lenalidomide than placebo (p=0·031).\n\nTable 1 Adjudicated response rates\n\n\tPlacebo (n=229)\n\tLenalidomide (n=231)\t\nNo Crossover\n(n=143)\tCrossover (n=86)\tAll Placebo\n(n=229)\t\n\n\t\nTime of Randomisation\tCR\t33 (14%)\t20 (9%)\t53 (23%)\t48 (21%)\t\n\tVGPR\t60 (26%)\t40 (17%)\t100 (44%)\t80 (35%)\t\n\tPR\t32 (14%)\t20 (9%)\t52 (23%)\t78 (34%)\t\n\tSD\t4 (2%)\t1 (<1%)\t5 (2%)\t7 (3%)\t\n\tRel/PD\t3 (1%)\t0 (0%)\t3 (1%)\t1 (<1%)\t\n\tNEa\t11 (5%)\t5 (2%)\t16 (7%)\t17 (7%)\t\n\tOff-studyb\t0 (0%)\t0 (0%)\t0 (0%)\t0 (0%)\t\n\tVGPR/CR rate\t41%\t26%\t67%\t55%\t\n\n\t\nOne year post-ASCT\tCR\t26 (11%)\t22 (10%)\t48 (21%)\t46 (20%)\t\n\tVGPR\t32 (14%)\t36 (16%)\t68 (30%)\t65 (28%)\t\n\tPR\t8 (3%)\t13 (6%)\t21 (9%)\t36 (16%)\t\n\tSD\t0 (0%)\t0 (0%)\t0 (0%)\t2 (1%)\t\n\tRel/PD\t15 (4%)\t6 (3%)\t13 (6%)\t19 (8%)\t\n\tNEa\t26 (11%)\t2 (1%)\t28 (12%)\t50 (22%)\t\n\tOff-studyb\t36 (16%)\t7 (3%)\t43 (19%)\t13 (6%)\t\n\tVGPR/CR rate\t25%\t25%\t51%\t48%\t\n\n\t\nTwo years post-ASCT\tCR\t16 (7%)\t17 (7%)\t33 (14%)\t41 (18%)\t\n\tVGPR\t8 (3%)\t22 (10%)\t30 (13%)\t43 (19%)\t\n\tPR\t2 (1%)\t13 (6%)\t15 (7%)\t19 (8%)\t\n\tSD\t0 (0%)\t0 (0%)\t0 (0%)\t1 (<1%)\t\n\tRel/PD\t10 (4%)\t9 (4%)\t12 (5%)\t22 (10%)\t\n\tNEa\t29 (13%)\t13 (6%)\t42 (18%)\t61 (26%)\t\n\tOff-studyb\t78 (34%)\t12 (5%)\t90 (39%)\t44 (19%)\t\n\tVGPR/CR rate\t10%\t17%\t27%\t36%\t\n\n\t\nThree years post-ASCT\tCR\t5 (2%)\t8 (3%)\t13 (6%)\t30 (13%)\t\n\tVGPR\t3 (1%)\t19 (8%)\t22 (10%)\t24 (10%)\t\n\tPR\t1 (<1%)\t4 (2%)\t5 (2%)\t8 (3%)\t\n\tSD\t0 (0%)\t0 (0%)\t0 (0%)\t1 (<1%)\t\n\tRel/PD\t8 (3%)\t6 (3%)\t9 (4%)\t21 (9%)\t\n\tNEa\t31 (14%)\t27 (12%)\t58 (25%)\t84 (36%)\t\n\tOff-studyb\t95 (41%)\t22 (10%)\t117 (51%)\t63 (27%)\t\n\tVGPR/CR rate\t3%\t12%\t15%\t23%\t\na Not evaluable because of missing data\n\nb Off-study because of prior disease relapse/progression\n\nTable 2 Adverse Eventsa\n\n\tArm\tGrade 1\nn (%)\tGrade 2\nn (%)\tGrade 3\nn (%)\tGrade 4\nn (%)\tGrade 5\nn (%)\t\n\n\t\nHaematologic\t\t\t\t\t\t\t\n\n\t\n Hemoglobin\tLen (n=231)\t15 (6%)\t6 (3%)\t9 (4%)\t2 (1%)\t0 (0%)\t\n\tPBO (n=143)\t3 (2%)\t3 (2%)\t0 (0%)\t0 (0%)\t0 (0%)\t\n\tCO (n=86)\t1 (1%)\t1 (1%)\t1 (1%)\t0 (0%)\t0 (0%)\t\n\n\t\n Leukocytes (total WBC)\tLen (n=231)\t4 (2%)\t5 (2%)\t28 (12%)\t3 (1%)\t0 (0%)\t\n\tPBO (n=143)\t2 (1%)\t1 (1%)\t1 (1%)\t1 (1%)\t0 (0%)\t\n\tCO (n=86)\t1 (1%)\t2 (2%)\t9 (10%)\t1 (1%)\t0 (0%)\t\n\n\t\n Lymphopenia\tLen (n=231)\t2 (1%)\t2 (1%)\t20 (9%)\t1 (0%)\t0 (0%)\t\n\tPBO (n=143)\t1 (1%)\t1 (1%)\t1 (1%)\t1 (1%)\t0 (0%)\t\n\tCO (n=86)\t1 (1%)\t1 (1%)\t5 (6%)\t0 (0%)\t0 (0%)\t\n\n\t\n Neutrophils\tLen (n=231)\t14 (6%))\t36 (16%)\t82 (35%)\t34 (15%)\t0 (0%)\t\n\tPBO (n=143)\t12 (8%)\t10 (7%)\t7 (5%)\t4 (3%)\t0 (0%)\t\n\tCO (n=86)\t8 (9%)\t15 (17%)\t26 (30%)\t4 (5%)\t0 (0%)\t\n\n\t\n Platelets\tLen (n=231)\t75 (32%)\t33 (14%)\t23 (10%)\t11 (5%)\t0 (0%)\t\n\tPBO (n=143)\t28 (20%)\t3 (2%)\t0 (0%)\t7 (5%)\t0 (0%)\t\n\tCO (n=86)\t29 (34%)\t8 (9%)\t3 (3%)\t2 (2%)\t0 (0%)\t\n\n\t\nNon-Haematologic\t\t\t\t\t\t\t\n\n\t\n Conduction abnormality\tLen (n=231)\t0 (0%)\t0 (0%)\t1 (0%)\t0 (0%)\t0 (0%)\t\n\tPBO (n=143)\t0 (0%)\t0 (0%)\t0 (0%)\t0 (0%)\t1 (1%)\t\n\tCO (n=86)\t0 (0%)\t0 (0%)\t1 (1%)\t0 (0%)\t0 (0%)\t\n\n\t\n Fatigue\tLen (n=231)\t10 (4%)\t9 (4%)\t0 (0%)\t0 (0%)\t0 (0%)\t\n\tPBO (n=143)\t5 (3%)\t1 (1%)\t0 (0%)\t0 (0%)\t0 (0%)\t\n\tCO (n=86)\t4 (3%)\t6 (7%)\t0 (0%)\t0 (0%)\t0 (0%)\t\n\n\t\n Rash\tLen (n=231)\t22 (10%)\t22 (10%)\t9 (4%)\t0 (0%)\t0 (0%)\t\n\tPBO (n=143)\t10 (7%)\t7 (5%)\t1 (1%)\t0 (0%)\t0 (0%)\t\n\tCO (n=86)\t5 (6%)\t4 (5%)\t1 (1%)\t0 (0%)\t0 (0%)\t\n\n\t\n Diarrhea\tLen (n=231)\t54 (23%)\t36 (16%)\t12 (5%)\t0 (0%)\t0 (0%)\t\n\tPBO (n=143)\t15 (10%)\t3 (2%)\t2 (1%)\t0 (0%)\t0 (0%)\t\n\tCO (n=86)\t9 (10%)\t12 (14%)\t3 (3%)\t0 (0%)\t0 (0%)\t\n\n\t\n Febrile neutropenia (fever of unknown origin)\tLen (n=231)\t2 (1%)\t0 (0%)\t14 (6%)\t1 (0%)\t0 (0%)\t\n\tPBO (n=143)\t1 (1%)\t0 (0%)\t2 (1%)\t1 (1%)\t0 (0%)\t\n\tCO (n=86)\t1 (1%)\t0 (0%)\t1 (1%)\t0 (0%)\t0 (0%)\t\n\n\t\n Infection (documented clinically or microbiologically)\tLen (n=231)\t1 (0%)\t4 (2%)\t13 (6%)\t2 (1%)\t0 (0%)\t\nPBO (n=143)\t0 (0%)\t2 (1%)\t3 (2%)\t0 (0%)\t0 (0%)\t\nCO (n=86)\t0 (0%)\t2 (1%)\t4 (5%)\t0 (0%)\t0 (0%)\t\n\n\t\n Infection with normal ANC or grade 1 or 2 neutrophils\tLen (n=231)\t0 (0%)\t6 (3%)\t13 (6%)\t0 (0%)\t1 (0%)\t\nPBO (n=143)\t0 (0%)\t3 (2%)\t3 (2%)\t0 (0%)\t0 (0%)\t\n\tCO (n=86)\t1 (1%)\t9 (10%)\t1 (1%)\t0 (0%)\t0 (0%)\t\n\n\t\n Pain\tLen (n=231)\t7 (3%)\t4 (2%)\t6 (3%)\t0 (0%)\t0 (0%)\t\n\tPBO (n=143)\t5 (3%)\t2 (1%)\t6 (4%)\t0 (0%)\t0 (0%)\t\n\tCO (n=86)\t3 (3%)\t10 (12%)\t2 (2%)\t0 (0%)\t0 (0%)\t\n\n\t\n Vascular\tLen (n=231)\t0 (0%)\t0 (0%)\t0 (0%)\t0 (0%)\t1 (0%)\t\n\tPBO (n=143)\t0 (0%)\t0 (0%)\t0 (0%)\t0 (0%)\t0 (0%)\t\n\tCO (n=86)\t0 (0%)\t0 (0%)\t0 (0%)\t0 (0%)\t0 (0%)\t\na Adverse events that occurred in at least 10% for grades 1–2, at least 2% for grades 3–4, or any grade 5.\n\nAbbreviations: ANC (absolute neutrophil count); CO (crossover); Len (lenalidomide); PBO (placebo).\n\nTable 3 Second primary malignancies\n\n\tSPM type\t\n\n\t\nTreatment Arm\tHaematologic (n)\tSolid tumour (n)\tNoninvasive (n)\t\n\n\t\nLen (231)\tMDS/AML (10)\tBreast (3)\tSCC (5)\t\n\tB-cell ALL (6)\tColon (3)\tBCC + SCC (3)\t\n\tHodgkin lymphoma (1)\tProstate (2)\tDCIS (2)\t\n\tWaldenstrom macroglobulinemia (1)\tEndometrial (2)\tBCC (1)\t\n\t\tGlioblastoma multiforme (1)\t\t\n\t\tMelanoma (1)\t\t\n\t\tPapillary Thyroid (1)\t\t\n\t\tSalivary gland carcinoma (1)\t\t\n\n\t\nPlacebo (229)\t\t\t\t\nCrossover to Len (86)\tB-cell ALL (2)\tMelanoma (2)\tBCC (3)\t\nMDS (1)\tEndometrial (1)\tBCC + SCC (2)\t\n\t\tRenal cell (1)\t\t\n\t\tInvasive SCC (1)\t\t\n\t\tBreast (1)\tSCC (1)\t\nNo crossover (143)\t\tMelanoma (1)\t\t\n\tOvarian/endometrial (1)\t\t\n\t\tLung carcinoid (1)\t\t\nAbbreviations: ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; BCC, basal cell carcinoma; DCIS, ductal carcinoma in situ; MDS, myelodysplastic syndrome; SCC, squamous cell carcinoma.\n\nNote: Two patients had MDS/AML and SCC, two patients had MDS and colon cancer, one patient had MDS and melanoma, one patient had breast and endometrial cancer, and one patient had endometrial cancer and SCC.\n\nResearch in context panel\nEvidence before the study\nWe searched PubMed up until 10/19/2016 for any clinical trial publications with the terms multiple myeloma, thalidomide, lenalidomide, maintenance, and autologous stem cell transplant (ASCT). These terms were also searched in conference abstracts from the American Society of Hematology, the American Society of Clinical Oncology, and the European Hematology Association. At the time the present study was initiated, the use of thalidomide was being studied, however no publications had yet been published. Preliminary results from two randomised studies had been presented in conference abstracts. No clinical studies had been conducted in this setting with lenalidomide. Since this study was initiated, there have been four other randomised phase 3 studies which have assessed lenalidomide maintenance following ASCT for myeloma: one placebo-controlled, two without a placebo, and one involving lenalidomide vs lenalidomide-prednisone maintenance. Data from the other lenalidomide vs placebo/no treatment studies have demonstrated a significant progression-free survival (PFS) benefit but not overall survival (OS) benefit for lenalidomide maintenance.\n\nAdded value of this study\nWe report the long-term follow-up of this randomised phase 3 study evaluating lenalidomide vs placebo maintenance therapy following single ASCT. This analysis confirms the TTP and overall survival benefit of lenalidomide maintenance, regardless of the response achieved post-ASCT. This analysis provides a detailed update of the SPMs that have been observed and confirms that while lenalidomide maintenance is associated with an increased risk of both haematological and solid tumour SPMs, the risk is off-set by the magnitude of the TTP and overall survival benefit.\n\nImplications of all the available evidence\nThis updated analysis, in concert with the available literature, confirms that continuous lenalidomide maintenance post-ASCT until disease progression provides significant TTP and overall survival benefit, and can therefore be considered a standard of care.\n==== Refs\n1 Morgan GJ Gregory WM Davies FE The role of maintenance thalidomide therapy in multiple myeloma: MRC Myeloma IX results and meta-analysis Blood 2012 119 1 7 15 22021371 \n2 McCarthy PL Owzar K Hofmeister CC Lenalidomide after stem-cell transplantation for multiple myeloma N Engl J Med 2012 366 19 1770 81 22571201 \n3 Attal M Lauwers-Cances V Marit G Lenalidomide maintenance after stem-cell transplantation for multiple myeloma N Engl J Med 2012 366 19 1782 91 22571202 \n4 Palumbo A Cavallo F Gay F Autologous transplantation and maintenance therapy in multiple myeloma N Engl J Med 2014 271 10 895 905 \n5 Jackson GH Davies FE Pawlyn C Lenalidomide is a highly effective maintenance therapy in myeloma patients of all ages; results of the phase III Myeloma XI study Blood (ASH Abstracts) 2016 128 1143 \n6 Attal M Palumbo A Holstein SA Lenalidomide (LEN) maintenance (MNTC) after high-dose melphalan and autologous stem cell transplant (ASCT) in multiple myeloma (MM): A meta-analysis (MA) of overall survival (OS) J Clin Oncol 2016 34 15 suppl 8001 \n7 Blade J Samson D Reece D Criteria for evaluating disease response and progression in patients with multiple myeloma treated by high-dose therapy and haemopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant Br J Haematol 1998 102 5 1115 23 9753033 \n8 Durie BG Harousseau JL Miguel JS International uniform response criteria for multiple myeloma Leukemia 2006 20 9 1467 73 16855634 \n9 Emerson SS Fleming TR Symmetric group sequential test designs Biometrics 1989 45 3 905 23 2675998 \n10 Kaplan EL Meier P Nonparametric estimation from incomplete observations J Am Stat Assoc 1958 53 457 81 \n11 Cox DR Oakes D Analysis of Survival Data Monographs on Statistics and Applied Probability 21 Chapman & Hall 1984 \n12 Kalbfleisch JD Prentice RL The statistical analysis of failure time data 2 Hoboken John Wiley & Sons, Inc 2002 \n13 Gray RJ A class of K-sample tests for comparing the cumulative incidence of a competing risk Ann Stat 1988 16 3 1141 54 \n14 Fisher RA The logic of inductive inference J R Stat Soc 1935 98 39 54 \n15 Palumbo A Hajek R Delforge M Continuous lenalidomide and dexamethasone in transplant-ineligible patients with myeloma N Engl J Med 2012 366 19 1759 69 22571200 \n16 Benboubker L Dimopoulos MA Dispenzieri A Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma N Engl J Med 2014 371 10 906 17 25184863 \n17 Attal M Lauwers-Cances V Hulin C Lenalidomide, bortezomib, and dexamethasone with transplantation for myeloma N Engl J Med 2017 376 14 1311 20 28379796 \n18 Stadtmauer EA Pasquini MC Blackwell B Comparison of autologous hematopoietic cell transplant (autoHCT), bortezomib, lenalidomide (Len) and dexamethasone (RVD) consolidation with Len maintenance (ACM), tandem autoHCT with Len maintenance (TAM) and autoHCT with Len maintenance (AM) for up-front treatment of patients with multiple myeloma (MM): primary results from the randomized phase III trial of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0702-StaMINA trial) Blood (ASH Abstracts) 2016 128 LBA-1 \n19 Gay F Oliva S Petrucci MT Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicenter, phase 3 trial Lancet Oncol 2015 16 16 1617 29 26596670 \n20 Cavo M Palumbo A Zweegman S Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): a randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial) J Clin Oncol 2016 34 15 suppl 8000 \n21 Genovese G Kahler AK Handsaker RE Clonal hematopoiesis and blood-cancer risk inferred from blood DNA sequence N Engl J Med 2014 371 26 2477 87 25426838 \n22 Jaiswal S Fontanillas P Flannick J Age-related clonal hematopoiesis associated with adverse outcomes N Engl J Med 2014 371 26 2488 98 25426837 \n23 Tzeng HE Lin CL Tsai CH Time trend of multiple myeloma and associated secondary primary malignancies in Asian patients: a Taiwan population-based study PLoS One 2013 8 7 e68041 23844152 \n24 Razavi P Rand KA Cozen W Patterns of second primary malignancy risk in multiple myeloma patients before and after the introduction of novel therapeutics Blood Cancer J 2013 3 e121 23811785 \n25 Mailankody S Pfeiffer RM Kristinsson SY Risk of acute myeloid leukemia and myelodysplastic syndromes after multiple myeloma and its precursor disease (MGUS) Blood 2011 118 15 4086 92 21795746 \n26 Hasskarl J Ihorst G De Pasquale D Association of multiple myeloma with different neoplasms: systematic analysis in consecutive patients with myeloma Leuk Lymphoma 2011 52 2 247 59 21054148 \n27 Palumbo A Bringhen S Kumar SK Second primary malignancies with lenalidomide therapy for newly diagnosed myeloma: a meta-analysis of individual patient data Lancet Oncol 2014 15 3 333 42 24525202 \n28 Mullighan CG Goorha S Radtke I Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia Nature 2007 446 7137 758 64 17344859 \n29 Mullighan CG Miller CB Radtke I BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros Nature 2008 453 7101 110 4 18408710 \n30 Iacobucci I Storlazzi CT Cilloni D Identification and molecular characterization of recurrent genomic deletions on 7p12 in the IKZF1 gene in a large cohort of BCR-ABL1-positive acute lymphoblastic leukemia patients: on behalf of Gruppo Italiano Malattie Ematologiche dell’Adulto Acute Leukemia Working Party (GIMEMA AL WP) Blood 2009 114 10 2159 67 19589926 \n31 Kumar S Paiva B Anderson KC International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma Lancet Oncol 2016 17 8 e328 46 27511158 \n32 Paiva B Vidriales MB Cervero J Multiparameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation Blood 2008 112 10 4017 23 18669875 \n33 Rawstron AC Child JA de Tute RM Minimal residual disease assessed by multiparatmeter flow cytometry in multiple myeloma: impact on outcome in the Medical Research Council Myeloma IX Study J Clin Oncol 2013 31 20 2540 7 23733781\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2352-3026",
"issue": "4(9)",
"journal": "The Lancet. Haematology",
"keywords": null,
"medline_ta": "Lancet Haematol",
"mesh_terms": "D000328:Adult; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D010919:Placebos; D016019:Survival Analysis; D013792:Thalidomide; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e431-e442",
"pmc": null,
"pmid": "28826616",
"pubdate": "2017-09",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "25426838;27511158;23811785;19589926;22571201;18408710;28379796;22571200;22021371;21795746;24525202;23733781;25184862;21054148;25184863;16855634;25426837;18669875;9753033;17344859;26596670;22571202;2675998;23844152",
"title": "Updated analysis of CALGB (Alliance) 100104 assessing lenalidomide versus placebo maintenance after single autologous stem-cell transplantation for multiple myeloma: a randomised, double-blind, phase 3 trial.",
"title_normalized": "updated analysis of calgb alliance 100104 assessing lenalidomide versus placebo maintenance after single autologous stem cell transplantation for multiple myeloma a randomised double blind phase 3 trial"
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"abstract": "A wide variety of drugs can cause myoclonus. To illustrate this, we first discuss two personally observed cases, one presenting with generalized, but facial-predominant, myoclonus that was induced by amantadine; and the other presenting with propriospinal myoclonus triggered by an antibiotic. We then review the literature on drugs that may cause myoclonus, extracting the corresponding clinical phenotype and suggested underlying pathophysiology. The most frequently reported classes of drugs causing myoclonus include opiates, antidepressants, antipsychotics, and antibiotics. The distribution of myoclonus ranges from focal to generalized, even amongst patients using the same drug, which suggests various neuro-anatomical generators. Possible underlying pathophysiological alterations involve serotonin, dopamine, GABA, and glutamate-related processes at various levels of the neuraxis. The high number of cases of drug-induced myoclonus, together with their reported heterogeneous clinical characteristics, underscores the importance of considering drugs as a possible cause of myoclonus, regardless of its clinical characteristics.",
"affiliations": "Department of Neurology 935, Radboud University Medical Center, Donders Institute of Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.;Department of Neurology 935, Radboud University Medical Center, Donders Institute of Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.;Department of Neurology 935, Radboud University Medical Center, Donders Institute of Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands. Bart.vandewarrenburg@radboudumc.nl.",
"authors": "Janssen|Sabine|S|http://orcid.org/0000-0001-8470-3050;Bloem|Bastiaan R|BR|;van de Warrenburg|Bart P|BP|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000978:Antiparkinson Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00415-016-8357-z",
"fulltext": "\n==== Front\nJ NeurolJ. NeurolJournal of Neurology0340-53541432-1459Springer Berlin Heidelberg Berlin/Heidelberg 835710.1007/s00415-016-8357-zReviewThe clinical heterogeneity of drug-induced myoclonus: an illustrated review http://orcid.org/0000-0001-8470-3050Janssen Sabine sabineneuro.janssen@radboudumc.nl 12Bloem Bastiaan R. bas.bloem@radboudumc.nl 1van de Warrenburg Bart P. 0031-243613396Bart.vandewarrenburg@radboudumc.nl 11 Department of Neurology 935, Radboud University Medical Center, Donders Institute of Brain, Cognition and Behaviour, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands 2 0000 0004 0399 8953grid.6214.1Biomedical Signal and Systems Group, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, P.O. 217, 7500 AE Enschede, The Netherlands 16 12 2016 16 12 2016 2017 264 8 1559 1566 11 11 2016 30 11 2016 1 12 2016 © The Author(s) 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.A wide variety of drugs can cause myoclonus. To illustrate this, we first discuss two personally observed cases, one presenting with generalized, but facial-predominant, myoclonus that was induced by amantadine; and the other presenting with propriospinal myoclonus triggered by an antibiotic. We then review the literature on drugs that may cause myoclonus, extracting the corresponding clinical phenotype and suggested underlying pathophysiology. The most frequently reported classes of drugs causing myoclonus include opiates, antidepressants, antipsychotics, and antibiotics. The distribution of myoclonus ranges from focal to generalized, even amongst patients using the same drug, which suggests various neuro-anatomical generators. Possible underlying pathophysiological alterations involve serotonin, dopamine, GABA, and glutamate-related processes at various levels of the neuraxis. The high number of cases of drug-induced myoclonus, together with their reported heterogeneous clinical characteristics, underscores the importance of considering drugs as a possible cause of myoclonus, regardless of its clinical characteristics.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1007/s00415-016-8357-z) contains supplementary material, which is available to authorized users.\n\nKeywords\nDrug-induced myoclonusMyoclonus/phenotypeMyoclonus/physiopathologyNetherlands Organization for Scientific ResearchNetherlands Brain Foundationhttp://dx.doi.org/10.13039/501100001826ZonMwhttp://dx.doi.org/10.13039/100001262National Parkinson Foundationhttp://dx.doi.org/10.13039/501100003246Nederlandse Organisatie voor Wetenschappelijk OnderzoekInternationaal Parkinson FondsHersenstichting NederlandUCBhttp://dx.doi.org/10.13039/100006483AbbvieMichael J. Fox foundationAdamashttp://dx.doi.org/10.13039/100007773DanoneZambonissue-copyright-statement© Springer-Verlag GmbH Germany 2017\n==== Body\nIntroduction\nMyoclonus are involuntary sudden, brief, shock-like ‘jerky’ movements due to muscular contractions (‘positive myoclonus’) or sudden lapses of muscle contraction in active muscles (‘negative myoclonus’ or ‘asterixis’) [40, 44]. Myoclonus can be classified by distribution (focal, segmental, multifocal, and generalized) [75], by localization of the ‘pulse generator’ (cortical, subcortical, brainstem, spinal, or peripheral) [44], and by aetiology (physiological, essential, epileptic, symptomatic, and psychogenic) [44, 52]. In this paper, we review the phenomenon of drug-induced myoclonus, a subgroup of symptomatic myoclonus, with an emphasis on the clinical and pathophysiological heterogeneity of this phenomenon, which could mislead clinicians and result in insufficient consideration of drugs as the cause of myoclonus.\n\nWe first describe two personally observed cases of drug-induced myoclonus. Next, we present the results of our literature search on those drugs reported to cause myoclonus, including details of the corresponding clinical phenotype and, whenever available, data on the neuro-anatomical origins and pathophysiological processes.\n\nCase description\nCase A\nPatient A was a 79-year-old woman who developed her first ever epileptic seizure 2 days after the start of intravenous penicillin and ciprofloxacin prescribed for pneumonia. On neurological examination after the seizure she was alert but showed jerky movements of trunk, abdomen, and arms (particularly the right shoulder) more than of her legs that she could not suppress (video 1). The spread and temporal gradient of these jerks were particularly indicative of propriospinal myoclonus. EEG showed no epileptic phenomena, not even at the time when the movements occurred during recording. Antibiotic therapy was switched to claritromycin and ceftazidim, after which the myoclonus disappeared. The final diagnosis was that of ciprofloxacin and/or penicillin-induced propriospinal myoclonus.\n\nCase B\nPatient B was a 66-year-old man who had been diagnosed 12 years previously with Parkinson’s disease for which he took levodopa/benserazide 125 mg t.i.d. plus 125 mg b.i.d. as dispersible tablets, and ropinirole 6 mg b.i.d. His medical history reported a left-sided stereotactic thalamotomy because of a troublesome tremor of his right hand and a cervical disc herniation. Because of peak-dose dyskinesias and marked off periods during the night, amantadine was started and augmented to 100 mg t.i.d. Slow-release levodopa/benserazide ante noctum was added to the treatment regimen. One month after these treatment adjustments, the patient developed involuntary jerks through his whole body but predominantly in his face and neck, also severely affecting his speech. These jerks were not sensitive to stimuli and occurred mainly during action (both positive and negative) but were also present at rest. During walking, axial action myoclonus was apparent (video 2). The remaining examination showed an asymmetric hypokinetic-rigid syndrome, the severity of which was similar to prior examination. Suspecting drug-induced generalized myoclonus, amantadine was tapered off, and the myoclonus disappeared within 2 weeks.\n\nMethods\nSearch strategy\nWe searched PubMed using the MeSH terms “Myoclonus/chemically induced”, “Myoclonus/etiology”, “Myoclonus/pharmacology”, “Myoclonus/physiology”, “Myoclonus/physiopathology”, “Drug-Related Side Effects and Adverse Reactions”, and “Dyskinesia, Drug-Induced”. Only articles in English, published before September 2016, were reviewed for relevance.\n\nResults\nOur literature search on drug-induced myoclonus mainly identified case reports and (mostly small) case series (the largest involving 32 patients). Table 1 summarizes the number of cases reported per subclass of drugs associated with myoclonus, the distribution of myoclonus, and one or two relevant references per category. The full table with all references considered (Table 2) is available as supplementary material. Almost all classes of drugs have been linked to myoclonus. The clinical phenotype covered the whole spectrum, from a focal to a generalized distribution. The presumed anatomic structures and neurotransmitters involved are suggested to differ per causative agent. Drug-induced myoclonus was usually reversible following withdrawal of the offending drug [10, 44], and only a single case of persistent myoclonus has been reported [75]. We here describe the characteristics of myoclonus caused by the four classes of drugs most often reported in relation to myoclonus (opiates, antidepressants, antipsychotics, and antibiotics) and by the group of drugs involved in our case B (NMDA antagonists).Table 1 Case reports and illustrative references upon medication-induced myoclonus\n\nPharmacological class\tPharmacological subclass\tNumber of cases reported Illustrative reference(s)\n\t\nAll distributions\tFocal\tSegmental\tMultifocal\tGeneralized\tDistribution not described\t\nOpiates\tFull agonists\t105\t1 [47]\t–\t18 [32]\t13 [19]\t73 [7, 83\n78 ]\t\nPartial agonist–antagonist\t7\t–\t–\t–\t–\t7 [7]\t\nAntidepressants\tSelective serotonin-reuptake inhibitors (SSRIs)\t44\t–\t–\t2 [30]\t6 [86]\t36 [74]\t\nTricyclic antidepressants (TCAs)\t55\t5 [54]\t–\t2 [20]\t4 [68]\t44 [7, 8]\t\nLithium\t10\t–\t–\t6 [11, 20]\t2 [14]\t2 [7]\t\nMonoamine oxidase (MAO) inhibitors\t4\t–\t–\t1 [5]\t–\t3 [7]\t\nSerotonin-norepinephrine reuptake inhibitor (SNRI)\t1\t–\t–\t–\t1 [18]\t–\t\nNoradrenalin and dopamine reuptake inhibitors\t1\t1 [31]\t–\t–\t–\t–\t\nAntipsychotics\tTypical\t65\t–\t–\t56 [93]\t1 [16]\t8 [7]\t\nAtypical\t15\t–\t–\t5 [6]\t3 [92]\t7 [7]\t\nAntibiotics\tβ-lactams\t40\t–\t–\t3 [80]\t3 [87]\t34 [7, 79]\t\nQuinolones\t34\t–\t–\t2 [81]\t2 [21]\t30 [7]\t\nSulfonamides\t3\t–\t–\t2 [41]\t1 [58]\t–\t\nAminoglycosides\t6\t–\t–\t–\t1 [75]\t5 [7]\t\nAnxiolytics\tBenzodiazepines\t66\t–\t–\t7 [51]\t–\t59 [7]\t\nAnti-epileptics\tGabapentin\t27\t3 [4]\t–\t17 [4, 101]\t3 [77, 101]\t4 [7]\t\nPregabalin\t9\t1 [35]\t–\t8 [63]\t–\t–\t\nValproic acid\t10\t–\t–\t–\t1 [98]\t9 [1, 7]\t\nLamotrigine\t7\t–\t–\t3 [23]\t1 [13]\t3 [74]\t\nCarbamazepine\t5\t1 [50]\t–\t–\t–\t4 [7, 27]\t\nPhenytoine\t4\t–\t–\t–\t2 [17]\t2 [7]\t\nTopiramate\t4\t2 [45]\t–\t1 [3]\t1 [64]\t–\t\nPhenobarbital\t2\t–\t–\t–\t–\t2 [7]\t\nVigabatrin\t2\t–\t–\t2 [62]\t–\t–\t\nClobazam\t1\t–\t–\t–\t–\t1 [27]\t\nAnti-parkinsonians\tL-dopa\t28\t–\t–\t–\t–\t28 [7, 43, 90]\t\nDopamine agonists\t8\t–\t–\t–\t–\t8 [7, 90]\t\nNon-competitive (NMDA)-glutamatereceptor-antagonist (amantadine) (also see ‘anti-dementia’)\t10\t2 [31]\t–\t\t1 [96]\t7 [55]\t\nCOMT inhibitors\t1\t–\t–\t–\t–\t1 [7]\t\nMAO-inhibitors\t1\t–\t–\t–\t–\t1 [7]\t\nAnesthetics\tGeneral anesthetics\t42\t1 [89]\t15 [97]\t8 [97]\t7 [97, 46]\t11 [7]\t\nLocal anesthetics\t4\t–\t–\t4 [2]\t–\t–\t\nAnti-dementia\tCholinesterase inhibitors\t18\t–\t–\t–\t–\t18 [7]\t\nNon-competitive (NMDA)-glutamatereceptor-antagonist (memantine) (also see anti-parkinsonians)\t9\t–\t1 [69]\t–\t3 [60]\t5 [7, 66]\t\nCytostatics\tIfosfamide\t5\t–\t–\t1 [56]\t4 [76]\t–\t\nPrednimustine\t4\t–\t–\t3 [53, 59]\t1 [53]\t–\t\nChlorambucil\t2\t–\t–\t1 [95]\t–\t1 [95]\t\nOthers\tAnti-emetics\t23\t1 [36]\t1 [61]\t2 [12]\t–\t19 [7]\t\nAnti-arrhythmics\t5\t–\t–\t3 [91]\t1 [84]\t1 [7]\t\nVitamins\t5\t–\t–\t4 [99]\t1 [65]\t–\t\nAnti-hypertensives\t2\t–\t–\t2 [88]\t–\t–\t\nContrast agents\t3\t1 [24]\t–\t2 [9]\t–\t–\t\nImmunomodulating drugs\t2\t–\t–\t1 [22]\t–\t1 [7]\t\nAnti-fibrinolytic agents\t1\t–\t–\t1 [34]\t–\t–\t\nAnti-histamines\t1\t–\t–\t–\t1 [37]\t–\t\nAnti-hypotensives\t1\t–\t–\t–\t–\t1 [94]\t\nAnti-tussives\t1\t–\t–\t–\t1 [82]\t–\t\nAdrenergic bronchodilators\t3\t–\t–\t3 [57]\t–\t–\t\nNSAID\t1\t–\t–\t–\t–\t1 [7]\t\nAnti-viral agents\t1 \t– \t– \t1 [28]\t– \t– \t\nAnti-malaria prophylaxis\t1 \t– \t– \t1 [39]\t– \t– \t\nClasses and subclasses of drugs described to cause drug-induced myoclonus. References were sorted to distribution of myoclonus. The numbers of reported cases of drug-induced myoclonus are listed. One or two illustrative reference(s) per distribution is/are listed in superscript\n\n– No studies describing myoclonus with this distribution, for this class of drugs. The references used to count the number of cases reported are listed in Table 2 available as ‘supplementary material’\n\n\n\n\nOpiates\nMyoclonus may occur as a result of initial administration, change, or withdrawal of opiates [19, 32, 47]. Mainly generalized, but also multifocal and a single case of focal myoclonus have been described (Table 1, and supplementary Table 2). Opiate-related myoclonus occurs more frequently in patients concurrently treated with antidepressant, antipsychotic, antiemetic, or nonsteroidal anti-inflammatory drugs [47]. The precise pathophysiology remains poorly understood. A neuro-excitatory effect of opioid compounds and metabolites has been attributed to glutamate activation of N-methyl-D-aspartate (NMDA) receptors, glycine-mediated disinhibition of neural pathways at the cortical or spinal level, antagonism of gamma-amino-butyric acid (GABA) activity in the spinal cord, serotonergic and GABAergic pathways in the brainstem, and dopaminergic pathways in the basal ganglia [32].\n\nAntidepressants\nVarious classes of antidepressants have been associated with myoclonus (Table 1, and supplementary Table 2). Selective serotonin-reuptake inhibitors (SSRIs) can cause multifocal [30, 67] or generalized myoclonus [48, 64, 86]. Tricyclic antidepressants (TCAs) can cause either focal (especially jaw) [26, 54], multifocal [20, 42], and generalized [14, 49, 68, 98] myoclonus. Lithium has been observed to cause multifocal [11, 20] and generalized [14] myoclonus. An EEG transient over the contralateral sensorimotor region preceding the myoclonus suggested a cortical origin of myoclonus in patients treated with a TCA [20] or lithium [11]. Serotoninergic mechanisms are probably involved in the generation of antidepressant-induced myoclonus [30]. While SSRIs increase serotonin levels in the synaptic cleft, TCAs increase serotonin activity, and lithium facilitates the presynaptic release of serotonin [20]. A combination of two serotonergic active drugs, such as a TCA and lithium, appears more likely to cause myoclonus than a single drug [14, 20].\n\nAntipsychotics\nClassic antipsychotics, including haloperidol, have been reported to cause multifocal myoclonus of both arms, sensitive to posture [25, 85]; of limbs and of the face [16]; and of the trunk and limbs [93]. Atypical antipsychotics, including quetiapine and olanzapine, can cause both multifocal [33, 72] and generalized [29, 73, 92] myoclonus. The exact pathogenesis of antipsychotic-induced myoclonus has not yet been unraveled, but involvement of serotonergic [16, 72], dopaminergic [93], and GABA-ergic [92] mechanisms have all been suggested.\n\nAntibiotics\nAntibiotic-induced myoclonus mainly occurs in association with high or toxic doses of antibiotics and/or underlying renal disease [75]. It is commonly accompanied by other symptoms, such as altered mental state, seizures (similar to our case A), aphasia, chorea, and skin rash [75]. Myoclonus due to β-lactam antibiotics clinically varies from subtle peri-ocular twitching to generalized myoclonus [75]. Myoclonus due to quinolones can be generalized [21, 38] or multifocal [81]. It is hypothesized that β-lactam antibiotics selectively antagonize [75] and quinolones completely inhibit [71] gamma aminobutyric acid (GABA) receptors, decreasing their inhibitory activity at nerve terminals, thus inducing a hyperexcitable neuronal state of the central nervous system that triggers myoclonus. Sulfonamides have been associated with multifocal and generalized myoclonus. A causative role of altered dopamine metabolism due to inhibition of dihydrofolate reductase [15] as well as increased phenylalanine levels due to the inhibition of phenylalanine metabolism have been proposed [41]. Multifocal myoclonus that is due to aminoglycosides has been attributed to NMDA receptor activation and subsequent excitotoxicity.\n\nNMDA antagonists\nMyoclonus due to N-methyl-D-aspartate (NMDA) receptor antagonists has rarely been reported. Amantadine has been shown to reduce levodopa-induced dyskinesias [100] but paradoxically has also been reported to induce jaw myoclonus in two patients [31, 70] and generalized myoclonus in four patients [55, 96]. In addition, memantine gave rise to myoclonus in patients with dementia [58, 60, 66]. The mechanism underlying amantadine and memantine induced myoclonus remains unclear, but might involve altered levels of dopamine, serotonin, and/or glutamate release [55, 96].\n\nConclusion\nA French pharmacovigilance database study [7], registering all compulsorily reported adverse drug reactions in France, reported an incidence of drug-induced myoclonus of 0.2% (423/185.634 reported adverse events over a 20-year period), which might be an underestimation due to underreporting [7]. Our literature survey is not suitable to extract epidemiological data, but the large number of case reports that we identified does suggest that drug-induced myoclonus is not an uncommon phenomenon in movement disorder consultations. Of course, we cannot offer certainty about causality for the observed associations between drugs and myoclonus, which is inherent to a literature review of case reports and case series. However, in many cases, myoclonus appeared shortly after the prescription of a new (and presumably causally involved) drug, and disappeared again readily after this same drug was stopped, suggesting a causal relationship.\n\nOur survey—as well as the French pharmacovigilance database study—found that the most important groups of drugs with links to myoclonus are: opiates, antidepressants, antipsychotic drugs, and antibiotics. However, drug-induced myoclonus may also be caused by a wide variety of other drugs. Drug-induced myoclonus is usually reversible upon discontinuation of the offending drug, and this stresses the importance of making the correct diagnosis of drug-induced myoclonus. Importantly, the phenomenology of the myoclonus can vary within a group of drugs and even for one particular drug, suggesting that the neuro-anatomical generator varies. From a clinical perspective, this also means that drugs as a cause cannot be discarded based solely on clinical myoclonus characteristics. The precise cellular and neurochemical alterations that make a certain drug cause myoclonus remain largely unclear and therefore need further study.\n\nElectronic supplementary material\nBelow is the link to the electronic supplementary material.\nSupplementary material 1 (DOCX 215 kb)\n\n \nSupplementary material 2 (DOCX 11 kb)\n\n \nSupplementary material 3 (MP4 18275 kb)\n\n \nSupplementary material 4 (MP4 11868 kb)\n\n \n\n\nElectronic supplementary material\n\nThe online version of this article (doi:10.1007/s00415-016-8357-z) contains supplementary material, which is available to authorized users.\n\nS Janssen: is supported by a research Grant from the Netherlands Organization for Scientific Research. BP van de Warrenburg: receives research support from the Radboud University Medical Center, the Netherlands Brain Foundation, and ZonMW. BR Bloem: receives research funding from the National Parkinson Foundation, the Netherlands organization for scientific research, International Parkinson Fonds, Hersenstichting Nederland, UCB, Abbvie and the Michael J Fox Foundation. He received honoraria from Adamas, Abbvie, Danone, Zambon. We are very grateful to J.P. Bulstra and J.H.M. Janssen for their help with editing the video material.\n\nCompliance with ethical standards\nConflicts of interest\nS Janssen: no conflicts of interest to declare. BP van de Warrenburg: no conflicts of interest to declare. BR Bloem: no conflicts of interest to declare.\n==== Refs\nReferences\n1. Aguglia U Gambardella A Zappia M Valentino P Quattrone A Negative myoclonus during valproate-related stupor. Neurophysiological evidence of a cortical non-epileptic origin Electroencephalogr Clin Neurophysiol 1995 94 103 108 10.1016/0013-4694(94)00268-P 7532570 \n2. 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Patterson JF Myoclonus caused by a tricyclic antidepressant South Med J 1990 83 463 465 10.1097/00007611-199004000-00026 2181694 \n69. Pei LJ Tianzhi IL Lim WS Memantine-induced myoclonus precipitated by renal impairment and drug interactions J Am Geriatr Soc 2015 63 2643 2644 10.1111/jgs.13847 26691710 \n70. Pfeiffer RF Amantadine-induced “vocal” myoclonus Mov Disord 1996 11 104 106 10.1002/mds.870110123 8771080 \n71. Post B Koelman JH Tijssen MA Propriospinal myoclonus after treatment with ciprofloxacin Mov Disord 2004 19 595 597 10.1002/mds.10717 15133830 \n72. Praharaj SK Venkatesh BG Sarkhel S Zia-ul-Haq M Sinha VK Clozapine-induced myoclonus: a case study and brief review Prog Neuropsychopharmacol Biol Psychiatry 2010 34 242 243 10.1016/j.pnpbp.2009.10.006 19833162 \n73. Rosen JB Milstein MJ Haut SR Olanzapine-associated myoclonus Epilepsy Res 2012 98 247 250 10.1016/j.eplepsyres.2011.07.020 22196307 \n74. Rosenhagen MC Schmidt U Weber F Steiger A Combination therapy of lamotrigine and escitalopram may cause myoclonus J Clin Psychopharmacol 2006 26 346 347 10.1097/01.jcp.0000219927.49799.c0 16702909 \n75. Sarva H Panichpisal K Gentamicin-induced myoclonus: a case report and literature review of antibiotics-induced myoclonus Neurologist 2012 18 385 388 10.1097/NRL.0b013e3182704d78 23114671 \n76. Savica R Rabinstein AA Josephs KA Ifosfamide associated myoclonus-encephalopathy syndrome J Neurol 2011 258 1729 1731 10.1007/s00415-011-5990-4 21399985 \n77. Shea YF Mok MM Chang RS Gabapentin-induced myoclonus in an elderly with end-stage renal failure. Journal of the Formosan Medical Association = Taiwan yi zhi 2014 113 660 661 10.1016/j.jfma.2012.06.001 25103080 \n78. Sjogren P Thunedborg LP Christrup L Hansen SH Franks J Is development of hyperalgesia, allodynia and myoclonus related to morphine metabolism during long-term administration? Six case histories Acta Anaesthesiol Scand 1998 42 1070 1075 10.1111/j.1399-6576.1998.tb05378.x 9809090 \n79. Sonck J Laureys G Verbeelen D The neurotoxicity and safety of treatment with cefepime in patients with renal failure Nephrol Dial Transplant 2008 23 966 970 10.1093/ndt/gfm713 18175786 \n80. Spina Silva T Dal-Pra Ducci R Zorzetto FP Braatz VL de Paola L Kowacs PA Meropenem-induced myoclonus: a case report Seizure 2014 23 912 914 10.1016/j.seizure.2014.06.017 25066813 \n81. Striano P Zara F Coppola A Ciampa C Pezzella M Striano S Epileptic myoclonus as ciprofloxacin-associated adverse effect Mov Disord 2007 22 1675 1676 10.1002/mds.21456 17516482 \n82. Tanaka A Nagamatsu T Yamaguchi M Nomura A Nagura F Maeda K Tomino T Watanabe T Shimizu H Fujita Y Ito Y Myoclonus after dextromethorphan administration in peritoneal dialysis Ann Pharmacother 2011 45 e1 10.1345/aph.1P301 21228393 \n83. Thwaites D McCann S Broderick P Hydromorphone neuroexcitation J Palliat Med 2004 7 545 550 10.1089/jpm.2004.7.545 15353098 \n84. Ting SM Lee D Maclean D Sheerin NS Paranoid psychosis and myoclonus: flecainide toxicity in renal failure Cardiology 2008 111 83 86 10.1159/000119694 18376118 \n85. Tominaga H Fukuzako H Izumi K Koja T Fukuda T Fujii H Matsumoto K Sonoda H Imamura K Tardive myoclonus Lancet 1987 1 322 10.1016/S0140-6736(87)92042-3 2880125 \n86. Tremolizzo L Fermi S Fusco ML Susani E Frigo M Piolti R Ferrarese C Appollonio I Generalized action myoclonus associated with escitalopram in a patient with mixed dementia J Clin Psychopharmacol 2011 31 394 395 10.1097/JCP.0b013e318218f4d5 21532372 \n87. Uchihara T Tsukagoshi H Myoclonic activity associated with cefmetazole, with a review of neurotoxicity of cephalosporins Clin Neurol Neurosurg 1988 90 369 371 10.1016/0303-8467(88)90013-3 3233864 \n88. Vadlamudi L Wijdicks EF Multifocal myoclonus due to verapamil overdose Neurology 2002 58 984 10.1212/WNL.58.6.984 11914425 \n89. Van Keulen SG Burton JH Myoclonus associated with etomidate for ED procedural sedation and analgesia Am J Emerg Med 2003 21 556 558 10.1016/j.ajem.2003.08.004 14655236 \n90. Vardi J Glaubman H Rabey JM Streifler M Myoclonic attacks induced by L-dopa and bromocryptin in Parkinson patients: a sleep EEG study J Neurol 1978 218 35 42 10.1007/BF00314716 77316 \n91. Velasco SL Sierra-Hidalgo F Rodriguez RM Guerreo AJ Morales JR Flecainide-induced myoclonus Clin Neuropharmacol 2014 37 65 66 10.1097/WNF.0000000000000025 24614665 \n92. Velayudhan L Kirchner V Quetiapine-induced myoclonus Int Clin Psychopharmacol 2005 20 119 120 10.1097/00004850-200503000-00011 15729090 \n93. Vural A Tezer FI Myoclonus induced by haloperidol in the intensive care unit J Neuropsychiatry Clin Neurosci 2012 24 E41 10.1176/appi.neuropsych.11080179 23037679 \n94. Wierre L Decaudin B Barsumau J Vairon MX Horrent S Odou P Azar R Dobutamine-induced myoclonia in severe renal failure Nephrol Dial Transplant 2004 19 1336 1337 10.1093/ndt/gfh132 15102987 \n95. Wyllie AR Bayliff CD Kovacs MJ Myoclonus due to chlorambucil in two adults with lymphoma Ann Pharmacother 1997 31 171 174 10.1177/106002809703100207 9034417 \n96. Yarnall AJ Burn DJ Amantadine-induced myoclonus in a patient with progressive supranuclear palsy Age Ageing 2012 41 695 696 10.1093/ageing/afs043 22421702 \n97. Yates AM Wolfson AB Shum L Kehrl T A descriptive study of myoclonus associated with etomidate procedural sedation in the ED Am J Emerg Med 2013 31 852 854 10.1016/j.ajem.2013.02.042 23558062 \n98. Yoon JH Lee PH Yong SW Park HY Lim TS Choi JY Movement disorders at a university hospital emergency room. An analysis of clinical pattern and etiology J Neurol 2008 255 745 749 10.1007/s00415-008-0789-7 18338197 \n99. Zanus C Alberini E Costa P Colonna F Zennaro F Carrozzi M Involuntary movements after correction of vitamin B12 deficiency: a video-case report Epileptic Disord 2012 14 174 180 22591802 \n100. Zesiewicz TA Sullivan KL Hauser RA Levodopa-induced dyskinesia in Parkinson’s disease: epidemiology, etiology, and treatment Curr Neurol Neurosci Rep 2007 7 302 310 10.1007/s11910-007-0046-y 17618536 \n101. Zhang C Glenn DG Bell WL O’Donovan CA Gabapentin-induced myoclonus in end-stage renal disease Epilepsia 2005 46 156 158 10.1111/j.0013-9580.2005.20804.x 15660783\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0340-5354",
"issue": "264(8)",
"journal": "Journal of neurology",
"keywords": "Drug-induced myoclonus; Myoclonus/phenotype; Myoclonus/physiopathology",
"medline_ta": "J Neurol",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000978:Antiparkinson Agents; D004409:Dyskinesia, Drug-Induced; D004831:Epilepsies, Myoclonic; D005260:Female; D006801:Humans; D008297:Male; D009207:Myoclonus; D010300:Parkinson Disease; D011014:Pneumonia",
"nlm_unique_id": "0423161",
"other_id": null,
"pages": "1559-1566",
"pmc": null,
"pmid": "27981352",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "24238149;21399985;25784625;15353098;27510560;25802272;12640092;3233864;21339907;8771080;23114671;20817933;19050415;19099135;23037679;25956204;16702909;1971187;23558062;3148641;7737496;8635188;11160978;17632233;9034417;21228393;11436961;18344744;12084448;18376118;3934939;15102987;15188079;831550;9813796;26317045;24614665;20740488;11779671;18226283;14655236;2181694;19526195;19833162;17336778;3379388;17618536;8474499;16960855;17516482;6886043;10756416;8998190;20932710;12633152;10202603;8835715;2880125;26691710;11914425;3827519;11483404;3966657;18175786;20578939;15133830;15380156;22421702;16772816;18581470;9921884;8041377;1082146;25103080;8033934;14728056;17922777;18303133;9809090;18338197;8142134;3372713;22591802;14702438;22584239;15729090;1474184;15660783;21532372;3693873;11422338;12410053;7532570;9776334;8937794;77316;10822452;16157917;25066813;22196307",
"title": "The clinical heterogeneity of drug-induced myoclonus: an illustrated review.",
"title_normalized": "the clinical heterogeneity of drug induced myoclonus an illustrated review"
} | [
{
"companynumb": "NL-ACCORD-097537",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENSERAZIDE\\LEVODOPA"
},
"drugadditional": "3",
... |
{
"abstract": "Acanthamoeba encephalitis is a rare, often fatal condition, particularly after HSCT, with 9 reported cases to date in the world literature. Our case was originally diagnosed with ALL at age 3 years, and after several relapses underwent HSCT at age 9 years. At 17 years of age, he was diagnosed with secondary AML for which he underwent a second allogeneic HSCT. He presented with acute-onset worsening neurological deficits on day +226 after the second transplant and a post-mortem diagnosis of Acanthamoeba encephalitis was established, with the aid of the CDC.",
"affiliations": "Department of Pediatrics, Division of Hematology/Oncology/BMT, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.;Department of Pediatrics, Division of Infectious Diseases, Host Defense Program, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.;Department of Pediatrics, Division of Critical Care, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.;Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH, USA.;Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA.;Centers for Disease Control and Prevention (CDC), Atlanta, GA, USA.;Department of Pediatrics, Division of Infectious Diseases, Host Defense Program, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.;Department of Pediatrics, Division of Critical Care, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.;Department of Pediatrics, Division of Critical Care, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.;Department of Pediatrics, Division of Hematology/Oncology/BMT, Nationwide Children's Hospital and The Ohio State University, Columbus, OH, USA.",
"authors": "Coven|Scott L|SL|http://orcid.org/0000-0003-2763-7928;Song|Eunkyung|E|;Steward|Sarah|S|;Pierson|Christopher R|CR|;Cope|Jennifer R|JR|;Ali|Ibne K|IK|;Ardura|Monica I|MI|;Hall|Mark W|MW|;Chung|Melissa G|MG|;Bajwa|Rajinder P S|RPS|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13060",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "21(8)",
"journal": "Pediatric transplantation",
"keywords": "bone marrow transplantation; infectious disease; secondary leukemia",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000048:Acanthamoeba; D000293:Adolescent; D000562:Amebiasis; D017809:Fatal Outcome; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D000069544:Infectious Encephalitis; D015470:Leukemia, Myeloid, Acute; D008297:Male",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28921764",
"pubdate": "2017-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acanthamoeba granulomatous amoebic encephalitis after pediatric hematopoietic stem cell transplant.",
"title_normalized": "acanthamoeba granulomatous amoebic encephalitis after pediatric hematopoietic stem cell transplant"
} | [
{
"companynumb": "US-ASTELLAS-2017US052421",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nDisability weights (DWs) are used in disease burden studies, with the calculation of the weight of the disability as years lived with disability versus years of lost life accounting for mortalities. Currently, there is a single DW score available for poisoning, which is considered to be a single health state. This makes it difficult to evaluate the differing burdens of poisonings involving various substances/conditions in comparison with other health states in countries with different patterns of substance abuse. The aim of this study is therefore to estimate the DWs of 18 common poisonings based on the expert elicitation method.\n\n\nMETHODS\nA panel of 10 medical clinicians who were familiar with the clinical aspects of different poisonings estimated the DWs of 50 health states by interpolating them on a calibrated Visual Analogue Scale. The DWs of some poisonings, such as alcohol, cannabis and heroin, had been estimated in previous studies and so were used to determine the external consistency of our panel. As a matter of routine, the DWs could vary on a scale between 0 (best health state) and 1 (worst health state).\n\n\nRESULTS\nStatistical analysis showed that both the internal (Cronbach's α = 0.912) and external consistency of the panel were acceptable. The DWs for the different poisonings were estimated along a range from 0.830 for severe aluminium phosphide to 0.022 for mild benzodiazepine.\n\n\nCONCLUSIONS\nDifferent poisonings should be weighted differently since they vary widely. Unfortunately, they are currently all weighted the same.",
"affiliations": "Medical Toxicology Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran.;Addiction Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran BC Disease Control Center, Vancouver, Canada afsharir@mums.ac.ir afsharireza@yahoo.com.;Addiction Research Centre, Mashhad University of Medical Sciences, Mashhad, Iran.",
"authors": "Asadi|R|R|;Afshari|R|R|;Dadpour|B|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/0960327115617229",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-3271",
"issue": "35(10)",
"journal": "Human & experimental toxicology",
"keywords": "Acute poisoning; disability weights; disability-adjusted life year; intentional substance abuse; medical toxicology",
"medline_ta": "Hum Exp Toxicol",
"mesh_terms": "D000208:Acute Disease; D003627:Data Interpretation, Statistical; D004185:Disability Evaluation; D006233:Disabled Persons; D006304:Health Status; D006801:Humans; D015588:Observer Variation; D017063:Outcome Assessment, Health Care; D011041:Poisoning; D019057:Quality-Adjusted Life Years; D012720:Severity of Illness Index; D011795:Surveys and Questionnaires",
"nlm_unique_id": "9004560",
"other_id": null,
"pages": "1033-40",
"pmc": null,
"pmid": "26655638",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The measurement of disability weights for 18 prevalent acute poisoning conditions.",
"title_normalized": "the measurement of disability weights for 18 prevalent acute poisoning conditions"
} | [
{
"companynumb": "IR-JNJFOC-20161012835",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Anticoagulation with unfractionated heparin is vital to reduce the risk of thromboembolic events during cardiopulmonary bypass and left ventricular assist device placement. However patients with heparin-induced thrombocytopenia are at risk of developing immune-mediated thrombotic events. We describe 2 patients with heparin-induced thrombocytopenia confirmed via serotonin release assay who were successfully treated with plasmapheresis exchange before left ventricular assist device placement.",
"affiliations": "Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, Houston, Texas.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, Houston, Texas; Department of Cardiopulmonary Transplantation and the Center for Cardiac Support, Texas Heart Institute, Houston, Texas. Electronic address: lamba@bcm.edu.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, Houston, Texas; Department of Cardiopulmonary Transplantation and the Center for Cardiac Support, Texas Heart Institute, Houston, Texas.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, Houston, Texas; Department of Cardiopulmonary Transplantation and the Center for Cardiac Support, Texas Heart Institute, Houston, Texas.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, Houston, Texas; Department of Cardiopulmonary Transplantation and the Center for Cardiac Support, Texas Heart Institute, Houston, Texas.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, Houston, Texas; Department of Cardiopulmonary Transplantation and the Center for Cardiac Support, Texas Heart Institute, Houston, Texas.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, Houston, Texas; Department of Cardiopulmonary Transplantation and the Center for Cardiac Support, Texas Heart Institute, Houston, Texas.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, Houston, Texas; Department of Cardiopulmonary Transplantation and the Center for Cardiac Support, Texas Heart Institute, Houston, Texas.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, Houston, Texas; Department of Cardiopulmonary Transplantation and the Center for Cardiac Support, Texas Heart Institute, Houston, Texas.;Division of Cardiothoracic Transplantation and Circulatory Support, Baylor College of Medicine, Houston, Texas.",
"authors": "Maffei|Salvador R|SR|;Lamba|Harveen K|HK|;Mensah|Cassius Kwasi|CK|;Bracey|Arthur|A|;Civitello|Andrew|A|;Delgado|Reynolds|R|;Simpson|Leo|L|;Nair|Ajith|A|;Frazier|O H|OH|;Morgan|Jeffrey A|JA|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2019.09.056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "109(6)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D000925:Anticoagulants; D006353:Heart-Assist Devices; D006493:Heparin; D006801:Humans; D008297:Male; D008875:Middle Aged; D010956:Plasmapheresis; D013921:Thrombocytopenia; D013927:Thrombosis",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e439-e440",
"pmc": null,
"pmid": "31715152",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Plasmapheresis in Patients With Heparin-induced Thrombocytopenia Requiring Ventricular Assist Device.",
"title_normalized": "plasmapheresis in patients with heparin induced thrombocytopenia requiring ventricular assist device"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK202005988",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null... |
{
"abstract": "BACKGROUND\nProphylactic granulocyte-colony stimulating factor(G-CSF)is necessary for some cancer patients receiving anti-cancer drugs. However, it is difficult for cancer patients in rural areas to receive G-CSF as outpatients because of inconvenient official transport, lack of public support, and low activity levels due to age. To resolve this problem, we began conducting a critical path(G-path)with regional medical institutions from 2011.\n\n\nMETHODS\nWe retrospectively surveyed the clinical records of cancer patients receiving prophylactic G-CSF using G-path at our hospital.\n\n\nRESULTS\nEighty-two patients who were administered a total of 254 cycles of chemotherapy were examined between January 2011 and December 2016. Diseases included malignant lymphoma(n=64), pancreatic cancer(n=7), soft tissue sarcoma(n=5), and others(n=6). The median age of the patients was 70(range: 24-94)years. Fifty-three patients visited medical offices, and 31 patients visited regional hospitals. In 245 of 254(96%)cycles, planned G-CSF administration was performed. In 37 of 254(15%)cycles, infectious episodes developed, but patients needed hospitalization for only 5 cycles(2%).\n\n\nCONCLUSIONS\nCooperation between clinics and hospitals using G-path reduced ambulatory burden and prevented severe infection. Cooperation in supportive care may allow for equal accessibility to cancer treatment.",
"affiliations": "Dept. of Oncology/Hematology, Shimane University Hospital.",
