article dict | reports listlengths 1 3.97k |
|---|---|
{
"abstract": "Primary biliary cirrhosis (PBC) is an autoimmune disease in which intrahepatic bile ducts are targeted by an immune-mediated injury. This disease tends to progress to fibrosis and cirrhosis with hepatic failure. The authors report a case of a 50-year-old rheumatoid arthritis (RA) patient, with erosions and seropositive for rheumatoid factor and anti-citrullinated peptide antibodies, with 18 years disease duration refractory to prednisolone and several disease-modifying antirheumatic drugs, either conventional or biological (adalimumab and etanercept). In April 2007, she started therapy with rituximab (RTX) with good European League Against Rheumatism response achieved 9 months later. In June 2008, she was admitted with intrahepatic cholestasis, steatorrhea, and spontaneous fractures of various ribs. After excluding cholelitiasis, as well as infectious and neoplastic diseases a liver biopsy was performed that was compatible with the diagnosis of PBC. The antinuclear antibodies (1/160) were positive as well as the antimitochondrial antibodies (1/640). Other antibodies were negative such as anti-SSA and anti-SSB. Afterwards, the patient started ursodesoxycholic acid 15 mg kg(-1) day(-1) with progressive improvement of cholestatic markers. A labial salivary gland biopsy was performed and showed findings compatible with the concomitant diagnosis of Sjögren's syndrome. Based on this clinical report, a detailed review of the clinical aspects of PBC is presented as well as its association with other immune-mediated inflammatory diseases, particularly, with RA.",
"affiliations": "Rheumatology Research Unit, Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal. polidopereira@gmail.com",
"authors": "Polido-Pereira|Joaquim|J|;Rodrigues|Ana Maria|AM|;Canhão|Helena|H|;Saraiva|Fernando|F|;da Silva|José Alberto Pereira|JA|;Fonseca|João Eurico|JE|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-011-1879-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0770-3198",
"issue": "31(2)",
"journal": "Clinical rheumatology",
"keywords": null,
"medline_ta": "Clin Rheumatol",
"mesh_terms": "D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006801:Humans; D008105:Liver Cirrhosis, Biliary; D008875:Middle Aged; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "8211469",
"other_id": null,
"pages": "385-9",
"pmc": null,
"pmid": "22042492",
"pubdate": "2012-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "11602476;305233;20955967;14594129;17570008;20087196;6896227;19333938;3488708;1400901;7237912;17709548;7791541;15208427;589109;6123527;6628157;3802575;18328158;17043441;20880057;16250040;16177252;8114302;9287980;19078064;12516200;17369071;890417;1940780;14722198;2228066",
"title": "Primary biliary cirrhosis in a rheumatoid arthritis patient treated with rituximab, a case-based review.",
"title_normalized": "primary biliary cirrhosis in a rheumatoid arthritis patient treated with rituximab a case based review"
} | [
{
"companynumb": "PT-SANOFI-AVENTIS-2012SA011614",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "A 70-year-old woman with a background of portopulmonary hypertension, managed with sildenafil and oral diuretics, and cirrhosis, presented with acute on chronic haemorrhoidal bleeding, iron deficiency anaemia and worsening right heart failure. She presented in a normal conscious and cognitive state. Management involved intravenous diuresis with frusemide and blood transfusion. She quickly begun to develop fever, severe polyarticular arthropathy and progressive encephalopathy. Analgesia was started and antibiotics administered for potential septic sources. Extensive investigations, including full septic screen and neurological imaging, revealed no explainable aetiology for her precipitous decline. She continued to have febrile episodes, worsening polyarticular arthropathy and progressive encephalopathy eventually becoming unresponsive. Given the severe polyarticular arthropathy knee aspiration was performed. Urate crystals were identified and intravenous hydrocortisone and colchicine were started. Within 2 days she achieved full resolution of her systemic, musculoskeletal and neurological symptoms. We propose this as a rare case of gout-induced encephalopathy.",
"affiliations": "Sir Charles Gairder Hospital, Perth, Western Australia, Australia.;St John of God Subiaco, Perth, Western Australia, Australia.;Bendat Respiratory Research and Development Fund, Perth, Western Australia, Australia.",
"authors": "Lewis|Cameron Scott|CS|;Skiba|Rohen|R|;Gabbay|Eli|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227058",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "11(1)",
"journal": "BMJ case reports",
"keywords": "delirium; metabolic disorders; rheumatology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D015210:Arthritis, Gouty; D001927:Brain Diseases; D005260:Female; D005334:Fever; D006801:Humans; D007719:Knee Joint",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30567247",
"pubdate": "2018-12-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16407889;25427113;24610863;16204625;9247047;23669801;28585290;8963753;21159831;16758506",