"authors": "Takahashi|Tsutomu|T|;Takahashi|Fumimasa|F|;Okada|Yusuke|Y|;Ito|Shunsuke|S|;Ugata|Norimi|N|;Shimasaki|Yasumasa|Y|;Mochida|Hiroshi|H|;Matsuda|Shinichiro|S|;Okada|Takahiro|T|;Kumanomidou|Satoshi|S|;Jo|Yumi|Y|;Adachi|Koji|K|;Ikejiri|Fumiyoshi|F|;Onishi|Chie|C|;Kawakami|Koshi|K|;Moriyama|Ichiro|I|;Inoue|Masaya|M|;Miyake|Takaaki|T|;Suzuki|Ritsuro|R|;Suzumiya|Junji|J|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(3)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D019091:Critical Pathways; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008875:Middle Aged; D009503:Neutropenia; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "457-461",
"pmc": null,
"pmid": "30914584",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cooperation between Clinics and Hospitals Using a Critical Path for G-CSF Prophylaxis in Cancer Chemotherapy.",
"title_normalized": "cooperation between clinics and hospitals using a critical path for g csf prophylaxis in cancer chemotherapy"
} | [
{
"companynumb": "JP-ROCHE-2303004",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LENOGRASTIM"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nPrimary Central Nervous System Lymphoma (PCNSL) remains a diagnostic challenge due to the variable clinical manifestations. Liquid biopsies, particularly those involving cell-free DNA (cfDNA) from plasma, are rapidly emerging as important and minimally invasive adjuncts to traditional biopsies. However, conventional pathology may be still essential to obtain a diagnosis.\nA 56-year-old woman presented with a progressive headache, dizziness, blurred vision, and lower limbs weakness with dysesthesia. Atypical clinical and radiological presentations, previous empirical treatment in another hospital, together with the patient's refusal to stereotactic brain biopsy made it challenging to diagnose. Her status deteriorated continuously during hospitalization.\n\n\nMETHODS\nLumber punctual was performed, and CSF cytological analysis revealed malignancy cells with a high nuclear-cytoplasmic ratio. However, these cells were too loose to perform immunohistochemical stains. Genetic aberrations detections with CSF and peripheral blood sample were also inconclusive. We made a \"cell-block\" using the sedimentary cells collected from CSF collected through multiple aspirations via an Omaya reservoir. We further performed cytopathological and immunohistochemical analysis using this \"cell-block,\" which finally confirmed the diagnosis of diffuse large-B cell PCNSL.\n\n\nMETHODS\nIntracranial chemotherapy began afterwards (MTX 15 mg and dexamethasone 5 mg, twice per weeks).\n\n\nRESULTS\nUnfortunately, this patient was dead 2 weeks later due to severe myelosuppression and secondary septic shock.\n\n\nCONCLUSIONS\nWe provided \"cell-block\" method, which collects cell components from large amount of CSF for cytology and immunohistochemical analysis. \"Cell-block\" cytology can be an alternative diagnostic method in diagnosis of PCNSL.",
"affiliations": "The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.",
"authors": "Huang|Kaiyuan|K|;Zhou|Lei|L|;Tong|Ying|Y|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1097/MD.0000000000019598",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\n32243381\nMD-D-19-05823\n10.1097/MD.0000000000019598\n19598\n5700\nResearch Article\nClinical Case Report\nCell-Block cytology in diagnosis of primary central nervous system lymphoma\nA case reportHuang Kaiyuan MD Zhou Lei MD Tong Ying MD∗ NA. The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.\n∗ Correspondence: Ying Tong, The First Affiliated Hospital, Zhejiang University School of Medicine, #79 Qingchun Road, Hangzhou, Zhejiang Province 310003, China (e-mal: 1194054@zju.edu.cn).\n4 2020 \n03 4 2020 \n99 14 e1959801 8 2019 30 12 2019 18 2 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nIntroduction:\nPrimary Central Nervous System Lymphoma (PCNSL) remains a diagnostic challenge due to the variable clinical manifestations. Liquid biopsies, particularly those involving cell-free DNA (cfDNA) from plasma, are rapidly emerging as important and minimally invasive adjuncts to traditional biopsies. However, conventional pathology may be still essential to obtain a diagnosis.\n\nPatient concerns:\nA 56-year-old woman presented with a progressive headache, dizziness, blurred vision, and lower limbs weakness with dysesthesia. Atypical clinical and radiological presentations, previous empirical treatment in another hospital, together with the patient's refusal to stereotactic brain biopsy made it challenging to diagnose. Her status deteriorated continuously during hospitalization.\n\nDiagnosis:\nLumber punctual was performed, and CSF cytological analysis revealed malignancy cells with a high nuclear-cytoplasmic ratio. However, these cells were too loose to perform immunohistochemical stains. Genetic aberrations detections with CSF and peripheral blood sample were also inconclusive. We made a “cell-block” using the sedimentary cells collected from CSF collected through multiple aspirations via an Omaya reservoir. We further performed cytopathological and immunohistochemical analysis using this “cell-block,” which finally confirmed the diagnosis of diffuse large-B cell PCNSL.\n\nInterventions:\nIntracranial chemotherapy began afterwards (MTX 15 mg and dexamethasone 5 mg, twice per weeks).\n\nOutcomes:\nUnfortunately, this patient was dead 2 weeks later due to severe myelosuppression and secondary septic shock.\n\nConclusion:\nWe provided “cell-block” method, which collects cell components from large amount of CSF for cytology and immunohistochemical analysis. “Cell-block” cytology can be an alternative diagnostic method in diagnosis of PCNSL.\n\nKeywords\nCell-blockcell-free DNAcerebrospinal fluidliquid biopsyPrimary Central Nervous System LymphomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPrimary Central Nervous System Lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma (NHL), which can involve the brain, eye leptomeninges, and rarely spinal cord without evidence of systemic disease.[1] It remains a diagnostical challenge as PCNSL may present with diverse neurological symptoms.[2–4] Radiologically, PCNSL lesions most typically enhance homogeneously on T1-weighted magnetic resonance imaging (MRI) and appear T2-hypointense, but high variability in MRI features is commonly encountered.[2] Besides, these MRI findings can mimic high-grade gliomas, metastatic tumors, tumefactive demyelinating lesions, or infectious and granulomatous diseases.[5,6] Some recent studies suggest a role of advanced MRI and metabolic imaging such as fluorodeoxyglucose positron emission tomography (FDG-PET) in distinguishing PCNSL from these entities.[7,8] However, the histological analysis of biopsy material is still regarded as a gold standard. Unfortunately, major complications can arise during the procedure of a brain biopsy, such as intracranial hemorrhage or functional impairment.[9]\n\nThe NCCN guideline for PCNSL also suggests 15 to 20 mL spinal CSF sampling to increase diagnostic yield under a safe condition. CSF analysis should include flow cytometry and CSF cytology and possibly gene rearrangements. However, the predictive value is still very low due to the sparsity of malignant cells in the CSF. Presently, liquid biopsies often use cerebrospinal fluid (CSF) for cytomorphologic and flow cytometric analysis in PCNSL diagnosis.[9] Liquid biopsy also is a real-time sampling of circulating tumor cells, nucleotides from biofluids, which offers a promising, less-invasive mean to obtain tumor genetics and monitor tumor evolution in patients with both primary and secondary CNS malignancies.[2,9–11] Presently, mutations in specific genes (e.g., MYD88, PIM1, ATM, and TP53), dysregulation in signaling pathways (e.g., JAK/STAT, NF-kB, toll-like receptor, and B-cell receptor), and some translocations and copy number alterations (e.g., 9p.24/PD-L1/PD-2) has been identified as new biomarkers for PCNLS diagnosis, which further expand the diagnostic armamentarium.[6,9,12,13] Emerging data suggest a role for CSF molecular analysis in improving the sensitivity and specificity of liquid biopsies. Some biomarker may even predict prognosis and response to treatments.[3,9]\n\nHowever, it is incapable of concluding diagnose purely based on molecular diagnosis. Thus, a special CSF procedure may need to provide conventional pathological supports. Here, we present a case, in which a PCNSL patient with atypical clinical and radiological presentations failed to conclude a diagnosis by gene sequencing. The final diagnosis was achieved by a “cell-block” method and subsequent classic histopathological analysis.\n\n2 Case presentation\nA 56-year-old woman presented with a progressive headache, dizziness, blurred vision, and lower limbs weakness with dysesthesia. Her symptoms initiated four months before this presentation, and she went to the local hospital for examination. Gadolinium-enhanced contrast MRI revealed multiple intracranial mass with ring enhancement. Metastatic malignancy was the primary consideration. She underwent FDG-PET scan afterward, which showed an increased FDG uptake in the callosal area with a maximal standardized uptake value (SUV) of 16.5, and areas abutting the fourth ventricle with a maximal SUV of 16.2 (Fig. 1). However, PET-CT did not reveal any extracranial lesion. Spinal MRI revealed Chiari I malformation without lesions found at that time. Laboratory tests, including red-cell count, white-cell count, platelet count, renal- and liver function tests, were unrevealing except a decreased CD4+, CD8+, and CD3+ lymphocytes. The patient denied stereotactic biopsy, but she received radiotherapy for treatment of her lesions. Tumors margin was covered by 50% isodose line, and a total 2000 cGy in five fractions was delivered to each lesion (6 lesions in total). Her dizziness improved after treatment, while her blurred vision remained.\n\nFigure 1 FDG-PET performed 4 months before this presentation showed that FDG uptake increased in the callosal area with a maximal SUV of 16.5 (panel A), and the area abutting the fourth ventricle with a maximal SUV of 16.2 (panel B).\n\nTwo months before this presentation, her dizziness and gait imbalance recurred, in addition to a new onset headache and circumoral formication. Repeated gadolinium enhanced contrast MRI revealed diffuse lesion occupied areas around right cisterna ambiens, cerebellopontine angle areas, and the occipital lobe. She received another brain radiotherapy afterward. A total of 3600 cGy was given (200 cGy per fractions, 18 fractions in total), and she was in largely remission when discharged.\n\nTwo weeks before this presentation, she began to complain progressively intensifying low back pain, lower limb ache, and dysesthesia. Spinal MRI after administration of gadolinium showed multiple lesions occupied the whole spinal cord. The spinal spread of intracranial malignancy was considered. She was then referred to our department.\n\nHer medical history was notable for coronary heart disease, second-degree atrioventricular block, hyperlipidemia, pulmonary tuberculosis, chronic HBV infection, and chronic atrophic gastritis. Medications on presentation were atorvastatin, gabapentin, caltrate, and lactulose.\n\nShe reported no fever, abdominal pain, chest pain, palpitations, or dyspnea.\n\nOn examination, her vital sign was normal, and she was alert, her vision was blurred, the hearing of her left ear was deceased, her muscle weakness of her lower and upper limbs was Grade II and Grade III, respectively. The muscular tension was normal, as well as the tendon reflexes. There was no neck stiffness and other sign of meningeal irritation.\n\nLumbar puncture was performed, and laboratory examination of the cerebrospinal fluids (CSF) reveals decreased chloride (110 mmol/L, normal range 120–131 mmol/L) and glucose (0.0 mmol/L, normal range 2.5–4.5 mmol/L), and increased protein (6.870 g/L, normal rage 0.150–0.450 g/L), erythrocytosis (10/μL) and leukocytosis (160/μL, neutrophil 10%, lymphocyte 55%, and endothelial cell 35%). CSF smear revealed malignancy cells with a high nuclear-cytoplasmic ratio, whereas these cells were too loose for immunohistochemical stains. On hospitalization, her condition was deteriorating continuously. She began to show multiple cranial nerve palsy, including right ptosis and dysphagia. Repeated cranial and spinal MRI revealed malignancy progression (Figs. 2 and 3).\n\nFigure 2 Spinal MRI revealed diffuse thickening of the dura matter and multiple tuberous lesion, which were enhanced after gadolinium administration (panel A: T1-weighted, panel B: T2-weighted, panel C: gadolinium contrast enhanced T1-weighted).\n\nFigure 3 Cranial MRI showed an isointense nodular lesion in the pineal region on T1-weighted (panel A) and T2-weighted phases (panel B), which lead to mild hydrocephalus. Sagittal view of T2-weighted MRI also revealed a hyperintense lesion in the dorsal medulla (panel C, yellow arrowhead). Both two lesions were enhanced after gadolinium enhancement.\n\nTo determine the malignancy, CSF and peripheral blood sample were sent for further genetic sequencing and detection. The results from CSF showed genetic variation of ABL1, AR, CDK6, ERBB2, ERBB4, FGFR2, FGFR3, FLT3, HRAS, JAK2, KDR, MET, MPL, MYC, NTRK1, PDGF RB, PIK3C A, PTEN, RET, SMAD4, SMAR CB1, SMO, STK11, TP53, and VHL. The result from peripheral blood showed a genetic variation of MYC, PDGFRA, PIK3R1, and TP53. No gene rearrangement and copy number variation were detected. However, these results failed to certain the malignancy histogenesis. Therefore, alternative diagnostic method was wanted.\n\nIn the next days, this patient experienced increased intracranial pressure caused by hydrocephalus. Thus, we placed an Omaya reservoir for daily CSF drainage. We aspirated 10 to 15 mL CSF from the Omaya reservoir to decrease intracranial pressure. Considering the number of malignant cells in CSF sample obtained by each lumbar puncture was too few for immunohistochemical stain, we collected the daily drained CSF, and centrifuged the cell contents in the CSF. After we collected abundant CSF cells (about 0.2 mL), we made a compact cell-block processed with paraffin wax just like processing normal biopsied tissue specimen, and further immunohistochemical stains were performed (Fig. 4). The results showed CK(pan)(−), Ki-67(+++,90%), P63(partly+), ALK(−), Napsin A(−), CD30(−), CD34(−), CD43(+), MPO(−), CD2(−), CD3(−), CD4(−), CD7(−), CD5(−), CD20(+), CD79a(+), CD10(−), Bcl-6(+), MUM1(+), suggesting the diagnosis of diffuse large-B cell lymphoma (non-GCB type).\n\nFigure 4 Microscopy of the “cell-block” revealed numerous malignant cells with a high nuclear-cytoplasmic ratio, which further confirmed the diagnosis of large B cell lymphoma by immunohistochemical stains (∗40∗10).\n\nAfterward, this patient began her intracranial chemotherapy (MTX 15 mg and dexamethasone 5 mg, twice per weeks). Unfortunately, she was dead 2 weeks later due to severe myelosuppression and secondary septic shock during the process of chemotherapy.\n\n3 Discussion\nPrimary Central Nervous System Lymphoma is a rare extranodal NHL, involving the brain, eye, leptomeningitis, and rarely spinal cord.[3,14] The diagnosis of CNS lymphoma is always challenging. Presently, it is mainly based on clinical characteristics, imaging, CSF analysis, and brain biopsy.[2,13,15–17] Magnetic resonance imaging is the cornerstone for PCNSL lesions determination, which most typically enhance homogeneously on T1-weighted (MRI) and appear T2-hypointense, but high variability in MRI features is commonly encountered.[3]Advanced MRI (MR diffusion, spectroscopy, and perfusion) and metabolic imaging, such as FDG-PET may help to distinguish PCNSL with other entities, such as high-grade gliomas, tumefactive demyelinating lesions, or infectious and granulomatous diseases.[3,16]Multiple MRIs and PET-CT were applied in this case. However, the radiological features were atypical regarding both the manifestation and location (multiple lesions, unusual places, and spinal involvement), which was more consistent with metastatic CNS malignancy than PCNSL.[18,19]\n\nFor PCNSL, histological analysis through a brain biopsy or liquid biopsy of biopsy material is still regarded as the gold standard.[9] While brain biopsy provides histologic and genetic information, it is an invasive procedure with the risk of major complications. Brain biopsy is not conducive to obtaining multiple samples over time, and previous treatments may alter the diagnostic yield of biopsies, such as steroids and radiotherapies.[2,10,20,21] Alternatively, the liquid biopsy is a promising, less-invasive means to obtain the histologic diagnosis, from multi-analysis of the cytology, flow cytometry, molecular markers, and specific gene mutations.[2,13] Among these CSF analyses, cytology or cytopathology (leukocyte count and differentiation, cytomorphology, and immunohistochemistry) entails the gold standard.[13] Unfortunately, this method has a low diagnostic yield as often no malignant cell detected, or cells are too lose or too lytic for proper analysis.[9,13] Despite malignant cells were found in the initial CSF analysis in our case, the number was not abundant to perform the immunohistochemistry. As is often the case, diagnosis of PCNSL from CSF cytology occurs in only 10% to 20% patients, as malignant cells detected are too loosely or too lytic for proper analysis.[2,22] Flow cytometry, a method of immunophenotyping (detection for clonal B-cell population), can increase the sensitivity in the diagnosis of PCNSL, which usually works together with cytology.[23,24] In our case, flow cytometric analysis was not performed due to initial suspicion of metastatic malignancy. However, sensitivity is disappointing even for this analysis approach, and detection of clonal B-cell populations does not distinguish between lymphoma entities.[9]\n\nThe advent of lymphoma-specific mutations and unique combinations of biomarkers (cytokines, receptors, immunoglobulins, and miRNAs) that can be tested in CSF further increase the diagnostic value of this liquid biopsy for PCNSL.[25,26] Multiple studies have tried to identify a molecular signature specific for PCNSL, using many different analysis strategies on tumor tissue. Interleukin (IL)-10 with its receptors, IL-6 and CXCL13 are shown to be upregulated in the CSF of patients with PCNSL, which are related to lymphoid cells growth and immunity regulation.[25,27] Osteopontin and neopterin are proinflammatory cytokines involved in immune cell activation and B-cell migration and proliferation, which are significantly higher in patients with PCNSL than in those with other CNS disorders.[12,28] microRNAs (miRNAs) are very promising biomarkers as well, not only for diagnostic purposes but also for monitoring therapy response.[13] Furthermore, emerging data suggest a role for gene aberrations in predicting prognosis and response to treatments. Presently, genetic aberrations reported in PCNSL include CARD11, CD79B, CDKN2A (9p21; p16), ETV6, MYD88, PIM1, PRDM1, TBL1XR1, TNFAIP3(A20), and TOX.[9,16] Half of the selected genes are involved in the NFκB pathway (CARD11, CD79B, MYD88, TBL1XR1, and TNFAIP3), while the other half is not (CDKN2A, ETV6, PIM1, PRDM1, and TOX).[9] Unfortunately, none of these genetic aberrations were detected in this patient. The results of CNS specific gene mutation detection are often inconclusive and hard to interpret in clinical practice, on which the diagnostic criteria based still has a long way to validation.\n\nThe final diagnosis of our case relied on the cytopathologic and combined immunohistochemistry analysis of the “cell-block,” which made from CSF cells collected from repeatedly aspirated patient's CSF. To the best of our knowledge, this is the first case demonstrating such a “cell-block” methods. As the major constraint is removed (the hypocellular composition of CSF), classical histopathological diagnostic methods can function effectively in liquid biopsy, such as cytopathology and immunohistochemistry analysis.[29] Therefore, this “cell-block” method can improve the effectiveness of liquid biopsy, and especially useful in cases where the molecular analysis is unavailable or inconclusive.\n\nHowever, it is not known if this methods help if PCNSL did not invade the CSF circulation system. As this is only a case report, further clinical studies should performed to address the sensitivity and specificity of this cell-block method.\n\n4 Conclusion\nThis case demonstrated a safe, easy-practicing and cost-effective method for CSF procedure for PCNSL diagnosis. Presently, molecular diagnosis is still far from an essential diagnostic method for PCNSL; this “cell-block” method is especially useful in the scenario where brain biopsy, molecular analysis are unavailable or inconclusive.\n\nAuthor contributions\nData curation: Lei Zhou.\n\nWriting – original draft: Kaiyuan Huang.\n\nWriting – review & editing: Ying Tong.\n\nAbbreviations: ABL1 = Abelson murine leukemia viral oncogene homolog 1, ALK = Anaplastic lymphoma kinase, AR = Androgen receptor, ATM = ataxia-telangiectasia mutated, Bcl-6 = B-cell lymphoma 6, CB1 = SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1, CD = cluster of differentiation, CDK6 = Cell division protein kinase, CDKN2A = cyclin-dependent kinase Inhibitor 2A, cfDNA = cell-free deoxyribonucleic acid, cGy = centigray, CK = Cytokinin, CNS = central nervous system, CSF = Cerebrospinal fluid, CXCL = chemokine (C-X-C motif) ligand, FDG-PET = fluorodeoxyglucose positron emission tomography, FGFR2 = Fibroblast growth factor receptor 2, FLT3 = fms like tyrosine kinase 3, HBV = hepatitis B virus, IL = interleukin, JAK/STAT = Janus kinase/signal transducers and activators of transcription, KDR = kinase insert domain receptor, MET = mesenchymal–epithelial transition, miRNAs = micro-ribonucleic acid, MPL = myeloproliferative leukemia protein, MRI = magnetic resonance imaging, MTX = methotrexate, MYC = myelocytomatosis, MYD88 = myeloid differentiation primary response 88, NF-kB = nuclear factor kappa-light-chain-enhancer of activated B cells, NHL = non-Hodgkin lymphoma, NTRK1 = neurotrophic tyrosine kinase receptor type 1, PCNSL = Primary Central Nervous System Lymphoma, PDGF = platelet-derived growth factor, PD-L1/PD-2 = programmed cell death protein-ligand 1/ programmed cell death protein-ligand 2, PIK3C A = Polyteknikkojen Ilmailukerho3C A, PIM1 = proto-oncogene serine/threonine-protein kinase 1, PRDM1 = PR domain zinc finger protein 1, PTEN = phosphatase and tensin homolog, RB = reticuloblstoma, RET = rearranged during transfection SMAR, SMO = smoothened, STK11 = serine/threonine kinase 11, SUV = standardized uptake value, TNFAIP3(A20) = tumor necrosis factor, alpha-induced protein 3 or A20, TOX = thymocyte selection-associated high mobility group box protein, TP53 = tumor protein53, VHL = von Hippel–Lindau tumor suppressor.\n\nHow to cite this article: Huang K, Zhou L, Tong Y. Cell-Block cytology in diagnosis of primary central nervous system lymphoma: A case report. Medicine. 2020;99:14(e19598).\n\nKH and LZ contribute equally to this work.\n\nPatient consent: Informed consent for publication of the case has been obtained from patient's husband.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Royer-Perron L Hoang-Xuan K Alentorn A \nPrimary central nervous system lymphoma: time for diagnostic biomarkers and biotherapies?\n\nCurr Opin Neurol \n2017 ;30 :669 –76\n.28922238 \n[2] Sinicrope K Batchelor T \nPrimary Central Nervous System Lymphoma\n. Neurol Clin \n2018 ;36 :517 –32\n.30072069 \n[3] Chiavazza C Pellerino A Ferrio F \nPrimary CNS lymphomas: challenges in diagnosis and monitoring\n. Biomed Res Int \n2018 ;2018 :3606970 .30035121 \n[4] Schlegel U Korfel A \nThe challenge of adequate imaging surveillance in primary central nervous system lymphoma\n. Neuro Oncol \n2017 ;19 :307 –8\n.28025387 \n[5] Bataille B Delwail V Menet E \nPrimary intracerebral malignant lymphoma: report of 248 cases\n. J Neurosurg \n2000 ;92 :261 –6\n.10659013 \n[6] Patrick LB Mohile NA \nAdvances in Primary Central Nervous System Lymphoma\n. Curr Oncol Rep \n2015 ;17 :60 .26475775 \n[7] Zhao J Yang ZY Luo BN \nQuantitative evaluation of diffusion and dynamic contrast-enhanced MR in tumor parenchyma and peritumoral area for distinction of brain tumors\n. PLoS One \n2015 ;10 :e0138573 .26384329 \n[8] Haldorsen IS Espeland A Larsson EM \nCentral nervous system lymphoma: characteristic findings on traditional and advanced imaging\n. AJNR Am J Neuroradiol \n2011 ;32 :984 –92\n.20616176 \n[9] Hiemcke-Jiwa LS Leguit RJ Snijders TJ \nMolecular analysis in liquid biopsies for diagnostics of primary central nervous system lymphoma: review of literature and future opportunities\n. Crit Rev Oncol Hematol \n2018 ;127 :56 –65\n.29891112 \n[10] Nevel KS Wilcox JA Robell LJ \nThe utility of liquid biopsy in central nervous system malignancies\n. Curr Oncol Rep \n2018 ;20 :60 .29876874 \n[11] Mok TS Wu YL Thongprasert S \nGefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma\n. N Engl J Med \n2009 ;361 :947 –57\n.19692680 \n[12] Strehlow F Bauer S Martus P \nOsteopontin in cerebrospinal fluid as diagnostic biomarker for central nervous system lymphoma\n. J Neurooncol \n2016 ;129 :165 –71\n.27294357 \n[13] Baraniskin A Schroers R \nModern cerebrospinal fluid analyses for the diagnosis of diffuse large B-cell lymphoma of the CNS\n. CNS Oncol \n2014 ;3 :77 –85\n.25054902 \n[14] Villano JL Koshy M Shaikh H \nAge, gender, and racial differences in incidence and survival in primary CNS lymphoma\n. Br J Cancer \n2011 ;105 :1414 –8\n.21915121 \n[15] Carnevale J Rubenstein JL \nThe challenge of Primary Central Nervous System Lymphoma\n. 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J Neurooncol \n1997 ;32 :63 –9\n.9049864 \n[22] Baraniskin A Deckert M Schulte-Altedorneburg G \nCurrent strategies in the diagnosis of diffuse large B-cell lymphoma of the central nervous system\n. Br J Haematol \n2012 ;156 :421 –32\n.22077417 \n[23] Bromberg JE Breems DA Kraan J \nCSF flow cytometry greatly improves diagnostic accuracy in CNS hematologic malignancies\n. Neurology \n2007 ;68 :1674 –9\n.17502548 \n[24] Schroers R Baraniskin A Heute C \nDiagnosis of leptomeningeal disease in diffuse large B-cell lymphomas of the central nervous system by flow cytometry and cytopathology\n. Eur J Haematol \n2010 ;85 :520 –8\n.20727005 \n[25] Song Y Zhang W Zhang L \nCerebrospinal fluid IL-10 and IL-10/IL-6 as accurate diagnostic biomarkers for primary central nervous system large B-cell lymphoma\n. Sci Rep \n2016 ;6 :38671 .27924864 \n[26] Sasagawa Y Akai T Tachibana O \nDiagnostic value of interleukin-10 in cerebrospinal fluid for diffuse large B-cell lymphoma of the central nervous system\n. J Neurooncol \n2015 ;121 :177 –83\n.25258254 \n[27] Nguyen-Them L Costopoulos M Tanguy ML \nThe CSF IL-10 concentration is an effective diagnostic marker in immunocompetent primary CNS lymphoma and a potential prognostic biomarker in treatment-responsive patients\n. Eur J Cancer \n2016 ;61 :69 –76\n.27156226 \n[28] Viaccoz A Ducray F Tholance Y \nCSF neopterin level as a diagnostic marker in primary central nervous system lymphoma\n. Neuro Oncol \n2015 ;17 :1497 –503\n.26014047 \n[29] Gleissner B Siehl J Korfel A \nCSF evaluation in primary CNS lymphoma patients by PCR of the CDR III IgH genes\n. Neurology \n2002 ;58 :390 –6\n.11839837\n\n",
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"abstract": "Poisoning caused by calcium-channels blockers (CCB) can cause refractory vasoplegic shock, resulting in multiple-organ failure and death despite maximal therapy including high doses of vasopressors. We report one CCB-induced refractory shock complicated with lactate acidosis despite very high doses of epinephrine and norepinephrine. The hemodynamic status of the patient dramatically improved after intermittent boluses of terlipressin, which corrected the acidosis.",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DILTIAZEM"
},
"drugadditional": null,
... |
{
"abstract": "Reactivation of human parvovirus B19 is exceptional and characteristic of immunosuppression, with anaemia being the predominant manifestation although pancytopenia and thrombotic microangiopathy may also occur. We describe a patient with a history of diffuse large B-cell lymphoma with pure erythrocyte aplasia due to reactivation of parvovirus B19, who was treated with corticosteroids and immunoglobulins.\nInfection with human parvovirus B19 is identified by polymerase chain reaction (PCR) testing of blood and the presence of typical giant proerythroblasts in the bone marrow.Cytomegalovirus infection should be considered in immunosuppressed patients with fever and non-specific symptoms with haematological changes.The treatment of persistent infection in immunosuppressed patients is based on the administration of IV immunoglobulins at high doses.",
"affiliations": "Hospital Universitario Virgen de las Nieves, Granada, Spain.;Hospital Universitario Virgen de las Nieves, Granada, Spain.;Hospital Universitario Virgen de las Nieves, Granada, Spain.;Hospital Universitario Virgen de las Nieves, Granada, Spain.",
"authors": "Escobar-Sevilla|Joaquín|J|;Bustos Merlo|Antonio|A|;Garcia Martínez|Carmen|C|;Mediavilla Garcia|Juan Diego|JD|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2020_001596",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2284-2594",
"issue": "7(9)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Human parvovirus B19; pure red cell aplasia; viral reactivation",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001596",
"pmc": null,
"pmid": "32908820",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "23588740;23465012;31351772;22931551;8641299;10852625;18067026;16758416;14762186;23916377;16313320;28741797;27364410;30973192;17098597;29184906;23791089;19144091;15976179",
"title": "Severe Refractory Anaemia and Fever of Unknow Origin: Human Parvovirus B19 Reactivation.",
"title_normalized": "severe refractory anaemia and fever of unknow origin human parvovirus b19 reactivation"
} | [
{
"companynumb": "ES-PFIZER INC-2020486862",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"druga... |
{
"abstract": "Osteonecrosis of jaws (ONJ) is a chronic disease characterized by necrotic bone from any number of causes. ONJ can also occur due to several systemic and local factors which compromise blood flow within the bone. Among anti-resorptive medications, a very low risk of ONJ development is associated with oral bisphosphonates used for the management of osteopenia, osteoporosis, and Paget's disease. Raloxifene is a nonsteroidal benzothiophene which is classified as a selective estrogen receptor modulator (SERM). It is commonly used for the prevention and the treatment of osteoporosis in postmenopausal women and was recently approved to reduce the risk of breast cancer. Raloxifene is regarded as a safe alternative in the management of osteoporosis in terms of ONJ development. This report presents a case of ONJ in a patient receiving raloxifene, who presented with existing comorbidities and a history of discontinued oral bisphosphonates use. The clinical report is followed by a discussion aimed to clarify how the general practitioner should consider similar cases.",
"affiliations": null,
"authors": "Baur|Dale A|DA|;Altay|Mehmet Ali|MA|;Teich|Sorin|S|;Schmitt Oswald|Meghan|M|;Quereshy|Faisal A|FA|",
"chemical_list": "D050071:Bone Density Conservation Agents; D020849:Raloxifene Hydrochloride",
"country": "Germany",
"delete": false,
"doi": "10.3290/j.qi.a32918",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-6572",
"issue": "46(5)",
"journal": "Quintessence international (Berlin, Germany : 1985)",
"keywords": null,
"medline_ta": "Quintessence Int",
"mesh_terms": "D000368:Aged; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D005260:Female; D006801:Humans; D020849:Raloxifene Hydrochloride",
"nlm_unique_id": "0342677",
"other_id": null,
"pages": "423-8",
"pmc": null,
"pmid": "25328920",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Osteonecrosis of the jaw in a patient on raloxifene: a case report.",
"title_normalized": "osteonecrosis of the jaw in a patient on raloxifene a case report"
} | [
{
"companynumb": "US-TEVA-752978USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RALOXIFENE HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "The study aims to analyse the clinical and immunological manifestations of paediatric antiphospholipid syndrome (APS) in patients, based on the 2006 revised classification criteria of definite APS. Fifty-eight paediatric patients with APS were enrolled and analysed retrospectively. A total of 37 female and 21 male patients with a mean age of 14 ± 3 years at disease onset were included. Fourteen (24%) cases were primary APS, and 40 (69%) cases were secondary to systemic lupus erythaematosus (SLE). Anti-nuclear antibody (ANA) positivity and hypocomplementemia were more common in secondary APS than in primary APS. The most common manifestations of thrombosis were deep vein thrombosis of the lower extremities (25 cases, 37%). Non-thrombotic manifestations were mainly immunologic thrombocytopenia, autoimmune haemolytic anaemia, skin lesions, arthritis, pulmonary hypertension, heart valve vegetations and spontaneous abortion. LA, ACL and anti-β2GPI were positive in 42 (95%), 28 (64%) and 34 (77%) cases, respectively. Over half (23 cases, 52%) of the patients were triple-positive for antiphospholipid (aPL) antibodies. Among patients with single-positive LA and anti-β2GPI, the proportion with venous thrombosis was 100% (5 cases) and 0% (0 cases), respectively. The arterial thrombosis proportions were 22% (5 cases), 21% (3 cases) and 14% (1 case) in the triple-, double- and single-aPL-positive groups, respectively (P > 0.05). Fifty-three (91%) cases were followed up for 3 to 140 months, with a median time of 32 months. Seven (13%) cases had recurrences or appearances of thrombosis during follow-up, all of which were double- or triple-aPL positive. APS in the paediatric patients is mostly secondary to SLE. ANA positivity and hypocomplementemia are more common in secondary APS, but there are no differences in the other clinical manifestations between the primary and secondary APS groups. Deep vein thrombosis is the most common thrombotic event. Positive LA may increase the risk of venous thrombosis. Multiple-aPL positivity does not increase the proportion of thrombosis. Long-term anticoagulant or antiplatelet therapy is needed to prevent thrombosis recurrence in double- or triple-positive aPL cases.",
"affiliations": "Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Dongcheng District, Beijing, 100730, China.;Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Dongcheng District, Beijing, 100730, China. songhm1021@hotmail.com.;Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Dongcheng District, Beijing, 100730, China.;Department of Pediatrics, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Dongcheng District, Beijing, 100730, China.",
"authors": "Ma|Jingran|J|;Song|Hongmei|H|;Wei|Min|M|;He|Yanyan|Y|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-017-3776-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "37(5)",
"journal": "Clinical rheumatology",
"keywords": "Antiphospholipid antibody; Paediatric antiphospholipid syndrome; Thrombosis",
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D000293:Adolescent; D019268:Antibodies, Antineutrophil Cytoplasmic; D000925:Anticoagulants; D016736:Antiphospholipid Syndrome; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D010975:Platelet Aggregation Inhibitors; D063189:Symptom Assessment; D013927:Thrombosis; D016896:Treatment Outcome",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "1295-1303",
"pmc": null,
"pmid": "28748509",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "25166960;22988029;23219767;27336701;15387947;27615277;15094931;18207064;15507287;12892385;27428014;15345914;21953404;21765019;10622682;24824074;25697769;22799058;14667097;15147339;17139660;12816875;9382667;24418303;21652586;18955411;8804321;16420554;19545416;20079318;12393574;7607290;27143190;11953980;24464962;26573550;18720307;10403256",
"title": "Clinical characteristics and thrombosis outcomes of paediatric antiphospholipid syndrome: analysis of 58 patients.",
"title_normalized": "clinical characteristics and thrombosis outcomes of paediatric antiphospholipid syndrome analysis of 58 patients"
} | [
{
"companynumb": "CN-NOVAST LABORATORIES, LTD-CN-2018NOV000285",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugaddition... |
{
"abstract": "OBJECTIVE\nTissue inhibitor of matrix metalloproteinase (TIMP)-3 has many functions, including preventing the constituent formation of tumor necrosis factor-alpha (TNFα) in tissue. Sorsby macular dystrophy is caused by a mutation in the gene responsible for TIMP-3, suggesting a potential treatment.\n\n\nMETHODS\nComprehensive ophthalmologic examination with multimodal imaging to include optical coherence tomography (OCT) and OCT angiography were used to evaluate a patient with Sorsby fundus dystrophy treated first with intravitreal triamcinolone, then with adalimumab.\n\n\nRESULTS\nA 35-year-old woman presented in 2003 with aggressive macular neovascularization in both eyes related to Sorsby macular dystrophy c.610A>T (p.Ser204Cys). Her visual acuity was 20/25 in the right and 20/400 in the left eye. She was treated with periodic intravitreal injections of 4 mg triamcinolone, which caused the neovascularization to become inactive. When switched to intravitreal bevacizumab, she showed disease activity. She was switched back to intravitreal triamcinolone with minimal signs of exudation and hemorrhage. Because of the high lifetime risk of complication, she was switched to subcutaneous adalimumab and in follow-up over 18 months had no signs of disease activity. The visual acuity in the right eye was 20/20.\n\n\nCONCLUSIONS\nTIMP3 has numerous effects including controlling local TNFα production. It is possible with the mutation in the gene for TIMP-3, abnormally high tissue levels of TNFα are produced in the eye. Direct inhibition of TNFα action by adalimumab offers a molecularly targeted approach to the disease pathophysiology and merits increased study.",
"affiliations": "Vitreous Retina Macula Consultants of New York, New York, NY, USA. rickspaide@gmail.com.",
"authors": "Spaide|Richard F|RF|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41433-021-01735-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0950-222X",
"issue": null,
"journal": "Eye (London, England)",
"keywords": null,
"medline_ta": "Eye (Lond)",
"mesh_terms": null,
"nlm_unique_id": "8703986",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34376817",
"pubdate": "2021-08-10",
"publication_types": "D016428:Journal Article",
"references": "19093006",
"title": "Treatment of Sorsby fundus dystrophy with anti-tumor necrosis factor-alpha medication.",
"title_normalized": "treatment of sorsby fundus dystrophy with anti tumor necrosis factor alpha medication"
} | [
{
"companynumb": "US-ROCHE-2894722",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "4",
"drug... |
{
"abstract": "A 48-year-old man presented to our lipid clinic with statin intolerance and elevated serum creatine kinase levels, being affected by mitochondrial myopathy because of heteroplasmic mitochondrial DNA missense mutation in MTCO1 gene (m.7671T>A). He had just been treated with a coronary artery bypass 4 years before because of acute coronary syndrome, and he had consistently high levels of both low-density lipoprotein cholesterol and triglycerides. Dyslipidemia was successfully treated using 75 mg of alirocumab subcutaneously every 2 weeks, 10 mg of ezetimibe daily, 2 g of marine omega-3 fatty acids daily, and 145 mg of micronized fenofibrate every 2 days. Although muscle weakness persisted, myalgia did not reoccur and serum creatine kinase levels remained almost stable over the time.",
"affiliations": "Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy. Electronic address: arrigo.cicero@unibo.it.;Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy.;Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy.;Medical and Surgical Sciences Department, University of Bologna, Bologna, Italy.",
"authors": "Cicero|Arrigo F G|AFG|;Fogacci|Federica|F|;Bove|Marilisa|M|;Borghi|Claudio|C|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D003576:Electron Transport Complex IV; C581860:cytochrome c oxidase subunit I, human; C571059:alirocumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacl.2020.07.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-4789",
"issue": "14(5)",
"journal": "Journal of clinical lipidology",
"keywords": "Alirocumab; Hypercholesterolemia; Mitochondrial myopathy; PCSK9 inhibitor",
"medline_ta": "J Clin Lipidol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D003576:Electron Transport Complex IV; D006801:Humans; D006949:Hyperlipidemias; D008297:Male; D008875:Middle Aged; D017240:Mitochondrial Myopathies; D020125:Mutation, Missense; D011379:Prognosis",
"nlm_unique_id": "101300157",
"other_id": null,
"pages": "646-648",
"pmc": null,
"pmid": "32800583",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of a patient with mitochondrial myopathy with alirocumab.",
"title_normalized": "successful treatment of a patient with mitochondrial myopathy with alirocumab"
} | [
{
"companynumb": "IT-ACCORD-199431",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": "3",
"drug... |
{
"abstract": "We report the development of minimal change disease superimposed on preexisting chronic kidney disease secondary to chronic calcineurin inhibitor nephrotoxicity in a hematopoietic stem cell transplantation (HSCT) recipient and review the renal complications of HSCT.",
"affiliations": "Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, MI, USA.;Department of Pathology, Henry Ford Hospital, Detroit, MI, USA.;Division of Hematology/Oncology, Henry Ford Hospital, Detroit, MI, USA.;Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, MI, USA.",
"authors": "Liquete|E|E|;Williamson|S R|SR|;Janakiraman|N|N|;Venkat|K K|KK|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijn.IJN_230_16",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-27-46810.4103/ijn.IJN_230_16Case ReportRenal Complications of Hematopoietic Stem Cell Transplantation: Report of a Case and Review of the Literature Liquete E. Williamson S. R. 1Janakiraman N. 2Venkat K. K. Division of Nephrology and Hypertension, Henry Ford Hospital, Detroit, MI, USA1 Department of Pathology, Henry Ford Hospital, Detroit, MI, USA2 Division of Hematology/Oncology, Henry Ford Hospital, Detroit, MI, USAAddress for correspondence: Dr. K. K. Venkat, Division of Nephrology and Hypertension, Henry Ford Hospital, CFP-5, 2799 West Grand Boulevard, Detroit, MI 48202, USA. E-mail: kvenkat1@hfhs.orgNov-Dec 2017 27 6 468 471 Copyright: © 2017 Indian Journal of Nephrology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.We report the development of minimal change disease superimposed on preexisting chronic kidney disease secondary to chronic calcineurin inhibitor nephrotoxicity in a hematopoietic stem cell transplantation (HSCT) recipient and review the renal complications of HSCT.\n\nChronic calcineurin inhibitor nephrotoxicitygraft-versus-host diseasehematopoietic stem cell transplantationminimal change diseasenephrotic syndrome\n==== Body\nIntroduction\nHematopoietic stem cell transplantation (HSCT), autologous or allogeneic, is well established as a therapy for a variety of malignant and benign disorders.[1] Graft-versus-host disease (GVHD), wherein donor-origin immune-competent cells target “foreign” human leukocyte antigens in recipient tissues (mainly skin, gastrointestinal tract, and liver), is the major problem in allogeneic HSCT, in contrast to rejection of the transplanted organ by the recipient's immune system in solid organ transplantation.[1] We report a HSCT recipient who developed nephrotic syndrome and acute kidney injury (AKI) due to minimal change disease (MCD) superimposed on chronic kidney disease (CKD) secondary to chronic calcineurin inhibitor (CNI) nephrotoxicity in the setting of chronic GVHD and review the renal complications of HSCT.\n\nCase Report\nA 40-year-old-man received an allogeneic, unrelated donor HSCT for thalassemia intermedia because transfusion dependence and hemosiderosis persisted after splenectomy. HSCT preconditioning with fludarabine, busulfan, and rabbit anti-thymocyte globulin (no radiation) was followed by tacrolimus and methotrexate prophylaxis for 1 month. Thalassemia-associated anemia and microcytosis normalized post-HSCT. GVHD (predominantly cutaneous with mild liver involvement) developed 1-month post-HSCT. Over the next 2 years, GVHD was treated with daily oral tacrolimus, methylprednisolone, and sirolimus (latter discontinued 22 months post-HSCT; at the time of sirolimus discontinuation, our patient had no edema and the most recent available urinalysis had shown only trace albuminuria) and subcutaneous etanercept and extracorporeal photopheresis intermittently. Other medications included acyclovir, amlodipine, and alendronate. Serum creatinine (SCr) level during the initial hospitalization for HSCT ranged between 0.9 and 1.1 mg/dl. Over the next 1.5 years, SCr fluctuated between 1.3 and 1.5 mg/dl, and occasionally up to 2.0 mg/dl, with multiple urinalyses showing negative to trace albuminuria and an unremarkable sediment.\n\nTwo years post-HSCT, lower extremity swelling and 18.2 kg weight gain developed over 3 weeks. Examination revealed severe, symmetrical edema up to the groins, cutaneous features of GVHD, and blood pressure of 132/84 mm Hg. SCr had increased to 4.1 mg/dl from 1.4 mg/dl a month earlier. Urinalysis showed 300 mg/dl albuminuria, 4–6 red blood cells/high power field, and 4–5 granular and 0–3 hyaline casts/low power field. Random urine albumin/creatinine ratio (UAlb/Cr) was 11.6 g/g (previously 50 mg/g). Serum albumin (SAlb) level was 0.8 g/dl (3.5 g/dl 6 weeks earlier). Other relevant results were markedly elevated serum cholesterol and triglyceride levels markedly elevated; tacrolimus trough level 7.7 ng/ml; anti-nuclear, anti-neutrophil cytoplasmic, HIV and hepatitis-C antibodies, and hepatitis-B surface antigen negative; serum C3 and C4 complement levels normal; serum and urine negative for monoclonal proteins and light chains. Renal ultrasonography revealed normal renal lengths bilaterally without hydronephrosis. Because of elevated SCr, tacrolimus, alendronate, and acyclovir were stopped. Lisinopril, furosemide, and atorvastatin were added.\n\nRenal biopsy\nLight microscopic examination revealed nodular hyaline arteriolosclerosis [Figure 1a and b] and “striped” interstitial fibrosis and tubular atrophy (IF-TA) with 9/28 globally sclerotic glomeruli [Figure 1c]. Direct immunofluorescence showed scattered, predominantly mesangial, nonspecific staining for IgG, IgA, IgM, c1q, C3 and C4 complements, and fibrinogen. Electron microscopy revealed widespread foot process effacement with no electron-dense deposits [Figure 1d]. The final renal biopsy diagnoses were nodular hyaline arteriolosclerosis, global glomerulosclerosis and band-like IF-TA, compatible with chronic CNI-nephrotoxicity, and widespread foot process effacement compatible with MCD.\n\nFigure 1 Photomicrographs from the patient's kidney biopsy. (a) Nodule of hyaline arteriolosclerosis at the vascular pole of the glomerulus (arrow). (b) Nodular hyaline arteriolosclerosis (arrows) - higher power view. (c) Band-like (striped) tubular atrophy and interstitial fibrosis along the top and bottom edges of the biopsy core (black arrows) and a globally sclerosed glomerulus (white arrow). (d) Diffuse podocyte (foot process) effacement/fusion on electron microscopy (arrows). There are no electron-dense deposits\n\nFollowing biopsy, oral methylprednisolone was increased to 48 mg daily (tapered over 12 weeks to 10 mg daily) and rituximab was given intravenously (375 mg/m2, 4 weekly doses). Within 3 months, edema resolved completely (permitting furosemide discontinuation), SAlb normalized (3.9 g/dl), and UAlb/Cr decreased to 1.26 g/g. Over the next 18 months, UAlb/Cr has fluctuated between 204 and 438 mg/g (without lisinopril) with most recent SAlb of 4.0 g/dl. SCr decreased to 1.5 mg/dl 8 weeks postrituximab and has fluctuated between 1.2 and 1.4 mg/dl over the next 18 months. Cutaneous features of GVHD also improved and are currently well controlled on methylprednisolone 8 mg/day alone. Blood pressure is normal without medications. Hematological test results which became normal approximately 2 months post-HSCT have remained normal till now, indicating a well-functioning HSCT (based on peripheral blood cell counts only; follow-up bone marrow/flow cytometry/chimerization studies not done).\n\n\nTable 1 shows selected laboratory values in our patient at different time intervals after HSCT.\n\nTable 1 Laboratory values at different times after hematopoietic stem cell transplantation\n\nDiscussion\nHSCT may be complicated by a variety of renal disorders.[23456] AKI of different etiologies is common in the first 100 days following HSCT (incidence of 21%–73%). Thereafter, CKD becomes increasingly prevalent. Glomerular disease and nephrotic syndrome are uncommon complications of HSCT. Thus, our patient developed both a common (CKD) and an uncommon (MCD) renal complication of HSCT.\n\nPathologically, chronic CNI-nephrotoxicity is characterized by nodular preglomerular arteriolar hyalinosis originating in the media, global, and/or focal segmental glomerulosclerosis (FSGS) and IF-TA (initially band-like/“striped,” eventually becoming diffuse).[7] In transplanted kidneys, these changes are nonspecific, occurring also in chronic rejection, older donor kidneys, polyoma virus nephropathy, and transplant renal artery stenosis.[8] Diabetes and hypertension also cause arteriolar hyalinosis (originating in the subendothelium). However, nodular arteriolar hyalinosis affecting the native kidneys (which are not subject to rejection) of patients on long-term CNI-therapy (such as ours) favors the diagnosis of chronic CNI-nephrotoxicity.[9]\n\nThe diagnosis of MCD is difficult when it is superimposed on preexisting pathological changes as in our patient. The term podocytopathy has been used instead of MCD when an MCD-like disorder is superimposed on a different renal disorder such as lupus nephritis.[10] The diagnosis of superimposed MCD/podocytopathy in this patient is supported by the following features. While nephrotic syndrome develops insidiously in most glomerulopathies, sudden onset of severe nephrotic syndrome is typical of MCD.[11] Widespread podocyte effacement may be seen in any heavily proteinuric disorder.[12] However, as an isolated finding without pathological features of other glomerulopathies, it defines MCD. Rapid resolution of proteinuria following increased corticosteroid dose and rituximab also suggests MCD, which is corticosteroid-responsive in most patients and also responds to rituximab.[13] Rituximab was chosen in our patient because it is effective in treating both MCD and GVHD. These features support the diagnosis of MCD in our patient. Nephrotic syndrome was associated with reversible AKI in our patient, a complication most commonly reported in MCD (especially in adults).[1114] AKI in this setting was previously attributed to anasarca-associated renal interstitial edema but is now believed to be due to ischemic tubular injury.[1114] MCD typically resolves without residual proteinuria or renal dysfunction. Persistence of CKD and minimal albuminuria in our patient was due to chronic CNI-nephrotoxicity, which may not be reversible even after discontinuation of CNI. Glomeruli in MCD usually appear unremarkable on light microscopy. The 32% global glomerulosclerosis in our patient's biopsy was also due to preexisting chronic CNI-nephrotoxicity.\n\nIn addition to generic causes of AKI, hepatic sinusoidal obstruction syndrome which mimics hepatorenal syndrome (putative mechanisms: Sinusoidal endothelial injury due to drugs or radiation used for preconditioning and/or acute GVHD), tumor-lysis syndrome caused by preconditioning chemotherapy for leukemia or lymphoma, acute thrombotic microangiopathy (TMA) caused by CNI and/or acute GVHD-associated generalized endothelial injury, and acute GVHD-mediated direct renal tubular injury are special etiological considerations for AKI occurring in the initial 100 days post-HSCT.[26] CKD develops after the first 3 months in 7 to 48% of HSCT recipients and progresses to end-stage renal disease in approximately 4% of patients with CKD.[346] The major causes of post-HSCT CKD are chronic CNI-nephrotoxicity (as in our patient), chronic TMA (“bone marrow transplant nephropathy”) attributed to chronic endothelial injury due to CNI and/or chronic GVHD, and (uncommonly) BK-polyoma virus nephropathy.[346]\n\nNephrotic syndrome is rare after HSCT, occurring only in 0.4%–6.0% of adult HSCT-recipients.[6] It can develop within a few months of HSCT, but usually occurs after the 1st year, almost exclusively in the setting of chronic GVHD, and has an incidence of 0.4%–6% with biopsy revealing membranous nephropathy in approximately two-thirds and MCD in one-quarter of patients.[56] A number of observations suggest that common immunopathogenic mechanisms may underlie both GVHD and glomerulopathies complicating HSCT:[615] (1) Nephrotic syndrome develops only rarely in the absence of coexisting GVHD. (2) Increased production of potentially glomerulopathic cytokines such as interferon and tumor necrosis factor has been documented in GVHD. (3) Renal tubulointerstitial lymphoplasmacytic infiltrate of donor origin has been demonstrated in the biopsy of some patients with HSCT-associated nephrotic syndrome. (4) Reduction/discontinuation of immunosuppression has been reported to precede the development of nephrotic syndrome in association with exacerbation of GVHD. (5) Finally, reinstitution of immunosuppression frequently results in remission of both the nephrotic syndrome and GVHD (as in our patient). We did not perform any studies aimed at identifying the immunopathogenesis of MCD/podocytopathy (such as CD4/CD8 cell subtyping in the peripheral blood or CD80 staining of the renal biopsy) in our patient. There are rare reports of FSGS, mesangial proliferative, or crescentic glomerulonephritis in association with chronic GVHD, but a cause-effect relationship between GVHD and these glomerulopathies is not established.[56] Sirolimus-associated nephrotic syndrome is unlikely in our patient since this drug was discontinued a few months before nephrotic syndrome developed. Etanercept and photopheresis used in this patient for treating GVHD have not been associated with the development of nephrotic syndrome. Given a variety of renal disorders that may cause nephrotic syndrome in HSCT recipients and since it is impossible to diagnose these disorders on clinical grounds, nephrology consultation and renal biopsy are appropriate when this complication develops. The clinical presentation, prognosis, and response to therapy of HSCT-associated MCD appear to be similar to idiopathic MCD, with reinstitution/intensification of Immunosuppression causing prompt remission of nephrotic syndrome.[5] However, persistence of AKI, CKD, and proteinuria, irrespective of etiology, adversely affects long-term survival of HSCT patients.[6]\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Copelan EA Hematopoietic stem-cell transplantation N Engl J Med 2006 354 1813 26 16641398 \n2 Kogon A Hingorani S Acute kidney injury in hematopoietic cell transplantation Semin Nephrol 2010 30 615 26 21146126 \n3 Cohen EP Pais P Moulder JE Chronic kidney disease after hematopoietic stem cell transplantation Semin Nephrol 2010 30 627 34 21146127 \n4 Sawinski D The kidney effects of hematopoietic stem cell transplantation Adv Chronic Kidney Dis 2014 21 96 105 24359992 \n5 Reddy P Johnson K Uberti JP Reynolds C Silver S Ayash L Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation Bone Marrow Transplant 2006 38 351 7 16862167 \n6 Hingorani S Renal complications of hematopoietic-cell transplantation N Engl J Med 2016 374 2256 67 27276563 \n7 Liptak P Ivanyi B Primer: Histopathology of calcineurin-inhibitor toxicity in renal allografts Nat Clin Pract Nephrol 2006 2 398 404 16932468 \n8 Snanoudj R Royal V Elie C Rabant M Girardin C Morelon E Specificity of histological markers of long-term CNI nephrotoxicity in kidney-transplant recipients under low-dose cyclosporine therapy Am J Transplant 2011 11 2635 46 21883915 \n9 Fioretto P Najafian B Sutherland DE Mauer M Tacrolimus and cyclosporine nephrotoxicity in native kidneys of pancreas transplant recipients Clin J Am Soc Nephrol 2011 6 101 6 21051744 \n10 Hu W Chen Y Wang S Chen H Liu Z Zeng C Clinical-morphological features and outcomes of lupus podocytopathy Clin J Am Soc Nephrol 2016 11 585 92 26983707 \n11 Waldman M Crew RJ Valeri A Busch J Stokes B Markowitz G Adult minimal-change disease: Clinical characteristics, treatment, and outcomes Clin J Am Soc Nephrol 2007 2 445 53 17699450 \n12 Deegens JK Dijkman HB Borm GF Steenbergen EJ van den Berg JG Weening JJ Podocyte foot process effacement as a diagnostic tool in focal segmental glomerulosclerosis Kidney Int 2008 74 1568 76 18813290 \n13 Bruchfeld A Benedek S Hilderman M Medin C Snaedal-Jonsdottir S Korkeila M Rituximab for minimal change disease in adults: Long-term follow-up Nephrol Dial Transplant 2014 29 851 6 24121763 \n14 Keskar V Jamale TE Kulkarni MJ Kiggal Jagadish P Fernandes G Hase N Minimal-change disease in adolescents and adults: Epidemiology and therapeutic response Clin Kidney J 2013 6 469 72 26064510 \n15 Brukamp K Doyle AM Bloom RD Bunin N Tomaszewski JE Cizman B Nephrotic syndrome after hematopoietic cell transplantation: Do glomerular lesions represent renal graft-versus-host disease? Clin J Am Soc Nephrol 2006 1 685 94 17699273\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "27(6)",
"journal": "Indian journal of nephrology",
"keywords": "Chronic calcineurin inhibitor nephrotoxicity; graft-versus-host disease; hematopoietic stem cell transplantation; minimal change disease; nephrotic syndrome",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "468-471",
"pmc": null,
"pmid": "29217887",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "24121763;24359992;21883915;16862167;21146126;16641398;26064510;21051744;17699450;17699273;21146127;18813290;26983707;16932468;27276563",
"title": "Renal Complications of Hematopoietic Stem Cell Transplantation: Report of a Case and Review of the Literature.",
"title_normalized": "renal complications of hematopoietic stem cell transplantation report of a case and review of the literature"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP014771",
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"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugaddition... |
{
"abstract": "Nicotine has been documented to regulate the release of plasma arginine vasopressin (AVP). The literature is inconclusive about the effects of nicotine replacement therapy on AVP release, although cigarette smoking has been shown to increase the release of AVP. No clinical case reports have documented the possible association between nicotine replacement and hyponatremia through AVP release. We report a case of a 39-year-old man who experienced syndrome of inappropriate antidiuretic hormone while on nicotine patch therapy. We theorize that the constant serum concentration of nicotine levels provided through the patch may cause hyponatremia through the continuous stimulation of vasopressin.",
"affiliations": "Harrison School of Pharmacy, Auburn University, USA. finchc@methodisthealth.org",
"authors": "Finch|Christopher K|CK|;Andrus|Miranda R|MR|;Curry|William A|WA|",
"chemical_list": "D009538:Nicotine; D012964:Sodium",
"country": "United States",
"delete": false,
"doi": "10.1097/01.SMJ.0000082007.09497.5A",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0038-4348",
"issue": "97(3)",
"journal": "Southern medical journal",
"keywords": null,
"medline_ta": "South Med J",
"mesh_terms": "D000328:Adult; D006801:Humans; D007177:Inappropriate ADH Syndrome; D008297:Male; D009538:Nicotine; D012907:Smoking; D012964:Sodium",
"nlm_unique_id": "0404522",
"other_id": null,
"pages": "322-4",
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"pmid": "15043349",
"pubdate": "2004-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nicotine replacement therapy-associated syndrome of inappropriate antidiuretic hormone.",
"title_normalized": "nicotine replacement therapy associated syndrome of inappropriate antidiuretic hormone"
} | [
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"companynumb": "US-JNJFOC-20141108563",
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{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "NICOTINE"
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"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nLipid emulsion is gaining popularity as an antidote for lipophilic drug overdose, and is generally considered safe at doses recommended for antidotal therapy. We report a case of asymptomatic pancreatitis following extended infusion lipid emulsion.\n\n\nMETHODS\nA 14-year-old female presented to the emergency department actively seizing after ingesting 9 g of bupropion and unknown amounts of hydroxyzine and citalopram. She was intubated for airway protection, and gastrointestinal decontamination was performed with activated charcoal. She was treated with potassium and magnesium for a prolonged QT interval and sodium bicarbonate for metabolic acidosis and QRS complex widening. Upon transfer to the pediatric intensive care unit, she seized again, became hypotensive, and developed a junctional cardiac rhythm. A lipid emulsion bolus was recommended which improved her hypotension and conduction abnormalities. The lipid emulsion was continued for several hours and she received a total dose of 46 mL/kg in less than 12 h. She developed lipemia, which interfered with laboratory analysis, a severe elevation in her triglycerides, as well as a mild pancreatitis that resolved over several days, although she was asymptomatic.\n\n\nMETHODS\nLarge doses of lipid emulsion may result in lipemia, severe hypertriglyceridemia, interference in laboratory analyses, and pancreatitis. This is the third reported adverse event due to lipid emulsion therapy used for overdose.",
"affiliations": "University of Rochester Medical Center , Rochester, NY , USA.",
"authors": "Bucklin|M H|MH|;Gorodetsky|R M|RM|;Wiegand|T J|TJ|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D018765:Dopamine Uptake Inhibitors; D005217:Fat Emulsions, Intravenous; D016642:Bupropion",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2013.831436",
"fulltext": null,
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"issn_linking": "1556-3650",
"issue": "51(9)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000293:Adolescent; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D018765:Dopamine Uptake Inhibitors; D062787:Drug Overdose; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D015228:Hypertriglyceridemia; D010195:Pancreatitis; D013406:Suicide, Attempted; D016896:Treatment Outcome",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "896-8",
"pmc": null,
"pmid": "23992445",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prolonged lipemia and pancreatitis due to extended infusion of lipid emulsion in bupropion overdose.",
"title_normalized": "prolonged lipemia and pancreatitis due to extended infusion of lipid emulsion in bupropion overdose"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-117516",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
... |
{
"abstract": "Retinal toxicity involving the macula as a complication of the antiretroviral protease inhibitor ritonavir has been described in a few cases. We report retinal pigment epitheliopathy involving the macula with a bull's eye pattern in a 36-year-old man with well-controlled HIV receiving ritonavir with gradually progressive bilateral vision loss.",
"affiliations": "Division of Infectious Diseases, Washington University School of Medicine, St Louis, MO, USA. lnon@dom.wustl.edu.",
"authors": "Non|Lemuel|L|;Jeroudi|Abdallah|A|;Smith|Bradley T|BT|;Parsaei|Shadi|S|",
"chemical_list": "D019380:Anti-HIV Agents; D019438:Ritonavir",
"country": "England",
"delete": false,
"doi": "10.3851/IMP3007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1359-6535",
"issue": "21(4)",
"journal": "Antiviral therapy",
"keywords": null,
"medline_ta": "Antivir Ther",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D004334:Drug Administration Schedule; D015658:HIV Infections; D006801:Humans; D008268:Macular Degeneration; D008297:Male; D019438:Ritonavir",
"nlm_unique_id": "9815705",
"other_id": null,
"pages": "365-7",
"pmc": null,
"pmid": "26555254",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bull's eye maculopathy in an HIV-positive patient receiving ritonavir.",
"title_normalized": "bull s eye maculopathy in an hiv positive patient receiving ritonavir"
} | [
{
"companynumb": "US-ABBVIE-16P-163-1725216-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "STAVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "Two cases with partial onset epilepsy who developed status epilepticus (SE) on lacosamide (LCM) monotherapy are reported. LCM is an effective adjunctive antiepileptic drug (AED) for partial-onset epilepsy and as infusion in SE. It has also shown efficacy in monotherapy. The reported cases achieved control of seizures with adjunctive LCM treatment and were afterwards converted to monotherapy. Both patients subsequently developed SE while on LCM monotherapy. They were on monotherapy for at least 2 months after withdrawal of concomitant AEDs precluding the possibility of withdrawal-induced SE. Pharmacovigilance is indicated when LCM is administered in monotherapy in order to assess its proper therapeutic potential and its putative limitations especially in cases where it may prove ineffective. Moreover, vigilance is necessary whenever any concomitant antiepileptic is tapered regardless of the substances used. Higher doses may be needed when an AED is used in monotherapy.",
"affiliations": "Neurology Clinic B and School of Molecular Medicine, Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.",
"authors": "Papacostas|Savvas S|SS|",
"chemical_list": "D000081:Acetamides; D000927:Anticonvulsants; D000078334:Lacosamide",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000081:Acetamides; D000328:Adult; D000927:Anticonvulsants; D004305:Dose-Response Relationship, Drug; D004828:Epilepsies, Partial; D006801:Humans; D000078334:Lacosamide; D008297:Male; D008875:Middle Aged; D012640:Seizures; D013226:Status Epilepticus; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25628098",
"pubdate": "2015-01-27",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17199030;24915838;21090839;22650166;21890421;23983867;23940830;23750855;7249508;22197124;22281192;23293881",
"title": "Status epilepticus developing during lacosamide monotherapy.",
"title_normalized": "status epilepticus developing during lacosamide monotherapy"
} | [
{
"companynumb": "CY-MYLANLABS-2015M1006434",
"fulfillexpeditecriteria": "1",
"occurcountry": "CY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugadditional": null,
... |
{
"abstract": "Precision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities.\n\n\n\nWe utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient's tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options.\n\n\n\nWES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK.\n\n\n\nThis clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.",
"affiliations": "Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. delacrf1@mskcc.org.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.;Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.;Department of Systems Biology, Columbia University Medical Center, New York, NY, 10032, USA.;Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.;Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.;Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, 10032, USA.;Darwin Health Inc., New York, NY, 10032, USA.;Department of Systems Biology, Columbia University Medical Center, New York, NY, 10032, USA.;Department of Biological Sciences, Columbia University, New York, NY, 10027, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.;Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.;Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.;Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.;Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.;Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. kunga@mskcc.org.",
"authors": "Dela Cruz|Filemon S|FS|;Diolaiti|Daniel|D|;Turk|Andrew T|AT|;Rainey|Allison R|AR|;Ambesi-Impiombato|Alberto|A|;Andrews|Stuart J|SJ|;Mansukhani|Mahesh M|MM|;Nagy|Peter L|PL|;Alvarez|Mariano J|MJ|;Califano|Andrea|A|;Forouhar|Farhad|F|;Modzelewski|Beata|B|;Mitchell|Chelsey M|CM|;Yamashiro|Darrell J|DJ|;Marks|Lianna J|LJ|;Glade Bender|Julia L|JL|;Kung|Andrew L|AL|",
"chemical_list": "D005047:Etoposide; D016190:Carboplatin; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1186/s13073-016-0366-0",
"fulltext": "\n==== Front\nGenome MedGenome MedGenome Medicine1756-994XBioMed Central London 36610.1186/s13073-016-0366-0ResearchA case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma Dela Cruz Filemon S. delacrf1@mskcc.org 1Diolaiti Daniel 1Turk Andrew T. 3Rainey Allison R. 1Ambesi-Impiombato Alberto 4Andrews Stuart J. 3Mansukhani Mahesh M. 3Nagy Peter L. 37Alvarez Mariano J. 6Califano Andrea 4Forouhar Farhad 5Modzelewski Beata 1Mitchell Chelsey M. 2Yamashiro Darrell J. 2Marks Lianna J. 2Bender Julia L. Glade 2Kung Andrew L. kunga@mskcc.org 11 Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 2 Department of Pediatrics, Columbia University Medical Center, New York, NY 10032 USA 3 Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA 4 Department of Systems Biology, Columbia University Medical Center, New York, NY 10032 USA 5 Department of Biological Sciences, Columbia University, New York, NY 10027, USA 6 Darwin Health Inc., New York, NY 10032, USA 7 Present Address: Medical Neurogenetics Laboratories, Atlanta, GA 30342, USA 31 10 2016 31 10 2016 2016 8 1161 7 2016 12 10 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nPrecision medicine approaches are ideally suited for rare tumors where comprehensive characterization may have diagnostic, prognostic, and therapeutic value. We describe the clinical case and molecular characterization of an adolescent with metastatic poorly differentiated carcinoma (PDC). Given the rarity and poor prognosis associated with PDC in children, we utilized genomic analysis and preclinical models to validate oncogenic drivers and identify molecular vulnerabilities.\n\nMethods\nWe utilized whole exome sequencing (WES) and transcriptome analysis to identify germline and somatic alterations in the patient’s tumor. In silico and in vitro studies were used to determine the functional consequences of genomic alterations. Primary tumor was used to generate a patient-derived xenograft (PDX) model, which was used for in vivo assessment of predicted therapeutic options.\n\nResults\nWES revealed a novel germline frameshift variant (p.E1554fs) in APC, establishing a diagnosis of Gardner syndrome, along with a somatic nonsense (p.R790*) APC mutation in the tumor. Somatic mutations in TP53, MAX, BRAF, ROS1, and RPTOR were also identified and transcriptome and immunohistochemical analyses suggested hyperactivation of the Wnt/ß-catenin and AKT/mTOR pathways. In silico and biochemical assays demonstrated that the MAX p.R60Q and BRAF p.K483E mutations were activating mutations, whereas the ROS1 and RPTOR mutations were of lower utility for therapeutic targeting. Utilizing a patient-specific PDX model, we demonstrated in vivo activity of mTOR inhibition with temsirolimus and partial response to inhibition of MEK.\n\nConclusions\nThis clinical case illustrates the depth of investigation necessary to fully characterize the functional significance of the breadth of alterations identified through genomic analysis.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s13073-016-0366-0) contains supplementary material, which is available to authorized users.\n\nKeywords\nPoorly differentiated carcinoma (PDC)Patient-derived xenograft (PDX) modelsPrecision medicineMAXmTORBRAFTemsirolimusWhole exome sequencing (WES)Jamie Deutsch Foundationhttp://dx.doi.org/10.13039/100002344Ira Sohn Research Conference Foundationissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nPrecision medicine approaches are being increasingly utilized in the diagnostic characterization and the development of molecularly informed therapeutic plans in both common and rare cancers [1–9]. Although improved insight into the biology and the refinement of treatment approaches for more commonly encountered cancers are obvious merits of precision medicine, the genomic characterization and the development of individualized treatment plans informed by the mutational status of patients with rare cancers epitomizes the power and potential of precision medicine. To illustrate this view, metastatic carcinomas with an occult primary site of origin represent a diagnostic and therapeutic dilemma for clinicians and are exceedingly rare in children [1, 10]. Undifferentiated or poorly differentiated carcinomas (PDC) are often treated as a single entity using platinum-based combination chemotherapies despite the clinicopathologic heterogeneity of this group of tumors [3]. Attempts have been made to classify PDCs based on immunohistochemical profiles along with clinical presentation in order to assign a putative anatomic site of origin which would then direct site-specific therapy [2]. Several studies have suggested that treatment of cancers of unknown primary site (CUP), which often include PDCs, have improved clinical outcomes when treated with site-specific therapy in comparison to empiric chemotherapy [3, 4].\n\nWith advances in molecular diagnostics, the application of next-generation sequencing technologies has enabled deeper insight into the tissue of origin for occult tumors and PDCs as well as offered therapeutic guidance to clinicians. However, despite improvements in the molecular characterization enabled by precision medicine, the biologic significance and the clinical relevance of identified mutations to treatment of the patient often remain unclear without additional investigation. The diagnostic and treatment challenges characteristic of rare tumors, such as CUPs and PDCs, represent a category of disease that would significantly benefit from a precision medicine-based approach to diagnosis and treatment planning. We present a case study of a pediatric PDC that involved the genomic and functional evaluation of identified variants and in vivo assessment of putative targets within the framework of a pediatric precision medicine program.\n\nClinical presentation and family history\nA 14-year-old boy with a history of asthma, attention deficit-hyperactivity disorder, and recurrent epidermoid cysts of the scalp presented to an outside hospital with a two-month history of malaise and back and abdominal pain which had been increasing in severity. He had also recently developed a progressively enlarging and discolored scalp lesion (Fig. 1a). Initial clinical workup was remarkable for elevated inflammatory markers (elevated erythrocyte sedimentation rate (ESR) and C-reactive protein), hyperuricemia, transaminitis, and elevations in lactate dehydrogenase and gamma-glutamyl transferase (GGT). He had no history of significant weight loss, pruritus, or night sweats, but presented with several days of intermittent fevers for which he had begun empiric antibiotic therapy. A complete blood count showed no abnormalities and levels of carcinoembryonic antigen (CEA), α-fetoprotein (AFP), and ß-human chorionic gonadotropin (ß-HCG) were normal. Diagnostic computed tomography (CT) imaging of the head revealed multi-focal lesions of the scalp, including several discrete, enhancing extra-axial masses and an ill-defined lytic calvarial lesion (Fig. 1b). Magnetic resonance imaging (MRI) also confirmed the multiple scalp lesions as well as multiple vertebral, pelvic, and femoral bone lesions. Due to the patient’s presentation of persistent abdominal pain in the setting of transaminitis and an elevated GGT, an abdominal ultrasound was performed and revealed an enlarged heterogeneous, nodular liver with multiple hypoechoic masses. A subsequent CT scan of the abdomen confirmed the presence of hepatosplenomegaly and infiltrative lesions within the liver (Fig. 1c). A chest X-ray showed no pulmonary lesions. The presenting physical exam was notable for scattered, firm red papules and nodules on the scalp, ranging in size between 5 mm and 3 cm. A distant mobile, subcutaneous nodule (8 mm) was also noted over an elbow. Abdominal exam revealed hepatosplenomegaly. The patient displayed no dysmorphic features and the remainder of the physical exam was unremarkable.Fig. 1 Clinical presentation of metastatic PDC. a Representative scalp nodule. b, c Diagnostic imaging demonstrating the presence of multiple lytic lesions of the calvarium (b) as well as heterogeneous lesions within the liver with associated hepatosplenomegaly (c). d–i Immunohistochemical staining consistent with diagnosis of a PDC with high proliferative index: (d) H&E (200X), (e) cytokeratin 5 (200X), (f) cytokeratin 10 (100X), (g) EpCAM (400X), (h) ß-catenin (400X), (i) Ki67 (200X). Scale bar = 100 μm\n\n\n\n\nThe patient’s past medical history was significant for a history of recurrent epidermoid cysts since the age of 2 years. Over his lifetime, he had over 15 cysts removed with pathology consistent with either an epidermoid cyst or hybrid lesions comprising an epidermoid cyst and pilomatricoma. Review of the family history was notable for multiple members on the maternal side with a history of cancer. The patient’s mother had recurrent breast cancer initially diagnosed at the age of 36 years. Additionally, cases of breast cancer were reported in the maternal grandmother and maternal aunt. A maternal great grandmother was diagnosed with ovarian cancer, a maternal great grandfather and maternal great uncle were diagnosed with lung cancer, a maternal nephew with a “bone cancer,” and a maternal grandfather with colon cancer. Maternal siblings are healthy. The patient’s father was well with no significant medical issues. The paternal family history was significant for a paternal great grandfather and grand uncle diagnosed with lung cancer. The patient had two siblings who were healthy.\n\nA biopsy of the largest scalp lesion localized over the left occiput was performed which revealed the presence of a high-grade carcinoma positive for pancytokeratin (AE1/AE3) and diffuse nuclear staining for ß-catenin with a Ki67 proliferative index of 50 %. The tumor showed focal weak staining for synaptophysin and was negative for chromogranin, CD3, CD20, CD30, CD99, PLAP, P63, myogenin, MART-1, EMA, desmin, CK7, CK20, S100, Oct3/4. INI-1 showed intact nuclear staining. A needle biopsy of the liver lesions was also performed and demonstrated similar histology. Based on the histopathological features, a diagnosis of high-grade carcinoma of unknown origin was rendered.\n\nThe patient was transferred to Columbia University Medical Center (CUMC) for further medical management and workup given the rarity and clinical acuity of the diagnosis. Given the relative rarity of high grade carcinoma in children, the patient and family were consented for participation in the Precision In Pediatric Sequencing (PIPseq) program at CUMC. An excisional biopsy of a large scalp lesion was performed to confirm the original diagnosis and excess material was utilized for genomic analysis, as well as for the generation of patient-derived xenograft (PDX) tumor mouse models. Pathologic review of the excisional biopsy scalp lesion demonstrated histologic features similar to the initial biopsy specimen and remained positive for ß-catenin, cytokeratin 5 and 10, and EpCAM (Ber-EP4) with a proliferative index of 50 % (Fig. 1d–i). Additionally, there was focal positivity for synaptophysin and negativity for CK7, CK20, p63, S100, and chromogranin. These findings were considered consistent with a PDC with focal neuroendocrine features.\n\nBased on this histopathological diagnosis, therapy was initiated utilizing a combination of paclitaxel, carboplatin, and etoposide (PCE) administered intravenously and given as 21-day cycles. Stable to partial responses in the scalp, calvarial, vertebral, and hepatic lesions were observed on CT reassessment of all known disease sites after recovery from the first cycle of therapy. Furthermore, the patient reported overall improvement in pain with decreased requirements for opiate therapy. The patient completed ten cycles of PCE therapy with continued disease stabilization. Although all lesions demonstrated overall improvement, the patient remained a partial responder to PCE therapy with persistent lesions in the scalp, calvarium, vertebra, pelvic, femora, and liver. Pain symptoms had largely resolved and the patient was successfully weaned off opiate therapy.\n\nRestaging performed after ten cycles of PCE revealed a new lesion in the brain. Based on genomic analysis of the original tumor, the patient was started on a regimen that incorporated the mTOR (mammalian target of rapamycin) inhibitor, temsirolimus, given in combination with the alkylating agent, temozolomide, and the topoisomerase inhibitor, irinotecan [11]. After a single cycle of therapy, the patient demonstrated radiographic evidence of disease progression and chose to discontinue further therapy. The patient subsequently died of progressive liver failure.\n\nMethods\nChemical reagents\nSelumetinib, carboplatin, irinotecan, and temsirolimus were purchased from MedChem Express. JQ1 was kindly provided by Dr. James Bradner (Dana-Farber Cancer Institute, Boston, MA, USA). Drugs were resuspended in N-Methyl-2-pyrrolidone (NMP) to create a stock solution (Sigma Aldrich) and diluted in PTD buffer (30 % PEG-400; 5 % Tween 80; 65 % Dextrose water, D5W, Sigma Aldrich) before drug dosing.\n\nPatient-derived xenograft (PDX) generation\nAfter obtaining a portion of the biopsy specimen, the tumor tissue was fragmented into ~2 mm fragments and implanted subcutaneously into the flanks of NSG-HPRT null mice (NSG-H; NOD.Cg-Prkdcscid Il2rgtm1Wjl Hprtb-m3/EshJ, Strain 012480, Jackson Laboratory, Bar Harbor, ME, USA) to generate the passage 0 (P0) generation. When P0 tumors reached a size of ~1 cm in the widest dimension, the PDX tumors were collected after humane euthanasia and expanded into a P1 generation for therapeutic studies (P4 tumors were used for the selumetinib efficacy study). Mice were randomized and assigned to treatment groups once tumors reached a volume of 150–200 mm3. Tumor growth was measured biweekly using calipers and mice were euthanized as per institutional animal protocol guidelines at the indicated time points. Tumors were collected and fragments were either fixed in 4 % formalin for histologic analysis or snap frozen in liquid nitrogen for subsequent DNA, RNA, and protein isolation and analyses.\n\nPDX treatment studies\nPDX models were dosed with single agents as follows: carboplatin 16 mg/kg intraperitoneally (IP) twice a week; JQ-1 50 mg/kg IP daily (5 days on/2 days off); temsirolimus 20 mg/kg IP daily; irinotecan 20 mg/kg IP daily (5 days on/2 days off); and selumetinib 50 mg/kg orally (PO) twice daily (5 days on/2 days off). Combination treatment was given with temsirolimus 15 mg/kg IP along with irinotecan 20 mg/kg IP daily (5 days on/2 days off).\n\nCell culture\n293 T cells (Invitrogen), 293 T platinum E (Cell Biolabs, San Diego, CA, USA), wild-type and BRAF –/– mouse embryonic fibroblasts (MEFs) were maintained in DMEM (Gibco), 10 % FetalPlex™ animal serum complex (Gemini Bio-Products), and 1 % Antibiotic-Antimycotic Solution (Gibco). Wild-type MEF and BRAF –/– MEF were a kind gift of Dr. Catrin Pritchard (University of Leicester, Leicester, UK).\n\nImmunoblotting\nCells and xenograft tumor samples were resuspended in high SDS-RIPA Buffer (50 mM Tris-HCl, pH 7.5, 150 mM Sodium Chloride, 1 % Triton X-100, 1 % sodium deoxycholate, 1 % SDS, 2 mM EDTA; Sigma Aldrich). Tissues were disrupted and homogenized with a TissueLyser II (Qiagen) for 2 × 2 min intervals at 30Hz. Protein concentration was determined using the Pierce™ BCA Protein Assay Kit (Pierce). A total of 15–50 μg of protein extracts were loaded onto NuPAGE® Novex® 4–12 % Bis-Tris Protein Gels (Life Technologies) and subsequently transferred onto nitrocellulose membranes using the iBlot® Dry Blotting System (Life Technologies). The blots were developed using SuperSignal™ West Pico Chemiluminescent Substrate (Thermo Scientific). Antibodies: S6-Ribosomal protein (5G10), Phospho-S6 Ribosomal protein (Ser240/244) (D68F8), Phospho-4E-BP1 (Thr37/46) (236B4), p44/42 MAPK (Erk1/2) (137 F5), and Phospho-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) (D13.14.4E) were purchased from Cell Signaling Technology. C-MYC (Y69) and N-MYC (NCM II 100) were purchased from Abcam. FLAG (M2) and β-actin (A2066) antibodies were purchased from Sigma Aldrich.\n\nImmunohistochemistry\nImmunohistochemistry was performed by the Columbia University Medical Center Pathology Department and the Herbert Irving Comprehensive Cancer Center Molecular Pathology Core using standard procedures. Antibodies: LC3A/B (D3U4C), cleaved caspase-3 (Asp175), S6-Ribosomal Protein (5G10), and Phospho-S6-Ribosomal Protein (Ser240/244) (D68F8) were purchased from Cell Signaling Technology. Ki-67 (Clone MIB-1) was purchased from Dako. A minimum of five fields per section were analyzed for caspase 3 and Ki67 quantification.\n\nTransfection and retroviral transduction\npBABEbleo-Flag-BRAF-V600E was kindly provided by Christopher Counter (Addgene, plasmid # 53156). pBabe-bleo-Flag-BRAF-WT and pBABEbleo-FLAG-BRAF-K483E were generated by gene synthesis and cloning (GenScript, Piscataway, NJ, USA). 293 T cells were transfected using Lipofectamine® 3000 (Life Technologies) according to the manufacturer’s instructions.\n\nRetrovirus production and transduction were performed using 293 T platinum E cells following the manufacturer’s instructions and as previously described [12].\n\nElectrophoretic mobility shift assay (EMSA)\nMAX, MAXR60Q, C-MYC, and MXD1 cDNAs were generated by gene synthesis (GenScript) and cloned into pF3A WG (BYDV) Flexi® Vector (Promega). In vitro transcription and translation (IVT) was performed using the TNT® SP6 High-Yield Wheat Germ Protein Expression System (Promega). Wheat germ extracts containing the indicated IVT proteins were incubated in EMSA binding buffer (10 mM Tris-HCl, pH 7.5, 50 mM KCl, 1 mM DTT, 2.5 mM DTT, 0.25 % Tween-20, 50 ng poly(dIdC)), in the presence of 50 ng IRDye-800 labeled probe (Integrated DNA Technologies). Probe sense sequence: 5’-CGGCAGCGAGCCACGTGGACCAACTA-3’. Reactions were loaded onto a 4–12 % TBE gel and imaging was performed on an Odyssey® Fc Imaging System (LI-COR).\n\nStructural modeling\nVisualization and comparison of protein structures and modeling exercises were performed using XtalView. Crystallography and NMR System (CNS) was used for minimization of steric clashes within the heterodimer and between the protein and DNA. All structural figures were made using PyMol [13].\n\nNucleic acid extraction, clinical sequencing, and analysis\nDNA from macro-dissected paraffin-embedded tumor, OCT-embedded frozen tissue, bone marrow, peripheral whole blood, or buccal swabs was extracted using the QIAGEN QIAamp Tissue Kit (for tissue samples) on the QIAcube system; QIAsymphony DNA Mini Kit (blood and bone marrow); or the QIAGEN DNA Micro Kit (buccal swabs). RNA was extracted using the QIAGEN RNeasy Kit (fresh frozen tissue) or the RNeasy FFPE Kit (paraffin-embedded tissue). All slides were evaluated by a pathologist (AT or MM) to ensure that a minimum of 50 % viable tumor was present for subsequent extraction and analyses. Whole exome sequencing (WES) was performed using the Agilent SureSelectXT All Exon V5 + UTRs capture kit for library generation, and sequenced on the HiSeq 2500 System (Illumina), using paired-end 100 cycle × 2 sequencing. RNA was sequenced using the TruSeq Stranded Total RNA LT Sample Prep Kit (Illumina), with 100 cycles × 2 paired-end sequencing on the HiSeq 2500.\n\nDNA sequencing reads were de-multiplexed and converted to FASTQ files using CASAVA from Illumina. Following mapping and variant calling of both tumor and normal samples by NextGENe, resulting variants were subject to filtering. Variants in normal DNA were passed through a “reference range filter” of cancer predisposition genes, genes relevant to pharmacogenomics, and variants relevant to patient care; a “reportable range filter” which includes COSMIC variants in the patient’s mutation report file and variants in genes on the list of ACMG (American College of Medical Genetics and Genomics) recommendations for reporting of secondary findings; as well as a frequency filter which included variants whose minor allele frequency in The 1000 Genomes [14] is less than 1 %. Somatic mutations in the tumor were identified by subtracting all variants called in normal tissue (output at minor allelic fraction of 5 %) from variants called in the tumor (output at a minor allelic fraction of 10 %). Somatic mutations were further characterized as homozygous, compound heterozygous, “de novo.” or disruptive.\n\nCopy number changes were identified using the EXCAVATOR software 44 [15]. In addition, all high-quality heterozygous variants with allelic ratios of 45–55 % in the normal sample were outputted to allow identification of copy number neutral loss of heterozygosity (LOH) as well as to support the copy number variations (CNV) identified by EXCAVATOR.\n\nSanger sequencing\nPurified RNA from xenograft tissue samples were reverse-transcribed using ThermoScript™ RT-PCR System for First-Strand cDNA Synthesis (Life Technologies). PCR was performed using Platinum Blue PCR super mix (Life Technologies). Sanger sequencing was performed by Genewiz (South Plainfield, NJ, USA) on PCR products. Primer sequences are available upon request.\n\nData interpretation and reporting\nInterpretation of clinical WES, RNA sequencing (RNA-seq), and CNV was conducted by a multidisciplinary team representing pediatric oncologists, pathologists, surgeons, molecular and clinical geneticists, and bioinformaticians in the setting of a molecular tumor board.\n\nGene expression profile and expression outlier analyses\nRNA was prepared using a TruSeq Stranded Total RNA Kit (Illumina). Paired-end sequencing with 100 bp read lengths was performed on an Illumina HiSeq 2500. Transcription level estimation, measured in FPKM (fragments per kilobase per million reads sequenced), was performed by an RNA-seq processing pipeline developed by the Personalized Genomic Medicine Program at CUMC following standard practices. First, reads were bio-informatically filtered for rRNA using a program called SortMeRNA [16] and trimmed to remove poor quality tails using TrimGalore [17]. The remaining reads are then mapped to the human genome (hg19) using the Tuxedo Suite [18], consisting of Bowtie, TopHat, and Cufflinks. Non-uniquely mapped reads are excluded before estimation of FPKM by Cufflinks. For transcriptomic analysis, the Tuxedo Suite Package with custom modifications was used to generate BAM from FASTQ files from CASAVA, and mutation calling performed using NextGENe software. At least 50 million independent mapped reads were required. Transcriptomic variants were used to confirm DNA sequence variants. In addition, unmapped reads were analyzed using “FusionMap” to generate a list of fusions for review by molecular pathologists.\n\nRanking overexpressed genes was done by an algorithm developed by PGM: DiffExprOutlier. DiffExprOutlier quantitates transcript levels for genes in comparison to the general transcription levels of the tissues examined as determined by 2921 normal RNA-seq samples from the GTEx database (version 4) [19]. For normalization, the median transcription levels (FPKM) of 8000 housekeeping genes are used as a reference [20]. The normalized expression was determined for each gene in each normal sample, as well as in the test sample. For each gene, the test sample was ranked within the normal reference samples based on the relative normalized expression of that gene. Genes that rank the test sample in the top or bottom 10 % of all other samples were outputted for review.\n\nPublicly available RNA-seq data acquisition and normalization\nMessenger RNA (mRNA) expression data (RNA-seq) from 33 tissue types was obtained from The Cancer Genome Atlas (TCGA) [21]. Level-3 raw-counts per gene were obtained from TCGA data portal, normalized to correct for differences in library size and transformed to stabilize the variance by fitting the dispersion to the negative-binomial distribution, as implemented in the DESeq package from Bioconductor [22]. Alternatively, library-size normalized counts per gene were corrected by average transcript size to generate FPKM. RNA-seq data for gastro-entero-pancreatic neuroendocrine tumors were obtained using a HiSeq 2000 sequencer (Illumina). Reads were mapped to the human genome (UCSC-hg19) by Bowtie2 [23, 24] and uniquely mapping reads were summarized at the gene level using the GenomicFeatures package from Bioconductor [25]. Raw-counts per gene were normalized and variance stabilized as described for TCGA data. We performed absolute gene expression discretization by fitting a mixture of two Gaussian models, representing the non-expressed and expressed transcripts, to the probability density of expression, and estimating the relative likelihood of expression from the fitted distributions.\n\nT-distributed stochastic neighbor embedding (t-SNE)\nWe used t-SNE [26], as implemented in the t-SNE package from Bioconductor, to generate a two-dimensional (2D) representation of the similarity between samples as measured by correlation analysis in a transformed expression space to highlight the similarity in absolute expression terms. Briefly, the relative likelihood of expression was computed by fitting a mixture of two Gaussian distributions (the first representing very low to non-expressed genes and the second for expressed genes) to the probability density of expression represented as FPKM. This transformation efficiently shrinks the variance between expressed genes while amplifying the variance between expressed and non-expressed genes. In order to reduce computation time, this analysis was performed on 3167 samples, including at most 100 samples per tumor type selected at random from our TCGA pan-cancer expression database and the carcinoid sample under study.\n\nStatistical analyses\nAll in vitro experiments were performed at least three times. The statistical significance of differences was determined using the Student’s t-test with a minimal level of significance of P < 0.05. Differences in tumor volume response to drug treatments were compared using a two-way ANOVA. Statistical significance of differences in tumor growth among treatment groups was determined by the Mann–Whitney U test using GraphPad Prism 6.0 software. Two-sided P values were given at a 95 % significance level.\n\nResults\nGenomic characterization of primary tumor\nPrimary tumor tissue obtained from a scalp biopsy was processed for routine histopathological diagnostic evaluation, genomic analysis, and generation of a PDX model. Genomic analysis comprised tumor/normal WES and RNA sequencing of the tumor. Variant calls were independently determined for tumor and germline, and somatic variants determined based on subtraction. WES data were used to determine CNV and RNA-seq was mined to identify translocations and gene expression outliers by comparison to an expression model derived from the genotype-tissue expression database (GTEx) [27]. Genomic alterations identified through this analysis are summarized in Fig. 2a. Datasets are available through the cBioPortal for Cancer Genomics (http://cbioportal.org) [28, 29].Fig. 2 WES and transcriptome sequencing of a primary tumor. a\nCircos plot summarizing WES and transcriptome analysis of primary tumor. Inner circle represents structural variants and gene fusions; second tier, copy number variations (blue, loss; red, gain); third tier, mRNA expression outlier analysis of cancer related genes within the top and bottom 10th percentile (green, under-expressed; orange, over-expressed); fourth tier (outer circle), somatic mutations localized to respective chromosomes. b\nScatter-plot showing the t-SNE 2D projection for 3167 samples, including at least 100 samples (indicated in the figure) for each of the 34 tissue types represented in our pan-cancer database. Tissue ID is indicated by different colors and the carcinoid sample is indicated by a bold black dot and arrow. c Relative gene expression rank of outlier genes after z-normalization across a compendium of expression profiles from the GTEx database. A z-distribution is superimposed as reference. ACC adrenocortical carcinoma, BLCA bladder urothelial carcinoma, BRCA breast carcinoma, CESC cervical carcinoma, CHOL cholangiocarcinoma, COAD colon adenocarcinoma, DLBC diffuse large B-cell lymphoma, ESCA esophageal carcinoma, GBM glioblastoma multiforme, HNSC head and neck carcinoma, KICH kidney chromophobe, KIRC clear cell carcinoma of the kidney, KIRP renal papillary cell carcinoma, LAML acute myeloid leukemia, LGG low grade glioma, LIHC hepatocellular carcinoma, LUAD lung adenocarcinoma, LUSC lung squamous cell carcinoma, MESO mesothelioma, NET gastrointestinal neuroendocrine tumor, OV ovarian carcinoma, PAAD pancreatic adenocarcinoma, PCPG pheochromocytoma and paraganglioma, PRAD prostate adenocarcinoma, READ rectal adenocarcinoma, SARC sarcoma, SKCM cutaneous melanoma, STAD gastric adenocarcinoma, TGCT testicular germ cell tumor, THCA thyroid carcinoma, THYM thymoma, UCEC uterine corpus endometrial carcinoma, UCS uterine carcinosarcoma, UVM uveal melanoma\n\n\n\n\nGermline variants and somatic alterations\nA frameshift variant in APC (c.4660_4661insA, p.E1554fs) was identified in both the normal and tumor material and was determined to be a de novo germline mutation after sequencing of both parents. This finding supports a diagnosis of familial adenomatous polyposis (FAP)/Gardner syndrome. A second mutation in the APC tumor suppressor was identified (c.2368A > T, p.R790*) in the tumor. Additional somatic mutations in cancer-associated genes included missense mutations in TP53 (c.743G > A, p.R248Q), MAX (c.179G > A, p.R60Q), BRAF (c.1447A > G, p.K483E), and RPTOR (c.2252C > T, p.A751V), and a nonsense mutation in ROS1 (c.1176 T > A, p.C392*). The TP53 (p.R248Q) and APC (p.R790*) mutations had allelic frequencies consistent with loss of heterozygosity (LOH).\n\nThe identified TP53 (p.R248Q) mutation is a previously described gain-of-function mutation which is associated with early-onset development of many tumor types [30–32]. The somatic APC (p.R790*) mutation has also been previously reported in the Catalogue Of Somatic Mutations In Cancer (COSMIC) database [33, 34]. The newly identified de novo germline APC (p.E1554fs) mutation is localized on a codon where other frameshift mutations have been reported in COSMIC. Both APC mutations generate truncated proteins resulting in constitutive activation of canonical WNT pathway signaling. Immunohistochemical analysis of primary tumor showed diffuse ß-catenin nuclear staining (Fig. 1h) consistent with the described genetic lesions.\n\nGiven the role of MET in the progression of CUPs, we also evaluated the status of MET in the primary tumor [35, 36]. Analysis of MET revealed no evidence of amplification or other gene alterations (data not shown).\n\nCopy number variation\nSeveral segmental changes consistent with chromosomal instability were identified including -3, -5q, 8q, del(9p), -11p, del(11q), del(13q), -16,-17p, del(21q), and -Y. Among the genes localized within deleted regions are well-established tumor suppressor genes including the cell cycle inhibitors CDKN2A and RB1 and the mTOR inhibitor TSC2. Consistent with LOH suggested by the high allelic frequencies for TP53 (p.R248Q) and APC (p.R790*) mutations, we confirmed segmental loss of -17p and -5q containing the wild-type TP53 and APC (p.E1554fs) alleles, respectively. Finally, we observed a copy gain in the 8q region containing the MYC locus.\n\nGene expression analysis\nTo better understand the tissue of origin for the tumor, we used clustering to map the gene expression profile of the patient’s tumor to all tumor samples available in the TCGA dataset and an additional cohort of neuroendocrine tumors (NET). The patient’s transcriptome showed the highest similarity to a cohort of 212 enteropancreatic NETs representing primary tumors and liver metastases originating from pancreatic, small intestine, and colorectal primaries (Fig. 2b), providing support for the classification of this tumor as a PDC with neuroendocrine features.\n\nTo identify gene expression outliers (over-expressed and under-expressed), we compared the gene expression profile from the tumor with a model constructed from the mean expression of all genes derived from the GTEx database of 2921 transcriptomes. Gene expression outlier analysis showed several genes involved in the mTOR pathway which ranked in the top and lower 10th percentiles (Fig 2c). Notably, we observed over-expression of AKT3 (an mTOR activator) and reduced expression of TSC2 (consistent with single copy loss of the gene) and STK11 which both inhibit mTOR activity (Fig. 2c). These results suggest hyperactivation of the mTOR pathway, which was verified by immunohistochemical evaluation of the primary tumor demonstrating elevated phosphorylation levels of ribosomal protein S6 (RPS6), a biomarker of mTOR activation (Additional file 1: Figure S1). No other aberrant expression of genes involved in CUP progression, such as MET, was observed.\n\nProtein fusion events\nFusion events were observed but did not involve known cancer related genes or targetable signaling pathways. Most fusion events were intra-chromosomal and occurred within the region of chromosome 8q (Fig. 2a).\n\nFunctional characterization of MAX p.R60Q\nMAX is a transcription factor of the basic helix-loop-helix leucine zipper (bHLH-LZ) family which is the obligate heterodimer for C-MYC, N-MYC, and L-MYC oncoproteins. MAX can also form a homodimer or heterodimerize with MXDs and MNT which functionally antagonize MYC/MAX activity and promotes cell cycle arrest and differentiation (reviewed in [37, 38]). MAX (p.R60Q) is the most common MAX gene mutation reported in the COSMIC database suggesting it may promote MAX oncogenic activity [39]. Arg 60 is the first amino acid of Helix 2 and participates in crucial protein–protein and protein–DNA interactions necessary for both homodimerization and DNA binding [40]. To gain insight into the functional consequence of the MAX (p.R60Q) mutation, we performed in silico modeling of the mutation in the context of either the MAX homodimer or MAX/C-MYC and MAX/MXD1 heterodimers using published crystal structures [41] (Fig. 3a–c). The structure of the MAX homodimer in complex with DNA [40] confirms that the Arg 60 of each subunit plays a critical role in the stability of the DNA-bound MAX-MAX homodimer complex. Arg 60 forms two hydrogen bonds (H-bond) with the phosphate moiety of DNA in addition to forming π-π bond interactions with the invariant Phe 43 in each subunit (Fig. 3a). Therefore, the mutation of two invariant Arg 60 residues to glutamine at the MAX homodimer–DNA interface disrupts the continuity of the π-π interactions and inhibits both homodimerization and DNA binding. Consistent with our analysis, mutation of the equivalent basic amino acid at the beginning of Helix 2 in the bHLH transcription factor TCF3 abolishes its ability to dimerize and bind DNA [42]. Additionally, overexpression of the MAXR60Q mutant in pheochromocytoma PC12 cells, which lack endogenous wild-type MAX, is unable to repress the expression of an E-box-dependent luciferase reporter [43].Fig. 3 Structural and functional analyses of Variants of Unknown Significance (VUS). a–c Structures of MAX homodimer and C-MYC-MAX and MXD1-MAX heterodimers in complex with DNA. a MAX-MAX homodimer crystal structure (PDB id: 1AN2) in which the subunit A (yellow for carbon atoms) and B (cyan for carbon atoms) are represented and the side chains of several invariant residues are depicted with stick models and labeled. b Crystal structure of C-MYC/-MAX heterodimer in complex with DNA (PDB id: 1NKP). MAX and C-MYC carbon atoms are represented in yellow and purple, respectively. c Crystal structure of MAX-MXD1 heterodimer in complex with DNA (PDB id: 1NLW). MAX and MXD1 carbon atoms are represented in yellow and green, respectively. In all structures presented, the MAX p.R60Q mutation is shown in magenta. Dashed lines (black and magenta) represent hydrogen bonds. The sugar-phosphate backbone of DNA is shown in orange with two selected nucleotides from each subunit shown as stick models. d MAXR60Q mutant heterodimerizes with C-MYC and MXD1 and binds to DNA. The indicated proteins were transcribed and translated in vitro and incubated with an E-box containing probe. Specific proteins/DNA complex bands are indicated on the left. Non-specific (ns) binding products present in the probe-only and vector control lanes are indicated on the left. e, f Structures of wild-type BRAF and BRAF p.K483E mutant. e Model of the BRAF kinase domain in complex with ATP (black for carbon atoms) and a Mg2+ ion (dark green), in which the side chains of five essential residues in BRAF, are shown, and labeled. The helix αC in its active conformation (dark violet) (PDB id: 4MNE) and in inactive conformation (light gray) (PDB id: 4WO5) is represented as cartoon and the side chain of the invariant E501 is depicted with stick models in two orientations. f Model of the BRAF kinase domain in which K483 is replaced by E (magenta for carbon atoms). g Proteins levels and phosphorylation level of ERK1/2 upon transient transfection of the indicated BRAF proteins in HEK 293 T cells\n\n\n\n\nWhile the MAX p.R60Q mutation abolishes MAX homodimerization and DNA binding, its effects on MAX heterodimerization with C-MYC or other MYC family members is unknown. Structural comparison of DNA-bound MAX/MAX, C-MYC/MAX, or MXD1/MAX reveals significant differences in the dimer interfaces which correspond to the substitution of Arg 60 and Ala 61 of MAX with Lys 392 and Val 393 in C-MYC (Fig. 3b) and Thr 94 and Leu 95 in MXD1 (Fig. 3c), respectively. Lys 392 of C-MYC forms a strong H-bond with the phosphate group of DNA and its long hydrophobic side chain interacts with Phe 374 within C-MYC itself. In addition, the structure of the C-MYC/MAX heterodimer shows that Val 393 of C-MYC forms stronger hydrophobic interactions with Ile 39 of MAX as compared with the hydrophobic interaction between Ile 39 from subunit A of MAX with Ala 61 of subunit B of MAX in the MAX homodimer. Similar interactions are established by MXD1 Thr 94 and Leu 95 within the MXD1/MAX heterodimer. Taken together, these compensated interactions reinforce the heterodimeric assembly in the C-MYC/MAX and MXD1/MAX heterodimers.\n\nIn addition, while MAX Lys 40 does not interact with DNA in either subunit of the MAX homodimer (Fig. 3a), our model shows that MAX Lys 40, in the context of C-MYC/MAX and MXD1/MAX heterodimers, forms H-bonds with DNA (Fig. 3b, c) compensating the loss of the H-bond between Arg 60 and DNA in the MAX p.R60Q mutant. Overall, our analysis predicts that the MAX p.R60Q mutant could form a stable heterodimer with both C-MYC and MXD1. To formally evaluate if MAX p.R60Q could form functional heterodimers with C-MYC or MXD proteins, we expressed in vitro either C-MYC or MXD1 proteins in the presence of wild-type MAX or the mutant MAXR60Q (Additional file 1: Figure S2A). Evaluation by EMSA demonstrates that both MAX and MAXR60Q can equally dimerize with C-MYC and MXD1 and bind DNA (Fig. 3d). Hence, these structural and biochemical results suggest that the MAX p.R60Q mutation inhibits MAX homodimerization, but does not disrupt C-MYC/MAX heterodimerization, shifting the balance towards C-MYC activation in proliferating cells.\n\nStructural assessment of RPTOR p.A751V\nRPTOR, mTOR, and MLST8 constitute the core subunits of the mammalian TORC1 (mTORC1) complex which play a major role in the control of cell growth and metabolism and is often deregulated in cancer [44–46]. RPTOR is a critical component of the mTOR complex and regulates the catalytic activity and substrate recognition of mTOR [47, 48]. Analysis of the identified RPTOR p.A751V mutation by PolyPhen, SIFT, and PROVEAN [49–51] indicates that this mutation is tolerable and not likely to disrupt protein structure/function. This prediction is tenable given the similar sizes, hydrophobicity, and ionization status of alanine and valine. Furthermore, the RPTOR p.A751V residue is localized to a flexible polypeptide stretch that connects RPTOR’s armadillo and β-propeller domains and is contained within a region that does not directly contact either mTOR or mTOR substrates [52]. In addition, the RPTOR p.A751V mutation has been reported in The 1000 Genomes project database indicating that RPTOR p.A751V may represent a genetic variant of RPTOR that is present within the human population [53]. Hence, RPTOR p.A751V mutation would not be expected to negatively affect mTOR pathway activity and contribute to aberrant mTOR signaling.