"title": "Polyarticular arthropathy and encephalopathy in a 70-year-old woman.",
"title_normalized": "polyarticular arthropathy and encephalopathy in a 70 year old woman"
} | [
{
"companynumb": "PHHY2019AU022908",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "A female with gestational diabetes presented with hip pain characteristic of meralgia paresthetica and trochanteric bursitis. She had similar episodes prior to pregnancy that were treated successfully with non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroid injections. However, NSAID use during pregnancy poses risks to the fetus and corticosteroids carry a risk of hyperglycemia, especially in those with diabetes. Unfortunately, all attempts made to treat her conservatively failed to improve her symptoms. The use of antenatal corticosteroids as an intervention for preterm labor has been documented, but to our knowledge, there are no published reports of corticosteroid injections for orthopedic complaints in someone with gestational diabetes. Review of her glucose log showed well-controlled levels, and subsequently, a corticosteroid injection was administered. Blood glucose levels were monitored for the next 48 h, and all measurements were within normal limits. The patient's symptoms resolved, and she went on to vaginally deliver a healthy term infant without complications, suggesting that gestational diabetes should not be used as absolute criteria to withhold corticosteroid injections for orthopedic complaints.",
"affiliations": ", Birmingham, USA.;, Birmingham, USA.;, Birmingham, USA. sgould@uabmc.edu.",
"authors": "Myrex|Palee|P|;Harper|Lorie|L|;Gould|Sara|S|http://orcid.org/0000-0002-0713-1156",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1186/s40798-017-0115-y",
"fulltext": "\n==== Front\nSports Med OpenSports Med OpenSports Medicine - Open2199-11702198-9761Springer International Publishing Cham 11510.1186/s40798-017-0115-yShort CommunicationCorticosteroid Injection for an Orthopedic Complaint in a Female with Gestational Diabetes Myrex Palee palee@uab.edu Harper Lorie lmharper@uabmc.edu http://orcid.org/0000-0002-0713-1156Gould Sara sgould@uabmc.edu Birmingham, USA 5 1 2018 5 1 2018 12 2018 4 310 7 2017 7 12 2017 © The Author(s). 2018Open 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 female with gestational diabetes presented with hip pain characteristic of meralgia paresthetica and trochanteric bursitis. She had similar episodes prior to pregnancy that were treated successfully with non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroid injections. However, NSAID use during pregnancy poses risks to the fetus and corticosteroids carry a risk of hyperglycemia, especially in those with diabetes. Unfortunately, all attempts made to treat her conservatively failed to improve her symptoms. The use of antenatal corticosteroids as an intervention for preterm labor has been documented, but to our knowledge, there are no published reports of corticosteroid injections for orthopedic complaints in someone with gestational diabetes. Review of her glucose log showed well-controlled levels, and subsequently, a corticosteroid injection was administered. Blood glucose levels were monitored for the next 48 h, and all measurements were within normal limits. The patient’s symptoms resolved, and she went on to vaginally deliver a healthy term infant without complications, suggesting that gestational diabetes should not be used as absolute criteria to withhold corticosteroid injections for orthopedic complaints.\n\nKeywords\nGestational diabetes mellitusBlood glucoseCorticosteroid injectionissue-copyright-statement© The Author(s) 2018\n==== Body\nKey points\n\nOrthopedic complaints in pregnant patients can be difficult to treat as providers may be hesitant to employ certain traditional therapies in the gravid patient.\n\nCorticosteroid injections are often used to help fetal lung maturity during preterm labor, but corticosteroids have not been studied for their use to treat orthopedic complaints in the mother.\n\nAlthough corticosteroids carry the risk of hyperglycemia, gestational diabetes should not be used as absolute criteria to withhold corticosteroid injections for orthopedic complaints.\n\n\n\n\nFindings\nCase Report\nA 32-year-old female recently diagnosed with gestational diabetes after an abnormal glucose challenge test (blood glucose level of 206 mg/dL at 1 h) presented to the sports medicine clinic at 30 weeks pregnant with lateral hip pain. She described the pain as a “burning that started in the lateral aspect of the left hip and radiated down the lateral aspect of the thigh.” The patient also reported lateral hip pain which was worse when rising from a seated position, climbing stairs, and lying on her left side. The pain was rated as a 2/10 in severity and was similar to the pain she had prior to pregnancy that was treated successfully with NSAIDs and a corticosteroid injection into the trochanteric bursa. Physical exam was notable for the absence of skin changes and absence of tenderness to palpation in the left groin but positive for tenderness to palpation in the lateral aspect of the thigh as well as directly over the greater trochanter. Range of motion testing was limited by her gravid habitus, but there was normal external and internal rotation of the left hip. Complete patient history and physical exam were indicative of meralgia paresthetica as well as trochanteric bursitis.