\n\nFunctional characterization of BRAF p.K483E\nBRAF is one of the most frequently mutated genes in cancer [54, 55]. Mutations affecting BRAF normally result in aberrant activation of the downstream MEK/ERK pathway [56]. The identified BRAF p.K483E mutation in the patient’s tumor is localized to the BRAF kinase domain and is predicted to be deleterious by Polyphen, SIFT, and PROVEAN. Modeling of BRAF in complex with ATP (Fig. 3e and Additional file 1: Figure S2B) shows that Lys 483 makes several H-bonds critical for the proper orientation of the ATP molecule within the hydrophobic pocket. When Lys 483 is mutated to glutamic acid (Fig. 3f), the H-bonding network between Lys 483 and the surrounding residues is abolished which has a detrimental effect on the kinase activity. Since both BRAF p.K483M and BRAF p.D594A mutants (Additional file 1: Figure S2C, D) disrupt ATP binding and have been shown to be catalytically inactive [57, 58], we predicted that the BRAF p.K483E mutation is a kinase inactivating mutation. However, given that the BRAF p.K483E mutation is present at the high allelic frequency in the patient’s tumor (>40 %), it has previously been described in chronic lymphocytic leukemia and is catalogued in the COSMIC database suggests that BRAF p.K483E may paradoxically result in downstream pathway activation [59].\n\nTo functionally evaluate the consequence of the BRAF p.K483E mutation, we transiently expressed wild-type BRAF, mutant BRAFK483E, and the constitutively active BRAFV600E mutant in 293 T cells and evaluated ERK1/2 activation. Compared to a control vector, BRAFK483E expression increased the phosphorylation levels of ERK1/2 although at levels comparable to those induced by wild-type BRAF (Fig. 3g). We also confirmed that the BRAFK483E mutant is able to activate ERK1/2 signaling in wild-type MEFs as well as BRAF null MEFs (Additional file 1: Figure S2E). Since the BRAFK483E mutant is catalytically dead, ERK1/2 activation likely results from allosteric activation of wild-type BRAF or CRAF given the increased ERK1/2 phosphorylation observed in BRAF null cells. These results suggest that BRAF p.K483E mutation activates downstream signaling through the MEK/ERK pathway.\n\nPreclinical assessment of therapeutic targeting of mTOR, MEK, and MYC pathways\nWe generated a PDX model and used Sanger sequencing to verify the presence of mutations present in the original tumor (Additional file 1: Figure S3). In light of the genomic profiling studies suggesting alteration of mTOR, BRAF, and C-MYC activity, we evaluated targeted inhibition of these pathways in the PDX model. We decided to test the mTOR inhibitor temsirolimus, the BET inhibitor JQ1, which has been shown to have efficacy on tumors with deregulated C-MYC and N-MYC activity, and the MEK inhibitor selumetinib which inhibits the activity of the MEK/ERK pathway downstream of BRAF [60].\n\nPDX tumors exhibited differential sensitivities to treatment with selected inhibitors. In contrast to tumors treated with either vehicle or a standard-of-care chemotherapy agent, carboplatin, treatment with temsirolimus consistently demonstrated abrogation of tumor growth (Fig. 4a). Interestingly, the anti-proliferative effect of temsirolimus was sustained in comparison to carboplatin-treated and JQ1-treated tumors which showed an initial phase of anti-tumor response followed by the emergence of resistance despite continued treatment. Animals treated with the MEK inhibitor selumetinib showed a modest anti-tumor effect but whose overall treatment response would be deemed progressive disease (Additional file 1: Figure S4A). We confirmed effective target engagement in temsirolimus-treated tumors by showing reduced phosphorylation of downstream mTOR targets, RPS6 and 4EBP1, and an associated increase in autophagy (LC3A/B) (Fig. 4b and Additional file 1: Figure S4B). We also show a reduction in activated ERK1/2 (p-ERK1/2) in selumetinib-treated tumors suggesting that inhibition of ERK1/2 signaling is not sufficient to completely abrogate tumor growth in this model (Additional file 1: Figure S4C). JQ1 treatment did not reduce either C-MYC or N-MYC expression (Fig. 4c), indicating that the anti-proliferative effect of JQ1 on tumor growth may not be directly related to modulating MYC expression.Fig. 4 \na Sensitivity of PDX tumors to the mTOR inhibitor, temsirolimus. Chemoresistance to carboplatin and JQ1 were observed following a transient period of response. Mean and standard error of the mean (SEM) are shown. b Phosphorylation level of RPS6 upon temsirolimus treatment. c C-MYC and N-MYC protein levels upon JQ1 treatment. d Temsirolimus treatment results in decreased Ki-67 staining with concomitant increase in cleaved caspase 3 (Cl. CASP 3) following short-term (3 days) and long-term (50 days) treatments. * p < 0.05, ** p < 0.01. e Tumor growth after temsirolimus treatment withdrawal. Mean and SEM are shown. f Temsirolimus treatment can successfully rescue and induce tumor regression in carboplatin-resistant tumors. Mean and SEM are shown. g Combination therapy (temsirolimus and irinotecan) does not result in increased anti-tumor activity. Tumor regrowth is observed with withdrawal of treatment. Mean and SEM are shown\n\n\n\n\nAnalysis of the tumor proliferative index in the temsirolimus-treated tumor samples confirmed a decrease in proliferative rate, as indicated by reduced Ki67 staining, with an associated increase in apoptosis (increased cleaved caspase 3) in both short-term and long-term treated tumors (Fig. 4d). However, the anti-proliferative effect of temsirolimus is contingent on continued treatment and suppression of mTOR pathway signaling. We observed that upon withdrawal of temsirolimus treatment, there was a resumption of tumor growth in the PDX model (Fig. 4e) with consequent increase in proliferative activity (Fig. 4d), decrease in apoptosis (Fig. 4d), and re-activation of mTOR pathway signaling (Fig. 4b and Additional file 1: Figure S4B). The overall response to temsirolimus treatment is best characterized as a partial response, with residual tumor remaining despite ongoing therapy (Fig. 4a).\n\nModeling chemoresistance and evaluating retrieval therapy\nThe lack of durable clinical responses in patients with PDC treated with conventional chemotherapy regimens, such as PCE, underscores the need for identifying effective salvage therapies. Hence, models of chemoresistant tumors serve as valuable resources for testing salvage therapy approaches. We used the PDX model to determine if temsirolimus would be efficacious in relapsed disease after conventional chemotherapy. After a treatment period of ~30 days, carboplatin-treated tumors developed resistance manifested by a resurgence of tumor growth despite continued treatment with carboplatin (Fig. 4a). When carboplatin-resistant animals were crossed over to treatment with temsirolimus, tumor regression was evident demonstrating a lack of cross-resistance between the two drugs (Fig. 4f). However, similar to the effects of single agent temsirolimus treatment on naive PDX tumors, the anti-proliferative effects and inhibition of mTOR pathway proteins by temsirolimus remained effective only with sustained exposure to drug (data not shown).\n\nWhen the patient progressed on PCE therapy, he was changed to a multiagent regimen that included a topoisomerase I inhibitor (irinotecan) in combination with mTOR inhibition which has been used for the treatment of various solid tumors [11, 61–64] and based on findings from our genomic and preclinical studies. The patient rapidly progressed, suggesting that the combinatorial strategy may not have produced the desired additive effect. Therefore, we evaluated the combination of temsirolimus and irinotecan in our PDX model. Tumors treated with the combination of irinotecan and temsirolimus showed no additional anti-tumor effect compared to either agent alone (Fig. 4g). Following withdrawal of treatment, the rates of tumor regrowth were similar between single agent and combination-treated tumors (Fig. 4g). Hence, despite the single agent activity of temsirolimus and irinotecan in these tumors, combined treatment with both agents produced a non-additive effect. In fact, the rate of regrowth after cessation of therapy was faster than irinotecan monotherapy, suggesting an antagonistic effect in the combination. These results paralleled the lack of clinical response observed in the source patient who received treatment with a combination containing the combination of irinotecan and temsirolimus in addition to the alkylating agent, temozolomide.\n\nDiscussion\nThe rarity of carcinomas in children has made it challenging to determine effective treatments for this group of cancers. Furthermore, the lack of a primary site of disease often complicates the determination of a diagnosis and development of a treatment plan. A review of pediatric cancers treated at a single institution found that only ~0.2 % of cases would be categorized as an undifferentiated or PDC [10]. Hence, the literature provides very little guidance regarding the appropriate treatment of undifferentiated/PDCs in children. The adult experience for PDCs with unknown primary site does offer some insight into the management and treatment of these diseases [3, 4, 65, 66]. Platinum-based combination chemotherapies have generally been used to treat undifferentiated CUPs with modest response rates of 25–35 % and survival outcomes in the range of 6–16 months [67–69]. However, with the development and refinement of next-generation sequencing technologies, there has been a movement towards the genetic characterization of undifferentiated or PDCs with the hope of identifying driver mutations that would inform treatment recommendations [1, 3, 65]. Faced with a general lack of preclinical and clinical information for treating PDCs in a child, we adopted a precision medicine approach to molecularly profile and functionally characterize identified variants in the tumor of the adolescent presented in this report.\n\nWe identified lesions involving the mTOR, MEK/ERK, and MYC signaling pathways. Interrogation of identified somatic mutations in MAX (p.R60Q) and BRAF (p.K483E) predicted these mutations to be deleterious based on computational predictive tools such as PROVEAN, SIFT, and PolyPhen. However, determining the functional consequences of identified mutations or VUSs require further molecular and biochemical investigation. In the case of the MAX (p.R60Q) and BRAF (p.K483E) mutations, in silico modeling of the mutations in conjunction with biochemical assays suggest that these mutations are likely activating their associated pathways.\n\n\nMAX has recently been identified as a new susceptibility gene in hereditary pheochromocytoma (PCC) [70]. De novo mutations in MAX have also been implicated in sporadic PCC [71]. MAX is the central hub of the MYC-MAX-MXD1 network. Within this network, MAX homodimers repress the expression of C-MYC target genes through competition with C-MYC-MAX heterodimers for DNA binding [72, 73]. Our analysis confirms previous studies showing that the MAX p.R60Q mutation disrupts the ability of MAX to homodimerize [43], and we further show that MAX p.R60Q retains the ability to efficiently bind C-MYC. Hence, the MAX p.R60Q mutation promotes an imbalance of the MAX transcriptional network by reducing the intracellular concentration of repressive MAX homodimers without affecting the ability to heterodimerize with C-MYC.\n\nMutant BRAF proteins normally function as either activated monomers (e.g. BRAF p.V600E) or constitutive dimers with wild-type BRAF and CRAF [57, 74, 75]. In the latter case, even BRAF mutants with no kinase activity, such as BRAF p.D594A, are able to promote ERK phosphorylation by favoring the activation of the other protomer of the dimer [58, 76]. We demonstrated that BRAF p.K483E expression increased ERK1/2 activation despite the BRAF p.K483E mutant harboring a catalytically dead kinase domain. Therefore, ERK1/2 activation may result from allosteric activation of wild-type BRAF or CRAF. This finding is consistent with previous reports showing that BRAF mutants with reduced or no kinase activity are weak activators of ERK1/2 signaling [57, 76]. Additionally, a paradoxical activation of ERK1/2 has also been observed in wild-type BRAF tumors treated with BRAF inhibitors [77]. Therefore, we conclude that BRAF p.K483E is an activating mutation with effects likely mediated through allosteric activation of its dimer partner.\n\nTwo mutations in APC, including a somatic nonsense mutation (p.R790*) as well as a novel germline frameshift variant (p.E1554fs), were identified supporting a diagnosis of Gardner syndrome. Despite a strong family history of cancer in the index patient, the APC germline mutation was determined to be a de novo event after constitutional sequencing of the patient’s parents. The novel germline frameshift mutation is localized to a codon where other previously reported frameshift mutations have been observed and catalogued in COSMIC.\n\nIn addition to in silico, biochemical, and cell biological analyses, PDX tumor models represent an investigative tool that can be used to test biological and therapeutic hypotheses. We used the patient’s PDX model to assess the utility of JQ1 (a small molecule bromodomain inhibitor) and selumetinib (MEK inhibitor) as potential therapies. Although there were initial responses to both JQ1 and selumetinib, the magnitude and durability of effect were modest and insufficient, as single agents, to obtain a durable response. In contrast, treatment of PDXs with the mTOR inhibitor, temsirolimus, induced a durable partial response. Notably, PDCs with neuroendocrine features and gastrointestinal PDCs have shown hyperactivation of the AKT/mTOR pathway [78–82]. Additionally, given the role of MET in the progression of CUPs and the availability of MET-inhibitors in the clinic [35, 36], we evaluated MET status in both the primary patient tumor and PDX tumor models, but found no evidence of genetic or expression abnormalities.\n\nWhen the patient progressed on standard therapy, he was switched to a temsirolimus-containing combination (Tem/TMZ/Irino) which has shown efficacy in various pediatric solid tumors including sustained responses in neuroblastoma, Ewing sarcoma, and ependymoma [11]. However, the patient’s tumor progressed on triple combination therapy leading us to evaluate the combination of temsirolimus and irinotecan in the patient PDX model. Our preclinical studies showed that combination treatment provided no additional anti-tumor effect than either single agent alone, suggesting an antagonistic interaction between temsirolimus and irinotecan. An antagonistic interaction between temsirolimus and irinotecan has also been observed in carcinoma models [83]. These results suggest that preclinical PDX models should play a role in a precision medicine paradigm for evaluating the in vivo efficacy of drugs in clinically relevant combinations as a complement to the evaluation of individual drugs.\n\nConclusions\nAdvances in genome-scale sequencing now allow for the identification of key molecular alterations for patients with cancer. However, the existing methods for inferring functional consequences of genomic alterations is insufficient and many variants in cancer-associated genes are relegated as VUSs. The systematic evaluation of VUSs using structural, in silico, in vitro and in vivo assays is paramount to fully define the functional significance of genomic alterations. Furthermore, the development of PDX tumor models, which have demonstrated correlation between drug activity in the PDX model and clinical outcome [17, 84], is an investigational tool that can be used to evaluate therapeutic hypotheses that emanate from the genomic and functional analyses. This clinical case illustrates the challenges of translating the genomic profile for any given patient into clinical recommendations. The functional validation of VUSs, in vitro assessment of potential therapeutic approaches, and finally in vivo experimental therapeutic studies necessitates months of resource-intensive studies. Moreover, a reductionist experimental approach does not adequately model the complex reality of treating patients in the clinic, necessitating incorporation of approaches to identify synergistic combinatorial therapies. While the timeline for completion of preclinical validation studies may not match the clinical needs of the individual patient, the knowledge gained will be immediately applicable to future patients by converting an increasing number of variants of unknown significance to variants of known significance.\n\nAdditional file\n\nAdditional file 1: Figure S1. Activation of mTOR pathway in patient tumor sample. Figure S2 A. Levels of in vitro translated MAX, MAXR60Q, C-MYC, and MXD1 in samples used for EMSA. B Modeling BRAF kinase domain complexed with ATP and Mg2+. Figure S3. Validation of PDX tumor model by Sanger sequencing. Figure S4. Tumor response to selumetinib. (PDF 7254 kb)\n\n\n\n\nAbbreviations\nACMGAmerican College of Medical Genetics\n\nAFPAlpha fetoprotein\n\nbHLHBasic helix-loop-helix\n\nbHLHLZBasic helix-loop–helix leucine zipper domain\n\nCEACarcinoembryonic antigen\n\nCNVCopy number variations\n\nCOSMICCatalogue Of Somatic Mutations In Cancer\n\nCTComputed tomography\n\nCUMCColumbia University Medical Center\n\nCUPCancers of unknown primary site\n\nEMSAElectrophoretic mobility shift assay\n\nFAPFamilial adenomatous polyposis\n\nFPKMFragments per kilobase per million reads sequenced\n\nGGTGamma-glutamyl transferase\n\nIACUCInstitutional Animal Care and Use Committee\n\nIPIntraperitoneally\n\nIrinoIrinotecan\n\nLOHLoss of heterozygosity\n\nmTORMammalian target of rapamycin\n\nNETNeuroendocrine tumor\n\nNMPN-Methyl-2-pyrrolidone\n\nNSGNon-obese severe combined immunodeficiency gamma null mouse\n\nNSG-HNSG hypoxanthine phosphoribosyl transferase null mouse\n\nP0Passage 0 generation\n\nPCCPheochromocytoma\n\nPCEPaclitaxel, Carboplatin, Etoposide\n\nPDCPoorly differentiated carcinoma\n\nPDXPatient-derived xenograft\n\nPGMPersonalized Genomic Medicine program\n\nPIPseqPrecision in Pediatric Sequencing\n\nPOPer os/Orally\n\nPTD bufferPEG-400, Tween 80, Dextrose water\n\nRPS6Ribosomal protein S6\n\nß-HCGbeta-human chorionic gonadotropin\n\nTCGAThe Cancer Genome Atlas\n\nTemTemsirolimus\n\nTem/TMZ/IrinoTemsirolimus, temozolomide, irinotecan\n\nTMZTemozolomide\n\nt-SNET-Distributed stochastic neighbor embedding\n\nVUSVariants of unknown significance\n\nWESWhole exome sequencing\n\nAcknowledgements\nFDC would like to thank the St. Baldrick’s Foundation for its continuing research support through the NetApp St. Baldrick’s Scholar grant. FDC would also like to thank and acknowledge research support by the Hyundai Hope on Wheels Hope Grant, the Jamie Deutsch Foundation, and the John M Driscoll Jr Children’s Fund grant. We would also like to sincerely thank the patient’s family for the opportunity to share the findings of this case.\n\nFunding\nThis study was supported by funding from the Jamie Deutsch Foundation (FDC, JGB) and The Sohn Conference Foundation (ALK).\n\nAvailability of data and materials\nThe datasets supporting the conclusions of this article are included within the article. WES and RNA-seq datasets supporting the conclusions of this article can be obtained from the cBioPortal for Cancer Genomics (http://cbioportal.org).\n\nAuthors’ contributions\nDesigned the study: FDC, DD, and ALK. Performed experiments and analyzed data: DD (biochemical and functional assays), ATT (immunohistochemistry), AR, BM, and FDC (in vivo experiments), FF (crystal structure analysis), ATT, SJA, MMM, and PLN (genomic analyses), AAI, MJA, and AC (systems biology analysis), CM, DJY, LJM, and JGB (clinical). The manuscript was written by FDC and DD with input from the other authors. DD, FDC, and ALK directed the research. All authors provided input in data analysis and approved the final version of the manuscript.\n\nCompeting interests\nMJA is chief scientific officer of Darwin Health Inc. AC is a founder of Darwin Health Inc. All remaining authors declare that they have no competing interests.\n\nConsent for publication\nThe family of the case patient has provided written consent for the publication of the clinical details presented.\n\nEthics approval and consent to participate\nInformed and signed consent was obtained and archived for the research performed and publication of the results. The patient was consented for clinical sequencing at Columbia University Medical Center (CUMC) through the Precision in Pediatric Sequencing Program (PIPseq) and PDX tumor mouse model generation under the CUMC Institutional Review Board (IRB)-approved protocol AAAN8404 in accordance with the Declaration of Helsinki and Good Clinical Practice. Animal studies described in this manuscript have been approved by the Columbia University Medical Center Institutional Animal Care and Use Committee (IACUC) under protocol AAAF5850.\n==== Refs\nReferences\n1. 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Choi Y Chan AP PROVEAN web server: a tool to predict the functional effect of amino acid substitutions and indels Bioinformatics 2015 31 16 2745 7 10.1093/bioinformatics/btv195 25851949 \n50. Kumar P Henikoff S Ng PC Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm Nat Protoc 2009 4 7 1073 81 10.1038/nprot.2009.86 19561590 \n51. Adzhubei IA Schmidt S Peshkin L Ramensky VE Gerasimova A Bork P A method and server for predicting damaging missense mutations Nat Methods 2010 7 4 248 9 10.1038/nmeth0410-248 20354512 \n52. Aylett CH Sauer E Imseng S Boehringer D Hall MN Ban N Architecture of human mTOR complex 1 Science 2016 351 6268 48 52 10.1126/science.aaa3870 26678875 \n53. Auton A Brooks LD Durbin RM Garrison EP Kang HM Korbel JO A global reference for human genetic variation Nature 2015 526 7571 68 74 10.1038/nature15393 26432245 \n54. Davies H Bignell GR Cox C Stephens P Edkins S Clegg S Mutations of the BRAF gene in human cancer Nature 2002 417 6892 949 54 10.1038/nature00766 12068308 \n55. Garnett MJ Marais R Guilty as charged: B-RAF is a human oncogene Cancer Cell 2004 6 4 313 9 10.1016/j.ccr.2004.09.022 15488754 \n56. Dhomen N Marais R New insight into BRAF mutations in cancer Curr Opin Genet Dev 2007 17 1 31 9 10.1016/j.gde.2006.12.005 17208430 \n57. Wan PT Garnett MJ Roe SM Lee S Niculescu-Duvaz D Good VM Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF Cell 2004 116 6 855 67 10.1016/S0092-8674(04)00215-6 15035987 \n58. Kamata T Hussain J Giblett S Hayward R Marais R Pritchard C BRAF inactivation drives aneuploidy by deregulating CRAF Cancer Res 2010 70 21 8475 86 10.1158/0008-5472.CAN-10-0603 20978199 \n59. Damm F Mylonas E Cosson A Yoshida K Della Valle V Mouly E Acquired initiating mutations in early hematopoietic cells of CLL patients Cancer Discov 2014 4 9 1088 101 10.1158/2159-8290.CD-14-0104 24920063 \n60. Yao Z Torres NM Tao A Gao Y Luo L Li Q BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition Cancer Cell 2015 28 3 370 83 10.1016/j.ccell.2015.08.001 26343582 \n61. Pencreach E Guerin E Nicolet C Lelong-Rebel I Voegeli AC Oudet P Marked activity of irinotecan and rapamycin combination toward colon cancer cells in vivo and in vitro is mediated through cooperative modulation of the mammalian target of rapamycin/hypoxia-inducible factor-1alpha axis Clin Cancer Res 2009 15 4 1297 307 10.1158/1078-0432.CCR-08-0889 19190131 \n62. Hecht JR Reid TR Garrett CR Beck JT Davidson SJ Mackenzie MJ Phase I study of everolimus, cetuximab and irinotecan as second-line therapy in metastatic colorectal cancer Anticancer Res 2015 35 3 1567 73 25750312 \n63. Pandya KJ Dahlberg S Hidalgo M Cohen RB Lee MW Schiller JH A randomized, phase II trial of two dose levels of temsirolimus (CCI-779) in patients with extensive-stage small-cell lung cancer who have responding or stable disease after induction chemotherapy: a trial of the Eastern Cooperative Oncology Group (E1500) J Thorac Oncol 2007 2 11 1036 41 10.1097/JTO.0b013e318155a439 17975496 \n64. Spindler KL Sorensen MM Pallisgaard N Andersen RF Havelund BM Ploen J Phase II trial of temsirolimus alone and in combination with irinotecan for KRAS mutant metastatic colorectal cancer: outcome and results of KRAS mutational analysis in plasma Acta Oncol 2013 52 5 963 70 10.3109/0284186X.2013.776175 23514584 \n65. Hainsworth JD Spigel DR Clark BL Shipley D Thompson DS Farley C Paclitaxel/carboplatin/etoposide versus gemcitabine/irinotecan in the first-line treatment of patients with carcinoma of unknown primary site: a randomized, phase III Sarah Cannon Oncology Research Consortium Trial Cancer J 2010 16 1 70 5 10.1097/PPO.0b013e3181c6aa89 20164695 \n66. Greco FA Oien K Erlander M Osborne R Varadhachary G Bridgewater J Cancer of unknown primary: progress in the search for improved and rapid diagnosis leading toward superior patient outcomes Ann Oncol 2012 23 2 298 304 10.1093/annonc/mdr306 21709138 \n67. Culine S Lortholary A Voigt JJ Bugat R Theodore C Priou F Cisplatin in combination with either gemcitabine or irinotecan in carcinomas of unknown primary site: results of a randomized phase II study--trial for the French Study Group on Carcinomas of Unknown Primary (GEFCAPI 01) J Clin Oncol 2003 21 18 3479 82 10.1200/JCO.2003.12.104 12972523 \n68. Briasoulis E Kalofonos H Bafaloukos D Samantas E Fountzilas G Xiros N Carboplatin plus paclitaxel in unknown primary carcinoma: a phase II Hellenic Cooperative Oncology Group Study J Clin Oncol 2000 18 17 3101 7 10963638 \n69. Greco FA Erland JB Morrissey LH Burris HA 3rd Hermann RC Steis R Carcinoma of unknown primary site: phase II trials with docetaxel plus cisplatin or carboplatin Ann Oncol 2000 11 2 211 5 10.1023/A:1008369812295 10761758 \n70. Comino-Mendez I Gracia-Aznarez FJ Schiavi F Landa I Leandro-Garcia LJ Leton R Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma Nat Genet 2011 43 7 663 7 10.1038/ng.861 21685915 \n71. Burnichon N Cascon A Schiavi F Morales NP Comino-Mendez I Abermil N MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma Clin Cancer Res 2012 18 10 2828 37 10.1158/1078-0432.CCR-12-0160 22452945 \n72. Amati B Dalton S Brooks MW Littlewood TD Evan GI Land H Transcriptional activation by the human c-Myc oncoprotein in yeast requires interaction with Max Nature 1992 359 6394 423 6 10.1038/359423a0 1406955 \n73. McDuff FO Naud JF Montagne M Sauve S Lavigne P The Max homodimeric b-HLH-LZ significantly interferes with the specific heterodimerization between the c-Myc and Max b-HLH-LZ in absence of DNA: a quantitative analysis J Mol Recognit 2009 22 4 261 9 10.1002/jmr.938 19189276 \n74. Samatar AA Poulikakos PI Targeting RAS-ERK signalling in cancer: promises and challenges Nat Rev Drug Discov 2014 13 12 928 42 10.1038/nrd4281 25435214 \n75. Kortum RL Morrison DK Path forward for RAF therapies: inhibition of monomers and dimers Cancer Cell 2015 28 3 279 81 10.1016/j.ccell.2015.08.006 26373275 \n76. Heidorn SJ Milagre C Whittaker S Nourry A Niculescu-Duvas I Dhomen N Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF Cell 2010 140 2 209 21 10.1016/j.cell.2009.12.040 20141835 \n77. Poulikakos PI Zhang C Bollag G Shokat KM Rosen N RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF Nature 2010 464 7287 427 30 10.1038/nature08902 20179705 \n78. Catena L Bajetta E Milione M Ducceschi M Valente M Dominoni F Mammalian target of rapamycin expression in poorly differentiated endocrine carcinoma: clinical and therapeutic future challenges Target Oncol 2011 6 2 65 8 10.1007/s11523-011-0171-z 21468754 \n79. Shida T Kishimoto T Furuya M Nikaido T Koda K Takano S Expression of an activated mammalian target of rapamycin (mTOR) in gastroenteropancreatic neuroendocrine tumors Cancer Chemother Pharmacol 2010 65 5 889 93 10.1007/s00280-009-1094-6 19657638 \n80. Ikeda M Okuyama H Takahashi H Ohno I Shimizu S Mitsunaga S Chemotherapy for advanced poorly differentiated pancreatic neuroendocrine carcinoma J Hepatobiliary Pancreat Sci 2015 22 8 623 7 10.1002/jhbp.228 25755102 \n81. Hainsworth JD Spigel DR Litchy S Greco FA Phase II trial of paclitaxel, carboplatin, and etoposide in advanced poorly differentiated neuroendocrine carcinoma: a Minnie Pearl Cancer Research Network Study J Clin Oncol 2006 24 22 3548 54 10.1200/JCO.2005.05.0575 16877720 \n82. Yao JC Shah MH Ito T Bohas CL Wolin EM Van Cutsem E Everolimus for advanced pancreatic neuroendocrine tumors N Engl J Med 2011 364 6 514 23 10.1056/NEJMoa1009290 21306238 \n83. Galvez-Peralta M Flatten KS Loegering DA Peterson KL Schneider PA Erlichman C Context-dependent antagonism between Akt inhibitors and topoisomerase poisons Mol Pharmacol 2014 85 5 723 34 10.1124/mol.113.088674 24569089 \n84. Dong X Guan J English JC Flint J Yee J Evans K Murray N Patient-derived first generation xenografts of non-small cell lung cancers: promising tools for predicting drug responses for personalized chemotherapy Clin Cancer Res 2010 16 5 1442 51 10.1158/1078-0432.CCR-09-2878 20179238\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1756-994X",
"issue": "8(1)",
"journal": "Genome medicine",
"keywords": "BRAF; MAX; Patient-derived xenograft (PDX) models; Poorly differentiated carcinoma (PDC); Precision medicine; Temsirolimus; Whole exome sequencing (WES); mTOR",
"medline_ta": "Genome Med",
"mesh_terms": "D000293:Adolescent; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002277:Carcinoma; D004252:DNA Mutational Analysis; D005047:Etoposide; D017809:Fatal Outcome; D023281:Genomics; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D017239:Paclitaxel; D035583:Rare Diseases; D012535:Scalp; D023041:Xenograft Model Antitumor Assays",
"nlm_unique_id": "101475844",
"other_id": null,
"pages": "116",
"pmc": null,
"pmid": "27799065",
"pubdate": "2016-10-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1406955;8479534;25355519;25081646;15488754;23990214;26432245;26070438;24857747;22388286;25098767;12068308;2112746;23172776;20979621;12972523;20949619;24569089;24920063;22452945;25185190;20952405;2198823;22948899;17208430;23813044;23881926;26373275;10871756;20179705;23514584;21709138;10761758;22019887;22526456;21157483;23550210;20354512;20978199;26678875;25435214;23715323;15035987;17975496;16915295;18511570;21306238;20179238;19261174;19190131;26343582;11031250;25755102;12553908;21673092;24705963;22588877;22383036;24689876;24249672;20164695;10963638;12604610;19561590;22689213;21685915;24508104;25750312;22133722;23032625;23539594;25851949;21468754;20965424;19189276;20011106;24914950;16877720;12747827;23950696;20141835;19657638;17311302",
"title": "A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma.",
"title_normalized": "a case study of an integrative genomic and experimental therapeutic approach for rare tumors identification of vulnerabilities in a pediatric poorly differentiated carcinoma"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-17-01160",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"d... |
{
"abstract": "The study reports the treatment feasibility, and secondly efficacy, of a novel chemotherapy regimen, which adds vinorelbine to the ifosfamide-vincristine-actinomycin-D combination (VIVA regimen), used in four patients with high-risk rhabdomyosarcoma. All patients received nine cycles of the VIVA regimen followed by maintenance chemotherapy with vinorelbine and cyclophosphamide. All patients experienced significant hematological toxicity, but no other major complications (in particular neurotoxicity) or required treatment dose modifications. We observed a major response after three cycles in all patients, and they remained alive after a median follow up of 11 months from diagnosis.",
"affiliations": "Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Department of Pediatric Hematology and Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Department of Pediatric Hematology and Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Pediatric Hematology and Oncology Unit, Hematology-Oncology Department, Santo Spirito Hospital Pescara, Pescara, Italy.;Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.;Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy.",
"authors": "Ferrari|Andrea|A|0000-0003-2233-3810;Chiaravalli|Stefano|S|;Zecca|Marco|M|0000-0002-8818-1744;Recupero|Santina|S|;Pascale|Silvia|S|;Bergamaschi|Luca|L|0000-0003-2149-329X;Casanova|Michela|M|",
"chemical_list": "D003609:Dactinomycin; D014750:Vincristine; D000077235:Vinorelbine; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28649",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(11)",
"journal": "Pediatric blood & cancer",
"keywords": "VIVA; chemotherapy; feasibility; rhabdomyosarcoma; vinorelbine",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D003609:Dactinomycin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007069:Ifosfamide; D007223:Infant; D008297:Male; D011379:Prognosis; D012208:Rhabdomyosarcoma; D012307:Risk Factors; D014750:Vincristine; D000077235:Vinorelbine",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28649",
"pmc": null,
"pmid": "32893953",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "VIVA (vinorelbine, ifosfamide, vincristine, actinomycin-D): A new regimen in the armamentarium of systemic therapy for high-risk rhabdomyosarcoma.",
"title_normalized": "viva vinorelbine ifosfamide vincristine actinomycin d a new regimen in the armamentarium of systemic therapy for high risk rhabdomyosarcoma"
} | [
{
"companynumb": "IT-PFIZER INC-2020357963",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": "3",... |
{
"abstract": "Toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS) are severe mucocutaneous eruptions. There is currently no defined optimal approach to wound care. The objective of this study was to evaluate silver dressings in the wound-care management of TEN and SJS/TEN syndrome overlap with a retrospective case review of nine patients with TEN and SJS/TEN overlap presenting to our institution. Nanocrystalline silver dressings appear to be useful in the rapid commencement of healing in these patients. TEN and SJS/TEN overlap are rare conditions. This contributed to a relatively small number of cases included in the study. The ease of application, antimicrobial properties and low frequency of change make nanocrystalline silver dressings ideal in TEN/SJS.",
"affiliations": "Department of Dermatology, Royal North Shore Hospital, Sydney, Australia.;Department of Dermatology, Royal North Shore Hospital, Sydney, Australia.;Department of Dermatology, Royal North Shore Hospital, Sydney, Australia.;Department of Dermatology, Royal North Shore Hospital, Sydney, Australia.",
"authors": "Smith|Saxon D|SD|;Dodds|Annabel|A|;Dixit|Shreya|S|;Cooper|Alan|A|",
"chemical_list": "D012834:Silver",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.12254",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8380",
"issue": "56(4)",
"journal": "The Australasian journal of dermatology",
"keywords": "Stevens-Johnson syndrome; dressing; drug eruption; nanocrystalline silver; toxic epidermal necrolysis; wound care",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001458:Bandages; D005260:Female; D006801:Humans; D008297:Male; D053768:Metal Nanoparticles; D008875:Middle Aged; D012189:Retrospective Studies; D012720:Severity of Illness Index; D012834:Silver; D013262:Stevens-Johnson Syndrome; D055815:Young Adult",
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "298-302",
"pmc": null,
"pmid": "25368980",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Role of nanocrystalline silver dressings in the management of toxic epidermal necrolysis (TEN) and TEN/Stevens-Johnson syndrome overlap.",
"title_normalized": "role of nanocrystalline silver dressings in the management of toxic epidermal necrolysis ten and ten stevens johnson syndrome overlap"
} | [
{
"companynumb": "AU-LUPIN PHARMACEUTICALS INC.-2016-00787",
"fulfillexpeditecriteria": "2",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"drugaddit... |
{
"abstract": "Delirium in children is common but not widely understood by pediatric practitioners, often leading to underdiagnosis and lack of treatment. This presents a significant challenge in the young patients in the PICU who are most at risk for delirium and in whom the core features of delirium are difficult to assess and treat. However, because of the potential increased morbidity and mortality associated with untreated delirium in adults and children, it remains important to address it promptly. The literature for delirium in this age group is limited. Here we present the case of an infant with multiple underlying medical risk factors who exhibited waxing and waning motor restlessness with disrupted sleep-wake cycles contributing significantly to destabilization of vital parameters. Making a diagnosis of delirium was key to guiding further treatment. After appropriate environmental interventions are implemented and underlying medical causes are addressed, antipsychotic medications, although not Food and Drug Administration-approved in infants, are the mainstay of pharmacotherapy for delirium in older age groups. They may lengthen corrected QT interval (QTc) intervals, presenting a challenge in infants who frequently have other coexisting risks for QTc prolongation, as in our case. The risk from QTc prolongation needs to be balanced against that from untreated delirium. Low doses of risperidone were successfully used in this patient and without side effects or worsening of QTc interval. This case illustrates the importance of increased recognition of delirium in children, including infants, and the role for cautious consideration of atypical antipsychotics in the very young.",
"affiliations": "Department of Psychiatry, University of California, San Francisco, San Francisco, California; and Khyati.brahmbhatt@ucsf.edu.;Fellow in Developmental-Behavioral Pediatrics, Division of Neonatal and Developmental Medicine, Stanford University School of Medicine, Lucile Packard Children's Hospital.",
"authors": "Brahmbhatt|Khyati|K|;Whitgob|Emily|E|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2015-1940",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "137(3)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D000015:Abnormalities, Multiple; D014150:Antipsychotic Agents; D016638:Critical Illness; D003693:Delirium; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome; D018967:Risperidone",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "e20151940",
"pmc": null,
"pmid": "26908691",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Diagnosis and Management of Delirium in Critically Ill Infants: Case Report and Review.",
"title_normalized": "diagnosis and management of delirium in critically ill infants case report and review"
} | [
{
"companynumb": "US-LUPIN PHARMACEUTICALS INC.-2016-01984",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional... |
{
"abstract": "A 6-year-old girl presented with fever, skin rash, anuria, and conjunctivitis that rapidly progressed to toxic shock syndrome. Following hospital discharge, she developed a staphylococcal abscess on the lower extremity. She had recently received the first two doses of the interleukin-17 (IL-17) inhibitor secukinumab for resistant plaque psoriasis. IL-17 is known to be essential in host defense against Staphylococcus aureus. To our knowledge, this is the first reported case of staphylococcal toxic shock syndrome (STSS) associated with an IL-17 inhibitor.",
"affiliations": "Department of Pediatric Intensive Care, Hospital Universitario La Paz, Madrid, Spain.;Department of Pediatric Intensive Care, Hospital Universitario La Paz, Madrid, Spain.;Department of Pediatrics, Hospital Universitario La Paz, Madrid, Spain.;Department of Pediatrics, Hospital Universitario La Paz, Madrid, Spain.;Department of Pediatric Dermatology, Hospital Universitario La Paz, Madrid, Spain.;Department of Pediatric Infectious Diseases, Hospital Universitario La Paz, Madrid, Spain.;Department of Pediatric Emergency Care, Hospital Universitario La Paz, Madrid, Spain.;Department of Pediatric Emergency Care, Hospital Universitario La Paz, Madrid, Spain.",
"authors": "Sánchez Martín|María|M|https://orcid.org/0000-0002-0425-9883;Amores Hernández|Irene|I|;Argumánez García|David|D|;Silva Hernández|Mariano|M|;De Lucas Laguna|Raúl|R|;Aracil Santos|Francisco Javier|FJ|;López López|Rosario|R|;de Ceano-Vivas La Calle|María|M|",
"chemical_list": "D020381:Interleukin-17",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14228",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "37(5)",
"journal": "Pediatric dermatology",
"keywords": "infection-bacterial; pediatric; psoriasis; therapy-systemic; toxic shock syndrome",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D002648:Child; D005260:Female; D006801:Humans; D020381:Interleukin-17; D011565:Psoriasis; D012772:Shock, Septic; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "952-954",
"pmc": null,
"pmid": "32533569",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Staphylococcal toxic shock syndrome in a child with interleukin-17 inhibitor treatment for psoriasis.",
"title_normalized": "staphylococcal toxic shock syndrome in a child with interleukin 17 inhibitor treatment for psoriasis"
} | [
{
"companynumb": "NVSC2020ES172258",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SECUKINUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Kawasaki disease (KD) is one of the most common vasculitides of childhood. The aim of this retrospective study is to determine the incidence of KD and to evaluate its presenting symptoms, clinical course, laboratory tests, and treatment in patients with complete KD and incomplete KD at three pediatric rheumatology centers in Poland from January 2011 to December 2012. A total of 27 Caucasian children (12 boys and 15 girls) with median age of 3 years (range 4 months-12 years) were included in this study. The incidence of complete versus incomplete KD was 17 (63 %) versus 10 (37 %) children, respectively. Patients with incomplete KD significantly less presented cervical lymphadenopathy (20 vs. 88.2 %; p = 0.00075), changes in extremities (30 vs. 76.5 %; p = 0.04), and bilateral nonpurulent conjunctivitis (60 vs. 100 %; p = 0.01). Cardiac assessments show that the majority of patients with KD have not got coronary artery aneurysms (CAA). The median time from the onset of symptoms to intravenous immunoglobulin (IVIG) infusion was 7 days for complete KD and 11 days for incomplete KD. IVIG delay in the incomplete KD had no effect on the incidence of CAA. In conclusion, there were no differences in demographic features, age of onset, and laboratory tests of patients with complete and incomplete KD. Patients with incomplete KD significantly rarely presented cervical lymphadenopathy, changes in extremities, and conjunctival injection. Electrocardiography is a sensitive test to recognize cardiac involvement in the acute phase of KD. Despite the fact that incomplete forms of presentation often delay diagnosis, in most patients treatment with IVIG can avoid complication of CAA.",
"affiliations": "3rd Department and Clinic of Paediatrics, Immunology and Rheumatology of Developmental Age, Wroclaw Medical University, ul. Koszarowa 5, 51-149, Wrocław, Poland, daiva.gorczyca@am.wroc.pl.",
"authors": "Gorczyca|Daiva|D|;Postępski|Jacek|J|;Olesińska|Edyta|E|;Lubieniecka|Małgorzata|M|;Lachór-Motyka|Iwona|I|;Opoka-Winiarska|Violetta|V|;Gruenpeter|Anna|A|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00296-013-2836-7",
"fulltext": "\n==== Front\nRheumatol Int\nRheumatol. Int\nRheumatology International\n0172-8172\n1437-160X\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n23893035\n2836\n10.1007/s00296-013-2836-7\nShort Communication\nThe clinical profile of Kawasaki disease of children from three Polish centers: a retrospective study\nGorczyca Daiva +48-71-39255353 +48-71-3236446 daiva.gorczyca@am.wroc.pl\n\nPostępski Jacek\nOlesińska Edyta\nLubieniecka Małgorzata\nLachór-Motyka Iwona\nOpoka-Winiarska Violetta\nGruenpeter Anna\n3rd Department and Clinic of Paediatrics, Immunology and Rheumatology of Developmental Age, Wroclaw Medical University, ul. Koszarowa 5, 51-149 Wrocław, Poland\n1st Department of Paediatrics Pulmonology and Rheumatology, University of Medicine in Lublin, ul. Chodźki 2, 20-093 Lublin, Poland\nDepartment of Paediatric Rheumatology, John Paul II Paediatric Centre, ul. Gabrieli Zapolskiej 3, 41-218 Sosnowiec, Poland\n28 7 2013\n28 7 2013\n2014\n34 6 875880\n1 3 2013\n16 7 2013\n© The Author(s) 2013\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nKawasaki disease (KD) is one of the most common vasculitides of childhood. The aim of this retrospective study is to determine the incidence of KD and to evaluate its presenting symptoms, clinical course, laboratory tests, and treatment in patients with complete KD and incomplete KD at three pediatric rheumatology centers in Poland from January 2011 to December 2012. A total of 27 Caucasian children (12 boys and 15 girls) with median age of 3 years (range 4 months–12 years) were included in this study. The incidence of complete versus incomplete KD was 17 (63 %) versus 10 (37 %) children, respectively. Patients with incomplete KD significantly less presented cervical lymphadenopathy (20 vs. 88.2 %; p = 0.00075), changes in extremities (30 vs. 76.5 %; p = 0.04), and bilateral nonpurulent conjunctivitis (60 vs. 100 %; p = 0.01). Cardiac assessments show that the majority of patients with KD have not got coronary artery aneurysms (CAA). The median time from the onset of symptoms to intravenous immunoglobulin (IVIG) infusion was 7 days for complete KD and 11 days for incomplete KD. IVIG delay in the incomplete KD had no effect on the incidence of CAA. In conclusion, there were no differences in demographic features, age of onset, and laboratory tests of patients with complete and incomplete KD. Patients with incomplete KD significantly rarely presented cervical lymphadenopathy, changes in extremities, and conjunctival injection. Electrocardiography is a sensitive test to recognize cardiac involvement in the acute phase of KD. Despite the fact that incomplete forms of presentation often delay diagnosis, in most patients treatment with IVIG can avoid complication of CAA.\n\nKeywords\n\nKawasaki disease\nChildren\nIncomplete Kawasaki\nCoronary artery aneurysms\nissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2014\n==== Body\nIntroduction\n\nKawasaki disease (KD) is an acute vasculitis of the medium- and small-sized arteries of unknown etiology. It occurs worldwide and predominantly affects infants and preschool children.\n\nIn the last decades, an increase in the prevalence of KD in Japan [1], the United States [2], and Europe has been observed [3, 4]. The range of incidence of KD in European countries is 5–8/100,000 children under the age of 5 years [5, 6].\n\nThere is still no definitive diagnostic test to confirm KD. American Heart Association (AHA) in 2004 established diagnostic guidelines for the initial estimate, treatment in the acute phase, and long-term management of patients with KD [7]. Complete KD is defined by fever ≥5 days and more than or equal to four of the five principal clinical features (bilateral conjunctival injection, cervical lymphadenopathy, polymorphous skin rash, changes in the lips or oral mucosa, and changes in the distal extremities) [7]. In a case of a child with fever of unexplained origin, who does not fulfill the classic criteria, and other diseases with similar clinical features are excluded, incomplete KD is diagnosed. This diagnosis is often based on echocardiographic findings of coronary artery abnormalities [7]. Laboratory parameters in KD patients include leukocytosis with thrombocytosis, elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, transaminase level, and hypoalbuminemia [7, 8].\n\nThe current treatment strategy is based on intravenous immunoglobulin (IVIG) infusion and leads to reduction in coronary artery abnormalities [7]. Response to initial therapy, regression and/or evolution of coronary lesions, varies among individuals [9].\n\nThe purpose of the study is to determine the incidence of KD and to evaluate its presenting symptoms, clinical course, particularly cardiovascular involvement, laboratory tests, and treatment in children from three pediatric rheumatology centers in Poland.\n\nMaterials and methods\n\nMedical records of 27 patients with KD hospitalized at three pediatric rheumatology centers in Poland (Clinics of Pediatric Rheumatology in Wroclaw and Lublin Medical University, Department of Children Rheumatology in John Paul II Pediatric Center in Sosnowiec) between January 1, 2011, and June 31, 2012, were retrospectively reviewed. The study protocol was approved by the Ethics Committee of the Wroclaw Medical University.\n\nDemographic features, diagnostic clinical features of KD, and additional clinical findings including arthritis and/or arthralgia, gastrointestinal symptoms, respiratory symptoms, and central nervous system symptoms were recorded for each patient. Moreover, all laboratory findings collected prior to IVIG administration were reviewed, including complete blood count (CBC) parameters, ESR, serum CRP, alanine transaminase (ALT), aspartate transaminase (AST), and albumin levels, urine analysis.\n\nElectrocardiography (ECG), echocardiography, and cardiologist’s consultation of each patient were analyzed. Maximum coronary artery z scores were calculated for the right main coronary artery, the left main coronary artery, or the left anterior descending coronary artery. Patients were defined to have coronary artery abnormalities if their maximum coronary z score was >2.5 mm. They were further classified as small coronary artery aneurysms (CAA) if z score was between 2.5 and 5.0 mm, large if >5.0–10.0 mm, and giant if >10 mm.\n\nThe diagnosis of complete and incomplete KD was made using the AHA recommendations [7].\n\nEach patient had a pediatrician’s and cardiologist’s appointment/assessment 6 months after he/she was discharged from the hospital.\n\nStatistical analysis\n\nData are expressed as median and range of continuous variables. Categorical data are expressed as absolute number and percentage. Comparison was made for all of the parameters between complete KD and incomplete KD as well as the whole group. The mean ranks between groups were compared using the Mann–Whitney U test. Categorical variables were compared using χ2 test with Yate’s correction or Fisher’s exact test for data continuity. To investigate the correlations between the variables, we used Pearson correlation. A p value <0.05 was considered to be statistically significant. A statistical analysis was performed using the EPI INFO Software version 3.5.2 (Centers for Disease Control and Prevention, Atlanta, USA, 2010).\n\nResults\n\nPatients’ demographic, clinical, and laboratory features at the time of diagnosis are shown in Table 1. Among 27 Caucasian patients with KD (44 % males), 17 patients (63 %) had complete KD. The incidence of complete KD was higher in females (64.7 %) and incomplete KD in males (60 %), but these differences were not statistically significant. Table 1 Demographic characteristic of the patients with Kawasaki disease\n\nParameter\tWhole group\nn = 27\nn (%)\tComplete\nn = 17\nn (%)\tIncomplete\nn = 10\nn (%)\tp\t\nGender\t\n Male\t12 (44.4)\t6 (35.3)\t6 (60.0)\tNS\t\n Female\t15 (66.6)\t11 (64.7)\t4 (40.0)\t\nAge at diagnosis (months)\t\n <1\t4 (14.8)\t3 (17.6)\t1 (10.0)\tNS\t\n 1–9\t21 (77.8)\t12 (70.6)\t9 (90.0)\t\n >9 years\t2 (7.4)\t2 (11.8)\t–\t\nWeight, percentile\t\n <25\t10 (37.0)\t5 (29.4)\t5 (50.0)\tNS\t\n 25–75\t9 (33.3)\t6 (35.3)\t3 (30.0)\t\n >75\t6 (22.2)\t6 (35.3)\t–\t\nSeasonal onset\t\n Winter\t5 (18.5)\t3 (17.6)\t2 (20.0)\tNS\t\n Springs\t7 (25.9)\t5 (29.4)\t2 (20.0)\t\n Summer\t8 (29.6)\t4 (23.5)\t4 (40.0)\t\n Autumn\t4 (14.8)\t2 (11.8)\t2 (20.0)\t\nNS nonsignificant\n\nThe median age at disease onset was 3 years (range 4 months–12 years). Age did not differ significantly between patients with complete and incomplete KD.\n\nThe season of the onset of KD was winter in 18.5 %, spring in 25.9 %, summer in 29.6 %, and autumn in 14.8 % cases of the patients.\n\nClinical signs of patients with KD, complete and incomplete, at the time of diagnosis are presented in Table 2. All of the patients with complete KD presented polymorphous skin rash, oral mucosal changes, and bilateral nonpurulent conjunctivitis. Patients with incomplete KD compared with patients with complete KD significantly less presented cervical lymphadenopathy (20 vs. 88.2 %; p = 0.00075), changes in extremities (30 vs. 76.5 %; p = 0.04), and bilateral nonpurulent conjunctivitis (60 vs. 100 %; p = 0.01). Two (20 %) patients with incomplete KD presented two classical signs, and eight patients (80 %) presented three classical KD signs. There were also other symptoms presented by patients with KD (in the whole group): gastrointestinal symptoms (66.7 %), hepatic dysfunction (55.6 %), arthralgia and/or arthritis (44.4 %), and sterile pyuria (29.6 %). The differences between incomplete and complete KD were not significant. Table 2 Classical and “nonclassical” symptoms in complete and incomplete KD\n\n\tWhole group\nn = 27\nn (%)\tComplete\nn = 17\nn (%)\tIncomplete\nn = 10\nn (%)\tp\t\nClassic KD clinical symptoms\t\n Fever persisting at least 5 days\t25 (92.6)\t15 (88.2)\t10 (100)\t–\t\n Bilateral conjunctival injection without exudates\t23 (85.2)\t17 (100)\t6 (60.0)\t0.012\t\n Cervical lymphadenopathy (>1.5 cm diameter)\t17 (62.9)\t15 (88.2)\t2 (20.0)\t0.00075\t\n Changes in lips and oral cavity\t26 (96.3)\t17 (100)\t9 (90.0)\tNS\t\n Polymorphous exanthema\t26 (96.3)\t17 (100)\t9 (90.0)\tNS\t\n Changes in extremities\t16 (59.3)\t13 (76.5)\t3 (30.0)\t0.040\t\n 2/3 classic KD clinical signs\t–\t–\t2/8\t\t\n“Nonclassical” clinical symptoms\t\n Arthralgia, arthritis\t12 (44.4)\t8 (47.1)\t4 (40.0)\tNS\t\n Gastrointestinal symptoms (diarrhea, vomiting, abdominal pain)\t18 (66.7)\t10 (58.8)\t8 (80.0)\tNS\t\n Hepatic dysfunction\t15 (55.6)\t11 (64.7)\t4 (40.0)\tNS\t\n Respiratory symptoms (cough)\t4 (14.8)\t4 (23.5)\t–\tNS\t\n Sterile pyuria\t8 (29.6)\t6 (35.3)\t2 (20.0)\tNS\t\nKD Kawasaki disease, NS nonsignificant\n\nAnalysis of laboratory investigations is presented in Table 3. We found no statistical differences in laboratory investigations between complete and incomplete KD. Table 3 Laboratory investigations and cardiovascular findings at diagnosis in complete and incomplete KD\n\n\tWhole group\nn = 27\tComplete\nn = 17\tIncomplete\nn = 10\tp\t\nMedian (range)\tMedian (range)\tMedian (range)\t\nLaboratory investigations\t\n CRP (mg/l)\t22.4 (3.7–225.6)\t17.8 (3.7–179.9)\t31.0 (5.8–225.6)\tNS\t\n CRP ≥ 3 + (n, %)\t27 (100)\t17 (100)\t10 (100)\t–\t\n ESR (mm/h)\t81.0 (15.0–130.0)\t80.0 (28.0–112.0)\t90.0 (15.0–.0)\tNS\t\n ESR ≥40 mm/h\t23 (85.2 %)\t15 (88.2 %)\t8 (80.0 %)\tNS\t\n Red blood cells (×1012/l)\t4.20 (3.05–4.5)\t4.06 (3.05–4.54)\t4.29 (3.17–4.75)\tNS\t\n Hematocrit (%)\t32.2 (25.9–38.7)\t31.2 (25.9–38.7)\t35.7 (27.9–37.5)\tNS\t\n Hemoglobin (g/l)\t11.2 (8.6–12.9)\t10.9 (8.6–12.4)\t11.9 (9.1–12.9)\tNS\t\n Anemia for age (n, %)\t11 (40.7 %)\t7 (41.2 %)\t4 (40.0 %)\tNS\t\n White blood cells (× 109/l)\t14.6 (6.1–30.4)\t14.6 (6.1–30.4)\t14.9 (10.7–23.8)\tNS\t\n WBC count ≥15 × 109/l (n, %)\t13 (48.1\t8 (47.1 %)\t5 (50.0 %)\tNS\t\n Neutrophils (×109/l)\t12.0 (0.3–26.7)\t12.4 (0.3–26.7)\t8.6 (4.9–14.9)\tNS\t\n Platelets count (×109/l)\t643.0 (229.0–1121.0)\t630.0 (229.0–1121.0)\t689.5 (411.0–974.0)\tNS\t\n Platelets after 7 days ≥450 × 109/l (n, %)\t24 (88.8 %)\t15 (88.2 %)\t9 (90.0 %)\tNS\t\n Albumin (g/l)\t3.27 (2.20–39.0)\t3.27 (3.0–3.7)\t3.41 (2.2–39.0)\tNS\t\n Albumin ≤3.0 g/dl (n, %)\t22 (81.5 %)\t17 (100 %)\t5 (50.0 %)\tNS\t\n ALT (U/l)\t30.0 (10.0–146.0)\t28.5 (16.0–146.0)\t45.0 (10.0–.0)\tNS\t\n Elevated ALT (n, %)\t12 (44.45)\t7 (43.8 %)\t5 (50.0 %)\tNS\t\n AST (U/l)\t44.0 (17.0–117.0)\t42.0 (17.0–111.0)\t49.0 (17.0–117.0)\tNS\t\n Elevated AST (n, %)\t13 (48.1 %)\t8 (47.1 %)\t5 (50.0 %)\tNS\t\nCardiovascular findings\t\n Coronary artery abnormalities\t\t\t\t\t\n z ≤ 2.5\t15 (55.6 %)\t12 (70.6 %)\t6 (60.0 %)\tNS\t\n z 2.5–5.0\t7 (25.9 %)\t4 (23.5 %)\t3 (30.0 %)\t\t\n z > 5.0–10.0\t2 (7.4 %)\t1 (5.9 %)\t1 (10.0 %)\t\t\n Repolarization disorders\t11 (64.7 %)\t5 (29.4 %)\t6 (60.0 %)\tNS\t\n Congestive heart failure, myocarditis, pericarditis, valvular regurgitation\t4 (14.8 %)\t4 (23.5 %)\t–\tNS\t\nKD Kawasaki disease, NS nonsignificant\n\nCardiac assessments showed that the majority of patients with KD (whole group 55.6 %; complete KD 70.6 %, incomplete KD 60 %) had not developed coronary artery abnormalities (Table 3). The small CAA were noted in seven (25.9 %) patients, four (23.5 %) cases with complete KD and three (30 %) with incomplete KD. The large CAA were found in two patients, one (10 %) with complete KD and one (7.4 %) with incomplete KD. On ECGs the repolarization abnormalities were more often detected in patients with incomplete KD (60 %) compared to patients with complete KD (29.4 %); this difference was not statistically significant. Moreover, repolarization abnormalities were found in all cases with complete KD but without coronary artery abnormalities. In complete KD, congestive heart failure and/or myocarditis was presented in four (23.5 %) patients.\n\nAnalysis of patients’ medical records revealed that median time from first symptoms to KD diagnosis was 8.5 days (range 5–14 days) (Table 4). Despite the fact that the children with incomplete KD were diagnosed later (median time 11 days, range 5–14 days) than the children with complete KD (median time 7.50 days, range 5–13 days), this difference was not significant. The median time of hospitalization was 16.5 days (range 7–45 days) and did not significantly differ between patients with complete and incomplete KD. Table 4 Clinical history in complete and incomplete KD\n\n\tWhole group, n = 27\tComplete, n = 17\tIncomplete, n = 10\tp\t\nMedian (range)\tMedian (range)\tMedian (range)\t\nInterval symptoms onset diagnosis, days\t8.5 (5–14)\t7.5 (5–13)\t11 (5–14)\tNS\t\nLength of hospitalization, days\t16.5 (7–45)\t17 (7–45)\t14 (9–24)\tNS\t\nTreated <10 days after symptoms onset, n (%)\t16 (59.2 %)\t13 (76.5 %)\t3 (30 %)\t0.026a\t\nKD Kawasaki disease, NS nonsignificant\n\naFisher’s exact test\n\nWe investigated the clinical symptoms and laboratory results to find factors associated with the duration of fever and hospitalization. We found significant negative correlation between RBC count (r = −0.55, p = 0.017), Ht (r = −0.56, p = 0.016), Hb (r = −0.58, p = 0.011), and platelet count (r = −0.60, p = 0.009) and positive correlation between WBC count (r = 0.72, p = 0.001), neutrophil count (r = 0.73, p = 0.001), and the length of hospitalization (data not shown). Other parameters correlated neither with the duration of hospitalization nor with fever.\n\nWe found no statistical significant correlations between the presence of coronary artery abnormalities and clinical symptoms and results of laboratory tests (data not shown).\n\nAll patients were treated with IVIG at 2 g/kg together with aspirin at the time of established diagnosis. Two (7 %) patients required retreatment with IVIG. Intravenous methylprednisolone was given in one case. In our study group, IVIG was administrated significantly less before the 10th day of disease in patients with incomplete KD, compared to patients with complete KD (p = 0.026) (Table 4).\n\nSix months after discharge, an examination revealed that despite early treatment and three times IVIG retreatment, and three pulses of steroids, CAA had developed in one patient with complete KD and in one patient with incomplete KD (7 % of the whole group).\n\nNo mortality and recurrence were seen in the study group.\n\nMoreover, during the 6 months, five (18.5 %) patients with KD had recurrent upper respiratory tract infections, one (3.7 %) patient had been diagnosed with transient hypoimmunoglobulinemia G and M of infants, and one patient (3.7 %) had been diagnosed with idiopathic juvenile arthritis.\n\nDiscussion\n\nThe incidence of KD is increasing worldwide [5]. No study reporting incidence of KD has been published from Poland. In our study, 27 Caucasian children with KD were hospitalized in three pediatric rheumatology centers in Poland from January 2011 to June 2012. Incomplete KD was diagnosed in 37 % of children, which is consistent with other studies [10–12]. This proportion is higher than the 20 % reported in the previous studies [13, 14]. Published AHA guidelines, including supplementary laboratory criteria as well as the use of echocardiography, result in better recognition of KD [15].\n\nOur study showed no statistically significant differences in the patients’ age between the complete and incomplete KD groups. This finding is not consistent with earlier studies. Other data suggest that incomplete KD is more common in children younger than 1 year of age and over eight [16, 17].\n\nIn our study, we analyzed the frequency of clinical signs. Of the five cardinal symptoms, conjunctival injection, mucosal changes, and polymorphous rash occurred most frequently. This is consistent with the results reported by other authors [18]. Patients with incomplete KD presented conjunctival injection, changes in extremities, and cervical lymphadenopathy significantly less. This distribution of clinical signs was reported in the previous studies [10, 14].\n\nExcept for classical clinical signs, other clinical symptoms of KD have been reported previously [19]. In our study, we found the following “nonclassical” symptoms of KD: cough, abdominal pain, vomiting, diarrhea, and arthralgia, which is similar to what was reported in the previous studies [14, 19].\n\nPublished studies have shown that incomplete KD is associated with higher risk of developing coronary abnormalities [13, 20]. We did not find any differences in CAA incidence between complete KD and incomplete KD either at the time of diagnosis or after 6 months of follow-up. Interestingly, although we did not find CAA in incomplete KD children on echocardiography, in most cases ECG revealed depolarization disturbances. This finding may suggest ECG examination as a more sensitive test to recognize cardiac involvement in the acute phase of KD, which was shown in the previous reports [21, 22]. Further studies are needed to confirm this.\n\nWe also observed correlation between low RBC, Hb concentration, Ht values, platelet count, elevated WBC, neutrophil count, and duration of hospitalization. This may reflect severity of the disease. Printz et al. [23] reported the relationship between elevated WBC count and coronary cardiac abnormalities. Furthermore, Falcini et al. [18] suggested that unexplained febrile child with elevated acute-phase reactants and platelet count requires echocardiography assessment.\n\nOptimal time for the IVIG therapy is within 7–10 days of illness [7]. The data have shown that delayed IVIG administration due to delayed incomplete KD diagnosis increases the risk of developing CAA [24]. Although our results showed that patients with incomplete KD were treated with IVIG later than within the first 10 days of disease, there were no differences in the prevalence of CAA between the two groups.\n\nIn our study, its retrospective nature and the small size of the sample are the main limitations. Because of this, our findings are rather suggestive and not definitive.\n\nIn conclusion, we found no differences in demographic features, age of onset, and laboratory tests of patients with complete KD and incomplete KD. Incomplete KD may therefore be characterized by less frequent of cervical lymphadenopathy, changes in extremities, and bilateral nonpurulent conjunctivitis. High WBC and anemia may suggest a more severe course of disease. The ventricular repolarization disturbances in ECG of children with incomplete KD without coronary abnormalities may be the only manifestation of myocardial involvement. Despite the fact that incomplete forms of KD presentation often delay diagnosis, in most patients treatment with IVIG can help avoid complication of CAA.\n\nConflict of interest\n\nThe authors declare that we have no conflict of interest.\n==== Refs\nReferences\n\n1. Nakamura Y Yashiro M Uehara R Sadakane A Tsuboi S Aoyama Y Kotani K Tsogzolbaatar EO Yanagawa H Epidemiologic features of Kawasaki disease in Japan: results of the 2009–2010 Nationwide Survey J Epidemiol 2012 22 216 221 22447211\n2. Holman RC Belay ED Christensen KY Folkema AM Steiner CA Schonberger LB Hospitalizations for Kawasaki syndrome among children in the United States, 1997–2007 Pediatr Infect Dis J 2010 29 483 488 20104198\n3. 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Yeo Y Kim T Ha K Jang G Lee J Lee K Son C Lee J Incomplete Kawasaki disease in patients younger than 1 year of age: a possible inherent risk factor Eur J Pediatr 2009 168 157 162 10.1007/s00431-008-0722-1 18478263\n18. Falcini F Ozen S Magni-Manzoni S Candelli M Ricci L Martini G Cuttica RJ Oliveira S Calabri GB Zulian F Pistorio A La Torre F Rigante D Discrimination between incomplete and atypical Kawasaki syndrome versus other febrile diseases in childhood: results from an international registry-based study Clin Exp Rheumatol 2012 30 799 804 23020938\n19. Yun SH Yang NR Park SA Associated symptoms of Kawasaki disease Korean Circ J 2011 41 394 398 10.4070/kcj.2011.41.7.394 21860641\n20. Ha KS Jang G Lee J Lee K Hong Y Son C Lee J Incomplete clinical manifestation as a risk factor for coronary artery abnormalities in Kawasaki disease: a meta-analysis Eur J Pediatr 2012 23229186\n21. 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Sudo D Monobe Y Yashiro M Mieno MN Uehara R Tsuchiya K Sonobe T Nakamura Y Coronary artery lesions of incomplete Kawasaki disease: a nationwide survey in Japan Eur J Pediatr 2012 171 651 656 10.1007/s00431-011-1630-3 22159904\n\n",
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"medline_ta": "Rheumatol Int",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003231:Conjunctivitis; D003323:Coronary Aneurysm; D005260:Female; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D015994:Incidence; D007223:Infant; D008206:Lymphatic Diseases; D008297:Male; D009080:Mucocutaneous Lymph Node Syndrome; D011044:Poland; D012189:Retrospective Studies; D061665:Time-to-Treatment",
"nlm_unique_id": "8206885",
"other_id": null,
"pages": "875-80",
"pmc": null,
"pmid": "23893035",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": "19595368;17587262;21344290;17468651;18478263;23020938;18841257;22134803;21817952;21185506;20104198;15505111;22067065;23229186;22447211;22349679;22159904;19159953;20113416;21860641;22726311;7549295;3772656",
"title": "The clinical profile of Kawasaki disease of children from three Polish centers: a retrospective study.",
"title_normalized": "the clinical profile of kawasaki disease of children from three polish centers a retrospective study"
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"abstract": "OBJECTIVE\nTo investigate whether exposure to metformin during the first trimester of pregnancy, for diabetes or other indications, increases the risk of all or specific congenital anomalies.\n\n\nMETHODS\nPopulation based exploratory case-control study using malformed controls. Cases of 29 specific subgroups of non-genetic anomalies, and all non-genetic anomalies combined, were compared with controls (all other non-genetic anomalies or genetic syndromes).\n\n\nMETHODS\n11 EUROmediCAT European congenital anomaly registries surveying 1 892 482 births in Europe between 2006 and 2013.\n\n\nMETHODS\n50 167 babies affected by congenital anomaly (41 242 non-genetic and 8925 genetic) including live births, fetal deaths from 20 weeks' gestation, and terminations of pregnancy for fetal anomaly.\n\n\nMETHODS\nOdds ratios adjusted for maternal age, registry, multiple birth, and maternal diabetes status.\n\n\nRESULTS\n168 babies affected by congenital anomaly (141 non-genetic and 27 genetic) were exposed to metformin, 3.3 per 1000 births. No evidence was found for a higher proportion of exposure to metformin during the first trimester among babies with all non-genetic anomalies combined compared with genetic controls (adjusted odds ratio 0.84, 95% confidence interval 0.55 to 1.30). The only significant result was for pulmonary valve atresia (adjusted odds ratio 3.54, 1.05 to 12.00, compared with non-genetic controls; 2.86, 0.79 to 10.30, compared with genetic controls).\n\n\nCONCLUSIONS\nNo evidence was found for an increased risk of all non-genetic congenital anomalies combined following exposure to metformin during the first trimester, and the one significant association was no more than would be expected by chance. Further surveillance is needed to increase sample size and follow up the cardiac signal, but these findings are reassuring given the increasing use of metformin in pregnancy.",
"affiliations": "Administrative Data Research Centre Northern Ireland, Ulster University, Belfast BT37 0QB, UK.;Institute of Nursing and Health Research, Ulster University, Belfast BT37 0QB, UK.;Paediatric Department, Hospital Lillebaelt, Kolding, DK-6000, Denmark.;Medical Genetics, CHUV, Lausanne, CH-1011, Switzerland.;University of Groningen, University Medical Center Groningen, Department of Genetics, Eurocat Northern Netherlands, 9700RB, Netherlands.;Registre des Malformations Congenitales de la Reunion, Saint-Pierre, BP350, Ile de la Reunion.;Directorate for Health Information and Research, Guardamangia, PTA 1313, Malta.;Division of Mental and Physical Health, Norwegian Institute of Public Health, Bergen, Norway.;Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité and DHU Risks in pregnancy, Paris Descartes University, Paris, 75014, France.;Congenital Anomaly Register and Information Service for Wales, Public Health Wales, Swansea SA2 8QA, UK.;IMER Registry (Emilia Romagna Registry of Birth Defects), University of Ferrara and Azienda Ospedaliero Universitaria di Ferrara, Ferrara, 44100, Italy.;Tuscany Registry of Congenital Defects, Institute of Clinical Physiology, National Research Council/Fondazione Toscana Gabriele Monasterio, Pisa, 56126, Italy.;Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke University Magdeburg, Magdeburg, D-39120, Germany.;Institute of Nursing and Health Research, Ulster University, Belfast BT37 0QB, UK.",
"authors": "Given|Joanne E|JE|;Loane|Maria|M|;Garne|Ester|E|;Addor|Marie-Claude|MC|;Bakker|Marian|M|;Bertaut-Nativel|Bénédicte|B|;Gatt|Miriam|M|;Klungsoyr|Kari|K|;Lelong|Nathalie|N|;Morgan|Margery|M|;Neville|Amanda J|AJ|;Pierini|Anna|A|;Rissmann|Anke|A|;Dolk|Helen|H|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "England",
"delete": false,
"doi": "10.1136/bmj.k2477",
"fulltext": "\n==== Front\nBMJBMJBMJ-UKbmjThe BMJ0959-81381756-1833BMJ Publishing Group Ltd. givj04314410.1136/bmj.k2477Research13321470Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study Given Joanne E research associate1Loane Maria reader in public health2Garne Ester consultant paediatrician3Addor Marie-Claude clinical geneticist4Bakker Marian epidemiologist5Bertaut-Nativel Bénédicte midwife6Gatt Miriam programme director7Klungsoyr Kari professor8 9Lelong Nathalie project manager10Morgan Margery consultant obstetrician and gynaecologist11Neville Amanda J EUROCAT registry leader12Pierini Anna researcher13Rissmann Anke consultant paediatrician and registry leader14Dolk Helen professor of epidemiology and health services research15\n1 Administrative Data Research Centre Northern Ireland, Ulster University, Belfast BT37 0QB, UK\n2 Institute of Nursing and Health Research, Ulster University, Belfast BT37 0QB, UK\n3 Paediatric Department, Hospital Lillebaelt, Kolding, DK-6000, Denmark\n4 Medical Genetics, CHUV, Lausanne, CH-1011, Switzerland\n5 University of Groningen, University Medical Center Groningen, Department of Genetics, Eurocat Northern Netherlands, 9700RB, Netherlands\n6 Registre des Malformations Congenitales de la Reunion, Saint-Pierre, BP350, Ile de la Reunion\n7 Directorate for Health Information and Research, Guardamangia, PTA 1313, Malta\n8 Division of Mental and Physical Health, Norwegian Institute of Public Health, Bergen, Norway\n9 Department of Global Public Health and Primary Care, University of Bergen, N-5018, Norway\n10 Inserm UMR 1153, Obstetrical, Perinatal and Pediatric Epidemiology Research Team (Epopé), Center for Epidemiology and Statistics Sorbonne Paris Cité and DHU Risks in pregnancy, Paris Descartes University, Paris, 75014, France\n11 Congenital Anomaly Register and Information Service for Wales, Public Health Wales, Swansea SA2 8QA, UK\n12 IMER Registry (Emilia Romagna Registry of Birth Defects), University of Ferrara and Azienda Ospedaliero Universitaria di Ferrara, Ferrara, 44100, Italy\n13 Tuscany Registry of Congenital Defects, Institute of Clinical Physiology, National Research Council/Fondazione Toscana Gabriele Monasterio, Pisa, 56126, Italy\n14 Malformation Monitoring Centre Saxony-Anhalt, Medical Faculty Otto-von-Guericke University Magdeburg, Magdeburg, D-39120, Germany\n15 Institute of Nursing and Health Research, Ulster University, Belfast BT37 0QB, UKCorrespondence to: Joanne E Given je.given@ulster.ac.uk2018 25 6 2018 361 k247704 5 2018 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions2018BMJThis is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/.Abstract\nObjective\nTo investigate whether exposure to metformin during the first trimester of pregnancy, for diabetes or other indications, increases the risk of all or specific congenital anomalies.\n\nDesign\nPopulation based exploratory case-control study using malformed controls. Cases of 29 specific subgroups of non-genetic anomalies, and all non-genetic anomalies combined, were compared with controls (all other non-genetic anomalies or genetic syndromes).\n\nSetting\n11 EUROmediCAT European congenital anomaly registries surveying 1 892 482 births in Europe between 2006 and 2013.\n\nParticipants\n50 167 babies affected by congenital anomaly (41 242 non-genetic and 8925 genetic) including live births, fetal deaths from 20 weeks’ gestation, and terminations of pregnancy for fetal anomaly.\n\nMain outcome measure\nOdds ratios adjusted for maternal age, registry, multiple birth, and maternal diabetes status.\n\nResults\n168 babies affected by congenital anomaly (141 non-genetic and 27 genetic) were exposed to metformin, 3.3 per 1000 births. No evidence was found for a higher proportion of exposure to metformin during the first trimester among babies with all non-genetic anomalies combined compared with genetic controls (adjusted odds ratio 0.84, 95% confidence interval 0.55 to 1.30). The only significant result was for pulmonary valve atresia (adjusted odds ratio 3.54, 1.05 to 12.00, compared with non-genetic controls; 2.86, 0.79 to 10.30, compared with genetic controls).\n\nConclusions\nNo evidence was found for an increased risk of all non-genetic congenital anomalies combined following exposure to metformin during the first trimester, and the one significant association was no more than would be expected by chance. Further surveillance is needed to increase sample size and follow up the cardiac signal, but these findings are reassuring given the increasing use of metformin in pregnancy.\n==== Body\nIntroduction\nMetformin is an oral blood glucose lowering drug that has been used in the treatment of type 2 diabetes since the 1950s.1 Despite reservations about its use in pregnancy, metformin has been recommended for use in pregnancy in the UK since 2008 in women with gestational diabetes and in type 2 diabetes when the likely benefits outweigh the potential for harm.2\n3 The emergence of type 2 diabetes in children and younger women of childbearing age has driven a sharp increase in the prevalence of type 2 diabetes in pregnancy,4\n5 which, together with these recommendations,3 is likely to further increase the number of women exposed to metformin in pregnancy.\n\nMetformin is also prescribed in polycystic ovary syndrome, in which it improves insulin sensitivity, may aid weight reduction, and helps to normalise the menstrual cycle (increasing the rate of spontaneous ovulation).6 Exposure to metformin in early pregnancy among women undergoing treatment for polycystic ovary syndrome may therefore occur. The use of metformin to prevent diabetes in pre-diabetic populations, as a cancer treatment,7\n8 and as a weight loss medication for non-diabetic obesity is also of interest.9\n10 Expansion of indications for metformin use will increase the risk of unintentional exposures during pregnancy.\n\nThe use of metformin in pregnancy remains controversial.11\n12 Metformin affects stem cell function and has been shown to cross the human placenta at term, exposing the fetus to concentrations approaching those in the maternal circulation.13\n14\n15\n16\n17 Animal studies have shown no increased risk of congenital anomaly at therapeutic doses,18\n19\n20 but these are limited in terms of predicting risk in humans.21 Three meta-analyses have been conducted to explore the risk of congenital anomaly following exposure to metformin in humans and have concluded that no evidence exists to suggest a significantly increased risk of all major congenital anomalies compared with maternal disease matched control groups.22\n23\n24 These meta-analyses were, however, based on small heterogeneous samples from studies that were not specifically designed to evaluate the rate of congenital anomalies.22\n25 A recently published cohort study based on 392 women exposed to metformin who contacted teratogen information services found an increased risk of major birth defects among women taking metformin for diabetes but not for other indications. The authors concluded that the increased risk was due to the underlying diabetes, but they did not have a diabetic comparison group.26 Any investigation of the risk of congenital anomaly associated with metformin is complicated by the fact that pregestational diabetes increases the risk of major congenital anomaly two to threefold.27\n28 Metformin, if used for diabetes or pre-diabetes, may lead to a decreased risk of congenital anomaly as a result of achieving better glycaemic control,29 to an increased risk of congenital anomaly due to independent teratogenic action, or both.\n\nTo date, the size of the exposed population covered in the literature is too small to rule out risks of specific malformations. EUROmediCAT, a population based reproductive pharmacovigilance system based on the European Surveillance of Congenital Anomalies (EUROCAT) network,30\n31 provides an opportunity to contribute much needed epidemiological evidence from a large population to the available literature. The aim of this study was to investigate whether exposure to metformin during the first trimester increases the risk of all or specific congenital anomalies.\n\nMethods\nStudy design\nWe did an exploratory case-control study using malformed controls, using the EUROmediCAT central database. The use of malformed controls was initially proposed for birth defect epidemiology as a method of controlling for maternal recall bias (box 1).36\n38 It is used in EUROmediCAT to control for the source of drug exposure data and because data on non-malformed controls are not available.39\n\n\nBox 1 Case-control studies using malformed controls\nIn a case-control study, a group of patients who have the disease of interest (cases) and a group who do not have the disease (controls) are selected, and the proportion with the exposure of interest in each group is compared.32\n\n\nIn a case-control study using malformed controls, commonly used for congenital anomaly studies,33 a group of babies with a particular congenital anomaly of interest (cases) and a group who have different congenital anomalies (controls) are selected. This design is particularly suitable for investigating the specificity of association between specific malformations and specific exposures, rather than the overall risk of malformation.34\n\n\nCase-control studies using malformed controls were initially proposed to overcome maternal “recall bias.”35 Although this is not an problem for EUROmediCAT drug exposure data, which are mainly collected from prospective medical/maternity records, it is also a useful design when comparable data on non-malformed controls are not available.\n\nThe main potential disadvantage of using malformed controls is “teratogen non-specificity bias.”36\n37 This is where a teratogen causes many different malformations, some of which are included in the control group leading to an underestimation of risk. This can be avoided by excluding from the controls any malformation previously associated in the literature with the exposure in question and including a wide range of malformations in the control group, as no known teratogen increases the risk of all malformations to the same extent.36 An additional approach is to specify a control group of genetic syndromes, which cannot have been caused by environmental teratogens, but as their numbers are small this reduces statistical power.\n\nStudy population and data\nEUROCAT population based registries record all major congenital anomalies among live births, fetal deaths at 20 weeks’ gestation or later, and terminations of pregnancy for fetal anomaly, using ICD-10 (international classification of diseases, 10th revision) codes.40\n41 Detailed descriptions of registries and the methods used have been published previously.30\n42\n43 The EUROmediCAT database includes data, since 1995, from those EUROCAT registries that record first trimester drug exposure either directly or through linkage with healthcare databases with information on prescribing and dispensing of drugs.44 Exposure to metformin in the first trimester was rare before 2006, so this study was based on data from 2006 onwards. Registries with less than three exposures were excluded.\n\nCongenital anomalies are classified to 91 standard “EUROCAT subgroups.”40\n41 These include hierarchical subgroups—for example, spina bifida is a subgroup that forms part of the subgroup “neural tube defects,” which forms part of the group “nervous system.” These subgroups are furthermore divided into non-genetic and genetic categories, according to whether a genetic syndrome has been diagnosed in association with the congenital anomaly subgroup in question.\n\nCase and control groups\nCases and controls were live births, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly.41 The literature contains no signals for specific congenital anomalies potentially associated with metformin that would suggest previous hypotheses to test as “cases.” We did an exploratory analysis in which, for each analysis, we considered a single non-genetic EUROCAT subgroup of congenital anomaly to be the “case” group.40\n41\n\n\nWe used two control groups. “Non-genetic controls” were the remaining babies with non-genetic congenital anomalies after exclusion of the specific congenital anomaly being analysed as the case group and of any subgroup at a hierarchical level above. Genetic controls included chromosomal anomalies, skeletal dysplasias, congenital skin disorders, genetic syndromes, and microdeletions.\n\nWhen analysing hypospadias as a case group, we used only male controls. We excluded babies with isolated congenital hip dislocation/dysplasia owing to the association with large babies and potential for confounding.45 We excluded cases and controls with maternal epilepsy or exposure to antiepileptic drugs owing to the association with congenital anomalies.46\n47 We cleaned the limb reduction defect subgroup by searching anomaly text descriptions for shortening of the limbs. We then reviewed the diagnosis for cases with this text description and reclassified those that had been misclassified as limb reduction defects (31/122 (25%) cases with this text description, excluding Norway and Paris for which no text was available).\n\nWhen interpreting the results, we divided case subgroups according to whether or not they had previously been associated with pregestational diabetes in the EUROCAT database, according to Garne et al48—that is, neural tube defects, congenital heart defects, omphalocele, and syndactyly. This identified which results were most at risk of confounding by indication, requiring a more cautious interpretation.\n\nExposure\nWe obtained most data on maternal drug exposures in the first trimester retrospectively from prospective maternity records. Additional data sources available for some registries included the medical records of the infant, records from the general practitioner, pregnancy passports, and maternal interviews before or after birth.31\n42\n49 For the Norway registry, drug exposures were based on prescription redemption records during the first trimester of pregnancy. The supplementary table gives more details. We excluded all terminations of pregnancy for fetal anomaly in Emilia Romagna, as they had no information on drug exposure (fig 1). We recorded all drug exposures in the first trimester by using the World Health Organization’s Anatomical Therapeutic Chemical classification system.50 This is a hierarchical system, which allocates to a drug a code based on the organ or system on which it acts (first level) and its therapeutic (second level), pharmacological (third level), and chemical properties (fourth and fifth level). We defined exposure to metformin as use of metformin, or a combination product (two or more drugs in a single tablet) containing metformin, during the first trimester. The Anatomical Therapeutic Chemical codes used to identify metformin exposure were A10BA02 (metformin), A10BD02 (metformin and sulfonylureas), A10BD03 (metformin and rosiglitazone), A10BD05 (metformin and pioglitazone), A10BD07 (metformin and sitagliptin), A10BD08 (metformin and vildagliptin), A10BD10 (metformin and saxagliptin), A10BD11 (metformin and linagliptin), A10BD13 (metformin and alogliptin), A10BD14 (metformin and repaglinide), A10BD15 (metformin and dapagliflozin), A10BD16 (metformin and canagliflozin), A10BD17 (metformin and acarbose), A10BD18 (metformin and gemigliptin), and A10BD20 (metformin and empagliflozin). For all registries, we defined the first trimester as the period from the first day of the last menstrual period to the end of gestational week 12.\n\nFig 1 Flow diagram detailing number of congenital anomaly affected babies included in analysis. *Varies with case genetic anomaly; consists of all remaining non-case, non-genetic congenital anomalies excluding any congenital anomaly group at hierarchical level above case group\n\nData on maternal illness before and during the first 20 weeks of pregnancy were recorded, mostly prospectively from maternity records, using ICD-10 codes.41 This provided information on the potential indication for metformin use. In Norway, indications other than maternal diabetes were not recorded. We therefore excluded the Norway registry from all analyses relating to polycystic ovary syndrome and infertility. Registries individually verified all metformin exposures (cases or controls), the first trimester timing, indication for prescribing, and the malformation.\n\nStatistical analysis\nDescriptive analyses of metformin use and risk of congenital anomaly associated with disease indications\nWe explored the relation between characteristics of the sample and all congenital anomalies, metformin exposure, genetic syndromes, and non-genetic congenital heart defects by using the Pearson χ2 test for birth type and multiple birth and the χ2 test for trend for maternal age and gestational age at delivery. We calculated the risk of all non-genetic congenital anomaly (compared with genetic syndrome controls) in relation to pregestational/gestational diabetes, polycystic ovary syndrome, and infertility (all indications for metformin use) to assess the degree to which confounding by indication might be expected. We used logistic regression with listwise deletion to calculate odds ratios and 95% confidence intervals, adjusted for the confounders maternal age (<20, 20-24, 25-29, 30-34, 35-39, ≥40) and registry.\n\nAnalysis of risk of congenital anomaly associated with metformin exposure\nWe calculated odds ratios for the risk of each case congenital anomaly group/subgroup related to metformin exposure without adjustment and with adjustment for the confounding factors maternal age, registry, multiple birth (singleton, multiple birth), and maternal pregestational/gestational diabetes (yes/no). For stability of parameter estimates, we show results for only those subgroups with at least three cases exposed to metformin. Where the same number of exposed cases was observed in a congenital anomaly subgroup and a subgroup in a hierarchical level above, we analysed it at the lowest hierarchical level only. We used Stata version 12.1 for all analyses.\n\nPatient involvement\nNo patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for design or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community. Affected families are thanked in the acknowledgments.\n\nResults\nMetformin use in study population and risk of congenital anomaly associated with disease indications\nWe recorded 53 689 babies affected by congenital anomaly in the EUROmediCAT database (2006-13), out of 1 892 482 births surveyed, across the 11 registries that were eligible to take part in this study. After exclusions (fig 1), 50 167 babies with congenital anomaly were left for analysis, consisting of 41 242 with a non-genetic anomaly and 8925 with a genetic syndrome.\n\nIn all, 168 babies affected by congenital anomaly (141 non-genetic and 27 genetic) were exposed to metformin (3.3 per 1000 babies affected by congenital anomaly), of which two had a combined preparation (A10BD02 metformin and sulfonylureas). The prevalence of metformin exposure varied across registries from 0.8 exposures per 1000 babies affected by congenital anomaly in Tuscany to 17.9 exposures per 1000 babies affected by congenital anomaly in Malta (table 1).\n\nTable 1 Characteristics among all congenital anomaly affected babies, those exposed to metformin, and those with genetic syndromes and non-genetic congenital heart defects. Values are numbers (percentages) unless stated otherwise\n\n\tBabies with congenital anomaly\tMetformin exposed\tP value\tGenetic syndromes\tP value\tCongenital heart defects as proportion of babies with non-genetic congenital anomalies\tP value*\n\t\nTotal\t50 167 (100)\t168 (0.3)\t\t8925 (17.8)\t\t14 316/41 242 (34.7)\t\t\n\nRegistry (years)\n\t\nOdense (2006-12)\t1043 (2.1)\t8 (0.8)\t\t247 (23.7)\t\t287/796 (36.1)\t\t\nParis (2006-13)\t6723 (13.4)\t9 (0.1)\t\t1827 (27.2)\t\t1492/4896 (30.5)\t\t\nTuscany (2006-13)\t4980 (9.9)\t4 (0.1)\t\t1013 (20.3)\t\t1537/3967 (38.7)\t\t\nNorthern Netherlands (2006-13)\t3410 (6.8)\t6 (0.2)\t\t757 (22.2)\t\t846/2653 (31.9)\t\t\nEmilia Romagna (2006-13)†\n\t5910 (11.8)\t6 (0.1)\t\t614 (10.4)\t\t1865/5296 (35.2)\t\t\nVaud (2006-13)\t2288 (4.6)\t3 (0.1)\t\t558 (24.4)\t\t725/1730 (41.9)\t\t\nMalta (2006-13)\t780 (1.6)\t14 (1.8)\t\t110 (14.1)\t\t265/670 (39.6)\t\t\nSaxony Anhalt (2006-13)\t4237 (8.5)\t6 (0.1)\t\t511 (12.1)\t\t1618/3726 (43.4)\t\t\nWales (2006-13)\t9286 (18.5)\t59 (0.6)\t\t1581 (17.0)\t\t2411/7705 (31.7)\t\t\nNorway (2006-10)\t8210 (16.4)\t43 (0.5)\t\t1807 (13.2)\t\t2556/7129 (35.9)\t\t\nReunion (2006-13)\t3300 (6.6)\t10 (0.3)\t\t626 (19.0)\t\t684/2674 (25.6)\t\t\nMissing\t0\t0\t\t0\t\t0\t\t\n\nMaternal age (years)\n\t\n<20\t1764 (3.5)\t0 (0.0)\t0.02‡\n\n\n\n\n\n\n\n\n\n\n\t170 (9.6)\t<0.001‡\n\n\n\n\n\n\n\n\n\n\n\t465/1594 (29.2)\t<0.001‡\n\n\n\n\n\n\n\n\n\n\n\t\n20-24\t6920 (13.8)\t17 (0.3)\t741 (10.7)\t2052/6179 (33.2)\t\n25-29\t12 184 (24.3)\t41 (0.3)\t1391 (11.4)\t3738/10 793 (34.6)\t\n30-34\t14 766 (29.4)\t57 (0.4)\t2174 (14.7)\t4453/12 592 (35.4)\t\n35-39\t10 265 (20.5)\t39 (0.4)\t2652 (25.8)\t2686/7613 (35.3)\t\n≥40\t3742 (7.5)\t14 (0.4)\t1749 (46.7)\t708/1993 (35.5)\t\nMissing\t526 (1.1)\t0 (0.0)\t\t48 (9.13)\t\t214/478 (45)\t\t\n\nMultiple birth\n\t\nSingleton\t47 734 (95.2)\t150 (0.3)\t<0.001§\n\n\n\t8636 (18.1)\t<0.001§\n\n\n\t13 437/39 098 (34.4)\t<0.001§\n\n\n\t\nMultiple birth\t2202 (4.4)\t18 (0.8)\t253 (11.5)\t822/1949 (42.2)\t\nMissing\t231 (0.5)\t0\t\t36 (16)\t\t57/195 (29)\t\t\n\nBirth type\n\t\nLive birth\t41 140 (82.0)\t138 (0.3)\t0.09§\n\n\n\n\n\t4136 (10.1)\t<0.001§\n\n\n\n\n\t13 398/37 004 (36.2)\t<0.001§\n\n\n\n\n\t\nStillbirth\t784 (1.6)\t6 (0.8)\t236 (30.1)\t163/548 (29.74)\t\nTermination of pregnancy for fetal anomaly\t8243 (16.4)\t24 (0.3)\t4553 (55.2)\t755/3690 (20.46)\t\nMissing\t0\t0\t\t0\t\t0\t\t\n\nGestational length (weeks) (excluding terminations of pregnancy for fetal anomaly)\n\t\n<28\t830 (2.0)\t4 (0.5)\t0.003‡\n\n\n\n\n\n\n\n\n\t138 (16.6)\t<0.001‡\n\n\n\n\n\n\n\n\n\t254/692 (36.7)\t<0.001‡\n\n\n\n\n\n\n\n\n\t\n28-31\t1226 (2.9)\t12 (1.0)\t144 (11.8)\t459/1082 (42.4)\t\n32-36\t5663 (13.5)\t25 (0.4)\t840 (14.8)\t1810/4823 (37.5)\t\n37-41\t32 662 (77.9)\t98 (0.3)\t3090 (9.5)\t10 524/29 572 (35.6)\t\n≥42\t938 (2.2)\t5 (0.5)\t81 (8.6)\t300/857 (35.0)\t\nMissing\t605 (1.4)\t0 (0.0)\t\t79 (13.1)\t\t214/526 (40.68)\t\t\n* Based on ratio of babies with non-genetic congenital heart defects to babies with other non-genetic congenital anomalies.\n\n† Excludes terminations of pregnancy for fetal anomaly.\n\n‡ χ2 test for trend.\n\n§ Pearson χ2 test.\n\nFrom the exposure rate of 3.3 per 1000 and the total population surveyed of 1 892 482 births, we can estimated that approximately 6245 pregnancies in the surveyed population were exposed (assuming no or a small overall increased rate of metformin exposure among babies with congenital anomalies).\n\nMetformin exposure was more common among older mothers, multiple pregnancies, and preterm births (table 1). The proportion of genetic syndromes, among all babies with congenital anomalies, was higher in older mothers, singleton births, terminations of pregnancy for fetal anomaly, and preterm births (table 1). Congenital heart defects, the largest group of congenital anomalies and one associated with diabetes, formed a higher proportion of all non-genetic congenital anomalies with increasing maternal age, in multiple births, and in preterm births and a lower proportion of terminations of pregnancy for fetal anomaly (table 1).\n\nAfter exclusion of cases from Norway, where information on maternal illness was limited, 54.4% of mothers had either pregestational or gestational diabetes, including 44.0% with pregestational diabetes (table 2). Twenty four per cent had polycystic ovary syndrome, and 16.0% had infertility, indicated by an ICD-10 code for infertility or infertility treatment or exposure to a gonadotrophin or other ovulation stimulant. This left 18% (23/125) with no information available relating to the potential indication for metformin use (table 2).\n\nTable 2 Number and percentage of metformin exposures with maternal diabetes, polycystic ovary syndrome (PCOS), and infertility or a combination of these diagnoses\n\nIndication for metformin use\tMetformin exposures\t\n\nAll registries\n\t\n(n=168)\n\t\nAll diabetes (pregestational or gestational)\t86 (51)\t\nPregestational diabetes\t64 (38)\t\n\nExcluding Norway\n\n*\n\n\t\n(n=125)\n\t\nSingle indication:\t\t\n Pregestational or gestational diabetes\t59† (47)\t\n PCOS\t16 (13)\t\n Infertility\t11 (9)\t\nTwo indications:\t\t\n Pregestational or gestational diabetes and PCOS\t7‡ (6)\t\n Pregestational or gestational diabetes and infertility\t2‡ (2)\t\n PCOS and infertility\t7 (6)\t\nNo indication\t23 (18)\t\n* Owing to limited data on maternal illness from this registry.\n\n† 51 (41%) with pregestational diabetes.\n\n‡ 2 (2%) with pregestational diabetes.\n\nThe risk of all non-genetic anomalies compared with genetic controls was increased for maternal diabetes (pregestational or gestational) (adjusted odds ratio 2.04, 95% confidence interval 1.75 to 2.38) and maternal pregestational diabetes (2.51, 1.89 to 3.34). We found no evidence for an increased risk of all non-genetic anomalies compared with genetic controls for infertility (adjusted odds ratio 0.89, 0.66 to 1.19) or maternal polycystic ovary syndrome (0.81, 0.52 to 1.27).\n\nAnalysis of risk of congenital anomaly with metformin exposure\nWe found no evidence for an increased risk of all non-genetic anomalies combined after exposure to metformin in the first trimester (adjusted odds ratio 0.84, 0.55 to 1.30) (table 3). Twenty nine subgroups of congenital anomaly had three or more metformin exposed cases (table 3). Among the anomalies not previously associated with pregestational diabetes in the EUROCAT database, the risk of ano-rectal atresia and stenosis was increased, compared with non-genetic and genetic controls. This association attenuated slightly on adjustment for confounders and was no longer statistically significant. Among the anomalies previously associated with pregestational diabetes, we found increased risk of atrial septal defect, pulmonary valve atresia, and “patent ductus arteriosus as the only congenital heart defect in liveborn term infants” compared with genetic and non-genetic controls. The atrial septal defect and patent ductus arteriosus associations attenuated on adjustment, with maternal diabetes being the main confounder (data not shown). The only signal to remain after adjustment for diabetes and other confounders was for pulmonary valve atresia, compared with non-genetic controls (table 3). Of the three metformin exposed cases with pulmonary valve atresia, one mother had maternal pregestational diabetes and the other two were exposed to ovulation stimulants, suggesting that metformin had been administered as part of infertility treatment.\n\nTable 3 Number of congenital anomalies, number exposed, and odds ratios for metformin exposure in EUROCAT non-genetic congenital anomaly subgroups*\n\n\nCase congenital anomaly subgroup\tNo\n(exposed)\t\tNon-genetic controls\n(n=41 242; 141 exposed)\t\tGenetic controls\n(n=8925; 27 exposed)\t\nNo†\n\n(exposed)\tOdds ratio (95% CI)\tAdjusted odds ratio34 (95% CI)\tOdds ratio (95% CI)\tAdjusted odds ratio‡ (95% CI)\t\nAll non-genetic congenital anomalies\t41 242 (141)\t\t-\t-\t-\t\t1.13 (0.75 to 1.71)\t0.84 (0.55 to 1.30)\t\n\nAnomalies not previously associated with pregestational diabetes in EUROCAT\n48\n\t\nNervous system\t4198 (14)\t\t37 044 (127)\t0.97 (0.56 to 1.69)\t1.22 (0.70 to 2.15)\t\t1.10 (0.58 to 2.11)\t0.96 (0.49 to 1.92)\t\nOro-facial clefts\t2623 (7)\t\t38 619 (134)\t0.77 (0.36 to 1.64)\t0.75 (0.35 to 1.62)\t\t0.88 (0.38 to 2.03)\t0.74 (0.31 to 1.78)\t\nCleft lip with or without cleft palate\t1601 (4)\t\t38 619 (134)\t0.72 (0.27 to 1.95)\t0.73 (0.27 to 2.01)\t\t0.83 (0.29 to 2.36)\t0.78 (0.26 to 2.32)\t\nCleft palate\t1022 (3)\t\t38 619 (134)\t0.85 (0.27 to 2.66)\t0.78 (0.24 to 2.47)\t\t0.97 (0.29 to 3.20)\t0.73 (0.21 to 2.51)\t\nDigestive system\t3068 (15)\t\t38 174 (126)\t1.48 (0.87 to 2.54)\t1.52 (0.88 to 2.63)\t\t1.62 (0.86 to 3.05)\t1.33 (0.67 to 2.63)\t\nAno-rectal atresia and stenosis\t578 (5)\t\t38 174 (126)\t2.63 (1.07 to 6.47)\t2.49 (0.98 to 6.29)\t\t2.88 (1.10 to 7.50)\t2.24 (0.80 to 6.30)\t\nDiaphragmatic hernia\t480 (4)\t\t38 174 (126)\t2.54 (0.93 to 6.89)\t2.19 (0.78 to 6.14)\t\t2.77 (0.97 to 7.95)\t1.72 (0.56 to 5.29)\t\nUrinary\t6257 (23)\t\t34 985 (118)\t1.09 (0.70 to 1.71)\t1.40 (0.89 to 2.22)\t\t1.22 (0.80 to 2.12)\t1.23 (0.68 to 2.22)\t\nMulticystic renal dysplasia\t795 (5)\t\t34 985 (118)\t1.87 (0.76 to 4.59)\t1.91 (0.76 to 4.83\t\t2.09 (0.80 to 5.43)\t1.80 (0.66 to 4.92)\t\nCongenital hydronephrosis\t2217 (9)\t\t34 985 (118)\t1.20 (0.61 to 2.38)\t1.33 (0.66 to 2.67)\t\t1.34 (0.63 to 2.86)\t1.23 (0.55 to 2.73)\t\nHypospadias§\n\t3744 (8)\t\t20 061 (65)\t0.66 (0.32 to 1.37)\t0.65 (0.31 to 1.37)\t\t1.08 (0.40 to 2.87)\t1.12 (0.38 to 3.32)\t\nLimb\t6716 (26)\t\t34 526 (115)\t1.16 (0.76 to 1.78)\t1.07 (0.69 to 1.65)\t\t1.28 (0.75 to 2.20)\t0.91 (0.50 to 1.94)\t\nLimb reduction\t960 (5)\t\t34 526 (115)\t1.57 (0.64 to 3.84)\t1.84 (0.74 to 4.62)\t\t1.73 (0.66 to 4.49)\t1.77 (0.65 to 4.81)\t\nClubfoot—talipes equinovarus\t2238 (8)\t\t34 525 (115)\t1.07 (0.52 to 2.20)\t0.91 (0.44 to 1.88)\t\t1.18 (0.54 to 2.61)\t0.83 (0.36 to 1.94)\t\nPolydactyly\t1824 (4)\t\t34 526 (115)\t0.66 (0.24 to 1.78)\t0.69 (0.25 to 1.90)\t\t0.72 (0.25 to 2.07)\t0.64 (0.21 to 1.93)\t\n\nAnomalies previously associated with pregestational diabetes in EUROCAT\n48\n\t\nNeural tube defects\t1587 (6)\t\t37 044 (127)\t1.10 (0.49 to 2.51)\t1.36 (0.59 to 3.15)\t\t1.25 (0.52 to 3.03)\t1.12 (0.44 to 2.85)\t\nAnencephalus and similar\t565 (3)\t\t37 044 (127)\t1.55 (0.49 to 4.89)\t2.15 (0.66 to 6.98)\t\t1.76 (0.53 to 5.82)\t1.66 (0.47 to 5.87)\t\nHydrocephalus\t963 (3)\t\t37 044 (127)\t0.91 (0.29 to 2.86)\t1.10 (0.34 to 3.53)\t\t1.03 (0.31 to 3.40)\t0.94 (0.27 to 3.24)\t\nCongenital heart defects\t14 316 (55)\t\t26 926 (86)\t1.20 (0.86 to 1.69)\t0.95 (0.67 to 1.34)\t\t1.27 (0.80 to 2.02)\t0.83 (0.50 to 1.37)\t\nSevere congenital heart defects\t3600 (16)\t\t26 926 (86)\t1.39 (0.82 to 2.38)\t1.05 (0.61 to 1.81)\t\t1.47 (0.79 to 2.73)\t0.94 (0.48 to 1.85)\t\nTransposition of the great vessels\t641 (4)\t\t26 926 (86)\t1.96 (0.72 to 5.36)\t1.40 (0.50 to 3.93)\t\t2.07 (0.72 to 5.93)\t1.62 (0.53 to 4.95)\t\nVentricular septal defect\t7338 (25)\t\t26 926 (86)\t1.07 (0.68 to 1.67)\t0.94 (0.60 to 1.48)\t\t1.13 (0.65 to 1.94)\t0.81 (0.45 to 1.48)\t\nAtrial septal defect\t2840 (17)\t\t26 926 (86)\t1.88 (1.12 to 3.17)\t1.47 (0.85 to 2.53)\t\t1.98 (1.08 to 3.65)\t1.45 (0.72 to 2.91)\t\nTetralogy of Fallot\t532 (4)\t\t26 926 (86)\t2.36 (0.86 to 6.47)\t2.03 (0.72 to 5.74)\t\t2.50 (0.87 to 7.16)\t2.16 (0.72 to 6.47)\t\nPulmonary valve stenosis\t844 (4)\t\t26 926 (86)\t1.49 (0.54 to 4.06)\t1.12 (0.40 to 3.14)\t\t1.57 (0.55 to 4.50)\t0.98 (0.32 to 2.95)\t\nPulmonary valve atresia\t229 (3)\t\t26 926 (86)\t4.14 (1.30 to 13.20)\t3.54 (1.05 to 12.00)¶\n\t\t4.37 (1.32 to 14.53)\t2.86 (0.79 to 10.30)\t\nPatent ductus arteriosus as only congenital heart defect in liveborn term infants**\n\t744 (6)\t\t26 926 (86)\t2.54 (1.11 to 5.82)\t1.44 (0.60 to 3.43)\t\t2.68 (1.10 to 6.51)\t2.16 (0.77 to 6.03)\t\nOmphalocele\t350 (3)\t\t40 892 (138)\t2.52 (0.80 to 7.95)\t2.83 (0.86 to 9.30)\t\t2.85 (0.86 to 9.44)\t2.41 (0.69 to 8.36)\t\nSyndactyly\t810 (3)\t\t34 526 (115)\t1.11 (0.35 to 3.51)\t1.11 (0.34 to 3.55)\t\t1.23 (0.37 to 4.05)\t1.09 (0.31 to 3.80)\t\n* Congenital anomaly subgroups with <3 metformin exposed cases were: encephalocele (1), spina bifida (2), microcephaly (1), eye (2), anophthalmos/microphthalmos (1), anophthalmos (1), ear, face, and neck (1), anotia (1), common arterial truncus (1), single ventricle (1), atrioventricular septal defect (1), aortic valve atresia/stenosis (1), hypoplastic left heart (1), coarctation of aorta (1), total anomalous pulmonary venous return (1), bilateral renal agenesis including Potter syndrome (1), posterior urethral valve and/or prune belly (2), craniosynostosis (2), congenital constriction bands/amniotic band (1), and situs inversus (2).\n\n† No of controls used in each analysis will vary according to exclusion of case group and congenital anomaly subgroup at hierarchical level above where relevant.\n\n‡ Adjusted for maternal age, registry, multiple birth, and maternal pregestational/gestational diabetes.\n\n§ Male controls only.\n\n¶ P=0.04.\n\n** Gestational age ≥37 weeks.\n\nDiscussion\nWe found no evidence of an overall increased risk of all major congenital anomalies combined after exposure to metformin during the first trimester.Given the rise in exposure to metformin during pregnancy,51\n52 our findings are particularly timely. Our large international, population based database, with 168 cases of congenital anomaly exposed to metformin, from an estimated 6245 exposed pregnancies in Europe, represents more than five times the number of metformin exposures previously available in the literature.22\n23\n24\n26 Exposure to metformin during the study period remained rare; just over three in every 1000 babies affected by congenital anomaly were exposed to metformin in the first trimester, with considerable variation in the prevalence of metformin use across registries. Similar variation was evident across Europe in a study that used prescription redemption records.52 The variation in prescription of metformin between regions could be due to several factors—differences in the prevalence of pregestational diabetes, polycystic ovary syndrome, and infertility53\n54\n55; the diagnostic criteria used for polycystic ovary syndrome56; and the criteria for prescription of metformin for the different indications. The current prevalence of exposure to metformin during pregnancy would be expected to be higher because of the increasing prevalence of type 2 diabetes.4\n5 In keeping with the shared pathophysiological basis of the conditions for which metformin is indicated,57 some women had more than one indication for its use, also evidenced elsewhere.51\n\n\nOur results are reassuring regarding the risk of all non-genetic congenital anomalies combined and support the previously available evidence.22\n23\n24\n26 Teratogens, however, tend to increase the risk of specific, rather than all, congenital anomalies,58 so focusing on specific congenital anomalies is important. We found a signal for pulmonary valve atresia. Pulmonary valve atresia has previously been associated with maternal diabetes,48 and our signal may suggest some residual confounding by indication. The number of comparisons made mean that this signal may also have arisen by chance. Pulmonary valve atresia has not been previously described after exposure to metformin during pregnancy.22\n23\n26 A recent teratogen information system cohort study found an elevated risk of cardiac defects following metformin exposure, but this was not significant and attenuated after adjustment for confounders.26\n\n\nAlthough our findings are reassuring regarding the risk of congenital anomaly, further surveillance is recommended to increase the sample size and to follow up the pulmonary valve atresia signal in an independent dataset. The long term outcomes among babies who have been exposed to metformin in utero are also of interest. Metformin may have a direct influence on insulin action in the developing fetus, resulting in improved insulin sensitivity and a metabolically healthier pattern of growth into adulthood.59\n60\n\n\nStrengths and limitations of study\nThe main strength of this study is the use of the large international, population based, EUROmediCAT central database, the diverse nature of which improves the generalisability of our findings. EUROmediCAT also contains detailed and standardised coding of all congenital anomalies among live births and stillbirths, as well as terminations of pregnancy for fetal anomaly.30\n\n\nDrug exposure in the EUROmediCAT database is mostly recorded prospectively, before anomaly status is known, which reduces the risk of recall bias. The exact timing of exposure within the first trimester is not recorded. It is likely that many metformin exposures would have been early in the first trimester during the critical period of development for many congenital anomalies, as women taking metformin for polycystic ovary syndrome or infertility are likely to stop their drug treatment when they realise they are pregnant. In most registries, normal clinical practice during our study period would have been to switch women who became pregnant while taking metformin for type 2 diabetes to insulin.\n\nDrug data were not available for terminations of pregnancy for fetal anomaly from the Emilia Romagna registry. In Norway, drug exposure data were based on a prescription database, and we cannot be certain that mothers took the drug they collected at the pharmacy. Under-ascertainment of drug exposure in the EUROmediCAT database is known to occur for diseases other than diabetes and epilepsy, for which drugs are well recorded in medical records.31\n61 Comparison with Charlton et al suggests that metformin use may have been underreported in two of the registries.52 Any under-ascertainment of metformin exposure will be the same for cases and controls. This will have reduced the power of our analysis and may have slightly attenuated the estimated odds ratios. Teratogen non-specificity bias, whereby the exposure in question is associated with both cases and controls, may have attenuated odds ratios.39 To negate this, we used a very varied non-genetic control group, as well as a genetic control group.\n\nWe adjusted for confounding by indication by adjusting for maternal diabetes, but controlling for glycaemia (HbA1c) would have been more effective if this had been available.62 Other indications (polycystic ovary syndrome, infertility) were not associated in our data with the risk of non-genetic anomalies overall, but they may have confounded associations relating to specific subgroups.\n\nIn a fifth of metformin exposures, no information was available to suggest the reason for metformin use. Even in a large US cohort of insured pregnant women, where the nature of health insurance data would be expected to ensure that the indication for prescribing a drug was recorded, no indication for prescribing of metformin was available in 16.4% of cases.51 Where gestational diabetes was the only recorded indication (6% of those exposed to metformin), this may have been a first trimester diagnosis of gestational diabetes due to undiagnosed pregestational diabetes, or missing information on obesity/polycystic ovary syndrome,3 as these women are at high risk of going on to develop gestational diabetes.57\n\n\nOwing to multiple testing of many congenital anomaly subgroups, some positive associations are likely by chance alone. We did not find more significant associations than would be expected by chance.