\n\nAlthough her previous episodes had been treated successfully with NSAIDs and corticosteroid injections, NSAIDS are contraindicated in the third trimester of pregnancy and her gestational diabetes placed her at an increased risk of hyperglycemia from corticosteroid injections. Conservative measures such as physical therapy, education about weight loss, and instructions to wear loose clothing were recommended; however, the patient returned around 2 weeks later with no improvement in her symptoms. The patient’s daily blood glucose log was reviewed, and it showed an average fasting blood glucose level of 92 mg/dL and an average postprandial blood glucose level of 119 mg/dL. She was controlling her blood glucose by diet and exercise alone. Clearance was obtained by her OB/GYN to receive the corticosteroid injection, and subsequently, the patient received an ultrasound-guided injection of a sterile mixture containing 4 cc 0.5% marcaine and 40 mg methylprednisolone acetate into the left greater trochanteric bursa (Fig. 1). Blood glucose levels were closely monitored for the next 48 h, and all readings were within normal limits. At a 1-month follow-up, the patient reported that the pain was significantly improved, now rated as 0/10, and therefore, she had returned to her normal exercise routine. Approximately 6 weeks after the steroid injection, the patient vaginally delivered a 3000-g male at 38 weeks and 1-day gestation. There were no complications, and the baby tolerated delivery well, recording APGAR scores of 7 at 1 min and 9 at 5 min.Fig. 1 Ultrasound of the greater trochanter (GT) and inflamed bursa\n\n\n\nDiscussion\nOur patient was experiencing meralgia paresthetica and trochanteric bursitis, both orthopedic conditions that can be related to the physiologic and anatomic changes of pregnancy [1, 2]. Glucocorticoids are potent immunosuppressive and anti-inflammatory drugs indicated for various orthopedic complaints including refractory meralgia paresthetica and trochanteric bursitis. However, a potentially serious complication of corticosteroid use, especially in a patient with gestational diabetes, is their propensity to cause hyperglycemia and possibly diabetic ketoacidosis [3, 4]. Diabetic ketoacidosis during pregnancy poses significant risk to the fetus as a single episode of diabetic ketoacidosis is associated with a 10–25% fetal loss rate [5]. Despite the risks associated with these drugs, they can still be used safely in pregnancy. A prime example is the use of antenatal corticosteroids to accelerate lung maturity in the fetus of a threatened preterm labor [6]. The benefits of improved fetal survival are so great that the National Institute of Health and Care Excellence (NICE) state in their clinical guidelines that “diabetes should not be considered a contraindication to antenatal steroids for fetal lung maturation [7].” NICE provides general guidelines for managing this subset of patients, yet they emphasize that each individual should be managed on a case-by-case basis.\n\nAlthough the guidelines for administration of antenatal corticosteroids in threatened preterm labor are documented, there is little data about corticosteroid injections for orthopedic complaints in pregnant women, especially those with gestational diabetes [8]. As the prevalence of gestational diabetes is increasing, clinical scenarios such as the one with our patient are also likely to increase. Therefore, we felt it was necessary to share this report to draw attention to an important clinical complication and demonstrate the safety of an intervention that might otherwise be withheld during pregnancy due to concerns of the possible complications. Despite having gestational diabetes, our patient’s daily blood glucose levels were controlled and she tolerated the corticosteroid injection well. Her symptoms improved markedly, and there were no significant adverse effects on her blood glucose or subsequent impact on the baby. This absence of adverse effects may be due to non-fluorinated glucocorticoids, such as methylprednisolone, having minimal placental transfer [9]. In summary, all cases should be handled on an individual basis but gestational diabetes should not be an absolute contraindication for corticosteroid injections used to treat orthopedic injuries.\n\nAbbreviations\nNICENational Institute of Health and Care Excellence\n\nNSAIDsNon-steroidal anti-inflammatory drugs\n\nAcknowledgements\nNot applicable.\n\nFunding\nThere was no funding received for this research.\n\nAvailability of Data and Materials\nNot applicable.\n\nAuthors’ Contributions\nPM was involved in designing, collecting, and analyzing the information, as well as drafting of the manuscript. SG was involved in the conception and design, collection, and analysis of the information as well as revision of the manuscript. LH was involved in the analysis as well as revision of the manuscript. All authors read and approved the final version to be published.\n\nAuthors’ Information\nNot applicable.\n\nEthics Approval and Consent to Participate\nNot applicable.\n\nConsent for Publication\nConsent to publish has been obtained from the participant to report individual patient data.\n\nCompeting Interests\nPalee Myrex, Sara Gould, and Lorie Harper declare that they have no conflict of interest.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Borg-Stein J Dugan SA Musculoskeletal disorders of pregnancy, delivery and post-partum Phys Med Rehabil N Am 2007 18 3 459 476 10.1016/j.pmr.2007.05.005 \n2. Matthew LJ McConda DB Lalli TAJ Daffner SD Orthostetrics: management of orthopedic conditions in the pregnant patient Orthopedics 2015 38 10 874 880 10.3928/01477447-20151002-53 \n3. Holness MJ Sugden MC Dexamethasone during late gestation exacerbates peripheral insulin resistance and selectively targets glucose-sensitive functions in beta cell and liver Endocrinology 2001 142 3742 3748 10.1210/endo.142.9.8379 11517149 \n4. Myles TD Steroids—plenty of benefits, but not without risk Obstet Gynecol 2011 117 2 429 430 10.1097/AOG.0b013e31820711f0 21252777 \n5. Veciana M Diabetes ketoacidosis in pregnancy Semin Perinatol 2013 37 267 273 10.1053/j.semperi.2013.04.005 23916025 \n6. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;(3):CD004454. 10.1002/14651858.CD004454.pub2.\n7. National Institute for Health and Care Excellence. Diabetes in pregnancy: management from preconception to the postnatal period. 2008. https://www.nice.org.uk/guidance/ng3/chapter/1-Recommendations. Accessed 4 June 2016.\n8. Kalra S Kalra B Gupta Y Glycemic management after antenatal corticosteroid therapy N Am J Med Sci 2014 6 2 71 76 10.4103/1947-2714.127744 24696828 \n9. Marciniak B Malysza J Czajkowska E Trojnar Z Gorzelak B Oleszczuk J Glucocorticoids in pregnancy Curr Pharm Biotechno 2011 12 750 757 10.2174/138920111795470868\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2198-9761",
"issue": "4(1)",
"journal": "Sports medicine - open",
"keywords": "Blood glucose; Corticosteroid injection; Gestational diabetes mellitus",
"medline_ta": "Sports Med Open",
"mesh_terms": null,
"nlm_unique_id": "101662568",
"other_id": null,
"pages": "3",
"pmc": null,
"pmid": "29305780",
"pubdate": "2018-01-05",
"publication_types": "D016428:Journal Article",
"references": "26488781;17678762;21342122;11517149;24696828;16856047;23916025;21252777",
"title": "Corticosteroid Injection for an Orthopedic Complaint in a Female with Gestational Diabetes.",
"title_normalized": "corticosteroid injection for an orthopedic complaint in a female with gestational diabetes"
} | [
{
"companynumb": "US-TEVA-2018-US-977610",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DEXTROSE"
},
"drugadditional": null,
"... |
{
"abstract": "A patient with morbid obesity and several psychiatric comorbidities underwent laparoscopic sleeve gastrectomy and experienced success with weight loss. However, she experienced lightheadedness, nausea, and a fall and was admitted to the hospital for encephalopathy due to lithium toxicity. The pharmacokinetics of lithium is altered following bariatric surgery. Due to these factors, adjustments were made to the patient's lithium therapy, her levels were subsequently reduced into the therapeutic range, and she continued with no further issues. Mechanisms of lithium toxicity following bariatric surgery and a monitoring protocol to prevent toxicity are discussed.",
"affiliations": "Carilion Clinic, Roanoke, VA, USA.;Carilion Clinic, Roanoke, VA, USA.",
"authors": "Jamison|Suzanna Connick|SC|https://orcid.org/0000-0002-0129-9302;Aheron|Kelley|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X20953000",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X SAGE Publications Sage UK: London, England \n\n10.1177/2050313X20953000\n10.1177_2050313X20953000\nCase Report\nLithium toxicity following bariatric surgery\nhttps://orcid.org/0000-0002-0129-9302Jamison Suzanna Connick 123 Aheron Kelley 14 1 Carilion Clinic, Roanoke, VA, USA\n2 Virginia Tech Carilion School of Medicine, Roanoke, VA, USA\n3 804th Medical Brigade, Devens, MA, USA\n4 Virginia Commonwealth University School of Pharmacy, Richmond, VA, USA\nSuzanna Connick Jamison, Carilion Clinic, 3 Riverside Circle, Roanoke, VA 24016, USA. Email: scjamison@carilionclinic.org\n10 9 2020 \n2020 \n8 2050313X2095300013 3 2019 5 8 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).A patient with morbid obesity and several psychiatric comorbidities underwent laparoscopic sleeve gastrectomy and experienced success with weight loss. However, she experienced lightheadedness, nausea, and a fall and was admitted to the hospital for encephalopathy due to lithium toxicity. The pharmacokinetics of lithium is altered following bariatric surgery. Due to these factors, adjustments were made to the patient’s lithium therapy, her levels were subsequently reduced into the therapeutic range, and she continued with no further issues. Mechanisms of lithium toxicity following bariatric surgery and a monitoring protocol to prevent toxicity are discussed.