\n\nConclusion\nWe found no evidence of an overall increased risk of all major congenital anomalies combined after exposure to metformin during the first trimester. A signal for an increased risk of pulmonary valve atresia may be a chance finding. Although further surveillance is needed to increase sample size and follow up the cardiac signal, these findings are reassuring given the increasing use of metformin in pregnancy.\n\nWhat is already known on this topic\nMetformin affects stem cell function and has been shown to cross the human placenta at term, exposing the fetus to concentrations approaching those in the maternal circulation\n\nLimited evidence from three meta-analyses and a cohort study suggests that the rate of all major congenital anomalies combined is not significantly increased after exposure to metformin\n\nAs teratogens tend to increase the risk of specific, rather than all, congenital anomalies, an increased risk of specific congenital anomalies after first trimester metformin exposure cannot be ruled out\n\nWhat this study adds\nIn a large international, population based database, no evidence was found of an overall increased risk of congenital anomalies after first trimester metformin exposure\n\nA raised risk of one specific cardiac defect may be a chance finding\n\nFurther surveillance is needed to increase sample size and follow up the cardiac signal, but these results are reassuring given the increasing use of metformin in pregnancy\n\nWe thank the Zagreb, Antwerp, Basque Country, Ukraine, Wielkopolska, Poland, South East Ireland, and Valencia Region registries for their contribution to the data validation aspect of this study. We also thank the people throughout Europe involved in providing and processing information, including affected families, clinicians, health professionals, medical record clerks, and registry staff.\n\nWeb Extra Extra material supplied by the author\n\nSupplementary table\n\n Contributors: JEG and HD had the idea for the study. JEG did the statistical analysis and wrote the first draft of the paper. ML advised on the conduct and coordination of the study, as well as interpretation of the results. EG and HD advised on interpretation of the results. EG, MCA, MB, MG, NL, KK, MM, AJN, AP, HR, and AR provided and verified the data. All authors had full access to all of the data (including statistical reports and tables) in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. All authors commented on drafts and read and approved the final manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted. JEG is the guarantor.\n\nFunding: This work was supported by the Economic and Social Research Council grant number ESL/L007509/1 (Administrative Data Research Centre—Northern Ireland). EUROCAT registries are funded as fully described in Paper 6 of Report 9—EUROCAT Member Registries: Organisation and Activities: http://onlinelibrary.wiley.com/doi/10.1002/bdra.20775/pdf. The funders of this research were not involved in the study design, data analysis, or manuscript preparation or publication decisions.\n\nCompeting interests: All authors have completed the ICMJE uniform disclosure form at www.icmj.org/cio_disclosure.pdf (available on request from the corresponding author) and declare: JEG, ML, and HD received grants from the Economic and Social Research Council for the submitted work; ML and HD received grants from European Union Framework 7 for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.\n\nEthical approval: Ethical approval was provided by the University of Ulster Nursing Research Governance Filter Committee.\n\nData sharing: EUROmediCAT aims to encourage the use of its data and networks for pharmacovigilance and drug safety research. Data sharing can be requested as per the ENCePP Code of Conduct—Implementation Guidance for Sharing of Study Data; see http://www.encepp.eu/code_of_conduct/documents/ENCePPCoCAnnex4_ImplementationGuidanceonSharingofENCePPStudyData.pdf and http://euromedicat.eu/currentresearchanddata/howtoproposeorcommissionspecificstudies for more information.\n\nTransparency statement: The lead author affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.\n==== Refs\n1 \nRattan R Ali Fehmi R Munkarah A \nMetformin: an emerging new therapeutic option for targeting cancer stem cells and metastasis . J Oncol \n2012 ;2012 :928127 . 10.1155/2012/928127 \n22701483 \n2 \nNational Institute for Health and Clinical Excellence \nDiabetes in pregnancy: management of diabetes and its complications from pre-conception to the postnatal period. \nNICE , 2008 .\n3 \nNational Institute for Health and Care Excellence \nDiabetes in pregnancy: management of diabetes and its complications from pre-conception to the postnatal period. \nNICE , 2015 .\n4 \nDabelea D Mayer-Davis EJ Saydah S SEARCH for Diabetes in Youth Study \nPrevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009 . JAMA \n2014 ;311 :1778 -86 . 10.1001/jama.2014.3201 \n24794371 \n5 \nBell R Bailey K Cresswell T Hawthorne G Critchley J Lewis-Barned N Northern Diabetic Pregnancy Survey Steering Group \nTrends in prevalence and outcomes of pregnancy in women with pre-existing type I and type II diabetes . BJOG \n2008 ;115 :445 -52 . 10.1111/j.1471-0528.2007.01644.x \n18271881 \n6 \nJoint Formulary Committee \nBritish National Formulary (BNF) 70 . BMJ Publishing Group and Royal Pharmaceutical Society , 2015 : 588 -619 .\n7 \nViollet B Guigas B Sanz Garcia N Leclerc J Foretz M Andreelli F \nCellular and molecular mechanisms of metformin: an overview . Clin Sci (Lond) \n2012 ;122 :253 -70 . 10.1042/CS20110386 \n22117616 \n8 \nSivalingam VN Myers J Nicholas S Balen AH Crosbie EJ \nMetformin in reproductive health, pregnancy and gynaecological cancer: established and emerging indications . Hum Reprod Update \n2014 ;20 :853 -68 . 10.1093/humupd/dmu037 \n25013215 \n9 \nFeig DS Moses RG \nMetformin therapy during pregnancy: good for the goose and good for the gosling too? \nDiabetes Care \n2011 ;34 :2329 -30 . 10.2337/dc11-1153 \n21949224 \n10 \nMead E Atkinson G Richter B \nDrug interventions for the treatment of obesity in children and adolescents . Cochrane Database Syst Rev \n2016 ;11 :CD012436 .\n27899001 \n11 \nAmerican Diabetes Association \nStandards of Medical Care in Diabetes - 2015 . Diabetes Care \n2015 ;38 (Supplement 1 ):S1 -94 .\n12 \nMcElduff A Cheung NW McIntyre HD Australasian Diabetes in Pregnancy Society \nThe Australasian Diabetes in Pregnancy Society consensus guidelines for the management of type 1 and type 2 diabetes in relation to pregnancy . Med J Aust \n2005 ;183 :373 -7 .\n16201957 \n13 \nBednar F Simeone DM \nMetformin and cancer stem cells: old drug, new targets . Cancer Prev Res (Phila) \n2012 ;5 :351 -4 . 10.1158/1940-6207.CAPR-12-0026 \n22389436 \n14 \nCharles B Norris R Xiao X Hague W \nPopulation pharmacokinetics of metformin in late pregnancy . Ther Drug Monit \n2006 ;28 :67 -72 . 10.1097/01.ftd.0000184161.52573.0e \n16418696 \n15 \nKovo M Haroutiunian S Feldman N Hoffman A Glezerman M \nDetermination of metformin transfer across the human placenta using a dually perfused ex vivo placental cotyledon model . Eur J Obstet Gynecol Reprod Biol \n2008 ;136 :29 -33 . 10.1016/j.ejogrb.2007.01.013 \n17350747 \n16 \nNanovskaya TN Nekhayeva IA Patrikeeva SL Hankins GDV Ahmed MS \nTransfer of metformin across the dually perfused human placental lobule . Am J Obstet Gynecol \n2006 ;195 :1081 -5 . 10.1016/j.ajog.2006.05.047 \n16824464 \n17 \nVanky E Zahlsen K Spigset O Carlsen SM \nPlacental passage of metformin in women with polycystic ovary syndrome . Fertil Steril \n2005 ;83 :1575 -8 . 10.1016/j.fertnstert.2004.11.051 \n15866611 \n18 \nLee HY Wei D Loeken MR \nLack of metformin effect on mouse embryo AMPK activity: implications for metformin treatment during pregnancy . Diabetes Metab Res Rev \n2014 ;30 :23 -30 . 10.1002/dmrr.2451 \n23983188 \n19 \nDenno KM Sadler TW \nOral hypoglycemic agents: biguanides and their effects on developing mouse embryos . Teratology \n1992 ;45 :477 -8 .\n20 \nDenno KM Sadler TW \nEffects of the biguanide class of oral hypoglycemic agents on mouse embryogenesis . Teratology \n1994 ;49 :260 -6 . 10.1002/tera.1420490405 \n8073364 \n21 \nBrent RL \nUtilization of animal studies to determine the effects and human risks of environmental toxicants (drugs, chemicals, and physical agents) . Pediatrics \n2004 ;113 (Suppl ):984 -95 .\n15060191 \n22 \nCassina M Donà M Di Gianantonio E Litta P Clementi M \nFirst-trimester exposure to metformin and risk of birth defects: a systematic review and meta-analysis . Hum Reprod Update \n2014 ;20 :656 -69 . 10.1093/humupd/dmu022 \n24861556 \n23 \nGilbert C Valois M Koren G \nPregnancy outcome after first-trimester exposure to metformin: a meta-analysis . Fertil Steril \n2006 ;86 :658 -63 . 10.1016/j.fertnstert.2006.02.098 \n16879826 \n24 \nElmaraezy A Abushouk AI Emara A Elshahat O Ahmed H I Mostafa M \nEffect of metformin on maternal and neonatal outcomes in pregnant obese non-diabetic women: A meta-analysis . Int J Reprod Biomed (Yazd) \n2017 ;15 :461 -70 . 10.29252/ijrm.15.8.461 \n29082364 \n25 \nNicholson W Baptiste-Roberts K \nOral hypoglycaemic agents during pregnancy: The evidence for effectiveness and safety . Best Pract Res Clin Obstet Gynaecol \n2011 ;25 :51 -63 . 10.1016/j.bpobgyn.2010.10.018 \n21251886 \n26 \nPanchaud A Rousson V Vial T \nPregnancy outcomes in women on metformin for diabetes or other indications among those seeking teratology information services . Br J Clin Pharmacol \n2018 ;84 :568 -78 . 10.1111/bcp.13481 \n29215149 \n27 \nAllen VM Armson BA GENETICS COMMITTEE MATERNAL FETAL MEDICINE COMMITTEE \nTeratogenicity associated with pre-existing and gestational diabetes . J Obstet Gynaecol Can \n2007 ;29 :927 -34 . 10.1016/S1701-2163(16)32653-6 \n17977497 \n28 \nEidem I Stene LC Henriksen T \nCongenital anomalies in newborns of women with type 1 diabetes: nationwide population-based study in Norway, 1999-2004 . Acta Obstet Gynecol Scand \n2010 ;89 :1403 -11 . 10.3109/00016349.2010.518594 \n20929418 \n29 \nLanger O Conway DL \nLevel of glycemia and perinatal outcome in pregestational diabetes . J Matern Fetal Med \n2000 ;9 :35 -41 . 10.1002/(SICI)1520-6661(200001/02)9:1<35::AID-MFM8>3.0.CO;2-6 \n10757433 \n30 \nBoyd PA Haeusler M Barisic I Loane M Garne E Dolk H \nPaper 1: The EUROCAT network--organization and processes . Birth Defects Res A Clin Mol Teratol \n2011 ;91 (Suppl 1 ):S2 -15 . 10.1002/bdra.20780 \n21384531 \n31 Bakker M, de Jonge L. EUROCAT special report: sources of information on medication use in pregnancy. 2014. http://www.eurocat-network.eu/content/Special-Report-Medication-Use-In-Pregnancy.pdf.\n32 \nRothman KJ Greenland S Lash TL \nCase-control studies. In: Rothman KJ Greenland S Lash TL , eds. Modern epidemiology. \n3rd ed \nLippincott Williams & Wilkins , 2008 : 111 -27 .\n33 \nWeinberg CR Wilcox AJ \nMethodologic issues in reproductive epidemiology. In: Rothman KJ Greenland S Lash TL , eds. Modern epidemiology. \n3rd ed \nLippincott Williams & Wilkins , 2008 : 620 -40 .\n34 \nPrieto L Martínez-Frías ML \nCase-control studies using only malformed infants: are we interpreting the results correctly? \nTeratology \n1999 ;60 :1 -2 . 10.1002/(SICI)1096-9926(199907)60:1<1::AID-TERA1>3.0.CO;2-9 \n10413329 \n35 \nSchlesselman JJ Stolley PD \nSources of bias. In: Schlesselman JJ , ed. Case-control studeis: design, conduct, analysis. \nOxford University Press , 1982 : 124 -43 .\n36 \nHook EB \nNormal or affected controls in case-control studies of congenital malformations and other birth defects: reporting bias issues . Epidemiology \n1993 ;4 :182 -4 . 10.1097/00001648-199303000-00017 \n8452908 \n37 \nLieff S Olshan AF Werler M Savitz DA Mitchell AA \nSelection bias and the use of controls with malformations in case-control studies of birth defects . Epidemiology \n1999 ;10 :238 -41 . 10.1097/00001648-199905000-00008 \n10230831 \n38 \nSchlesselman JJ \nCase control studies: design, conduct, analysis. \nOxford University Press , 1982 .\n39 \nDolk H Wemakor A \nResponse to: Case-control studies require appropriate population controls: an example of error in the SSRI birth defect literature . Eur J Epidemiol \n2015 ;30 :1219 -21 . 10.1007/s10654-015-0099-1 \n26620807 \n40 \nCentral Registry EUROCAT \nEUROCAT guide 1.3 and reference documents: instructions for the registration and surveillance of congenital anomalies. \nEUROCAT , 2005 .\n41 Central Registry EUROCAT. EUROCAT guide 1.4 and reference documents. 2013. http://www.eurocat-network.eu/aboutus/datacollection/guidelinesforregistration/guide1_4.\n42 EUROmediCAT Central Database. EUROmediCAT registry descriptions. 2017. http://euromedicat.eu/content/Partners-Registry-Descriptions-February-2017.pdf.\n43 \nGreenlees R Neville A Addor M-C \nPaper 6: EUROCAT member registries: organization and activities . Birth Defects Res A Clin Mol Teratol \n2011 ;91 (Suppl 1 ):S51 -100 . 10.1002/bdra.20775 \n21381185 \n44 \nEUROmediCAT: Safety of Medication Use in Pregnancy . Pharmacoepidemiol Drug Saf \n2015 ;24 (Suppl 2 ):1 -2 .\n26395592 \n45 \nWemakor A Casson K Garne E \nSelective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study . Eur J Epidemiol \n2015 ;30 :1187 -98 . 10.1007/s10654-015-0065-y \n26148560 \n46 \nJentink J Dolk H Loane MA EUROCAT Antiepileptic Study Working Group \nIntrauterine exposure to carbamazepine and specific congenital malformations: systematic review and case-control study . BMJ \n2010 ;341 :c6581 . 10.1136/bmj.c6581 \n21127116 \n47 \nJentink J Loane MA Dolk H EUROCAT Antiepileptic Study Working Group \nValproic acid monotherapy in pregnancy and major congenital malformations . N Engl J Med \n2010 ;362 :2185 -93 . 10.1056/NEJMoa0907328 \n20558369 \n48 \nGarne E Loane M Dolk H \nSpectrum of congenital anomalies in pregnancies with pregestational diabetes . Birth Defects Res A Clin Mol Teratol \n2012 ;94 :134 -40 . 10.1002/bdra.22886 \n22371321 \n49 \nBergman JEH Lutke LR Gans ROB \nBeta-blocker use in pregnancy and risk of specific congenital anomalies: a European case-malformed control study . Drug Saf \n2018 ;41 :415 -27 . 10.1007/s40264-017-0627-x \n29230691 \n50 World Health Organization. ATC alterations from 1982-2015. 2015. http://www.whocc.no/atc_ddd_alterations__cumulative/atc_alterations/.[This goes to the 2018 version. Is it OK to reference that?]\n51 \nLawrence JM Andrade SE Avalos LA Medication Exposure in Pregnancy Risk Evaluation Program (MEPREP) Study Group \nPrevalence, trends, and patterns of use of antidiabetic medications among pregnant women, 2001-2007 . Obstet Gynecol \n2013 ;121 :106 -14 . 10.1097/AOG.0b013e318278ce86 \n23262934 \n52 \nCharlton RA Klungsøyr K Neville AJ \nPrescribing of antidiabetic medicines before, during and after pregnancy: A study in seven European regions . PLoS One \n2016 ;11 :e0155737 . 10.1371/journal.pone.0155737 \n27192491 \n53 \nLizneva D Suturina L Walker W Brakta S Gavrilova-Jordan L Azziz R \nCriteria, prevalence, and phenotypes of polycystic ovary syndrome . Fertil Steril \n2016 ;106 :6 -15 . 10.1016/j.fertnstert.2016.05.003 \n27233760 \n54 \nNg M Fleming T Robinson M \nGlobal, regional, and national prevalence of overweight and obesity in children and adults during 1980-2013: a systematic analysis for the Global Burden of Disease Study 2013 . Lancet \n2014 ;384 :766 -81 . 10.1016/S0140-6736(14)60460-8 \n24880830 \n55 \nMascarenhas MN Flaxman SR Boerma T Vanderpoel S Stevens GA \nNational, regional, and global trends in infertility prevalence since 1990: a systematic analysis of 277 health surveys . PLoS Med \n2012 ;9 :e1001356 . 10.1371/journal.pmed.1001356 \n23271957 \n56 \nSirmans SM Pate KA \nEpidemiology, diagnosis, and management of polycystic ovary syndrome . Clin Epidemiol \n2013 ;6 :1 -13 . 10.2147/CLEP.S37559 \n24379699 \n57 \nNathan N Sullivan SD \nThe utility of metformin therapy in reproductive-aged women with polycystic ovary syndrome (PCOS) . Curr Pharm Biotechnol \n2014 ;15 :70 -83 . 10.2174/1389201015666140330195142 \n24720592 \n58 \nMitchell AA \nSystematic identification of drugs that cause birth defects--a new opportunity . N Engl J Med \n2003 ;349 :2556 -9 . 10.1056/NEJMsb031395 \n14695418 \n59 \nHughes RC Rowan JA \nPregnancy in women with Type 2 diabetes: who takes metformin and what is the outcome? \nDiabet Med \n2006 ;23 :318 -22 . 10.1111/j.1464-5491.2006.01750.x \n16492217 \n60 \nRowan JA Rush EC Obolonkin V Battin M Wouldes T Hague WM \nMetformin in gestational diabetes: the offspring follow-up (MiG TOFU): body composition at 2 years of age . Diabetes Care \n2011 ;34 :2279 -84 . 10.2337/dc11-0660 \n21949222 \n61 \nde Jonge L Garne E Gini R \nImproving Information on Maternal Medication Use by Linking Prescription Data to Congenital Anomaly Registers: A EUROmediCAT Study . Drug Saf \n2015 ;38 :1083 -93 . 10.1007/s40264-015-0321-9 \n26153398 \n62 \nGabbay-Benziv R Reece EA Wang F Yang P \nBirth defects in pregestational diabetes: Defect range, glycemic threshold and pathogenesis . World J Diabetes \n2015 ;6 :481 -8 . 10.4239/wjd.v6.i3.481 \n25897357\n\n",
"fulltext_license": "CC BY",
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"issue": "361()",
"journal": "BMJ (Clinical research ed.)",
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"medline_ta": "BMJ",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents; D008423:Maternal Age; D008687:Metformin; D016017:Odds Ratio; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011254:Pregnancy in Diabetics; D012042:Registries; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "8900488",
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"pmid": "29941493",
"pubdate": "2018-06-25",
"publication_types": "D016428:Journal Article",
"references": "20558369;23271957;15060191;25013215;21127116;14695418;21384531;15866611;23983188;24720592;10413329;8452908;10230831;21949224;27899001;16492217;22389436;24861556;17350747;22117616;29215149;20929418;23262934;21251886;8073364;16201957;21381185;27192491;21949222;25897357;24880830;27233760;22701483;26153398;24794371;17977497;16824464;26395592;29082364;26620807;26148560;24379699;18271881;16418696;29230691;16879826;22371321;10757433",
"title": "Metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies: exploratory case-control study.",
"title_normalized": "metformin exposure in first trimester of pregnancy and risk of all or specific congenital anomalies exploratory case control study"
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"abstract": "BACKGROUND\nAntiretroviral combination therapy raises issues of long-term adherence and toxicity. Initial treatment simplification based on single-drug therapy was investigated in the MONARK trial, which compared first-line lopinavir/ritonavir monotherapy (arm A) with first-line lopinavir/ritonavir + zidovudine/lamivudine tritherapy (arm B). The MONARK trial is registered as a randomized trial at clinical trials.gov under identifier NCT 00234923.\n\n\nMETHODS\nImmune recovery was compared in patients with undetectable plasma virus (<50 copies/mL) after 60 weeks of treatment (arm A, n = 21; arm B, n = 13).\n\n\nRESULTS\nThe week 60 CD4 T cell count and CD4 T cell subset distribution did not differ significantly between the treatment arms. Memory CD4 T cell responses to HIV and recall antigens were better with triple therapy than with monotherapy. The frequencies of activated CD8 T cells and anti-HIV CD8 T cell effector responses were similar in the two arms. However, the repertoire of CD8 T cell effector responses was broader and persistent residual viraemia more frequent (by ultrasensitive PCR) in the monotherapy arm.\n\n\nCONCLUSIONS\nWhile viral control can be achieved with first-line lopinavir/ritonavir monotherapy, the quality of immune recovery is inferior to that obtained with triple therapy, possibly owing to a higher level of residual viral replication. Thus, the benefits of first-line lopinavir/ritonavir monotherapy in terms of toxicity and adherence might be offset by an increased risk of residual viral replication, which may also fuel latent viral reservoirs.",
"affiliations": "INSERM U-1184, Université Paris-Sud, Le Kremlin-Bicêtre, France Department of Pediatrics, Nimes University Hospital, Nimes, France.;Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, EA 7327 Paris, France APHP, UF de Thérapeutique en Immuno-Infectiologie, CHU Hotel Dieu, Paris, France.;Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, EA 7327 Paris, France APHP, Laboratoire de Virologie, Hôpital Necker-Enfants Malades, Paris, France.;INSERM U-1184, Université Paris-Sud, Le Kremlin-Bicêtre, France Laboratoire d'Immunologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.;INSERM U-1184, Université Paris-Sud, Le Kremlin-Bicêtre, France Laboratoire d'Immunologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.;AbbVie France, Rungis, France.;Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine, EA 7327 Paris, France APHP, Laboratoire de Virologie, Hôpital Necker-Enfants Malades, Paris, France.;INSERM U-1184, Université Paris-Sud, Le Kremlin-Bicêtre, France AP-HP, Department of Internal Medicine, Bicetre University Hospital, Le Kremlin-Bicetre, France.;INSERM U-1184, Université Paris-Sud, Le Kremlin-Bicêtre, France Laboratoire d'Immunologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France yassine.taoufik@bct.aphp.fr.",
"authors": "Tran|Tu-Anh|TA|;Ghosn|Jade|J|;Avettand-Fenoël|Véronique|V|;Hendel-Chavez|Houria|H|;de Goër de Herve|Marie-Ghislaine|MG|;Cohen-Codar|Isabelle|I|;Rouzioux|Christine|C|;Delfraissy|Jean-François|JF|;Taoufik|Yassine|Y|",
"chemical_list": "D019380:Anti-HIV Agents; D004338:Drug Combinations; C558899:lopinavir-ritonavir drug combination; D061466:Lopinavir; D019438:Ritonavir",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkv138",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "70(9)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": "HIV; antiviral; effector memory CD8 T cells",
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes; D018414:CD8-Positive T-Lymphocytes; D003430:Cross-Sectional Studies; D004338:Drug Combinations; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D061466:Lopinavir; D008297:Male; D008875:Middle Aged; D019438:Ritonavir; D016176:T-Lymphocyte Subsets; D016896:Treatment Outcome; D019562:Viral Load; D014779:Virus Replication",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "2627-31",
"pmc": null,
"pmid": "26023212",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Residual HIV-1 replication may impact immune recovery in patients on first-line lopinavir/ritonavir monotherapy.",
"title_normalized": "residual hiv 1 replication may impact immune recovery in patients on first line lopinavir ritonavir monotherapy"
} | [
{
"companynumb": "FR-CIPLA LTD.-2016FR02438",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
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"activesubstancename": "ZIDOVUDINE"
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{
"abstract": "Pregnant women with epilepsy on antiepileptic drugs (AEDs) may experience a reduction in serum AED levels. This has the potential to worsen seizure control.\n\n\n\nTo determine if, in pregnant women with epilepsy on AEDs, additional therapeutic drug monitoring reduces seizure deterioration compared with clinical features monitoring after a reduction in serum AED levels.\n\n\n\nA double-blind, randomised trial nested within a cohort study was conducted and a qualitative study of acceptability of the two strategies was undertaken. Stratified block randomisation with a 1 : 1 allocation method was carried out.\n\n\n\nFifty obstetric and epilepsy clinics in secondary and tertiary care units in the UK.\n\n\n\nPregnant women with epilepsy on one or more of the following AEDs: lamotrigine, carbamazepine, phenytoin or levetiracetam. Women with a ≥ 25% decrease in serum AED level from baseline were randomised to therapeutic drug monitoring or clinical features monitoring strategies.\n\n\n\nIn the therapeutic drug monitoring group, clinicians had access to clinical findings and monthly serum AED levels to guide AED dosage adjustment for seizure control. In the clinical features monitoring group, AED dosage adjustment was based only on clinical features.\n\n\n\nPrimary outcome - seizure deterioration, defined as time to first seizure and to all seizures after randomisation per woman until 6 weeks post partum. Secondary outcomes - pregnancy complications in mother and offspring, maternal quality of life, seizure rates in cohorts with stable serum AED level, AED dose exposure and adverse events related to AEDs.\n\n\n\nAnalysis of time to first and to all seizures after randomisation was performed using a Cox proportional hazards model, and multivariate failure time analysis by the Andersen-Gill model. The effects were reported as hazard ratios (HRs) with 95% confidence intervals (CIs). Secondary outcomes were reported as mean differences (MDs) or odds ratios.\n\n\n\nA total of 130 women were randomised to the therapeutic drug monitoring group and 133 to the clinical features monitoring group; 294 women did not have a reduction in serum AED level. A total of 127 women in the therapeutic drug monitoring group and 130 women in the clinical features monitoring group (98% of complete data) were included in the primary analysis. There were no significant differences in the time to first seizure (HR 0.82, 95% CI 0.55 to 1.2) or timing of all seizures after randomisation (HR 1.3, 95% CI 0.7 to 2.5) between both trial groups. In comparison with the group with stable serum AED levels, there were no significant increases in seizures in the clinical features monitoring (odds ratio 0.93, 95% CI 0.56 to 1.5) or therapeutic drug monitoring group (odds ratio 0.93, 95% CI 0.56 to 1.5) associated with a reduction in serum AED levels. Maternal and neonatal outcomes were similar in both groups, except for higher cord blood levels of lamotrigine (MD 0.55 mg/l, 95% CI 0.11 to 1 mg/l) or levetiracetam (MD 7.8 mg/l, 95% CI 0.86 to 14.8 mg/l) in the therapeutic drug monitoring group than in the clinical features monitoring group. There were no differences between the groups on daily AED exposure or quality of life. An increase in exposure to lamotrigine, levetiracetam and carbamazepine significantly increased the cord blood levels of the AEDs, but not maternal or fetal complications. Women with epilepsy perceived the need for weighing up their increased vulnerability to seizures during pregnancy against the side effects of AEDs.\n\n\n\nFewer women than the original target were recruited.\n\n\n\nThere is no evidence to suggest that regular monitoring of serum AED levels in pregnancy improves seizure control or affects maternal or fetal outcomes.\n\n\n\nFurther evaluation of the risks of seizure deterioration for various threshold levels of reduction in AEDs and the long-term neurodevelopment of infants born to mothers in both randomised groups is needed. An individualised prediction model will help to identify those women who need close monitoring in pregnancy.\n\n\n\nCurrent Controlled Trials ISRCTN01253916.\n\n\n\nThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 23. See the NIHR Journals Library website for further project information.",
"affiliations": "Women's Health Research Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.;Pragmatic Clinical Trials Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.;Women's Health Research Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.;Centre for Health and Social Care Research, Birmingham City University, Birmingham, UK.;Neuropsychiatry Department, The Barberry, Birmingham, UK.;Neuropsychiatry Department, The Barberry, Birmingham, UK.;Research and Development, Birmingham Children's Hospital, Birmingham, UK.;Women's Health Research Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.;Women's Health Research Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.;Department of Neurology, Royal London Hospital, London, UK.;Research and Development, Birmingham Women's Hospital, Birmingham, UK.;School of Clinical and Experimental Medicine, University of Birmingham, Birmingham, UK.;Patient and Public Involvement group member, Katie's Team, Katherine Twining Network, Queen Mary University of London, London, UK.;Health Economics Unit, University of Birmingham, Birmingham, UK.;Birmingham Clinical Trials Unit, University of Birmingham, Birmingham, UK.;Women's Health Research Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.;Epilepsy Action, Leeds, UK.;Pragmatic Clinical Trials Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.;Research and Development, Birmingham Women's Hospital, Birmingham, UK.;Centre for Health and Social Care Research, Birmingham City University, Birmingham, UK.;Neuropsychiatry Department, The Barberry, Birmingham, UK.;Women's Health Research Unit, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.",
"authors": "Thangaratinam|Shakila|S|;Marlin|Nadine|N|;Newton|Sian|S|;Weckesser|Annalise|A|;Bagary|Manny|M|;Greenhill|Lynette|L|;Rikunenko|Rachel|R|;D'Amico|Maria|M|;Rogozińska|Ewelina|E|;Kelso|Andrew|A|;Hard|Kelly|K|;Coleman|Jamie|J|;Moss|Ngawai|N|;Roberts|Tracy|T|;Middleton|Lee|L|;Dodds|Julie|J|;Pullen|Angela|A|;Eldridge|Sandra|S|;Pirie|Alexander|A|;Denny|Elaine|E|;McCorry|Doug|D|;Khan|Khalid S|KS|",
"chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine; D000077287:Levetiracetam; D010672:Phenytoin; D000077213:Lamotrigine",
"country": "England",
"delete": false,
"doi": "10.3310/hta22230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1366-5278",
"issue": "22(23)",
"journal": "Health technology assessment (Winchester, England)",
"keywords": null,
"medline_ta": "Health Technol Assess",
"mesh_terms": "D000927:Anticonvulsants; D002220:Carbamazepine; D004311:Double-Blind Method; D016903:Drug Monitoring; D004827:Epilepsy; D005260:Female; D006801:Humans; D000077213:Lamotrigine; D000077287:Levetiracetam; D010672:Phenytoin; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011788:Quality of Life; D012640:Seizures; D006113:United Kingdom",
"nlm_unique_id": "9706284",
"other_id": null,
"pages": "1-152",
"pmc": null,
"pmid": "29737274",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "AntiEpileptic drug Monitoring in PREgnancy (EMPiRE): a double-blind randomised trial on effectiveness and acceptability of monitoring strategies.",
"title_normalized": "antiepileptic drug monitoring in pregnancy empire a double blind randomised trial on effectiveness and acceptability of monitoring strategies"
} | [
{
"companynumb": "GB-UCBSA-2018023932",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nWe present the case of a septic patient with severe immunodeficiency, who developed QT interval prolongation followed by episodes of lethal cardiac arrhythmia. Cardiac events occurred after posaconazole administration, incriminating posaconazole use, alone or in combination with voriconazole, as the culpable agent.\n\n\nMETHODS\nA 26-year-old female patient underwent orthopedic surgery to remove ectopic calcifications in her left hip joint. On the first post-operative day she became septic due to a surgical wound infection. Despite being treated according to the therapeutic protocols for sepsis, no clinical improvement was noticed and further assessment revealed an underlying immunodeficiency. Considering the underlying immunodeficiency and to that point poor clinical response, an antifungal agent was added to the antibiotic regiment. Following discontinuation of multiple antifungal agents due to adverse effects, posaconazole was administered. Posaconazole oral intake was followed by episodes of bradycardia and QT interval prolongation. The patient suffered continuous incidents of cardiac arrest due to polymorphic ventricular tachycardia (torsades des pointes) that degenerated to lethal ventricular fibrillation. Posaconazole was immediately discontinued and a temporary pacemaker was installed. The patient finally recovered without any neurological deficit, and was discharged in a good clinical status.\n\n\nCONCLUSIONS\nClose cardiac monitoring is recommended in cases where posaconazole administration is combined with coexisting risk factors, as they may lead to severe ECG abnormalities and cardiac arrhythmias such as long QT interval syndrome and torsades de pointes. Posaconazole interactions with medications metabolized via the CYP3A4 pathway should be considered an additional risk factor for lethal cardiac incidents.",
"affiliations": "Department of Internal Medicine, University Hospital of Patras, Patras, Greece.;Department of Internal Medicine, University Hospital of Patras, Patras, Greece.;Department of Internal Medicine, University Hospital of Patras, Patras, Greece.;Department of Orthopedic Surgery, University Hospital of Patras, Patras, Greece.;Department of Orthopaedic Surgery, University Hospital of Patras, Patras, Greece.",
"authors": "Panos|George|G|;Velissaris|Dimitrios|D|;Karamouzos|Vasilios|V|;Matzaroglou|Charalampos|C|;Tylianakis|Minos|M|",
"chemical_list": "D000935:Antifungal Agents; D014230:Triazoles; C101425:posaconazole",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.896946",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5923",
"issue": "17()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D005260:Female; D006323:Heart Arrest; D006801:Humans; D016867:Immunocompromised Host; D008133:Long QT Syndrome; D018805:Sepsis; D013530:Surgical Wound Infection; D014230:Triazoles",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "295-300",
"pmc": null,
"pmid": "27125217",
"pubdate": "2016-04-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22338554;11994029;10784527;14594906;17109296;15472801;17697716;16135526;17210771;14624285;12936975;16705579;12695341;17101682;15328123;16310149;17489884",
"title": "Long QT Syndrome Leading to Multiple Cardiac Arrests After Posaconazole Administration in an Immune-Compromised Patient with Sepsis: An Unusual Case Report.",
"title_normalized": "long qt syndrome leading to multiple cardiac arrests after posaconazole administration in an immune compromised patient with sepsis an unusual case report"
} | [
{
"companynumb": "GR-PFIZER INC-2016253358",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Implementation of cytarabine into induction therapy became standard of care for younger patients with mantle cell lymphoma (MCL). On the basis of its beneficial impact, many centers incorporated cytarabine at lower doses also into first-line treatments of elderly patients. We conducted a multicenter observational study that prospectively analyzed safety and efficacy of alternating 3 + 3 cycles of R-CHOP and R-cytarabine for newly diagnosed transplant-ineligible MCL patients. A total of 73 patients were enrolled with median age 70 years. Most patients had intermediate (39.7%) and high-risk (50.7%) disease according to MCL international prognostic index. Rituximab maintenance was initiated in 58 patients. Overall response rate reached 89% by positron emission tomography-computed tomography, including 75.3% complete remissions. Two patients (2.7%) did not complete the induction therapy because of toxicity. Three patients (4.1%) were considered nonresponders, which led to therapy change before completion of induction. Estimated progression-free survival and overall survival were 51.3% and 68.6% at 4 years, respectively. Mantle cell lymphoma international prognostic index, bulky disease (≥ 5 cm), and achievement of positron emission tomography-negativity independently correlated with progression-free survival. Grade 3 to 4 hematologic and nonhematologic toxicity was documented in 48% and 20.5% patients, respectively. Alternation of R-CHOP and R-cytarabine represents feasible and very effective regimen for elderly/comorbid MCL patients. This study was registered at GovTrial (clinicaltrials.gov) NCT03054883.",
"affiliations": "First Medical Department, Charles University General Hospital in Prague, Prague, Czech Republic.;CLIP, Deparment of Pediatric Hematology/Oncology, Second Faculty of Medicine and University Hospital in Motol, Prague, Czech Republic.;Fourth Department of Internal Medicine-Hematology, Charles University Hospital in Hradec Kralove and Faculty of Medicine in Hradec Kralove, Hradec Králové, Czech Republic.;First Medical Department, Charles University General Hospital in Prague, Prague, Czech Republic.;First Medical Department, Charles University General Hospital in Prague, Prague, Czech Republic.;Department of Pathology and Molecular Medicine, Charles University Hospital in Motol, Prague, and Second Faculty of Medicine, Prague, Czech Republic.;Fourth Department of Internal Medicine-Hematology, Charles University Hospital in Hradec Kralove and Faculty of Medicine in Hradec Kralove, Hradec Králové, Czech Republic.;Department of Hematology and Oncology, Masaryk University Hospital in Brno, Brno, Czech Republic.;Department of Internal Medicine and Haematology, Faculty Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic.;Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Olomouc, Czech Republic.;First Medical Department, Charles University General Hospital in Prague, Prague, Czech Republic.;Department of Hematology and Oncology, Masaryk University Hospital in Brno, Brno, Czech Republic.;Department of Internal Medicine and Haematology, Faculty Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic.;Department of Hemato-Oncology, Faculty of Medicine and Dentistry, Palacky University and University Hospital Olomouc, Olomouc, Czech Republic.;Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, Prague, Czech Republic.;Institute of Nuclear Medicine, Charles University General Hospital in Prague, Prague, Czech Republic.;CLIP, Deparment of Pediatric Hematology/Oncology, Second Faculty of Medicine and University Hospital in Motol, Prague, Czech Republic.;CLIP, Deparment of Pediatric Hematology/Oncology, Second Faculty of Medicine and University Hospital in Motol, Prague, Czech Republic.;Department of Pathology and Molecular Medicine, Charles University Hospital in Motol, Prague, and Second Faculty of Medicine, Prague, Czech Republic.;Institute of Pathology, Charles University General Hospital Prague, Prague, Czech Republic.;Department of Pathology and Molecular Medicine, Charles University Hospital in Motol, Prague, and Second Faculty of Medicine, Prague, Czech Republic.;Center of Oncocytogenetics, Institute of Clinical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University, Prague, Czech Republic.;CLIP, Deparment of Pediatric Hematology/Oncology, Second Faculty of Medicine and University Hospital in Motol, Prague, Czech Republic.;First Medical Department, Charles University General Hospital in Prague, Prague, Czech Republic.",
"authors": "Klener|Pavel|P|http://orcid.org/0000-0001-7786-9378;Fronkova|Eva|E|;Belada|David|D|;Forsterova|Kristina|K|;Pytlik|Robert|R|;Kalinova|Marketa|M|;Simkovic|Martin|M|;Salek|David|D|;Mocikova|Heidi|H|;Prochazka|Vit|V|;Blahovcova|Petra|P|;Janikova|Andrea|A|;Markova|Jana|J|;Obr|Ales|A|;Berkova|Adela|A|;Kubinyi|Jozef|J|;Vaskova|Martina|M|;Mejstrikova|Ester|E|;Campr|Vit|V|;Jaksa|Radek|R|;Kodet|Roman|R|;Michalova|Kyra|K|;Trka|Jan|J|;Trneny|Marek|M|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D003561:Cytarabine; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1002/hon.2483",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-0232",
"issue": "36(1)",
"journal": "Hematological oncology",
"keywords": "PET-CT; elderly patients; high-dose cytarabine; mantle cell lymphoma; rituximab maintenance",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D003561:Cytarabine; D004317:Doxorubicin; D005260:Female; D006801:Humans; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D014750:Vincristine",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "110-115",
"pmc": null,
"pmid": "29083050",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Alternating R-CHOP and R-cytarabine is a safe and effective regimen for transplant-ineligible patients with a newly diagnosed mantle cell lymphoma.",
"title_normalized": "alternating r chop and r cytarabine is a safe and effective regimen for transplant ineligible patients with a newly diagnosed mantle cell lymphoma"
} | [
{
"companynumb": "PHHY2018CZ066717",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GRANULOCYTE COLONY-STIMULATING FACTOR NOS"
},
"drugadd... |
{
"abstract": "A case of hepatocellular carcinoma (HCC) with pulmonary recurrence after liver transplantation for HCC is presented in this report. The patient showed disease progression on sorafenib therapy demonstrated by computed tomography scans as well as serial serum α-fetoprotein (AFP) elevation. After his immunosuppression therapy was successfully transitioned to sirolimus and a continuation of sorafenib, he achieved partial remission based on RECIST criteria and normalization of AFP. Mammalian target of rapamycin inhibitors including sirolimus alone or in conjunction with sorafenib may be useful in the treatment of post transplant HCC.",
"affiliations": "Division of Hematology and Medical Oncology, Department of Medicine, University of Texas Health Science Center at San Antonio, 7979 Wurzbach Road, San Antonio, TX 78229, United States. wangy5@uthscsa.edu",
"authors": "Wang|Yubao|Y|;Speeg|Kermit V|KV|;Washburn|William Kenneth|WK|;Halff|Glenn|G|",
"chemical_list": "D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D007166:Immunosuppressive Agents; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v16.i43.5518",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "16(43)",
"journal": "World journal of gastroenterology",
"keywords": null,
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D006528:Carcinoma, Hepatocellular; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009536:Niacinamide; D010671:Phenylurea Compounds; D011725:Pyridines; D020123:Sirolimus; D000077157:Sorafenib; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "5518-22",
"pmc": null,
"pmid": "21086573",
"pubdate": "2010-11-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18675098;18391618;19707711;16305462;17318075;18307022;17321636;14990647;18466352;18650514;15818333;19220580;15057740;17923599;19301157;17087938;14667750;19208038",
"title": "Sirolimus plus sorafenib in treating HCC recurrence after liver transplantation: a case report.",
"title_normalized": "sirolimus plus sorafenib in treating hcc recurrence after liver transplantation a case report"
} | [
{
"companynumb": "US-MYLANLABS-2021M1024744",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "SORAFENIB"
},
"drugadditional": "1",
... |
{
"abstract": "Coronavirus disease 2019 (COVID-19) has led to a global pandemic that has also challenged the management of various other life-threatening conditions, such as malignant disorders. In this study, we present the clinical features and treatment outcomes of twenty-seven COVID-19 positive patients with leukemia across seven different centers in Istanbul. From March 1st to December 31st 2020, 116 patients were diagnosed with acute leukemia. Thirty-two cases with acute lymphocytic leukemia (ALL), 82 cases with acute myeloid leukemia (AML), and 2 cases with mixed phenotype acute leukemia (MPAL) were identified. Of the 27 patients with the COVID-19 infection, seven patients had ALL, 19 patients had AML and one patient had MPAL. The mortality rate was 37% among the patients with AML, whereas there were no deaths in the ALL group. The mortality rate of AML patients with the COVID-19 infection was higher compared to cases without the infection (P<0.05). We could not detect any significant difference in the ALL cohort. This study, which includes one of the largest acute leukemia series in literature proved that acute myeloid leukemia patients with the COVID-19 infection have worse outcomes than patients without the infection. The high mortality among patients with acute leukemias hospitalized with COVID-19 highlight the need for aggressive infection prevention, increased surveillance and protective isolation and even modification of the therapy, in case of minimal residual disease (MRD) negativity.",
"affiliations": "Department of Hematology, School of Medicine, Koc University Istanbul, Turkey.;Division of Hematology and Bone Marrow Transplantation Unit, Department of Internal Medicine and Hematology, Bahcelievler Medical Park Hospital Istanbul, Turkey.;Division of Hematology and Bone Marrow Transplantation Unit, Department of Internal Medicine and Hematology, Bahcelievler Medical Park Hospital Istanbul, Turkey.;Department of Hematology, Marmara University Medical Faculty Istanbul, Turkey.;Department of Hematology, School of Medicine, Koc University Istanbul, Turkey.;Division of Hematology, Department of Internal Medicine, Medipol University Istanbul, Turkey.;Division of Hematology, Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University Istanbul, Turkey.;Division of Hematology, Department of Internal Medicine, Istanbul Medical Faculty, Istanbul University Istanbul, Turkey.;Department of Hematology, Başkent University Istanbul Hospital Istanbul, Turkey.;Department of Hematology, School of Medicine, Koc University Istanbul, Turkey.;Department of Hematology, School of Medicine, Koc University Istanbul, Turkey.",
"authors": "Buyuktas|Deram|D|;Acar|Kadir|K|;Sucak|Gulsan|G|;Toptas|Tayfur|T|;Kapucu|Irem|I|;Bekoz|Huseyin|H|;Erdem|Simge|S|;Nalcaci|Meliha|M|;Atalay|Figen|F|;Akay|Meltem Olga|MO|;Ferhanoglu|Burhan|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2160-1992",
"issue": "11(4)",
"journal": "American journal of blood research",
"keywords": "COVID-19; SARS-Cov2; acute leukemia; acute lymphoblastic leukemia; acute myeloid leukemia",
"medline_ta": "Am J Blood Res",
"mesh_terms": null,
"nlm_unique_id": "101569577",
"other_id": null,
"pages": "427-437",
"pmc": null,
"pmid": "34540352",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "32379921;32369409;23365464;32318330;32499538;18827183;32066541;33415422;33053381;32376969;32991251;32528122;33275765;32798473;32561842",
"title": "COVID-19 infection in patients with acute leukemia; Istanbul experience.",
"title_normalized": "covid 19 infection in patients with acute leukemia istanbul experience"
} | [
{
"companynumb": "TR-AMGEN-TURSP2021183137",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "4",
... |
{
"abstract": "Prolonged hospitalization and exposure to third generation cephalosporins are reported to facilitate the acquisition and colonization of Vancomycin Resistant Enterococci (VRE). Though VRE is not uncommon in India, urinary tract infection with a vanA genotype is a cause of serious concern as VRE co-exhibit resistance to aminoglycosides. In India, majority of the VRE isolates recovered from hospitalized patients include Enterococcus faecium. We report a case of catheter associated urinary tract infection by an endogenous, multidrug resistant E. faecalis of vanA genotype following prolonged hospitalization, ICU stay, catheterisation and exposure to 3G cephalosporin and metronidazole. The patient responded to linezolid therapy.",
"affiliations": "Assosciate Professor, Research Laboratory for Oral and Systemic Health, Department of Microbiology, Sree Balaji Dental College and Hospital, Bharath University , Chennai, India .;Lecturer, Department of Microbiology, SRM Medical College Hospital and Research Centre, SRM University , Kattankulathur, Chennai, India .;Professor and Head, Department of Microbiology, SRM Medical College Hospital and Research Centre, SRM University , Kattankulathur, Chennai, India .;Post Graduate Student, Department of Microbiology, SRM Medical College Hospital and Research Centre, SRM University , Kattankulathur, Chennai, India .;Lecturer, Department of Microbiology, Priyadarshini Dental College and Hospital , Pandur, Thiruvallur, India .",
"authors": "Padmavathy|Kesavaram|K|;Praveen|Shabana|S|;Madhavan|Radha|R|;Krithika|Nagarajan|N|;Kiruthiga|Alexander|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2015/13856.6378",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-709X",
"issue": "9(8)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "High level aminoglycoside resistance (HLAR); Multidrug resistance; Vancomycin resistant Enterococci (VRE)",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "DD05-6",
"pmc": null,
"pmid": "26435949",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports",
"references": "11294702;14679235;12654683;16610573;19736416;15324549;22754254;15385507;18033823;9665988;15055486;10987725;15232156;11112676",
"title": "Clinico-Microbiological Investigation of Catheter Associated Urinary Tract Infection by Enterococcus faecalis: vanA Genotype.",
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"abstract": "Interstitial lung disease is recognized as a group of diseases with a different etiopathogenesis characterized by chronic lung inflammation with the accumulation of inflammatory cells, lymphocytes and macrophages, and the consequent release of proinflammatory cytokines. Various degrees of pulmonary fibrosis can be associated with this inflammatory condition. Interstitial lung disease related to oncological drugs is a relevant problem in clinical practice. The etiopathogenetic mechanisms underlying this adverse event are not completely known but can be partly explained by the mechanism of action of the drug involved. Therefore, knowledge of the relevance of this potentially fatal adverse event supported by the reported safety data of pivotal studies becomes fundamental in the management of patients. The prompt diagnosis of drug-related pneumonia and the consequent differential diagnosis with other forms of pneumonia allow a rapid suspension of treatment and the establishment of an immunosuppressive treatment if necessary. In the context of the health emergency related to SARS CoV2 infection and COVID-19-related interstitial lung disease, such knowledge holds decisive relevance in the conscious choice of cancer treatments. Our intent was to describe the oncological drugs most correlated with this adverse event by reporting, where possible, the percentages of insurgency in pivotal studies to provide an overview and therefore promote greater awareness of this important toxicity related to oncological treatment.",
"affiliations": "Unit of Medical Oncology, Department of Oncology, Fondazione Poliambulanza, 25124 Brescia, Italy.;Unit of Medical Oncology, Department of Oncology, Fondazione Poliambulanza, 25124 Brescia, Italy.;Medical Oncology Unit, University Hospital of Modena, 41124 Modena, Italy.;Unit of Radiology, Department of Diagnostic Imaging, Fondazione Poliambulanza, 25124 Brescia, Italy.;Unit of Medical Oncology, Department of Oncology, Fondazione Poliambulanza, 25124 Brescia, Italy.;Unit of Radiology, Department of Diagnostic Imaging, Fondazione Poliambulanza, 25124 Brescia, Italy.;Nuclear Medicine Department, Fondazione Poliambulanza, 25124 Brescia, Italy.;Unit of Medical Oncology, Department of Oncology, Fondazione Poliambulanza, 25124 Brescia, Italy.",
"authors": "Cherri|Sara|S|;Noventa|Silvia|S|0000-0001-7423-6065;Fanelli|Martina|M|;Calandra|Giulio|G|;Prochilo|Tiziana|T|;Bnà|Claudio|C|;Savelli|Giordano|G|0000-0002-4898-7647;Zaniboni|Alberto|A|",