\n\nPsychopharmacologymental health/psychiatrybariatric surgerylithiumcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nMany patients undergoing bariatric surgery have a comorbid psychiatric diagnosis. Lithium is often used in the treatment of patients with mood disorders. The pharmacokinetics of lithium changes following bariatric surgery. It is vital for those involved in the treatment of the bariatric surgery patient with psychiatric conditions to know the changes in the pharmacokinetics of many medications following bariatric surgery and how to make adjustments to achieve therapeutic drug levels while avoiding adverse effects.\n\nWe describe a patient with morbid obesity and several psychiatric comorbidities who underwent laparoscopic sleeve gastrectomy and experienced success with weight loss. According to the Centers for Disease Control and Prevention (CDC), prevalence rates of obesity increased by 12% from 1999–2000 to 2017–2018, reaching 42.4%.1 The American Society of Metabolic and Bariatric Surgery2 showed an increase in the number of bariatric surgeries performed, from 158,000 in 2011 to 252,000 in 2018. Studies from several countries show that around 40% of all bariatric surgery patients have at least one psychiatric diagnosis.3 Thus, the case presentation is a typical dilemma that the bariatric surgeon, primary care physician, or psychiatrist might encounter.\n\nThe patient experienced encephalopathy due to lithium toxicity on her pre-surgery dose of lithium. Other cases of lithium toxicity after both sleeve gastrectomy and Roux-en-Y have been reported.4–9 In this case report, we discuss the mechanisms of lithium toxicity following bariatric surgery and a monitoring protocol to prevent toxicity.\n\nCase presentation\nThe patient was a 36-year-old female with a history of morbid obesity, major depressive disorder, borderline personality disorder, posttraumatic stress disorder, migraine headaches, and back pain. She possessed the decisional capacity to provide informed consent. She was under the regular care of an internist and a psychiatrist. She had tried numerous weight loss strategies without sustained success. The patient underwent laparoscopic sleeve gastrectomy, after receiving nutrition counseling and psychological clearance for the procedure. An upper gastrointestinal series done prior to the procedure was normal. An x-ray esophagram showed interrupted primary peristalsis with mild stasis, with eventual clearing with secondary peristalsis. The study was otherwise unremarkable. The patient’s weight at the time of surgery was 269.6 pounds (body mass index (BMI) = 41.0). The patient underwent the sleeve gastrectomy with no complications. Following surgery, she experienced intermittent nausea and vomiting. She had difficulty with swallowing all of her medications, which were liquid, crushable tablets, or capsules whose contents could be emptied into liquid. Medications included promethazine suppositories, ondansetron rapidly dissolving tablet, hydrocodone/acetaminophen solution, acetaminophen-butalbital caffeine tablet, pantoprazole granules, suvorexant tablet, zolpidem tablet, gabapentin capsule, multivitamin tablet, lurasidone tablet, prazosin capsule, duloxetine capsule, trazodone tablet, fexofenadine tablet, propranolol tablet, dicyclomine capsule, sumatriptan injector, and lithium carbonate capsule (300 mg taken in the morning and 600 mg taken in the evening).\n\nPrior to the sleeve gastrectomy, the lithium level had been 0.62 mmol/L. About 4 months after the surgery, the lithium level had increased to 1.47 mmol/L on the same dose of lithium.\n\nApproximately 6 months after the sleeve gastrectomy, the patient presented to the emergency department after a fall. She reported feeling lightheaded and nauseous and felt as though her legs gave out. She denied pain or loss of consciousness. Laboratory evaluation in the emergency department showed a urinalysis that was negative for glucose with a specific gravity of 1.010, negative for blood, positive for nitrite and leukocyte esterase, and was positive for bacteria and many squamous epithelial cells. A basic metabolic panel showed sodium of 138 mmol/L, potassium of 3.6 mmol/L, chloride of 102 mmol/L, urea nitrogen of 8 mg/dL, creatinine of 0.92 mg/dL, glucose of 135 mg/dL, and calcium of 10.1 mg/dL. A complete blood count showed a white blood cell count of 6.7 K/µL, hemoglobin of 12.6 g/dL, hematocrit of 38.4%, and platelet count of 299 K/µL. A lithium level was elevated at 1.63 mmol/L. The patient had lost approximately 40 pounds (BMI = 34.9; 14.8% body weight lost) since the time of the sleeve gastrectomy. Differential diagnosis included dehydration and gastrointestinal infection in addition to lithium toxicity.\n\nAt this emergency department, the patient was instructed to hold her lithium for 2 days, which the patient did. The patient’s primary physician and a clinical pharmacist reviewed the patient’s record and made the decision to decrease the patient’s lithium dose to 300 mg twice daily.\n\nThe patient returned to the emergency department approximately 10 days after the first emergency department visit with difficulty walking and one fall, as well as somnolence. A family friend who brought the patient to the emergency department stated that there was no suspicion of overdose. The emergency department workup revealed a urine toxicology screen that was negative for amphetamine, barbiturate, benzodiazepine, cannabinoid, cocaine, opiates, phencyclidine, and oxycodone. Computed tomography scan of the head showed no acute intracranial abnormalities. Lithium level at that time was 1.10 mmol/L. She was admitted to the hospital for encephalopathy. A differential diagnosis, in addition to lithium toxicity, of dehydration, acute kidney injury, and infection were considered. Psychiatry consultation was obtained, and in collaboration with the primary physician, the decision was made to reduce the patient’s lithium dose to 150 mg bid. The patient has had no further episodes of somnolence, falls, or supratherapeutic lithium level since this dose reduction. A lithium level obtained several months later on the 150 mg bid dose was 1.02 mmol/L. One year following surgery, the patient’s lithium level was 0.53 mmol/L at a weight of 199 pounds (BMI = 30.26; 26.2% body weight lost).\n\nThe following table summarizes the patient’s weight loss, creatinine, lithium dosing, and lithium level at baseline, at her presentations to the emergency department, and at follow-up.\n\n\tBMI (kg/m2)\tCreatinine (mg/dL)\tDaily lithium dose (mg)\tLithium level (mmol/L)\t\nBaseline\t41\t1.08\t900\t0.62\t\n4 months post-surgery\t36.8\t0.72\t900\t1.47\t\n6 months post-surgery\t34.9\t0.92\t900\t1.63\t\n6 months 10 days post-surgery\t34.2\t0.64\t600\t1.10\t\n9 months post-surgery\t33.3\t0.68\t300\t1.02\t\n1 year post-surgery\t31.6\t0.79\t300\t0.53\t\nDiscussion\nIn a sleeve gastrectomy procedure, the stomach is divided and stapled vertically, removing more than 85% of the stomach, creating a tube- or banana-shaped pouch that restricts the amount of food that can be consumed and absorbed by the body. Risks of sleeve gastrectomy include gastritis, heartburn, stomach ulcers, injury to the stomach, intestines, or other organs during surgery, leaking from the line where the parts of the stomach have been stapled together, poor nutrition, scarring inside the belly that could lead to a future blockage in the bowel, and vomiting.10 Furthermore, the Roux-en-Y and sleeve gastrectomy procedures affect gastric pH and surface area, but the way these changes affect drug dissolution and absorption is not fully elucidated.6–11\n\nThe Roux-en-Y and sleeve gastrectomy procedures affect absorption within the gut. It may be presumed that in addition to a decreased absorption of nutrients, we would expect a decrease in absorption of medications. However, with lithium, the opposite is the case. Increases in gastric pH can actually increase the deprotonated form of lithium and lead to increased absorption.8,10\n\nThe elimination and distribution of lithium throughout the body is multifactorial. Renal blood flow, glomerular filtration rate (GFR), lean tissue mass, and total body water can affect the pharmacokinetics of the medication. All of these factors are affected during weight loss. In a weight loss situation, there is a decrease in renal blood flow and GFR. This is secondary to a decrease in total body water.7\n\nLithium follows sodium’s path in the kidney, so in instances of dehydration or gastrointestinal fluid loss, lithium would be avidly reabsorbed. Given that our patient experienced inadequate hydration and nutrition postoperatively, her renal absorption of lithium was increased. This may have also contributed to her lithium toxicity.\n\nReiss et al.10 compared the clearance of lithium in obese subjects with that of normal-weight subjects. They found that the steady-state volume of distribution for the obese group was significantly less than that for the control group. The steady-state volume of distribution was significantly correlated with ideal body weight and fat-free mass, but not creatinine clearance. The clearance of lithium was significantly correlated with total body weight, but not with creatinine clearance. These results suggest that obese patients may require larger lithium maintenance doses than non-obese patients.\n\nGong et al.12 report that short-term courses of a low dose of lithium may ameliorate kidney injury. Furthermore, this pathway may explain lithium’s mechanism of action.13 However, this patient required a lifelong treatment course with lithium for antidepressant augmentation and mood stability. The patient maintained a consistent response to the lowered dose of lithium following bariatric surgery.\n\nIn evaluating the patient’s variable response to lithium, we did consider the role of pharmacogenetics.14 However, her response to lithium had been consistent prior to bariatric surgery, and her lithium level remained in the therapeutic range on the same dose prior to the surgery. Her variation in response appeared to vary with her BMI and GFR following surgery. She responded to a typical dose of lithium before the surgery and achieved a similar therapeutic level with a much smaller dose when her stomach surface was smaller, gastric pH was higher, and her GFR and BMI were lower.