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"doi": "10.3390/cancers13051052",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n10.3390/cancers13051052\ncancers-13-01052\nReview\nDrug-Related Pneumonitis in Cancer Treatment during the COVID-19 Era\nCherri Sara 1*\nhttps://orcid.org/0000-0001-7423-6065\nNoventa Silvia 1\nFanelli Martina 2\nCalandra Giulio 3\nProchilo Tiziana 1\nBnà Claudio 3\nhttps://orcid.org/0000-0002-4898-7647\nSavelli Giordano 4\nZaniboni Alberto 1\nGupta Sanjay Academic Editor\n1 Unit of Medical Oncology, Department of Oncology, Fondazione Poliambulanza, 25124 Brescia, Italy; silvia.noventa@poliambulanza.it (S.N.); tiziana.prochilo@poliambulanza.it (T.P.); alberto.zaniboni@poliambulanza.it (A.Z.)\n2 Medical Oncology Unit, University Hospital of Modena, 41124 Modena, Italy; martinafun89@gmail.com\n3 Unit of Radiology, Department of Diagnostic Imaging, Fondazione Poliambulanza, 25124 Brescia, Italy; giulio.calandra@poliambulanza.it (G.C.); claudio.bna@poliambulanza.it (C.B.)\n4 Nuclear Medicine Department, Fondazione Poliambulanza, 25124 Brescia, Italy; giordano.savelli@poliambulanza.it\n* Correspondence: sara.cherri@poliambulanza.it; Tel.: +39-03035151; Fax: +39-0303518270\n02 3 2021\n3 2021\n13 5 105215 2 2021\n24 2 2021\n© 2021 by the authors.\n2021\nLicensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nInterstitial lung disease is a group of diseases characterized by chronic lung inflammation that can be related to oncological treatments, such as traditional chemotherapy drugs and the newest targeted therapies and immunotherapies. Awareness about this potentially fatal adverse event is paramount in patient management and to make a conscious therapeutic choice. It represents a differential diagnostic challenge, especially in the context of the COVID-19 pandemic. Our aim is to describe the incidence and characteristics of this adverse event across oncological treatment groups and to promote greater knowledge about this important toxicity.\n\nAbstract\n\nInterstitial lung disease is recognized as a group of diseases with a different etiopathogenesis characterized by chronic lung inflammation with the accumulation of inflammatory cells, lymphocytes and macrophages, and the consequent release of proinflammatory cytokines. Various degrees of pulmonary fibrosis can be associated with this inflammatory condition. Interstitial lung disease related to oncological drugs is a relevant problem in clinical practice. The etiopathogenetic mechanisms underlying this adverse event are not completely known but can be partly explained by the mechanism of action of the drug involved. Therefore, knowledge of the relevance of this potentially fatal adverse event supported by the reported safety data of pivotal studies becomes fundamental in the management of patients. The prompt diagnosis of drug-related pneumonia and the consequent differential diagnosis with other forms of pneumonia allow a rapid suspension of treatment and the establishment of an immunosuppressive treatment if necessary. In the context of the health emergency related to SARS CoV2 infection and COVID-19-related interstitial lung disease, such knowledge holds decisive relevance in the conscious choice of cancer treatments. Our intent was to describe the oncological drugs most correlated with this adverse event by reporting, where possible, the percentages of insurgency in pivotal studies to provide an overview and therefore promote greater awareness of this important toxicity related to oncological treatment.\n\nlung toxicity\ninterstitial lung disease\npneumonitis\ncancer treatment\ntarget therapy\nchemotherapy\nimmunotherapy\nCOVID-19\n==== Body\n1. Introduction\n\nOn 9 January 2020, a new coronavirus, SARS-CoV-2, was defined as the causative agent of a cluster of pneumonia cases reported in Wuhan, China. The disease caused by the new coronavirus was named COVID-19. On 11 March 2020, the World Health Organization (WHO) Director General indicated that the spread of COVID-19 was no longer an epidemic confined to certain geographical areas, but a pandemic spread throughout the planet. Thus, a dramatic period began worldwide that led to the collapse of the health system as we know it. Within this context, medical oncology has had to question the benefit–risk ratio of cancer treatments during the pandemic not only because of the increased risk of contagion for patients when going to the hospital to receive cancer treatments, but also because of worrying data about the impact of cancer on the prognosis of SARS-CoV-2 infection [1].\n\nSARS-CoV-2 infection does not present with the same severity in all patients, in particular, three potential scenarios are recognized: mild, severe and critical illness. In mild disease, mild pneumonia or no pneumonia develops, and usually in this form, symptoms of viral upper respiratory tract infection prevail. Conversely, critical illness is characterized by severe pneumonia with a systemic presentation and potential multiorgan failure. X-ray images are characterized by the presence of interstitial lung disease with uneven ground glass opacities and uneven consolidation in the intermediate, outer and subpleural areas of the lung [2].\n\nMany cancer drugs can also cause interstitial lung damage [3]. Pulmonary toxicities are not among the most common adverse events of drugs used in the treatment of solid tumors; however, there are no clear data on their incidence. In this context, case reports and real-life data can make a valuable contribution to better quantify the impact of this toxicity, which in some cases can be fatal. It is important to take this toxicity into account in the decision-making process and, second, to suspect drug-related interstitial lung disease in case of suggestive symptoms to promptly suspend the therapy when necessary. Therefore, the choice of oncological treatment during the era of COVID-19 can be difficult. We conducted a qualitative review of the evidence in the literature regarding pulmonary toxicity from oncological drugs, focusing in particular on immunotherapy, target therapy and conjugated antibodies recently approved by the FDA (Food and Drug Administration) and EMA (European Medicines Agency) for the treatment of solid tumors with the aim of understanding the relevance of this issue.\n\n2. Chemotherapy and Lung Toxicity\n\nInterstitial pneumonitis related to chemotherapy drugs represents a relevant oncological problem that has been investigated both in preclinical and clinical studies to understand the underlying mechanisms. Pulmonary toxicity of some of the older chemotherapy standard drugs may be dose-dependent, i.e., bleomycin [4], or it can be observed several years after their use, i.e., cyclophosphamide [5]. To date, there are no tools to prevent the onset of interstitial pneumonitis other than the careful clinical evaluation of patients who develop respiratory symptoms and radiological monitoring in the most fragile subjects. Table 1 presents the main chemotherapy drugs that can lead to the development of interstitial pneumonia.\n\nBleomycin is a chemotherapy drug that is classically related to such toxicity, as noted in the first clinical trials in the 1960s. A prevalence of pulmonary toxicity of 40–45% has been reported with regimens including bleomycin, with a fatal outcome in 1–3% of these cases. There is currently no protocol to prevent this adverse event; however, some risk factors are recognized, such as the cumulative dose of bleomycin, reduction in glomerular filtration rate (GFR), elevated creatinine and advanced age [6]. With regard to the mechanism of lung damage induced by bleomycin, a possible interpretative key is oxidative damage, which could lead to pulmonary toxicity in subjects with deficiency of the enzyme that physiologically deactivates bleomycin hydrolase, leading to the release of inflammatory cytokines and consequent pulmonary fibrosis [7]. Bleomycin hydrolase, an enzyme that degrades bleomycin, is active in all tissues except for skin and lung, partly explaining the drug’s specific toxicity to these organs. Studies examining the different susceptibilities of mouse strains to bleomycin reveal that a bleomycin-resistant strain produces considerably more bleomycin hydrolase than a bleomycin-sensitive strain. The acute lung damage observed in bleomycin-sensitive mice was attributed to DNA strand splitting, resulting in chromosomal damage. The chronic fibrotic response to bleomycin-induced damage is associated with an acquired loss of bleomycin hydrolase activity and is mediated by the migration of activated effector cells into the lung with the release of proinflammatory mediators. Nude (athymic) mice are resistant to bleomycin-induced lung damage, suggesting that the inflammatory process is necessary for the pathogenesis of the disease. Proinflammatory lung injury mechanisms, similar to those reported in bleomycin studies, are also observed with methotrexate and cyclophosphamide [8,9]. Studies have demonstrated that in response to excess free radicals resulting from methotrexate use, an interleukin response may be induced with activation of p38 mitogen-activated protein kinases (MAPK p38), kinases involved in pulmonary inflammation and fibrosis [10,11]. In the case of cyclophosphamide, inflammatory processes are also described with an increased inflammatory cascade (TGFβ, fibronectin and procollagen) in response to DNA damage and oxidative stress.\n\nDespite a reduced incidence, drug-related reports of interstitial pneumonia also involve other widely used chemotherapeutic drugs, such as platinoids, taxanes and gemcitabine (see Table 1). With regard to gemcitabine, a systematic review on severe lung toxicity reported an incidence of up to 5% [12]. The clinical presentation is mostly nonspecific and requires a diagnosis of exclusion from other causes of interstitial pneumonitis. The predominant radiographic pattern is represented by reticulo-nodular interstitial infiltrates. It has been postulated that the pathophysiological mechanism of gemcitabine-mediated lung injury is a cytokine-mediated inflammatory reaction of the capillary-alveolar walls, with consequent alteration of membrane permeability [13]. For platinoids, when used alone, pulmonary toxicities are very rare, if not anecdotal. On the other hand, interstitial pneumonia associated with the use of taxanes is of greater relevance, with an incidence of grade 3 or higher in approximately 1% to 5% of patients receiving paclitaxel or docetaxel at conventional doses thrice weekly [14]. As previously mentioned, an increased risk is reported in the combined treatments [15].\n\n3. Target Therapies and Lung Toxicity\n\nThis list of target therapies leading to ILD is certainly destined to extend the updated safety data of drugs that have been used in clinical oncology for the past few years [42]. For example, the FDA recently published updated safety data for the cyclin inhibitor drugs palbociclib, ribociclib and abemaciclib, warning that these drugs can cause rare but serious pneumonitis [43]. This topic will also deserve careful consideration in the coming years given that this type of toxicity was reported for drugs not yet approved in Europe but that are likely to be available in the next few years. Table 2 reports target therapies causing lung injury.\n\n3.1. Tyrosine Kinases Inhibitors\n\nTyrosine kinase inhibitors (TKIs) are small molecules that inhibit the activation of protein kinases that, by means of protein phosphorylation, are involved in the activation mechanisms of proteins involved in cell growth processes. These proteins are often hyper-expressed or hyperactivated in some forms of cancer, making these drugs a very important therapeutic weapon in the treatment of solid tumors. Table 2 presents the TKIs for which cases of drug-related interstitial pneumonia were reported in the technical data sheet and registration studies.\n\nThe underlying mechanism of pulmonary toxicity can be different from one molecule to another. However, the mechanism is not completely known and partly depends on the mechanism of action of the drug itself. For example, it was postulated that interstitial lung disease caused by gefitinib, an EGFR inhibitor used in the treatment of EGFR-mutated non-squamous NSCLC, is most likely related to a decrease in alveolar regeneration, a process normally regulated by EGFR, in a population with a high co-incidence of lung disease [44]. In a meta-analysis conducted to define the different toxicity profiles of EGFR TKI, erlotinib, gefitinib and afatinib, toxicity-related deaths were rare (1.7%), with pneumonitis being the most frequent cause and no significant difference between the different drugs [44]. Another meta-analysis conducted to evaluate the risk of ILD associated with the use of EGFR-TKIs, gefitinib, erlotinib and afatinib, concluded that the incidences of all-grade and high-grade ILD were 1.6% and 0.9%, respectively. Again, no significant difference in ILD risk was found in the subgroup analysis by EGFR-TKI drugs [45]. For osimertinib, the latest generation of anti-EGFR TKIs, in the pivotal study FLAURA, 4% of patients in the osimertinib arm developed interstitial lung disease compared to 2% of patients in the standard EGFR-TKI arm (gefitinib or erlotinib) [46].\n\nALK inhibitors, either first (crizotinib), second (alectinib, ceritinib, brigatinib) or third generation (lorlatinib), can also lead to lung interstitial toxicity. Several hypotheses have been suggested to better clarify the mechanisms responsible for pulmonary toxicity exerted by ALK-TKIs with particular regard to crizotinib, but they all derive from case reports and retrospective studies [51]. In a systematic review conducted by Pellegrino and colleagues, pulmonary adverse events attributed to crizotinib occurred in 1.8% of cases, 1.1% attributed to ceritinib, 2.6% to alectinib, 1.8% to lorlatinib and 7% to brigatinib, which was therefore identified as the ALK inhibitor with the highest percentage of ILD [47]. Across all studies of brigatinib, at a starting dose of 90 mg once daily, 4.5% of patients experienced any grade event of pneumonitis with a median time to onset of 2 days. Three percent of patients had grade 3 or higher events that led to drug discontinuation [48,51]. In a recent study by Hwang et al. in patients with NSCLC treated with ALKs, COP was the most common pattern (64% of the sample), followed by HP and AIP. All patients with COP were successfully cured, whereas half of them with AIP died [85].\n\nILD during treatment with anti-HER2 tyrosine kinase inhibitors is rarely reported in the literature. Four studies totaling 4470 patients who received lapatinib were reported in a recently published review, eight of whom (0.2%) had at least one reported ILD event [52]. Tucatinib is a highly selective oral tyrosine kinase inhibitor for the kinase domain of HER2, with minimal inhibition of the epidermal growth factor receptor. In the pivotal study, Her2climb, a percentage of 1.2% of patients in the tucatinib arm reported ILD [53]. Several antiangiogenic TKIs with different binding capacities to angiogenic kinases are used in clinical practice: sorafenib, sunitinib, pazopanib, regorafenib, cabozantinib, nintedanib and axitinib. It is important to remember that these molecules act not only on vascular endothelial growth factor receptor (VEGFR) but also on multiple kinase receptors. For example, cabozantinib is a multi-kinase inhibitor of VEGFR-1, -2 and -3, KIT, TRKB, FLT-3, AXL, RET, MET and TIE -2, and regorafenib exhibits a broad spectrum of activity with inhibition of tyrosine kinases involved in tumor angiogenesis mechanisms (e.g., PDGFR, FGFRs 1–2, VEGFRs 1–3, TIE2), proliferation (RET, RAF, KIT), tumor microenvironment and metastasis processes (VEGFR2–3, PDGFR).\n\nWhen used alone, adverse pulmonary events are rare and mostly described in case reports. ILD is more common when a multi-kinase inhibitor also inhibits platelet-derived growth factor receptor (PDGFR). A PDGFRα and PDGFRβ inhibitor associated with ILD, although rarely, is imatinib [58]. A possible mechanism of lung injury could be related to PDGFR inhibition. Imatinib-induced ILD is likely to develop in more susceptible patients, such as those with a history of pneumonia. However, ILD occurs less frequently with VEGFR and PDGFR-TKIs than with EGFR-TKIs. Sorafenib in particular has rarely been associated with cryptogenic organizing pneumonia (COP) and non-specific interstitial pneumonia (NSIP) patterns [55].\n\nAnother class of TKIs with great clinical relevance in oncological treatments, especially melanoma, non-small-cell lung cancer (NSCLC) and, recently, colorectal cancers, is BRAF and MEK tyrosine kinase receptor inhibitors. Respiratory complications are extremely rare with BRAF inhibitor monotherapy, such as vemurafenib or dabrafenib. Regarding mek-inhibitors (MEKi), in the pivotal trametinib + dabrafenib doublet study conducted by Flaherty and colleagues [59], interstitial pneumonia occurred in 2.4% of patients treated with trametinib alone, and all patients who presented this adverse event required hospitalization. The median time to first presentation was 160 days (range 60–172 days). Therefore, in all patients treated with trametinib who present with cough or suspicious symptoms and signs of pneumonitis, radiological examinations and temporarily suspended treatment should be investigated [59].\n\n3.2. mTOR\n\nRegarding mTOR inhibitor (mTORi) drugs, ILD is a widely described and studied adverse event with high relevance and incidence in clinical practice. Although the majority of patients with mTORi-related ILD are asymptomatic or mildly symptomatic, it is important not to underestimate this clinical finding and to adhere to the recommendation regarding the management of this toxicity, as in some cases, it can lead to important respiratory outcomes. All mTORi drugs can be related to this adverse event; however, among them, the pulmonary toxicity profile appears to differ. A retrospective analysis of 196 patients revealed a higher incidence of ILD in patients receiving everolimus than in those receiving temsirolimus (38% vs. 22%, p = 0.018) [63]. The reported incidence of mTORi pulmonary toxicity in the literature differs from that of clinical studies, probably due to a greater awareness of this adverse event and greater precision in radiological diagnostic criteria. The first phase 2 clinical trials with everolimus and temsirolimus reported incidences of clinically manifest ILD of 3–13%. Real-life studies report an incidence of ILD that ranges from 14% to 45% for temsirolimus and from 3% to 54% for everolimus [86,87]. Regarding the mechanisms of lung damage, unlike bleomycin, a dose-dependent correlation is not evident [67]. The pathophysiological mechanisms of mTORi-mediated lung injury are complex. Preclinical studies have described direct damage to the endothelium and epithelium, depletion of alveolar macrophages and accumulation of surfactant lipids. Both epithelial and endothelial damage with accumulation of surfactant contribute to a pulmonary inflammatory state. Furthermore, mTORi-mediated epithelial damage could expose cryptic antigens, activating a T-mediated immune response, resulting in lymphocytic alveolitis and interstitial pneumonia [88]. It is also possible that the mTORi molecule leads to a delayed-type hypersensitivity reaction. Indeed, mTORi has a high affinity for plasma proteins, and the resulting mTORi-protein complex can be immunogenic, processed by antigen-presenting cells and recognized by T cells. This process leads to cytokine release and preferential differentiation of Th0 cells into Th1 cells with recruitment and activation of macrophages and other inflammatory cells. Finally, several preclinical studies have demonstrated how mTOR inhibitors interfere with the pathways of damage and repair of lung tissue by inducing a sustained inflammatory response through the downregulation of the phosphatidylinositol-3-kinase (PI3K) pathway and the consequent production of pro-cytokines, such as interleukin (IL)-12, IL-23, tumor necrosis factor (TNF) and IL-1β [89]. Again, clinically, the symptoms and signs are nonspecific. The time to onset of ILD after initiation of treatment is relatively short, mostly occurring within 6 months after starting treatment.\n\nA diagnosis of noninfectious pneumonitis should be considered in patients presenting with nonspecific respiratory signs and symptoms, such as cough, dyspnoea, hypoxia, fever and fatigue, and in whom infectious, neoplastic and other nonmedicinal causes have been excluded by means of appropriate investigations. Patients who develop radiological changes and have few or no symptoms may continue everolimus without dose adjustments (Grade 1). If symptoms are moderate (Grade 2) or severe (Grade 3), the drug should be discontinued, and the use of corticosteroids (such as oral prednisone 0.75–1.0 mg/kg or in severe cases, intravenous methylprednisolone) may be indicated until clinical symptoms resolve. Given the immunosuppressive properties of everolimus, the use of corticosteroids and possible respiratory distress, the coadministration of broad-spectrum antibiotics may also be considered for Grade 3 or 4. Opportunistic infections should also be considered; indeed, prophylaxis for Pneumocystis jirovecii (carinii) pneumonia is recommended [90].\n\nGenerally, in mTOR inhibitor pneumonitis, pulmonary function tests are associated with a restrictive pattern or an isolated reduction in diffusing capacity [91]. The most characteristic radiological changes include ground-glass and reticular opacities, in particular of the lower lobes of the lungs. mTOR inhibitor-associated pneumonitis most commonly presents as either cryptogenic organizing pneumonia (COP) or nonspecific interstitial pneumonia (NSIP) [92,93].\n\nSome evidence suggests that everolimus-related pneumonia is associated with improved prognosis and may be used as a biomarker for the efficacy of the drug, especially in breast cancer [94].\n\n3.3. Phosphatidylinositol 3-Kinase (PI3K) Inhibitors\n\nActivation of the PI3K signaling pathway is frequently associated with tumorigenesis. Moreover, dysregulated PI3K signaling may contribute to tumor resistance to a variety of cancer drugs. Several molecules that act on the Pi3k-AKT signaling pathway are being studied. A PIK3 inhibitor approved by the FDA and EMA for the treatment of solid tumors is alpelisib. This new molecule has recently entered clinical practice, and the possible range of side effects is not completely known. Pneumonitis occurred in 1.8% of patients receiving alpelisib in the pivotal SOLAR-1 study [62]. Specific monitoring guidelines have been established to address this side effect. In particular, permanent discontinuation of alpelisib is advised in any patient who develops pneumonitis [95].\n\n3.4. Monoclonal Antibodies\n\nMonoclonal antibodies used in clinical practice in the treatment of solid tumors are monoclonal antibodies against Her family receptors, such as panitumumab, cetuximab and trastuzumab, and monoclonal antibodies that target vascular endothelial growth factor (VEGF), such as bevacizumab, or its receptor, such as ramucirumab.\n\nFor monoclonal antibodies targeting Her family receptors, panitumumab and cetuximab bind directly to EGFR, whereas trastuzumab and pertuzumab bind to the HER2 protein expressed on the cell surface, inhibiting the EGFR pathway. Unlike tyrosine kinase inhibitors acting on EGFR, for which ILD is a widely described adverse event, its incidence is not known for monoclonal antibodies, and reports of this event are very rare. In pivotal studies of panitumumab and cetuximab, interstitial pneumonia was not a reported event. Regarding trastuzumab, in a pivotal study in the adjuvant setting, the rate of interstitial pneumonitis was 0.6% [71]. COP is the prevailing high resolution computed tomography (HRCT) pattern [96]. A review of the literature conducted with the aim of determining the incidence of ILD in patients undergoing anti-HER treatments showed 162 cases (9.9%) of drug-related ILD. Overall, there were 3 (0.2%) ILD-related deaths among those receiving trastuzumab therapy [55]. In the EMA datasheet for pertuzumab, ILD is reported as a rare event; to our knowledge, there are no case reports for pertuzumab concerning this topic. In the CLEOPATRA combination study of docetaxel, pertuzumab and trastuzumab in the metastatic first-line Her2+ breast cancer, no significant rates of pneumonia were reported compared to the docetaxel and trastuzumab placebo arms, which occurred in a very low percentage of patients [72].\n\nFor monoclonal antibodies targeting VEGF or its receptor (VEGFR), interstitial pneumonitis is a very rare event and mostly reported as case reports. A study on bevacizumab, a monoclonal antibody directed at VEGF, hypothesized a protective role of bevacizumab on interstitial pulmonary toxicity mediated by chemotherapy; however, there are no data in the literature to support this hypothesis [76]. Ramucirumab is a VEGFR-2 inhibitor. In the phase 3 RAINBOW pivotal trial of ramucirumab in combination with paclitaxel in second-line treatment of advanced gastric cancer, the incidence of treatment-related pneumonitis was lower in patients who received the combination treatment (1.5%) than in those who received paclitaxel alone (2.1%) [77]. In the REGARD study of ramucirumab monotherapy in pretreated advanced gastric cancer, ramucirumab-related pneumonia occurred in 0.4% of patients [78]. In a retrospective study of 44 gastric cancer patients who received combination treatment with ramucirumab and paclitaxel, six patients (13.6%) developed pneumonitis during the first five cycles of treatment. The onset of pneumonitis was independently associated with the presence of pre-existing ILD (p = 0.025; odds ratio = 206.4) [79].\n\n3.5. Antibody-Drug Conjugates (ADCs)\n\nAntibody-drug conjugates (ADCs) are complex molecules composed of a monoclonal antibody bound to a biologically active cytotoxic drug, thus combining the ability to “target” specific molecules, typical of monoclonal antibodies, with the cytotoxic properties of chemotherapy drugs. Among the ADCs are trastuzumab emtansine and a series of new drugs recently approved by the FDA but still under approval in Europe for the treatment of solid tumors, namely, enfortumab vedotin, trastuzumab deruxtecan and sacituzumab govitecan. The pulmonary toxicity profile is very different for this class of drugs.\n\nTrastuzumab emtansine (T-DM1) is an ADC that combines the monoclonal antibody trastuzumab with cytotoxic mertansin (DM1), a maytansinoid class anti-microtubule agent bound by a stable thioether. T-DM1 binds to the HER2 receptor, and the HER2 and T-DM1 complex enters target cells through receptor-mediated endocytosis. This process leads to the intracellular release of DM1, favoring its cytotoxic activity. In addition, the drug retains its anti-HER2 properties, including inhibition of HER2 intracellular signaling pathways and induction of cell-mediated cytotoxicity. Cases of ILD have been reported in patients receiving T-DM1. Pneumonitis of any grade shows an incidence rate up to 9%, whereas severe pneumonitis (grade ≥ 3) was recorded in 1–6% of all patients treated with T-DM1 [80].\n\nEnfortumab vedotin is a human IgG1 antibody directed against nectin-4, an adhesion protein located on the cell surface. The small molecule MMAE is an antimitotic agent that interferes with the formation of microtubules attached to the antibody via a clearable linker with protease. Additionally, in this case, internalization through the ligand allows the cytotoxic activity of the drug. In a pivotal study of enfortumab vedotin in urothelial carcinoma after treatment with platinum and immunotherapy, one treatment-related death from ILD was reported [81].\n\nSacituzumab govitecan is an anti-Trop-2 antibody conjugated with SN-38 Trop-2, an active metabolite of irinotecan. Irinotecan is a chemotherapeutic agent that has been associated with cases of interstitial pneumonia, so it is plausible that sacituzumab govitecan may present this toxicity as well. However, in the phase 1–2 study of sacituzumab govitecan in patients with metastatic triple-negative breast cancer, no cases of ILD were observed among the 108 patients enrolled. Among the 5 patients (5% of total) who experienced Grade 3 or 4 adverse respiratory events, none of the events were considered by the investigators to be related to sacituzumab govitecan. More data will certainly be needed to understand whether the drug may present such toxicity [82].\n\nTrastuzumab deruxtecan is an ADC where the antibody directed against HER-2 is conjugated to a topoisomerase inhibitor. In the single-arm study DESTINY-Breast01, ILD was reported in 13.6% of patients receiving trastuzumab deruxtecan, leading to death in 2.2% of patients [83,84]. Numerous ongoing trials are evaluating trastuzumab deruxtecan in the treatment of different tumor histotypes. Certainly, the problem of pulmonary toxicity will be of extreme importance in the near future, in which the rapidly increasing therapeutic scenario sees these drugs as the main leading actor in the target treatment across tumor types.\n\n4. Immunotherapy and Lung Toxicity\n\nImmunotherapy treatment has become the standard of care in the metastatic setting in several neoplastic diseases. Since the first immunotherapy studies, the problem of interstitial pulmonary toxicity has been highlighted as an important side effect to be taken into consideration. ILD resulting from immunotherapy drugs recognizes a clear pathophysiological mechanism linked to the activity of the drug itself.\n\nProgrammed death-1 (PD1), the PD-1 ligand (PDL1) and the cytotoxic T-4 lymphocyte-associated antigen (CTLA4) are called immune checkpoint molecules because they negatively regulate host immunity. This ability to evade immune surveillance is part of the tumor skipping and disease growth process. Immune checkpoint inhibitors are antibodies that inhibit PD-1, PD-L1 or CTLA-4, resulting in activation of the immune response. The toxicity profile of immunotherapy drugs differs from that of cytotoxic drugs and is characterized by peculiar adverse events, known as immune-related adverse events (irAEs) [97]. Immune-mediated interstitial pneumonia is rarer than other irAEs but more severe [98].\n\nThe incidence of this toxicity is higher in patients undergoing immunotherapy treatment for lung cancer than in other tumor types reported for targeted therapies is higher in patients with a history of previous pulmonary diseases [99]. It is important to emphasize that combination therapies with anti-PD-1 and anti-CTLA4 antibodies show a higher incidence of ILD than monotherapy. To date, no identifiable risk factors for ILD are known that could be considered to prevent its onset. A single-center retrospective study conducted by Okada and colleagues among 102 patients treated for lung cancer diagnosed with ILD concluded that ECOG PS (Performance Status according to Eastern Cooperative Oncology Group) ≥ 2 alone or the presence of both ECOG PS ≥ 2 and a history of smoking with ≥50 pack-years acted as risk factors for Grade ≥ 3 and all grades of ILD, respectively [100]. In descending order of toxicity, the most reported patterns are AIP (high grade), COP (intermediate grade) and finally, NSIP and HP (low grade) [101].\n\nSeveral literature reports propose the onset of irAEs, such as interstitial pneumonitis, as a predictor of response to immunotherapeutic drugs, but this assumption is not currently considered certain [102]. Table 3 reports the immunotherapy drugs currently used in clinical practice classified by the mechanism of action (anti-PD1, anti-PDL1 and anti-CTLA4), their indication in the various neoplastic pathologies and the relative incidence of interstitial pneumonitis reported in pivotal studies.\n\n4.1. Anti-PD1\n\nPD-1 is a member of the immunoglobulin superfamily that can be detected on activated T cells, B cells and natural killer (NK) cells, and binds PDL-1 and PDL-2. PD-L1, expressed by tumor cells and immune cells, also interacts with CD80, whereas PD-L2, expressed only on dendritic cells in normal tissue, interacts with RGMb (repulsive guide molecule B). All these interactions mediate an inhibitory signal that leads to the suppression of T cell activation. Anti-PD1-related lung toxicity, including ILD, recognizes autoimmune genesis following activation of T cells. Patients treated with PD1 antibodies should be monitored for signs and symptoms of pneumonia, clinical suspicion should be confirmed with radiographic images and other potential causes must be excluded [132]. In cases of Grade ≥ 2 pneumonia, immunotherapy is temporarily suspended, and steroid treatment is administered with an initial dose equivalent to 1–2 mg/kg/day prednisone. Instead, treatment should be permanently discontinued for Grade 3, Grade 4, or Grade 2 recurrent pneumonia. The anti-PD-1 monoclonal antibodies approved by the FDA and EMA for the treatment of solid tumors include nivolumab and pembrolizumab.\n\nThe incidence of pneumonia in pivotal studies of nivolumab monotherapy ranges from 1.3% to 5% and is higher in patients with NSCLC [107,108]. Regarding the combination of nivolumab with ipilimumab, an anti-CTLA4, in melanoma, the incidence of pneumonia was 6.4% [110]; however, in RCC, the incidence was 6.2% [111]. Pembrolizumab is an anti-PD 1 approved for the treatment of solid tumors both alone and in combination with chemotherapy. Keynote 426 enabled the registration of pembrolizumab in combination with axitinib as the first-line renal cell carcinoma treatment. In the pembrolizumab studies in NSCLC, the rate of interstitial pneumonia was higher than in the other studies, especially in patients with a history of chest radiation therapy (see Table 3).\n\n4.2. Anti-PDL1\n\nAnother class of immune checkpoint inhibitors are monoclonal antibodies that inhibit PDL-1. As mentioned, activation of PD-1/PD-L1 signaling negatively regulates T cell-mediated immune responses in peripheral tissues. Through antibody-mediated PD-L1 inhibition, the immunosuppressive signals present in the tumor microenvironment are reduced with a consequent increase in T cell-mediated immunity against tumors [133]. Currently, there are three FDA- and EMA-approved PD-L1 inhibitors for the treatment of various malignancies, namely, atezolizumab, durvalumab and avelumab. Table 3 shows their current indications in clinical practice and the percentage of pneumonia reported in pivotal studies.\n\nSpecial mention should be made of the Pacific study, which led to the approval of durvalumab in locally advanced, unresectable non-small cell lung cancer patients with PD-L1 expression ≥ 1% whose disease did not progress after platinum-based chemoradiotherapy [126]. As also reported for other oncological drugs, including chemotherapy, biology and immunotherapy, the percentage of interstitial pneumonia is higher in patients undergoing radiotherapy on the chest [134,135]. Therefore, a careful clinical evaluation of patient candidates to receive durvalumab in this setting is strongly recommended.\n\n4.3. Anti-CTLA4\n\nCTLA-4 is a coinhibitory molecule and is the counterpart of the costimulatory B7-CD28 axis. Upon activation, T lymphocytes positively regulate the surface expression of CTLA-4, which binds B7 with increased avidity and thereby overcomes the positive costimulatory signal of CD28. This dominance of negative signals results in a reduced proliferation of T cells and a decrease in the production of IL-2. The blockade of CTLA-4, and therefore the release of B7 for the interaction with the costimulatory molecule CD28, activates the immune response [136].\n\nAnti-CTLA4 monoclonal antibodies exhibit a higher rate of immune-related adverse events, including pneumonitis, compared with anti-PD1 and anti-PDL1 drugs. In the CheckMate 238 study, which randomized patients to receive nivolumab or ipilimumab as adjuvant treatment in resected stage III or IV melanoma, pneumonia occurred in 1.3% of cases in the nivolumab arm and in 2.4% in the ipilimumab arm [104]. The mechanisms underlying the higher rate of immune-related side effects from anti-CTLA-4 drugs remain unclear. Currently, their use as monotherapy in clinical practice remains confined to melanoma [130].\n\n5. Diagnosis and Therapy\n\nSeveral radiological patterns are used to describe interstitial lung disease (ILD), unfortunately mostly without specificity to differentiate the multitude of potential conditions, which include infections (especially viral), immunological diseases (also allergies), toxicities, idiopathic forms and even possibly mimic tumor progression. Radiology can be useful in grading the severity and guiding therapeutic management. As defined by the American Thoracic Society and the European Respiratory Society (ATS/ERS) in correlation with histological findings, the most common patterns are presented below [137]. It is worth noting that it may occasionally not be possible to identify a case with a specific pattern, and even overlapping among them is possible [138].\n\nAIP (acute interstitial pneumonia) has been historically associated with bleomycin, alkylating agents (such as cyclophosphamide) and antimetabolites (such as methotrexate). Extensive ground-glass opacities and dependent consolidations can be found in a setting that can correspond to ARDS (acute respiratory distress syndrome). Fibrosis may develop within one week, and the prognosis is mainly poor. Corticosteroid therapy is recommended.\n\nNSIP (non-specific interstitial pneumonia) is typically characterized by subtle evolution, distinguishable into cellular and fibrotic types, and is correlated with more indolent and aggressive clinical forms. Ground-glass opacities are the dominant feature, displaying basal predominance with sparing of subpleural spaces. Thickening of bronchovascular bundles with traction bronchiectasis and consequently lung volume loss are the expressions of the advanced stage. Early diagnosis can significantly impact therapeutic and prognostic responses that depend on the extent of fibrosis. Mycophenolate mofetil can improve lung function. Methotrexate and carmustine are among the most common related causative agents.\n\nCOP (cryptogenic organizing pneumonia) is commonly defined by patchy migratory consolidations, classically with a “reverse halo appearance” (atoll sign), predominantly with peribronchial and subpleural distribution in the lower lung zones and typically associated with nodules and perilobular fibrosis, describing “arches” (arcade-like sign). COP typically responds well to treatment withdrawal, and corticosteroids are occasionally still required. Bleomycin, methotrexate and cyclophosphamide can provoke this condition.\n\nHP (hypersensitivity pneumonia) is constituted by small, numerous, round and poorly defined centrilobular nodules, widespread areas of ground-glass opacities and hypoattenuating areas persistent even in expiration due to air-trapping phenomena (classically giving an appearance known as the “head cheese sign”). Chemotherapy withdrawal may be resolutive. Bleomycin and methotrexate are potential etiologies.\n\nIn comparison with the contingency COVID-19 pandemic, pneumonia typically presents with bilateral and peripheral ground-glass opacities accompanied by consolidations with typical interlobular septal thickening (“crazy paving” appearance). However, a broad spectrum of possible mimic patterns has been described, particularly including the aforementioned ILDs, especially COP and AIP [139]. See Figure 1.\n\nSince the mechanism of uptake of 18F-Fluorodeoxyglucose (18F-FDG) is shared by neoplastic cells and inflammatory cells, false positive results interpreted as of oncological significance are frequently caused by underlying infections instead. Therefore, during several antineoplastic treatments, drug-related pneumonitis of any form may be erroneously interpreted as progressive disease by 18F-FDG PET/CT [140,141,142,143,144]. To date, this represents a hard to solve diagnostic dilemma, at least on the basis of the conventional image qualitative analysis. A possible help in this scenario could come from quantitative imaging, made possible from advent of machine learning [145,146,147]. We provide some examples of ILD images by 18F-FDG PET/CT in Figure 2.\n\nAbout the clinical presentation, interstitial pneumonitis is often insidious. Dyspnea, dry cough, mild fever and fatigue may be the first clinical symptoms and signs. Differential diagnosis from other causes of pneumonia is essential.\n\nThe cornerstone of drug-induced pneumonitis treatment are corticosteroids, since the underlying mechanism of lung damage is the inflammatory and/or the immunological process. In severe cases, with the failure of high-dose steroid therapy, often the evolution to pulmonary fibrosis occurs, which may require other biological or immunosuppressive agents, such as cyclophosphamide, mycophenolate mofetil, azathioprine, infliximab, tocilizumab or rituximab [148,149]. In symptomatic disease, it is important to start treatment as early as possible, in order to achieve a better result.\n\nThe management of immunotherapy-related pneumonia, which is the most recently defined ILD, follows a specific guideline [150,151]. For non-immunotherapy related ILDs, if steroid therapy fails, the treatment is based on the therapy of connective tissue disease-related ILDs or idiopathic pulmonary fibrosis [149].\n\nThe management of drug-related toxicity is based on its severity. Table 4 reports the classification of pneumonia according to severity and Figure 3 summarizes management according to grade, based on the American Society of Clinical Oncology (ASCO) guidelines for the management of immune-related pneumonia [150] (Table 4).\n\nIt could be identified as an association between the radiographic pattern and the clinical severity of pneumonitis, classifying the different patterns by toxicity grades, where AIP/ARDS pattern had the highest grade, followed by COP pattern, whereas NSIP pattern and HP pattern had lower grade [152]. It appears that NSIP and COP patterns respond better to treatment than UIP patterns [149].\n\nGenerally, steroid therapy is recommended for Grade 2 and higher, with oral prednisone 1–2 mg/kg/day. Grade 3 or 4 requires patient’s hospitalization and intravenous (IV) methylprednisolone 1 to 4 mg/kg/day. Steroid therapy should be continued until the event is resolved or improved to G1 and progressively reduced (e.g., 5–10 mg/week) and then stopped over at least 4–6 weeks, in order to avoid a rebound effect. This is very important in immunotherapy pulmonary toxicities, where, differently from other anticancer agents, it appears that flare pneumonitis can be more severe and extensive than the initial episode. Therefore, the gradual and slow tapering of corticosteroids is essential [152]. In severe cases, if there is no improvement after 48 h of high-dose steroids, it may be appropriate to add infliximab (an anti-TNF-a immunosuppressive agent) 5 mg/kg or mycophenolate mofetil 1 g twice a day or intravenous immunoglobulins (IVIG) 2 g/kg/day for 5 days, or cyclophosphamide. In these cases, a pneumological or immunological consultation could be indicated [150].\n\nPatient’s immunosuppression (potentially caused by corticosteroids, oncological therapy, cancer, respiratory distress, poor performance status, etc.) requires the simultaneous administration of an empirical antibiotic prophylaxis to avoid superinfections, especially in Grades 3 and 4 (Figure 3).\n\nIn the case of prolonged steroid therapy (beyond 12 weeks), prophylaxis for opportunistic infections (e.g., trimethoprim/sulfamethoxozole for Pneumocystis jirovecii) should also be considered, just as calcium and vitamin D supplementation to avoid osteoporosis and proton pump inhibitors for gastric toxicity. The role of antifungal prophylaxis with fluconazole is less clear [150].\n\nIn addition, all other pharmacological and non-pharmacological symptomatic therapies, necessary for the management of the patient’s symptoms, must be adopted (e.g., oxygen therapy, therapy for cough, dyspnea, depression, anorexia, pain or any other potential associated symptoms and, of no lesser importance, pulmonary rehabilitation) [153].\n\n6. Conclusions\n\nThe clinical manifestations of antineoplastic-induced ILD are not specific, and the diagnosis is determined on the basis of the exclusion of other causative factors. As not all oncological treatments bear the same risk as ILD, it is important to know the percentage of risk associated with the use of each drug. The mechanism underlying the toxicity in some cases could be linked to the mechanism of action of the drug itself and is mediated by the activation of the inflammatory-cytokine cascade. Therefore, the therapy consists of steroid anti-inflammatory treatment. Several radiological patterns are used to describe ILDs, unfortunately mostly without specificity to differentiate the multitude of potential conditions; however, radiology can be useful in grading the severity and guiding therapeutic management. There is no protocol to forecast this toxicity, but some patient baseline conditions may increase the risk of ILD. Differential diagnosis recently became even more complicated and crucial in the context of the arising awareness about the clinical respiratory manifestations of COVID-19. It is important to promptly recognize and treat this adverse event, which in some cases can be fatal.\n\nAuthor Contributions\n\nStudy concept and design: S.C. and A.Z.; Drafting of the manuscript: S.C.; Creating tables and figures: M.F., S.N., S.C., G.C., and G.S.; Critical revision of the manuscript for important intellectual content: M.F., S.N., G.C., T.P., C.B., and G.S.; Study supervision: C.B., G.S., and A.Z. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nNot applicable.\n\nInformed Consent Statement\n\nNot applicable.\n\nData Availability Statement\n\nNo new data were created or analyzed in this study. Data sharing is not applicable to this article.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 (A) 56-year-old male affected by renal cell carcinoma in treatment with everolimus, (B) 83-year-old female affected by esophageal adenocarcinoma in treatment with FOLFOX regimen, (C) 69-year-old male affected by gastric adenocarcinoma in treatment with FOLFIRI regimen, (D) 65-year-old female affected by pancreatic adenocarcinoma in treatment with gemcitabine. In (A,B) are shown multifocal consolidations, partly ground glass, in a pattern compatible with COP. In (C,D) scattered and patchy ground-glass opacities with crazy paving appearances, expression of alveolar damage, can be observed. All these patients were hospitalized during the COVID-19 pandemic, nevertheless, despite similar findings for both pairs, only for (B,C) was SARS-CoV-2 recognized as the causative agent, while for (A,D) chemotherapy was considered the most suspected etiology.\n\nFigure 2 (Upper row): pre-therapy 18F-FDG PET/CT of a patient affected by lung cancer in treatment with atezolimumab, showing some areas of increased uptake of the radiopharmaceutical corresponding to mixed ground-glass and crazy paving lung CT alterations (black arrows). (Lower row): in PET/CT three months later, after atezolimumab suspension, no more areas of uptake are present, therefore indicative of an immune-related pneumonia.\n\nFigure 3 Management of pneumonitis according to severity.\n\ncancers-13-01052-t001_Table 1 Table 1 Chemotherapeutic agents related to lung injury in the treatment of solid tumors.\n\nDrug\tClass\tIncidence of Lung Toxicity (%) *\tMain Patterns of Lung Toxicity\t\nBleomycin [16,17]\tAntitumour antibiotics\t10% 1\tInterstitial pneumonitis\nPulmonary fibrosis\nCOP 2\t\nMitomycin C [18,19]\t5–10%\tInterstitial pneumonitis\nPulmonary fibrosis\nPVOD 3\t\nAnthracyclines [20]\tRare\tPulmonary fibrosis\t\nCyclophosphamide\nIfosfamide [8,21]\tAlkylating agents\nNitrogen mustards\t<1%\tInterstitial pneumonitis\nInterstitial fibrosis\nIntraalveolar fibrosis\nBilateral pleural thickening\nPulmonary hypertension\nCOP 2\nPneumothorax\t\nCarmustine [22]\nLomustine Fotemustine\tNitrosoureas\t10–30%\t\nTemozolomide [23,24]\tTriazene compounds\t<1% 4\t\nCisplatin [25]\tPlatinoids\tRare\tEosinophilic pneumonia\t\nCarboplatin [26]\tRare\tPulmonary fibrosis\t\nOxalplatin [27,28]\t<1% (0–4%)\tInterstitial pneumonitis\nPulmonary fibrosis\nCOP 2\t\nMethotrexate [9,10,11]\tAntimetabolites\t3–4%\n(up to 10% in arthritis patients)\tHypersensitivity pneumonitis\nObliterating bronchiolitis\nIntraalveolar fibrosis\t\nPemetrexed [29,30]\tRare\tInterstitial pneumonitis\t\nGemcitabine [12,31,32]\t1–4%\n(up to 20% if with taxanes)\tInterstitial pneumonitis\nInterstitial lung fibrosis\nPVOD 3\nNon-cardiogenic pulmonary oedema\nAIP/ARDS 5\nDiffuse alveolar haemorrhage\nPleural effusion\n↓DLCO (normal FEV1 eFVC)\t\nTopotecan [33]\tTopoisomerase inhibitors\tRare\tDiffuse alveolar damage\nInterstitial pneumonitis\nObliterating bronchiolitis\t\nIrinotecan [34,35,36]\t1–2%\n(up to 20% in lung cancer with paclitaxel)\tInterstitial pneumonitis\t\nEtoposide [37]\tRare\tInterstitial and alveolar infiltrates\nPulmonary fibrosis\t\nPaclitaxel [38,39]\nDocetaxel [13,40]\tAntimicrotubule agents\t1–5% in three-weekly schedule\n(up to 20% if with gemcitabine and up to 30% with radiotherapy)\tInterstitial pneumonitis\nHypersensitivity pneumonitis\nPulmonary fibrosis\nAIP/ARDS 5\nPleural effusions (capillary leak syndrome, especially for docetaxel)\t\nVinorelbine [41]\tRare\tInterstitial pneumonitis\t\n* Information regarding pivotal clinical trials or summary of drug/product characteristics is obtained from the literature. Information can be very different, depending on the sources, i.e., the criteria used to define pulmonary toxicity (clinical, radiological, etc.), the type of scheme in which the drug is contained, or the presence of concomitant radiotherapy and the type of patients and diseases analyzed (presence of possible risk factors for major lung damage). It was occasionally not possible to estimate a realistic incidence given the rarity of the event (mostly case reports) and because the drug is typically used in combination with other potentially toxic treatments. Therefore, the true incidence is often unknown, and we can only say that it is a rare/uncommon effect. 1 The incidence can be very different depending on the treatment regimen, i.e., from 5% to 16% in germ cell tumors treated with BEP (bleomycin, etoposide, cisplatin) or CVB (cisplatin, vinblastine, bleomycin) and from 10% to 53% in Hodgkin’s lymphomas treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). 2 COP = Cryptogenic Organizing Pneumonia 3 PVOD = Pulmonary veno-occlusive disease 4 In gliomas, the incidence of nitrosourea-mediated lung toxicity is probably lower due to the low cumulative doses that are reached or the early progression of disease/death. 5 AIP = Acute Interstitial Pneumonia; ARDS = Acute Respiratory Distress Syndrome.\n\ncancers-13-01052-t002_Table 2 Table 2 Incidence of pneumonitis with targeted cancer therapies approved by the FDA and EMA in the treatment of solid tumors.\n\nClass\tDrug\tUse\tIncidence of Lung Toxicity (%), Any Grade *\t\nTKIs (Tyrosine Kinase Inhibitors)\tEGFR inhibitors\tGefitinib [44,45]\tEGFR-mutated advanced NSCLC\t1.6%\t\nErlotinib [44,45]\tEGFR-mutated advanced NSCLC\t0.8–1.6%\t\nAdvanced pancreatic cancer (+Gemcitabine)\t1.6–2.5%\t\nAfatinib [44,45]\tEGFR-mutated advanced NSCLC\t0.7–1.6%\t\nOsimertinib [46]\tEGFR-mutated advanced NSCLC\nEGFR-T790M-mutated advanced NSCLC\t4%\t\nALK inhibitors\tCrizotinib [47,48,49]\tALK- and ROS-1-positive advanced NSCLC\t1.2–1.8%\t\nCeritinib [47]\tALK-positive advanced NSCLC\t1.1%\t\nAlectinib [47]\tALK-positive advanced NSCLC\t2.6%\t\nLorlatinib [47]\tALK positive advanced NSCLC\t1.8%\t\nBrigatinib [50,51]\tALK-positive advanced NSCLC\t4.5–7%\t\nHER2 inhibitors\tLapatinib [52]\tHER2-positive advanced BC\n(+Capecitabine/Trastuzumb/AI)\t0.2%\t\nTucatinib [53]\tHER2-positive advanced BC\n(+Capecitabine + Trastuzumab)\t1.2%\t\nNeratinib [54]\tHER2- and HR-positive BC, adjuvant setting\t0.07–0.1%\t\nMultikinase and angiogenesis inhibitors\tSorafenib [55]\tAdvanced HCC\nAdvanced RCC\nAdvanced differentiated thyroid carcinoma\tRare\t\nSunitinib [56]\tAdvanced GIST\nAdvanced RCC\nAdvanced pancreatic NET\tRare\t\nPazopanib [57]\tAdvanced RCC\nSelective subtypes of advanced STS\tRare\t\nImatinib [58]\tKit-positive GIST, advanced and adjuvant setting\nAdvanced dermatofibrosarcoma protuberans\tRare\t\nBRAF and MEK Inh.\tTrametinib [59]\tV600 BRAF-mutated advanced melanoma\t2.4%\t\nTrametinib + Dabrafenib [60,61]\tV600 BRAF-mutated advanced melanoma\t≤1%\t\nPI3K\nInh.\tAlpelisib [62]\tHR-positive HER2-negative advanced BC with a PIK3CA mutation, plus fulvestrant, second line\t0.7–1.8%\t\nmTORs\ninhibitors\tEverolimus\n[63,64,65,66]\tHR-positive advanced BC\t12–38%\t\nAdvanced RCC\t14%\t\nAdvanced NET\t12%\t\nAdvanced pancreatic NET\t17%\t\nTemsirolimus\n[63,67,68]\tAdvanced RCC\t2–22%\t\nMonoclonal antibodies\tHER2\ninhibitors\tTrastuzumab [69,70,71]\tHER2-positive BC\t0.6%\t\nPertuzumab [72]\tHER2-positive BC\t<1%\t\nEGFR\ninhibitors\tCetuximab [73,74]\tRAS wt advanced CRC\nAdvanced squamous HN cancer\t1%\t\nPanitumumab [75]\tRAS wt advanced CRC\tCase report\t\nVEGF\ninhibitors\tBevacizumab\n[76]\tAdvanced CRC\nAdvanced BC\nAdvanced NSCLC\nAdvanced RCC\nAdvanced ovarian cancer\nAdvanced uterine cervix cancer\tCase report\t\nVEGFR2\ninhibitors\tRamucirumab\n[77,78,79]\tAdvanced gastric and gastro-oesophageal cancer (alone or with paclitaxel)\t1.5% plus paclitaxe\nl0.4% alone\t\nADC\tTrastuzumab emtansine [80]\tHER2-positive BC\t9%\t\nEnfortumab vedotin [81]\tAdvanced urothelial cancer\t<1%\t\nSacituzumab govitecan [82]\tTriple-negative advanced BC\tUnknown\t\nTrastuzumab deruxtecan [83,84]\tHER2-positive BC\t13.6–17.4%\t\n* The incidence of pulmonary toxicity is derived from pivotal studies and the EMA summary of product characteristics. EGFR: epidermal growth factor receptor, NSCLC: non-small cell lung cancer, G: grade, ILD: interstitial lung disease, AEs: adverse events, ARDS: acute respiratory distress syndrome, ALK: anaplastic lymphoma kinase, ROS-1: reactive oxygen species, HER2: human epidermal growth factor receptor 2, BC: breast cancer, AI: aromatase inhibitors, HR: hormone receptors, HCC: hepatocellular carcinoma, RCC: renal cell carcinoma, STS: soft-tissue sarcoma, GIST: gastro-intestinal stromal tumor, NET: neuroendocrine tumor, CRC: colorectal cancer, HN: head and neck cancer, wt: wild type, VEGF: vascular endothelial growth factor, ADC: Antibody-drug conjugate.\n\ncancers-13-01052-t003_Table 3 Table 3 Incidence of pneumonitis with immune checkpoint inhibitors approved by the FDA and EMA in the treatment of solid tumors.\n\nDrug\tIndications\t% of Pneumonitis (Including ILD), Any Grade\t\nNivolumab\nmonotherapy [103,104,105,106,107,108,109]\tMetastatic melanoma\t1.5%\t\nAdjuvant melanoma\t1.3%\t\nSquamous NSCLC second line\t5%\t\nNon squamous NSCLC second line\t3%\t\nHNSCC second line\t2.1%\t\nRCC second line\t4%\t\nMetastatic urothelial carcinoma after platinum cht\t3%\t\nNivolumab + ipilimumab [110,111]\tMetastatic melanoma\t6.4%\t\nRCC first line for intermediate-high risk\t6.2%\t\nPembrolizumab\nmonotherapy [112,113,114,115,116,117,118,119]\tHNSCC first line, PD-L1 positive with a CPS ≥ 1\t6%\t\nHNSCC second line\t4%\t\nNSCLC first line, PDL1 ≥ 50%\t2.6%\t\nNSCLC second line, PDL1 ≥ 1%\t5%\t\nMetastatic melanoma\t1.8%\t\nAdjuvant stage III melanoma\t3.3%\t\nLocally advanced/metastatic urothelial carcinoma second line\t4.1%\t\nLocally advanced/metastatic urothelial carcinoma in adults not eligible for cisplatin-containing cht, PD-L1 positive and CPS ≥ 10\t2%\t\nPembrolizumab + chemotherapy [112,120,121]\tNCSLC first line in combination with carboplatin + pemetrexed\t4.4%\t\nNCSLC first line in combination with carboplatin + paclitaxel/nab-paclitaxel\t6.5%\t\nHNSCC first line in combination with platinum and 5-fluorouracil, PD-L1 positive and CPS ≥1\t5%\t\nPembrolizumab\n+ axitinib [122]\tRCC first line\t2.8%\t\nAtezolizumab\nmonotherapy [123,124]\tLocally advanced/metastatic urothelial carcinoma second line\t2%\t\nNSCLC second line\t1%\t\nAtezolizumab\n+ nab-paclitaxel [125]\tAdvanced TNBC first line\t3.1%\t\nDurvalumab\nmonotherapy [126]\tLocally advanced unresectable NSCLC, PD-L1 ≥ 1%, not progressed following platinum based cht\t12.6%\t\nDurvalumab + platinum-etoposide [127]\tExtensive-stage SCLC first line\t3%\t\nAvelumab\nmonotherapy [128]\tMetastatic Merkel cell carcinoma\t1%\t\nAvelumab + axitinib [129]\tAdvanced RCC first line\t0.6%\t\nIpilimumab monotherapy [130,131]\tAdvanced melanoma\t2%\t\nILD: interstitial lung disease; NSCLC: non-small cell lung cancer; HNSCC: head and neck squamous cell carcinoma; RCC: renal cell carcinoma; CHT: chemotherapy; CPS: combined positive score; TNBC: triple-negative breast cancer; SCLC: small cell lung cancer.\n\ncancers-13-01052-t004_Table 4 Table 4 Pneumonitis severity classification according to NCI-CTCAE version 5.0 and American Society of Clinical Oncology (ASCO) 2018 guidelines.\n\nGuidelines\tG1\tG2\tG3\tG4\t\nCTCAE Version 5.0\tAsymptomatic, clinical or\ndiagnostic observations only,\nintervention not indicated\tSymptomatic, medical\nintervention indicated,\nlimiting instrumental ADL\tSevere symptoms, limiting self-care ADL, oxygen indicated\tLife-threatening respiratory\nCompromise, urgent\nintervention indicated (e.g., tracheotomy or intubation)\t\nASCO guidelines\tAsymptomatic, confined to one lobe of the lung or <25%\nof lung parenchyma, clinical or diagnostic observations\nonly\tSymptomatic, involves more than one lobe of the lung or 25–50% of lung parenchyma, medical intervention\nindicated, limiting instrumental ADL\tSevere symptoms, hospitalization required, involves all lung lobes or >50% of lung parenchyma, limiting self-care\nADL, oxygen indicated\tLife-threatening respiratory compromise, urgent\nIntervention indicated (intubation)\t\nAbbreviation: NCI: National Cancer Institute; CTCAE: Common Terminology Criteria for Adverse Events; G: grade; ADL: activity of daily life; Instrumental ADL: activities of daily life such as shopping, preparing food, using the telephone, managing money, etc.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Immunol. 