\n\nEarly signs of lithium toxicity include nausea, tremor, diarrhea, blurred vision, vertigo, confusion, and a decrease in deep tendon reflexes. These can occur at a level of 1.2 mmol/L or greater. As toxicity worsens, typically when lithium levels are greater than 2.5 mmol/L, patients may experience seizures, coma, cardiac dysrhythmias, and potentially permanent neurologic impairment. Our patient experienced lightheadedness and nausea, suggesting that some component of volume depletion was at play. This, in addition to the pharmacokinetic changes associated with lithium distribution and elimination seen with weight loss, created a perfect storm for lithium toxicity.\n\nThere is one case of lithium toxicity after sleeve gastrectomy reported in the literature.6 The patient, who was on 900 mg of lithium daily, had a level of 2.6 mmol/L and required hemodialysis. That patient also was suffering from acute kidney injury. The authors propose both decreased lithium clearance with resolution of obesity and increased lithium absorption as mechanisms by which lithium toxicity may have ensued. Stomach pH increases after both Roux-en-Y and sleeve gastrectomy, leading to increased deprotonation of carbonate salt and increased dissolution of lithium ions.8 Walsh et al.7 suggest that crushing medications to facilitate dissolution in a gastric environment with a higher pH also affects absorption. Walsh et al.7 cite evidence that lithium dissolution is increased after Roux-en-Y gastric bypass, which is concerning given its narrow therapeutic window. The effect of a gastric sleeve bypass on lithium dissolution is not known, but it is reasonable to assume that it is similar, given the evidence presented in this case study and the other of lithium toxicity following gastric sleeve bypass.6\n\nMany patients undergoing bariatric surgery have a comorbid psychiatric diagnosis. About two-thirds of patients presenting for bariatric surgery have a psychiatric disorder,6,11 and 34% of patients undergoing psychological evaluation for gastric bypass are on a psychotropic medication.9 Given the narrow therapeutic window of lithium and the fact that its pharmacokinetics changes with body weight, it behooves physicians who treat bariatric surgery patients to appreciate the risk of lithium toxicity and make dose adjustments in order to prevent it. Walsh et al.7 further suggest that one clinician be responsible for ordering and evaluating the lithium level and making dose adjustments. Our patient’s lithium level more than doubled in the 2 months following surgery, and further increase was observed less than 2 months after that. Bariatric surgery physiology and the prescribed diet and diet-related complications all predispose to alterations in lithium pharmacokinetics. Therefore, a lithium level should be monitored frequently, with dose changes made accordingly. The half-life of lithium in normal patients is 18–36 h. In the presence of rapid weight loss (where lithium clearance would decrease), the elimination half-life of lithium dictates that it would be prudent to monitor the lithium level every 2–4 weeks until weight loss is stable.\n\nIn conclusion, this case illustrates the importance of monitoring lithium levels soon after bariatric procedures. Due to reduction in stomach surface area and increase in gastric pH, along with increases in lithium distribution and decreased elimination, significant increases in plasma concentration of this drug with a narrow therapeutic window could cause toxicity to ensue. Therefore, we recommend monitoring of lithium levels every 2–4 weeks after bariatric surgery. This requires collaboration among bariatric surgeons, primary physicians, and psychiatrists, preferably with the involvement of a clinical pharmacist to guide lithium dose changes based on pharmacokinetics.\n\nThe authors gratefully acknowledge the expertise and assistance of Rita McCandless, Head Librarian, VTCSOM Library. Dr Jamison thanks her family for their unwavering support.\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\nEthical approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iD: Suzanna Connick Jamison \nhttps://orcid.org/0000-0002-0129-9302\n==== Refs\nReferences\n1 \nProducts—data briefs—number 360—February 2020 , https://www.cdc.gov/nchs/products/databriefs/db360.htm (accessed 13 July 2020 ).\n2 \nAmerican Society for Metabolic & Bariatric Surgery . Fact sheet: metabolic and bariatric surgery . American Society for Metabolic & Bariatric Surgery ; 2013 , https://asmbs.org/resources/metabolic-and-bariatric-surgery (accessed 13 December 2018 ).\n3 \nYen Y-C Huang C-K Tai C-M. \nPsychiatric aspects of bariatric surgery\n. Curr Opin Psychiatry \n2014 ; 27 (5 ): 374 –379\n.25036421 \n4 \nMusfeldt D Levinson A Nykiel J , et al\nLithium toxicity after Roux-en-Y bariatric surgery\n. BMJ Case Rep \n2016 ; 2016 : bcr2015214056.