2019 10 108 10.3389/fimmu.2019.00108 30778352\n100. Okada N. Matsuoka R. Sakurada T. Mitsuhiro G. Masayuki C. Kenta Y. Yoshito Z. Yasuhiko N. Keisuke I. Risk factors of immune checkpoint inhibitor-related interstitial lung disease in patients with lung cancer: A single-institution retrospective study Sci. Rep. 2020 10 13773 10.1038/s41598-020-70743-2 32792640\n101. Nishino M. Hatabu H. Hodi F.S. Imaging of Cancer Immunotherapy: Current Approaches and Future Directions Radiology 2019 290 9 22 10.1148/radiol.2018181349 30457485\n102. Sugano T. Seike M. Saito Y. Kashiwada T. Terasaki Y. Takano N. Hisakane K. Takahashi S. Tanaka T. Takeuchi S. Immune checkpoint inhibitor-associated interstitial lung diseases correlate with better prognosis in patients with advanced non-small-cell lung cancer Thorac. Cancer 2020 11 1052 1060 10.1111/1759-7714.13364 32096610\n103. Robert C. Long G.V. Brady B. Dutriaux C. Maio M. Mortier L. Hassel J.C. Rutkowski P. McNeil C. Kalinka-Warzocha E. Nivolumab in previously untreated melanoma without BRAF mutation N. Engl. J. Med. 2015 372 320 330 10.1056/NEJMoa1412082 25399552\n104. Weber J. Mandala M. Del Vecchio M. Gogas H.J. Arance A.M. Cowey C.L. Dalle S. Schenker M. Chiarion-Sileni V. Marquez-Rodas I. Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma N. Engl. J. Med. 2017 377 1824 1835 10.1056/NEJMoa1709030 28891423\n105. Ferris R.L. Blumenschein G. Jr. Fayette J. Guigay J. Colevas A.D. Licitra L. Harrington K. Kasper S. Vokes E.E. Even C. Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck N. Engl. J. Med. 2016 375 1856 1867 10.1056/NEJMoa1602252 27718784\n106. Sharma P. Retz M. Siefker-Radtke A. Baron A. Necchi A. Bedke J. Plimack E.R. Vaena D. Grimm M.O. Bracarda S. Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial Lancet Oncol. 2017 18 312 322 10.1016/S1470-2045(17)30065-7 28131785\n107. Brahmer J. Reckamp K.L. Baas P. Crinò L. Eberhardt W.E. Poddubskaya E. Antonia S. Pluzanski A. Vokes E.E. Holgado E. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer N. Engl. J. Med. 2015 373 123 135 10.1056/NEJMoa1504627 26028407\n108. Borghaei H. Paz-Ares L. Horn L. Spigel D.R. Steins M. Ready N.E. Chow L.Q. Vokes E.E. Felip E. Holgado E. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer N. Engl. J. Med. 2015 373 1627 1639 10.1056/NEJMoa1507643 26412456\n109. Motzer R.J. Escudier B. McDermott D.F. George S. Hammers H.J. Srinivas S. Tykodi S.S. Sosman J.A. Procopio G. Plimack E.R. CheckMate 025 Investigators. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma N. Engl. J. Med. 2015 373 18013 10.1056/NEJMoa1510665\n110. Larkin J. Chiarion-Sileni V. Gonzalez R. Grob J.J. Cowey C.L. Lao C.D. Schadendorf D. Dummer R. Smylie M. Rutkowski P. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma N. Engl. J. Med. 2015 373 23 34 10.1056/NEJMoa1504030 26027431\n111. Motzer R.J. Tannir N.M. McDermott D.F. Frontera O.A. Melichar B. Choueiri T.K. Plimack E.R. Barthélémy P. Porta C. George S. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma N. Engl. J. Med. 2018 378 1277 1290 10.1056/NEJMoa1712126 29562145\n112. Burtness B. Harrington K.J. Greil R. Soulières D. Tahara M. de Castro G. Jr. Psyrri A. Basté N. Neupane P. Bratland Å. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048): A randomised, open-label, phase 3 study Lancet 2019 394 1915 1928 10.1016/S0140-6736(19)32591-7 31679945\n113. Cohen E.E.W. Soulières D. Le Tourneau C. Dinis J. Licitra L. Ahn M.J. Soria A. Machiels J.P. Mach N. Mehra R. 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Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma N. Engl. J. Med. 2018 378 1789 1801 10.1056/NEJMoa1802357 29658430\n117. Robert C. Schachter J. Long G.V. Arance A. Grob J.J. Mortier L. Daud A. Carlino M.S. McNeil C. Lotem M. Pembrolizumab versus Ipilimumab in Advanced Melanoma N. Engl. J. Med. 2015 372 2521 2532 10.1056/NEJMoa1503093 25891173\n118. Ribas A. Puzanov I. Dummer R. Schadendorf D. Hamid O. Robert C. Hodi F.S. Schachter J. Pavlick A.C. Lewis K.D. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): A randomised, controlled, phase 2 trial Lancet Oncol. 2015 16 908 918 10.1016/S1470-2045(15)00083-2 26115796\n119. Bellmunt J. de Wit R. Vaughn D.J. Fradet Y. Lee J.L. Fong L. Vogelzang N.J. Climent M.A. Petrylak D.P. Choueiri T.K. Pembrolizumab as Second-Line Therapy for Advanced Urothelial Carcinoma N. Engl. J. Med. 2017 376 1015 1026 10.1056/NEJMoa1613683 28212060\n120. Gandhi L. Rodríguez-Abreu D. Gadgeel S. Esteban E. Felip E. De Angelis F. Domine M. Clingan P. Hochmair M.J. Powell S.F. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer N. Engl. J. Med. 2018 378 2078 2092 10.1056/NEJMoa1801005 29658856\n121. Paz-Ares L. Luft A. Vicente D. Tafreshi A. Gümüş M. Mazières J. Hermes B. Çay Şenler F. Csőszi T. Fülöp A. Pembrolizumab plus Chemotherapy for Squamous Non-Small-Cell Lung Cancer N. Engl. J. Med. 2018 379 2040 2051 10.1056/NEJMoa1810865 30280635\n122. Rini B.I. Plimack E.R. Stus V. Gafanov R. Hawkins R. Nosov D. Pouliot F. Alekseev B. Soulières D. Melichar B. Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma N. Engl. J. Med. 2019 380 1116 1127 10.1056/NEJMoa1816714 30779529\n123. Rosenberg J.E. Hoffman-Censits J. Powles T. van der Heijden M.S. Balar A.V. Necchi A. Dawson N. O’Donnell P.H. Balmanoukian A. Loriot Y. Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial Lancet 2016 387 1909 1920 10.1016/S0140-6736(16)00561-4 26952546\n124. Rittmeyer A. Barlesi F. Waterkamp D. Park K. Ciardiello F. von Pawel J. Gadgeel S.M. Hida T. Kowalski D.M. Dols M.C. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): A phase 3, open-label, multicentre randomised controlled trial Lancet 2017 389 255 265 10.1016/S0140-6736(16)32517-X 27979383\n125. Schmid P. Adams S. Rugo H.S. Schneeweiss A. Barrios C.H. Iwata H. Diéras V. Hegg R. Im S.A. Shaw Wright G. Atezolizumab and Nab-Paclitaxel in Advanced Triple-Negative Breast Cancer N. Engl. J. Med. 2018 379 2108 2121 10.1056/NEJMoa1809615 30345906\n126. Antonia S.J. Villegas A. Daniel D. Vicente D. Murakami S. Hui R. Kurata T. Chiappori A. Lee K.H. de Wit M. Overall Survival with Durvalumab after Chemoradiotherapy in Stage III NSCLC N. Engl. J. Med. 2018 379 2342 2350 10.1056/NEJMoa1809697 30280658\n127. Paz-Ares L. Dvorkin M. Chen Y. Reinmuth N. Hotta K. Trukhin D. Statsenko G. Hochmair M.J. Özgüroğlu M. Ji J.H. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): A randomised, controlled, open-label, phase 3 trial Lancet 2019 394 1929 1939 10.1016/S0140-6736(19)32222-6 31590988\n128. Kaufman H.L. Russell J. Hamid O. Bhatia S. Terheyden P. D’Angelo S.P. Shih K.C. Lebbé C. Linette G.P. Milella M. Avelumab in patients with chemotherapy-refractory metastatic Merkel cell carcinoma: A multicentre, single-group, open-label, phase 2 trial Lancet Oncol. 2016 17 1374 1385 10.1016/S1470-2045(16)30364-3 27592805\n129. Motzer R.J. Penkov K. Haanen J. Rini B. Albiges L. Campbell M.T. Venugopal B. Kollmannsberger C. Negrier S. Uemura M. Avelumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma N. Engl. J. Med. 2019 380 1103 1115 10.1056/NEJMoa1816047 30779531\n130. Hodi F.S. O’Day S.J. McDermott D.F. Weber R.W. Sosman J.A. Haanen J.B. Gonzalez R. Robert C. Schadendorf D. Hassel J.C. Improved survival with ipilimumab in patients with metastatic melanoma N. Engl. J. Med. 2010 363 711 723 10.1056/NEJMoa1003466 20525992\n131. EMA Product Information: Ipilimumab Available online: https://www.ema.europa.eu/en/documents/product-information/yervoy-epar-product-information_en.pdf (accessed on 13 December 2020)\n132. Khunger M. Rakshit S. Pasupuleti V. Hernandez A.V. Mazzone P. Stevenson J. Pennell N.A. Velcheti V. Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: A systematic review and meta-analysis of trials Chest 2017 152 271 281 10.1016/j.chest.2017.04.177 28499515\n133. Akinleye A. Rasool Z. Immune checkpoint inhibitors of PD-L1 as cancer therapeutics J. Hematol. Oncol. 2019 12 92 10.1186/s13045-019-0779-5 31488176\n134. Takano T. Ohe Y. Kusumoto M. Tateishi U. Yamamoto S. Nokihara H. Yamamoto N. Sekine I. Kunitoh H. Tamura T. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib Lung Cancer 2004 45 93 104 10.1016/j.lungcan.2004.01.010 15196739\n135. Abid S.H. Malhotra V. Perry M.C. Radiation-induced and chemotherapy-induced pulmonary injury Curr. Opin. Oncol. 2001 13 242 248 10.1097/00001622-200107000-00006 11429481\n136. Blank C.U. Enk A. Therapeutic use of anti-CTLA-4 antibodies Int. Immunol. 2015 27 3 10 10.1093/intimm/dxu076 25038057\n137. Torrisi J.M. Schwartz L.H. Gollub M.J. Ginsberg M.S. Bosl G.J. Hricak H. CT findings of chemotherapy-induced toxicity: What radiologists need to know about the clinical and radiologic manifestations of chemotherapy toxicity Radiology 2011 258 41 56 10.1148/radiol.10092129 21183492\n138. Distefano G. Fanzone L. Palermo M. Tiralongo F. Cosentino S. Inì C. Galioto F. Vancheri A. Torrisi S.E. Mauro L.A. HRCT Patterns of Drug-Induced Interstitial Lung Diseases: A Review Diagnostics 2020 10 244 10.3390/diagnostics10040244\n139. Duzgun S.A. Durhan G. Demirkazik F.B. Akpinar M.G. Ariyurek O.M. COVID-19 pneumonia: The great radiological mimicker Insights Imaging 2020 11 118 10.1186/s13244-020-00933-z 33226521\n140. Buchler T. Bomanji J. Lee S.M. FDG-PET in bleomycin-induced pneumonitis following ABVD chemotherapy for Hodgkin’s disease—A useful tool for monitoring pulmonary toxicity and disease activity Haematologica 2007 92 e120-1 10.3324/haematol.11856 18024389\n141. Basu S. Saboury B. Werner T. Alavi A. Clinical utility of FDG-PET and PET/CT in non-malignant thoracic disorders Mol. Imaging Biol. 2011 13 1051 1060 10.1007/s11307-010-0459-x 21161689\n142. Van Diessen J. De Ruysscher D. Sonke J.J. Damen E. Sikorska K. Reymen B. van Elmpt W. Westman G. Persson G.F. Dieleman E. The acute and late toxicity results of a randomized phase II dose-escalation trial in non-small cell lung cancer (PET-boost trial) Radiother. Oncol. 2019 131 166 173 10.1016/j.radonc.2018.09.019 30327236\n143. Willemsen A.E.C.A.B. Tol J. van Erp N.P. Jonker M.A. de Boer M. Meek B. de Jong P.C. van Moorsel C. Gerritsen W.R. Grutters J.C. Prospective Study of Drug-induced Interstitial Lung Disease in Advanced Breast Cancer Patients Receiving Everolimus Plus Exemestane Target. Oncol. 2019 14 441 451 10.1007/s11523-019-00656-2 31325105\n144. Razzouk-Cadet M. Picard A. Grangeon-Chapon C. Lacour J.P. Montaudié H. Nivolumab-Induced Pneumonitis in Patient with Metastatic Melanoma Showing Complete Remission on 18F-FDG PET/CT Clin. Nucl. Med. 2019 44 806 807 10.1097/RLU.0000000000002707 31306191\n145. Endoh H. Yamamoto R. Ichikawa A. Shiozawa S. Nishizawa N. Satoh Y. Oriuchi N. Clinicopathological significance of false-positive lymph node status on 18F-FDG PET in lung cancer Clin. Lung Cancer 2020 10.1016/j.cllc.2020.05.002\n146. Erickson B.J. Korfiatis P. Akkus Z. Kline T.L. Machine learning for medical imaging Radiographics 2017 37 505 515 10.1148/rg.2017160130 28212054\n147. Carlos F. Uribe S.M. Vincent C. Gaudet K.C. Smith P.R.-N. Francois B. Sandra E.B. Katherine Z. Machine Learning in Nuclear Medicine: Part 1—Introduction J. Nucl. Med. 2019 60 451 458 10.2967/jnumed.118.223495 30733322\n148. Kim R. Meyer K.C. Therapies for interstitial lung disease: Past, present and future Ther. Adv. Respir. Dis. 2008 2 319 338 10.1177/1753465808096948 19124380\n149. Vacchi C. Sebastiani M. Cassone G. 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Nonpharmacological therapies for interstitial lung disease Curr. Pulmonol. Rep. 2018 7 126 132 10.1007/s13665-018-0211-6 31106117\n\n",
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"title": "Drug-Related Pneumonitis in Cancer Treatment during the COVID-19 Era.",
"title_normalized": "drug related pneumonitis in cancer treatment during the covid 19 era"
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"abstract": "We previously reported mother-to-child transmission of HIV-1 in nine (6.7%) of 135 children on nevirapine prophylaxis in Vietnam. In the current study, we investigated the appearance and profile of antiretroviral drug (ARV) resistance mutations, the predicted coreceptor usage, and the genetic diversity of HIV-1 strains isolated from the eight pairs of HIV-1-infected mothers and their children, who were followed up to 12 months after birth. Portions of the pol and env C2V3 regions of the HIV-1 strains were analyzed genetically. HIV-1 CRF01_AE RNA was detected in four (50%) children at delivery. Y181C, a nevirapine resistance mutation, appeared in two (25%) children 1 and 3 months after birth, respectively. No ARV resistance mutation was detected in the mothers, though three mothers were on ARV prophylaxis. Five mothers and their children harbored CCR5-tropic (R5) viruses. Two mothers harbored both R5 and CXCR4-tropic (X4) viruses, but their children harbored only R5 viruses even though the X4 viruses were dominant in the mothers. In the remaining one mother, HIV-1 RNA was not amplified and her child harbored both R5 and X4 viruses at birth, but only X4 virus 12 months after delivery. The infants' viruses were more homogeneous than their mothers' viruses (mean distance: 0.5% vs. 1.1%, respectively). This is the first molecular epidemiological study of vertical HIV-1 infections in Vietnam. These findings may provide useful knowledge for the prevention of mother-to-child transmission of HIV-1 and the antiretroviral treatment of children in Vietnam.",
"affiliations": "1 Department of Viral Infection and International Health, Kanazawa University , Graduate School of Medical Sciences, Kanazawa, Japan .;1 Department of Viral Infection and International Health, Kanazawa University , Graduate School of Medical Sciences, Kanazawa, Japan .;1 Department of Viral Infection and International Health, Kanazawa University , Graduate School of Medical Sciences, Kanazawa, Japan .;1 Department of Viral Infection and International Health, Kanazawa University , Graduate School of Medical Sciences, Kanazawa, Japan .;1 Department of Viral Infection and International Health, Kanazawa University , Graduate School of Medical Sciences, Kanazawa, Japan .;3 Department of Microbiology, National Institute of Hygiene and Epidemiology , Hanoi, Vietnam .;2 National Hospital of Pediatrics , Hanoi, Vietnam .;1 Department of Viral Infection and International Health, Kanazawa University , Graduate School of Medical Sciences, Kanazawa, Japan .",
"authors": "Phan|Chung Thi Thu|CT|;Pham|Hung Viet|HV|;Bi|Xiuqiong|X|;Ishizaki|Azumi|A|;Saina|Matilda|M|;Phung|Cam Dac|CD|;Khu|Dung Thi Khanh|DT|;Ichimura|Hiroshi|H|",
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"mesh_terms": "D019380:Anti-HIV Agents; D016000:Cluster Analysis; D024882:Drug Resistance, Viral; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008969:Molecular Sequence Data; D019829:Nevirapine; D010802:Phylogeny; D011247:Pregnancy; D012367:RNA, Viral; D015728:Receptors, HIV; D017422:Sequence Analysis, DNA; D017385:Sequence Homology; D014744:Vietnam; D056189:Viral Tropism; D054302:pol Gene Products, Human Immunodeficiency Virus",
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"title": "Genetic Analyses of HIV-1 Strains Transmitted from Mother to Child in Northern Vietnam.",
"title_normalized": "genetic analyses of hiv 1 strains transmitted from mother to child in northern vietnam"
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"abstract": "Cranial surgical site infections due to Salmonella species are rarely reported. Only eight cases of Salmonella enteritidis infection following intracranial surgery for brain tumor have been reported to date. We describe a unique case of both subgaleal and brain abscesses caused by S. enteritidis following craniotomy for a parafalcine giant cell glioblastoma multiforme. A literature review of the previously published cases is also provided.\nA 36-year-old previously healthy man presented with a posterior parietal parafalcine giant cell glioblastoma multiforme. 5 weeks after craniotomy for tumor resection, the patient presented with worsening headache and painful swelling at the cranial operative site. Head computed tomography and magnetic resonance imaging scans revealed both scalp and brain abscesses in the previous surgical site. He was treated with aspiration of the subgaleal abscess and ciprofloxacin antibiotic therapy; he made a full recovery. Cultures of the aspirate identified S. enteritidis, although the primary site of infection was not detected.\nAlthough postoperative S. enteritidis infections are rare, the large numbers of patients with malignant brain tumors who require tumor resections and receive corticosteroids are at great risk. Adequate drainage (if possible), early isolation of the pathogens, and control of the infection by antibiotic therapy guided by antimicrobial susceptibility testing are vital components to prevent this potentially fatal condition.",
"affiliations": "Department of Neurosurgery, Avicenne Military Hospital of Marrakech, Marrakech and Mohammed V University, Rabat, Morocco.;Department of Neurosurgery, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, United States.;Department of Neurosurgery, Avicenne Military Hospital of Marrakech, Marrakech and Mohammed V University, Rabat, Morocco.",
"authors": "Akhaddar|Ali|A|;Hall|Walter|W|;Boucetta|Mohammed|M|",
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"doi": "10.25259/SNI-31-2019",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSurgical Neurology International2229-50972152-7806Scientific Scholar USA SNI-10-3710.25259/SNI-31-2019Case ReportSubgaleal and brain abscesses due to Salmonella enteritidis following craniotomy for giant cell glioblastoma multiforme: A case report and literature review Akhaddar Ali 1akhaddar@hotmail.frHall Walter 2hallw@upstate.eduBoucetta Mohammed 1boucetta.mohamed@hotmail.com1 Department of Neurosurgery, Avicenne Military Hospital of Marrakech, Marrakech and Mohammed V University, Rabat, Morocco2 Department of Neurosurgery, State University of New York (SUNY), Upstate Medical University, Syracuse, New York, United States* Corresponding author: Ali Akhaddar, 267, Lotissement Masmoudi, Targa, 40120, Marrakech, Morocco. akhaddar@hotmail.fr2019 26 3 2019 10 3720 11 2018 10 1 2019 Copyright: © 2019 Surgical Neurology International2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nCranial surgical site infections due to Salmonella species are rarely reported. Only eight cases of Salmonella enteritidis infection following intracranial surgery for brain tumor have been reported to date. We describe a unique case of both subgaleal and brain abscesses caused by S. enteritidis following craniotomy for a parafalcine giant cell glioblastoma multiforme. A literature review of the previously published cases is also provided.\n\nCase Description:\nA 36-year-old previously healthy man presented with a posterior parietal parafalcine giant cell glioblastoma multiforme. 5 weeks after craniotomy for tumor resection, the patient presented with worsening headache and painful swelling at the cranial operative site. Head computed tomography and magnetic resonance imaging scans revealed both scalp and brain abscesses in the previous surgical site. He was treated with aspiration of the subgaleal abscess and ciprofloxacin antibiotic therapy; he made a full recovery. Cultures of the aspirate identified S. enteritidis, although the primary site of infection was not detected.\n\nConclusions:\nAlthough postoperative S. enteritidis infections are rare, the large numbers of patients with malignant brain tumors who require tumor resections and receive corticosteroids are at great risk. Adequate drainage (if possible), early isolation of the pathogens, and control of the infection by antibiotic therapy guided by antimicrobial susceptibility testing are vital components to prevent this potentially fatal condition.\n\nBrain abscesscomplicationgiant cell glioblastoma multiformeinfectionSalmonella enteritidisSalmonella infectionscalp abscesssurgical site infection\n==== Body\nINTRODUCTION\nCentral nervous system (CNS) infections due to Salmonella species are uncommon.[6,9,12,15] Among them, the occurrence of postoperative complications caused by Salmonella enteritidis is particularly rare.[11] Only eight cases of S. enteritidis infection following intracranial surgery for brain tumor have been reported in the world literature to date.[1,4,5,7,13,14,16] We describe a previously healthy man who developed both scalp and brain abscesses due to S. enteritidis after a craniotomy for the resection of a giant cell glioblastoma multiforme. The patient recovered as a result of aspiration of the subgaleal abscess followed by ciprofloxacin antibiotic therapy. A literature review of previously published cases is also presented.\n\nCASE DESCRIPTION\nA 36-year-old man with no significant medical history, presented to our medical center with headache, nausea, episodic seizures, and personality changes for 1 month. He was afebrile, had no focal neurologic deficits, and had no systemic abnormalities on clinical examination. Magnetic resonance imaging (MRI) of the head revealed a 3-cm diameter right posterior parietal parafalcine, dura based, enhancing lesion, suggesting an extra-axial tumor [Figure 1]. A right posterior interhemispheric approach was performed for tumor resection. At craniotomy, the tumor was found to be intra-axial with adjacent dural invasion. A near total resection of the tumor was performed. Histopathologic examination of the tumor demonstrated a giant cell glioblastoma multiforme. No bacteria were identified on histological analysis. Postoperatively, the patient demonstrated progressive improvement and was given valproic acid and methylprednisolone as antiepileptic and antiedema treatment. He was discharged to home on the 6th day postsurgery. The sutures were removed on the 14th postoperative day with normal appearing wound healing.\n\nFigure 1: Following gadolinium injection, axial. (a) Coronal. (b) And sagittal. (c) Sections of T1-weighted magnetic resonance imaging demonstrating the parafalcine tumor localized in the right posterior parietal region before the first operation. Note the close spatial relationship of the tumor to the falx cerebri.\n\n5 weeks after surgery, the patient presented with worsening headache and painful swelling at the cranial operative site. Head computed tomography (CT) scan demonstrated a subgaleal extracranial homogenous low-density lesion with rim enhancement following contrast administration. There was also another intracranial ring-enhancing collection at the glioblastoma resection cavity, suggesting a brain abscess [Figure 2a]. There was no contiguous cranial or bone flap osteomyelitis on CT bone window images. The MRI showed both extracranial and parasagittal cystic masses with homogenous, low-intensity signal on T1-weighted images, and high-intensity signal on fluid-attenuated inversion recovery sequences, with significant cerebral edema surrounding the resection cavity and peripheral enhancement after gadolinium injection [Figure 2b-2e]. Clinically, the patient was conscious and afebrile without signs of meningeal irritation or neurologic deficits. His wound was well-healed without purulent discharge. Laboratory studies disclosed a white blood cell count of 16 × 109/L (66.5% neutrophils and 22.7% lymphocytes) and a C-reactive protein (CRP) level of 36.2 mg/L, but blood cultures remained negative. Percutaneous needle aspiration of the subgaleal collection yielded approximately 80 mL of purulent material. The suppurative material was submitted for aerobic and anaerobic microbiological studies as well as for fungal analysis. Empiric antibiotic therapy was started with ciprofloxacin, gentamicin, and metronidazole. Gram stain of the pus revealed Gram-negative bacilli. Cultures demonstrated the growth of S. enterica, serotype Enteritidis. Ciprofloxacin was continued based on the culture sensitivities. The patient was discharged after 4 weeks of intravenous antibiotic therapy and was given oral ciprofloxacin at home for an additional month of treatment. Follow-up CT revealed a gradual reduction in abscess volume until its complete resolution 10 weeks after starting antibiotic therapy (CRP level was reduced to 5 mg/L). The patient was then sent to an oncologic center for further management.\n\nFigure 2: Postoperative axial computed tomography following contrast administration. (a) Revealing a subgaleal extracranial homogenous low-density lesion with rim enhancement (right). There was also another intracranial ring-enhancing collection at the site of the tumor resection cavity (left), suggesting a brain abscess (arrow). Postoperative magnetic resonance imaging showing both extracranial and parafalcine cystic masses with homogenous, low-intensity signal on T1-weighted images. (b and c) And high-intensity signal on the fluid-attenuated inversion recovery sequence. (d) There was peripheral enhancement after gadolinium injection (b and c) and significant cerebral edema surrounding the resection cavity. (d) Note the restricted diffusion-weighted image (bright signal) of the extracranial and parafalcine collections (e).\n\nDISCUSSION\nSalmonellosis is usually a self-limited disease that generally causes gastrointestinal tract infection in humans through the oral route. Extraintestinal infections are uncommon, especially in the CNS, and may remain undetected due to a lack of fever and gastroenteritis.[12,13,15] Until 2000, about 70 cases of focal intracranial salmonellosis were described in the world literature including brain abscesses, subdural empyemas, and epidural abscesses.[8] Few cases were added thereafter. However, infections following neurosurgical procedures are rare. Searches using MEDLINE database were performed and only eight cases of S. enteritidis infection following brain tumor resection were identified from 1966 to date.[1,4,5,7,13,14,16] A summary of the eight patients and the one described herein is provided in Table 1. 4 (44.4%) of the nine cases occurred in women. All but one of the nine cases was reported in a child and the average age was 41.5 years (range, 26 months–72 years). All patients were operated on for an intracranial supratentorial tumor: four patients with glioblastoma, one with a metastatic tumor due to embryonal carcinoma, one with ependymoma, one with astrocytoma, one with anaplastic oligodendroglioma, and one with craniopharyngioma. All patients were receiving systemic corticosteroid treatment except for one.[14]\n\nTable 1: Summary of nine cases (including our case) with Salmonella enteritidis infection following cranial tumor surgery reported in the world literature to date.\n\nAll patients had a cranial surgical site infection (SSI). In addition, two cases also had gastroenteritis and one patient had concomitant infectious arthritis of the hip. The organism was identified from samples of the cranial SSI in all patients and also from samples outside the SSI in eight cases (six from blood cultures and two from stool cultures). The most common predisposing factors to infection were corticosteroid use and malignancy, but no patient was seropositive for HIV infection.\n\nThe clinical features of these patients did not differ from those with SSI caused by other bacteria.[3] The most frequent symptoms at presentation were fever (five cases), altered awareness (four cases), and headache (three cases). Focal neurological deficits were observed in two patients. Meningismus was noted in two instances. Scalp swelling and scalp wound infection were observed in one patient each. The duration of symptoms was documented in seven patients and had an average duration of 2.21 weeks (from 3 days to 5 weeks).\n\nAdequate drainage (if possible), early isolation of the pathogens, and control of the infection by antibiotic therapy guided by antimicrobial susceptibility testing are essential to prevent this potentially fatal condition.[2,3] In our review, all of the nine patients were on antibiotics. Four received treatment with regimens including ceftriaxone and/or ciprofloxacin, in combination with other antimicrobial agents in three patients. Antibiotic regimens lasted between 1 and 4.5 months. Surgical drainage of the suppurative collection was undertaken in seven patients. Percutaneous scalp aspiration and bone flap removal were performed in one patient each. Complete clinical resolution was achieved in seven patients. One case recovered from neurological clinical symptoms but with subsequent sequelae (residual hemiparesis) and one patient who had severe meningitis died 8 days into antibiotic therapy. These relative favorable results reflect the fact that most of these cases received prompt surgical and antimicrobial treatment.\n\nAmong the few cases of reported S. enteritidis infection following craniotomy in literature, this is the first case of the simultaneous occurrence of brain abscess and extracranial scalp abscess. The ability of these bacteria to produce a cranial SSI remains unexplained. Although the origin of infection was unclear in our previously healthy patient, the course of corticosteroids that he received and the original malignant intracranial tumor could have predisposed him to infection followed by potential hematogenous spread to the cranial surgical site. Furthermore, the absence of underlying systemic disease seems to be crucial for the cure of our patient. Finally, the possibility of postoperative Salmonella infection should be considered in patients with malignant brain tumor having surgery.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Aissaoui Y Azendour H Balkhi H Haimeur C Atmani M Postoperative meningitis caused by an unusual etiological agent Salmonella enteritidis Neurochirurgie 2006 52 547 50 17203905 \n2 Akhaddar A Zalagh M Gazzaz M Boucetta M Brain abscess as a complication of intranasal ethmoidectomy for sinonasal polyposis Surg Infect (Larchmt) 2010 11 483 5 20575665 \n3 Akhaddar A Akhaddar A Surgical site infections in cranial surgery Atlas of Infections in Neurosurgery and Spinal surgery 2017 Switzerland Springer International Publishing 191 215 \n4 Blázquez D Muñoz M Gil C Ruibal JL El Knaichi F Aleo E Brain abscess and epidural empyema caused by Salmonella enteritidis in a child: Successful treatment with ciprofloxacin: A case report Cases J 2009 2 7131 19829916 \n5 Bossi P Mion G Brinquin L Bonsignour JP Postoperative brain abscess caused by Salmonella enteritidis Presse Med 1993 22 130 \n6 Diebold P Humbert J Djientcheu Vde P Gudinchet F Rilliet B Salmonella epidural abscess in sickle cell disease: Failure of the nonsurgical treatment J Natl Med Assoc 2003 95 1095 1098 14651377 \n7 Fiteni I Ruiz FJ Crusells MJ Sanjoaquin I Guillen G Salmonella enteritidis multifocal infection of the central nervous system. Efficacy of new cephalosporins Presse Med 1995 24 309 11 7899392 \n8 Hanel RA Araújo JC Antoniuk A da Silva Ditzel LF Flenik Martins LT Linhares MN Multiple brain abscesses caused by Salmonella typhi : Case report Surg Neurol 2000 53 86 90 10697239 \n9 Lloret MD Escudero JR Hospedales J Viver E Mycotic aneurysm of the carotid artery due to Salmonella enteritidis associated with multiple brain abscesses Eur J Vasc Endovasc Surg 1996 12 250 2 8760992 \n10 Luciani L Dubourg G Graillon T Honnorat E Lepidi H Drancourt M Salmonella enterica serovar enteritidis brain abscess mimicking meningitis after surgery for glioblastoma multiforme: A case report and review of the literature J Med Case Rep 2016 10 192 27387824 \n11 Millward CP McMullan NK Vaiude P da Rosa SP Riordan A Burn SC Extradural abscess secondary to Salmonella enteritidis in a child following fronto-orbital facial advancement and remodeling surgery J Craniofac Surg 2014 25 489 91 24514892 \n12 Noguerado A Cabanyes J Vivancos J Navarro E Lopez F Isasia T Abscess caused by Salmonella enteritidis within a glioblastoma multiforme J Infect 1987 15 61 3 2822812 \n13 Rodriguez RE Valero V Watanakunakorn C Salmonella focal intracranial infections: Review of the world literature (1884-1984) and report of an unusual case Rev Infect Dis 1986 8 31 41 3513285 \n14 Sait M Rahmathulla G Chen TL Barnett GH Rare case of intracranial Salmonella enteritidis abscess following glioblastoma resection: Case report and review of the literature Surg Neurol Int 2011 2 149 22059142 \n15 Sarria JC Vidal AM Kimbrough RC 3rd Salmonella enteritidis brain abscess: Case report and review Clin Neurol Neurosurg 2000 102 236 9 11154812 \n16 Schröder J Palkovic S Kipp F Wassmann H Salmonella enteritidis causing brain abscess and coxitis following intracranial surgery Acta Neurochir (Wien) 2003 145 919 21 14577015\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2152-7806",
"issue": "10()",
"journal": "Surgical neurology international",
"keywords": "Brain abscess; Salmonella enteritidis; Salmonella infection; complication; giant cell glioblastoma multiforme; infection; scalp abscess; surgical site infection",
"medline_ta": "Surg Neurol Int",
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"nlm_unique_id": "101535836",
"other_id": null,
"pages": "37",
"pmc": null,
"pmid": "31528375",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10697239;11154812;14577015;14651377;17203905;19829916;20575665;22059142;24514892;27387824;2822812;3513285;7899392;8493217;8760992",
"title": "Subgaleal and brain abscesses due to Salmonella enteritidis following craniotomy for giant cell glioblastoma multiforme: A case report and literature review.",
"title_normalized": "subgaleal and brain abscesses due to salmonella enteritidis following craniotomy for giant cell glioblastoma multiforme a case report and literature review"
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"abstract": "Metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and short survival. Today, the use of new polytherapeutic regimens increases clinical outcome of these patients opening new clinical scenario. A crucial issue related to the actual improvement achieved with these new regimens is represented by the occasional possibility to observe a radiological complete response of metastatic lesions in patients with synchronous primary tumor. What could be the best therapeutic management of these patients? Could surgery represent an indication? Herein, we reported a case of a patient with PDAC of the head with multiple liver metastases, who underwent first-line chemotherapy with mFOLFIRINOX. After 10 cycles, he achieved a complete radiological response of liver metastases and a partial response of pancreatic lesion. A duodenocephalopancreasectomy was performed. Due to liver a lung metastases after 8 months from surgery, a second-line therapy was started with a disease-free survival and overall survival of 8 months and 45 months, respectively. Improvement in the molecular characterization of PDAC could help in the selection of patients suitable for multimodal treatments. This trial is registered with NCT02892305 and NCT00855634.",
"affiliations": "Medical Oncology Unit, IRCCS Istituto Tumori \"Giovanni Paolo II\", Bari, Italy.;Radiology Unit, IRCCS Istituto Tumori \"Giovanni Paolo II\", Bari, Italy.;Medical Oncology Unit, IRCCS Istituto Tumori \"Giovanni Paolo II\", Bari, Italy.;Medical Oncology Unit, IRCCS Istituto Tumori \"Giovanni Paolo II\", Bari, Italy.;Medical Oncology Unit, IRCCS Istituto Tumori \"Giovanni Paolo II\", Bari, Italy.;Medical Oncology Unit, IRCCS Istituto Tumori \"Giovanni Paolo II\", Bari, Italy.",
"authors": "Argentiero|Antonella|A|;Calabrese|Angela|A|;Sciacovelli|Angela Monica|AM|;Delcuratolo|Sabina|S|;Solimando|Antonio Giovanni|AG|0000-0002-2293-9698;Brunetti|Oronzo|O|0000-0002-7014-6828",
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"doi": "10.1155/2020/8679751",
"fulltext": "\n==== Front\nCan J Gastroenterol Hepatol\nCan J Gastroenterol Hepatol\nCJGH\nCanadian Journal of Gastroenterology & Hepatology\n2291-2789 2291-2797 Hindawi \n\n10.1155/2020/8679751\nResearch Article\nComplete Response of Synchronous Liver Metastasis in a Pancreatic Ductal Adenocarcinoma, When Surgery Could Represent a Therapeutic Option\nArgentiero Antonella \n1\n Calabrese Angela \n2\n Sciacovelli Angela Monica \n1\n Delcuratolo Sabina \n1\n https://orcid.org/0000-0002-2293-9698Solimando Antonio Giovanni \n1\n\n3\n https://orcid.org/0000-0002-7014-6828Brunetti Oronzo dr.oronzo.brunetti@tiscali.it\n1\n \n1Medical Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy\n\n2Radiology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy\n\n3Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine “G. Baccelli”, University of Bari Medical School, Bari, Italy\nAcademic Editor: Yousuke Nakai\n\n\n2020 \n9 10 2020 \n2020 867975116 12 2019 21 9 2020 30 9 2020 Copyright © 2020 Antonella Argentiero et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Metastatic pancreatic ductal adenocarcinoma (PDAC) is characterized by poor prognosis and short survival. Today, the use of new polytherapeutic regimens increases clinical outcome of these patients opening new clinical scenario. A crucial issue related to the actual improvement achieved with these new regimens is represented by the occasional possibility to observe a radiological complete response of metastatic lesions in patients with synchronous primary tumor. What could be the best therapeutic management of these patients? Could surgery represent an indication? Herein, we reported a case of a patient with PDAC of the head with multiple liver metastases, who underwent first-line chemotherapy with mFOLFIRINOX. After 10 cycles, he achieved a complete radiological response of liver metastases and a partial response of pancreatic lesion. A duodenocephalopancreasectomy was performed. Due to liver a lung metastases after 8 months from surgery, a second-line therapy was started with a disease-free survival and overall survival of 8 months and 45 months, respectively. Improvement in the molecular characterization of PDAC could help in the selection of patients suitable for multimodal treatments. This trial is registered with NCT02892305 and NCT00855634.\n\nApulian Regional Project\n==== Body\n1. Introduction\nPancreatic ductal adenocarcinoma (PDAC) is one of the most important issues in the context of cancer being the fourth leading cause of death in USA and Japan and the sixth in Europe [1, 2] with a 5-year survival no greater than 6% [2] and an estimated increase in incidence that will bring it to the second leading cause of cancer death in 2030 [3]. At first diagnosis, only from 10% to 20% of PDAC patients present a primarily resectable disease. Approximately, 60% of patients are affected by metastatic disease [4].\n\nToday, according to international guidelines, distant metastases (including nonregional lymph nodes) and vascular infiltration are absolute contraindication to surgery [5]. Surgical resection of PDAC with synchronous distant metastases is not indicated as the average survival time which appears equivalent to that of chemotherapy alone [6].\n\nIn the past, in the absence of active primary chemotherapy regimens, many surgeons attempted to resect liver or lymph node metastasis in a single operation or in two different times after resection of the primary with detrimental results in terms of survival and quality of life [7].\n\nToday, the use of polychemotherapy regimens increases the chemosensitivity and the rate of response to the disease. In a phase III randomized study, the combination chemotherapy FOLFIRINOX gained a significant advantage in terms of progression-free survival (PFS) (6.4 months versus 3.3 months; p < 0.0001) and overall survival (OS) (11.1 months versus 6.8 months, 1-y OS versus 48.4%, 20.6%; p < 0.0001) compared to gemcitabine in patients with metastatic disease and age ≤70 years [8]. Furthermore, another randomized phase III study of 861 patients with mPDAC previously untreated have shown that the combination gemcitabine-nabpaclitaxel can improve PFS (HR 0.69; p < 0.0001) and OS (HR 0.72; p < 0.0001) compared to gemcitabine alone [9].\n\nA crucial issue related to the actual improvement achieved with these new regimens is represented by the occasional possibility to observe a radiological complete response of metastatic lesions in patients with synchronous primary tumor [10]. What could be the best therapeutic management of these patients? Could surgery represent an indication? Herein, we discuss the role of surgery in a long-term metastatic PDAC survivor who presented a complete response of synchronous liver metastases after modified FOLFIRINOX regimen.\n\n2. Case Report\nA Caucasian 64-year-old man suffering from hypertension and diabetes presented with a history of abdominal pain in the last two months. A computed tomography (CT) scan of the abdomen revealed a lesion of 4 cm in diameter localized in the head of pancreas with the presence of venous involvement of the superior mesenteric vein (Figure 1(a)) without a clear cleavage plane from the descending part of the duodenum and an initial dilatation of the intrahepatic bile duct. Six secondary liver lesions were concomitant (Figures 1(b)–1(d)). In particular, 2 of these lesions ranged from 1 to 2 cm and the other 4 were millimetric ones; so far, we consider it as an oligometastatic cancer. Serum levels of CEA and Ca 19.9 were 721 ng/mL and 11.200 U/mL, respectively (Figures 2(a) and 2(b)). A fine-needle biopsy of both pancreatic and the V segment lesion of the liver reported the diagnosis of malignant cells compatible with moderately differentiated PDAC. First-line chemotherapy according to the modified FOLFIRINOX regimen (oxaliplatin 85 mg/m2, irinotecan 180 mg/m2, folinic acid 400 mg/m2, continuous 44 hours infusion of 5FU 2400 mg/m2, every 2 weeks) was started. After 4 cycles, a CT scan of the abdomen documented a partial response of all target lesions according to RECIST 1.1 criteria [11]. Nevertheless, due to the appearance of a subocclusive clinical scenario associated with an acute bacterial pneumonia and a rapid decay of performance status, the patient underwent an esophageal-gastric-duodenum endoscopy showing duodenal stenosis associated with severe gastric displacement. Therefore, a palliative gastro-entero-anastomosis was performed associated with a targeted antibiotic therapy for pneumonia. In the following 3 months, only best-supportive care was initiated in order to improve patient's health status. At that time, a new CT scan documented the increase of both pancreatic and liver lesions, serum tumor markers, and obstructive jaundice with high total bilirubin levels (15.7 mg/dL). As a consequence, a biliary drainage was implanted with a rapid restoration of normal bilirubin values. In the next month, the FOLFIRINOX regimen was resumed and 6 cycles were administered without significant toxicities. A progressive decline of CEA and Ca 19.9 was achieved with values of 110 ng/mL and 152 U/mL, respectively. A new CT scan showed dimensional stability of both hepatic and pancreatic lesions associated with a prevalence of necrotic areas (Figures 3(a)–3(d)). Simultaneously, a PET was negative. After one month, an exploratory laparotomy was performed. Intraoperative extemporaneous histological examination of macrobiopsy of two liver lesions at the V segment was negative for malignancy. Thus, a duodenocephalopancreasectomy was performed. Microscopic examination reported the diagnosis of PDAC with negative surgical margins and 7 out of 25 metastatic pancreatic lymph nodes (ypT2N1). After 2 months, a CT scan of the chest and abdomen showed no secondary lesions. ASCO guidelines recommend a total of 6 mounts CT between neoadjuvant and adjuvant chemotherapy. So far, no systemic chemotherapy was administered in the following 6 months. Next, two consecutive CT scans identified no metastases, showing only three stable subcentimetric liver nodules. During this period, a slow progressive increase of tumor markers was documented.\n\nAt the third radiological evaluation after surgery, the liver and lung relapse was observed (Figures 4(a)–4(d)). The patient underwent administration of other 20 cycles of mFOLFIRINOX with a 1-year progression-free survival. The most frequently observed mFOLFIRINOX-related grade 1-2 adverse events were diarrhea, stomatitis, and anemia. Occasionally, grade 3 neutropenia, anemia, diarrhea, and fatigue required dosage adaptions. After that, a second line with gemcitabine was administered for 6 months due to the increase of liver and lung metastases. Overall, the patient achieved an OS of 45 months.\n\n3. Discussion\nLiver metastases strongly impact PDAC outcome and embody an unmet clinical need target, representing one of the main morbidity and mortality factors in these patients. However, sometimes liver metastases are sensitive to chemotherapy treatment due to greater drug delivery than pancreatic tissue [12]. Unfortunately, the clinical setting of a complete radiological response to liver metastases from PDAC is not supported by high-quality literature data. So far, the specialist has no strong evidences for clinical judgment-based therapeutic decision [13].\n\nIndeed, only scanty evidences derived from case reports and retrospective analyses have been published to date [14]. Limitations of these studies are the retrospective methodology employed, the population heterogeneity, the difference between the surgery volume of the referral centers involved, and the lack of homogeneity of the primary cytoreductive therapy utilized. Moreover, the concordance between experts in the field is also insufficient. Despite the available evidences do not support upfront synchronous resection of PDAC liver metastases, conversion surgery after optimal response to chemotherapy justifies a reasonable optimism for such integrated therapeutic window [14]. It is rational to include our case clinical course within the PDAC phenotype identified by Frigerio et al., in which the complete response obtained on liver metastases to a first-line cytoreduction might predict a favorable clinical outcome with a median overall survival (OS) of 56 months for 24 out of 535 subjects (4.5%) bridged to surgery. The regimen employed was either FOLFIRINOX (66%) or gemcitabine-based therapy (34%) [15], leading to 88% of R0 resection and to 17% of patients gaining a complete pathological response. The mortality rate was 0%. Furthermore, also primary tumor excision along with synchronous metastatic surgical resection for 23 patients out of 1147 (2%) in optimal response after either FOLFIRINOX (61%) or gemcitabine-based therapy (39%) showed a median OS of 34.1 months [16]. In light of the aforementioned data, further reports confirmed analogous clinical behavior [17].\n\nAnalogous reports are derived from Crippa et al. [18], who published the results of a retrospective bi-institutional study on the role of surgery in patients with liver metastatic PDAC with good performance status who underwent primary chemotherapy with subsequent radiological response and biochemistry. The study included 127 patients who underwent various chemotherapy schemes: gemcitabine-based (44%); FOLFIRINOX (8%); cisplatin, gemcitabine, capecitabine, and epirubicin (PEXG)/capecitabine and docetaxel (PDXG)/epirubicin and fluorouracil (PEFG) (48%). 56 patients (44%) had a complete (7%) or partial (37%) metastasis radiological response. Surgical treatment was considered in patients with complete or partial radiological response and with normalization of CA 19.9 or reduction of CA 19.9 >90% compared to the initial value. 11 patients (8.5%) underwent surgical resection. Median OS was 11 months in the entire cohort and 15 months for patients with complete/partial response. In this subgroup, OS was significantly longer in patients undergoing surgical resection (median OS: 46 months versus 11 months; p < 0.0001). Some authors identified the following as independent survival factors: multichemotherapy (HR: 0.512), surgical resection (HR: 0.360), >5 liver metastases at diagnosis (HR: 3.515), and reduction of CA 19.9 <50% compared to diagnosis (HR: 2.708). A retrospective analysis and a low number of patients undergoing surgical resection affect the study methodology. Nonetheless, the data obtained inspired further well-designed statistically powered clinical trial (i.e., ClinicalTrials.gov identifier: NCT02892305 and NCT00855634). Indeed, Crippa et al. highlighted the fundamental role of patient selection in driving the therapeutic strategy, taking into account risk factors, cytoreductive regimen employed, and prognostic determinants such as the radiological and biochemical responses [18].\n\nConversely, some authors showed that synchronous pancreatic and liver metastases resection upfront did not result in improved survival compared to palliative treatment (mOS range of 6 months) and does not appear to be justified [6, 19].\n\nOther evidences reported a small increase in survival for resection of synchronous PDAC liver metastases with acceptable safety in highly selected patients [20, 21]. Hackert et al. published the results of a single-center retrospective study in which postoperative complications and survival were evaluated in 62 patients with PDAC with synchronous liver metastases undergoing pancreatic and hepatic primary surgical resection. Patients suffered from limited liver disease (oligometastatic pancreatic cancer) and in 57 patients an atypical liver resection of one or two metastases was performed. About 10% of patients developed a clinically significant pancreatic fistula, 6.4% postoperative bleeding; 3.2% of patients underwent second-surgery and 30-day mortality was 1.6%. Median OS was 12.3 months and 5-year survival was 8.1%. Limitations of this study consisted of retrospective analysis and the lack of complete data regarding the adjuvant treatment employed [22].\n\nTherefore, according to current evidences, it is reasonable to suggest that in patients with liver oligometastatic PDAC cancer, surgery upfront indication would necessitate prospective controlled clinical trials to support clinical decisions.\n\nConversely, surgical treatment can be considered in highly selected metastatic PDAC cases with stringent response to primary chemotherapy in clinical trials at reference centers. However, to date, there are no selection criteria for primitive or liver metastasis resection of mPDAC.\n\nGiven the presented elements, it would be of paramount importance to identify two orders of criteria aimed to properly tailor the combination approach to mPDAC: biologic predictors might foster a personalized therapeutic plan and imaging criteria, able to resolve the response criteria dilemma and to hold the promise to dissect the potential cure rate of a given patient subgroup. In some carefully selected cases after primary chemotherapy, the objective response assessment by imaging and tumor markers can orientate the surgery choice.\n\nOur case report highlights an extraordinary and apparently unpredictable disease course, arising unsolved clinical and preclinical questions. Given that the complete response of hepatic metastasis in PDAC constitutes a rare event, an extensive biologic investigation can help to deeper characterize the underlying unsolved biologic phenotype. The genomic landscape appears to be one of the major challenging factors driving tumor heterogeneity [23, 24]. Both distant metastases [25, 26], nodal involvement [27, 28], and drug resistance [29–31] have been correlated with peculiar molecular signatures in PDAC. Cancer omics and biological signatures are able to stratify tumors depending on the cancer cell phenotype and the tumor niche, able to educate a neoplastic-friendly microenvironment for both solid and hematological cancer [32–36]. Resolving the spatial and clonal cancer heterogeneity might provide fundamental clues, able to deeper characterize translational target and oncogenic drivers, providing novel theragnostic targets.\n\nThe paradigm learned from colorectal carcinoma represents a pragmatic integration between biological prognostic factors and progressive resolution of comprehensive surgical-medical approach of metastatic colon carcinoma [37, 38]. The lesson from these evidences drove expanded indication for surgery in metastatic neuroendocrine [39] and renal cell carcinoma [40]. On the contrary, current guidelines do not support surgical approach for PDAC in metastatic setting [5].\n\nThere are other reports for conversion therapy for PDAC. There are other reports on mFOLFIRINOX long-term survival in PDAC. To our knowledge, this is the first report of coexistence of prolonged chemotherapeutic exposure along with clinical favorable outcome for a metastatic PDAC patient. In particular, the peculiarity of this report was given to achieving an OS of more than 40 months with a combined strategy of a conversion treatment of a metastatic PDAC patient with mFOLFIRINOX and a long-term administration of this treatment. He complained several related adverse events; nonetheless, we were able to administer more than 30 treatment cycles. Safety profile was acceptable in terms of supportive treatment. Even if this PDAC seemed to be a platinum-sensitive tumor, there was no family history of cancer among relatives of this patient. In any case, it was a BRCA wild type tumor. This multidimensional management displays paramount relevance, taking into account the frequent correlation between the length of treatment and the appearance of AE, which sometimes could require hospitalization [41, 42]. In frame of this thinking, the need of optimal patient selection would prevent unnecessary and unethical treatment, bridging the gap of stratified approach dedicated to subjects harboring clinical and biological signatures that predict more favorable outcome when approached with combined strategies [43, 44].\n\nAcknowledgments\nThis study was partially supported by the Apulian Regional Project “Medicina di Pecisione.”\n\nData Availability\nThe data used to support the findings of this study are included within the article and are available from the corresponding author upon request.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest.\n\nFigure 1 Staging: radiological evaluation of primary pancreatic lesion (a) and liver metastasis (b–d). 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"fulltext_license": "CC BY",
"issn_linking": "2291-2789",
"issue": "2020()",
"journal": "Canadian journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Can J Gastroenterol Hepatol",
"mesh_terms": "D000230:Adenocarcinoma; D000971:Antineoplastic Combined Chemotherapy Protocols; D021441:Carcinoma, Pancreatic Ductal; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "101623613",
"other_id": null,
"pages": "8679751",
"pmc": null,
"pmid": "33102398",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9626229;29079592;21376230;28516291;23660962;21561347;22000009;25812117;31110329;24084722;21460848;28383487;31285145;26049277;30866547;29064484;19097774;31231358;23148997;25702263;18309512;27423449;20495644;27856064;31277479;25944992;30620402;26909576;17066229;24840647;20585879;24587996;20573852;30487695;20427809;31180816;28083912;17941009;30207593;27604886;9164539;21197481;30582059;24131140",
"title": "Complete Response of Synchronous Liver Metastasis in a Pancreatic Ductal Adenocarcinoma, When Surgery Could Represent a Therapeutic Option.",
"title_normalized": "complete response of synchronous liver metastasis in a pancreatic ductal adenocarcinoma when surgery could represent a therapeutic option"
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