\n5 \nDahan A Porat D Azran C , et al\nLithium toxicity with severe bradycardia post sleeve gastrectomy: a case report and review of the literature\n. Obes Surg \n2019 ; 29 : 735 –738\n, https://pubmed.ncbi.nlm.nih.gov/30448980/ (accessed 13 July 2020 ).30448980 \n6 \nNiessen R Sottiaux T Schillaci A , et al\n[Lithium toxicity after bariatric surgery]\n. Rev Med Liege \n2018 ; 73 (2 ): 82 –87\n.29517871 \n7 Lithium toxicity following Roux-en-Y gastric bypass—Bariatric surgical practice and patient care . Mary Ann Liebert, Inc , https://www.liebertpub.com/doi/abs/10.1089/bari.2014.0007 (accessed 25 January 2019 ).\n8 \nAlam A Raouf S Recio FO. \nLithium toxicity following vertical sleeve gastrectomy: a case report\n. Clin Psychopharmacol Neurosci \n2016 ; 14 (3 ): 318 –320\n.27489390 \n9 \nBingham KS Thoma J Hawa R , et al\nPerioperative lithium use in bariatric surgery: a case series and literature review\n. Psychosomatics \n2016 ; 57 (6 ): 638 –644\n.27726858 \n10 \nReiss RA Haas CE Karki SD , et al\nLithium pharmacokinetics in the obese\n. Clin Pharmacol Ther \n1994 ; 55 (4 ): 392 –398\n.8162665 \n11 \nStemmer K Bielohuby M Grayson BE , et al\nRoux-en-Y gastric bypass surgery but not vertical sleeve gastrectomy decreases bone mass in male rats\n. Endocrinology \n2013 ; 154 (6 ): 2015 –2024\n.23554454 \n12 \nGong R Wang P Dworkin L. \nWhat we need to know about the effect of lithium on the kidney\n. Am J Physiol Renal Physiol \n2016 ; 311 (6 ): F1168 –F1171\n.27122541 \n13 \nFreland L Beaulieu J-M. \nInhibition of GSK3 by lithium, from single molecules to signaling networks\n. Front Mol Neurosci \n2012 ; 5 : 14 .22363263 \n14 \nAlda M. \nLithium in the treatment of bipolar disorder: pharmacology and pharmacogenetics\n. Mol Psychiatry \n2015 ; 20 (6 ): 661 –670\n.25687772\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
"issue": "8()",
"journal": "SAGE open medical case reports",
"keywords": "Psychopharmacology; bariatric surgery; lithium; mental health/psychiatry",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X20953000",
"pmc": null,
"pmid": "32974026",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "27726858;25687772;27122541;29517871;22363263;26994048;30448980;23554454;27489390;8162665;24963466;25036421",
"title": "Lithium toxicity following bariatric surgery.",
"title_normalized": "lithium toxicity following bariatric surgery"
} | [
{
"companynumb": "US-APOTEX-2020AP019704",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN\\BUTALBITAL\\CAFFEINE"
},
"drugadd... |
{
"abstract": "We describe a case of cardiomyopathy due to quetiapine. Atypical antipsychotics are known for their multiple and sometimes dangerous side effects. Various studies showed increased sudden cardiac death and sudden unexpected deaths. Quetiapine can cause tachycardia and QT prolongation, alongside a broad list of other side effects. Cardiomyopathy has been reported, but a causative relation was doubted. We report a case of a 37-year-old woman developing a cardiomyopathy under high doses of quetiapine. Symptoms and ultrasound signs largely recovered in the course of the next months after quetiapine was stopped.",
"affiliations": "Faculty of Medicine, University of Antwerp, Campus Drie Eiken, Building S, Universiteitsplein 1, 2610, Wilrijk, Antwerp, Belgium.;Department of Cardiology, AZ KLINA, Augustijnslei, 100, 2930, Brasschaat, Belgium. walter.smolders@klina.be.",
"authors": "Smolders|David M E|DME|;Smolders|Walter A P|WAP|",
"chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate",
"country": "United States",
"delete": false,
"doi": "10.1007/s12012-016-9390-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7905",
"issue": "17(4)",
"journal": "Cardiovascular toxicology",
"keywords": "Cardiomyopathy; Heart failure; Quetiapine",
"medline_ta": "Cardiovasc Toxicol",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D009202:Cardiomyopathies; D005260:Female; D006801:Humans; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "101135818",
"other_id": null,
"pages": "478-481",
"pmc": null,
"pmid": "27804065",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Case Report and Review of the Literature: Cardiomyopathy in a Young Woman on High-Dose Quetiapine.",
"title_normalized": "case report and review of the literature cardiomyopathy in a young woman on high dose quetiapine"
} | [
{
"companynumb": "BE-ACCORD-045758",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PRAZEPAM"
},
"drugadditional": null,
"druga... |
{
"abstract": "Acquired resistance to molecular targeted therapy is a significant challenge of the precision medicine era. The ability to understand these mechanisms of resistance may improve patient selection and allow for the development of rationally designed next-line or combination treatment strategies and improved patient outcomes. AKT is a critical effector of the phosphoinositide 3-kinase signaling cascade, one of the most commonly activated pathways in human cancer. Deregulation of signaling pathways, such as RAF/MEK/ERK are previously described mechanisms of resistance to AKT/PI3K inhibitors. Mutations in the mTOR gene, however, are exceedingly rare. We present a case of acquired mTOR resistance, following targeted AKT inhibition, and subsequent response to mTOR1/2 inhibitor in a patient with metastatic endometrial cancer, the first documented response to ATP-competitive mTOR inhibition in this setting. This case supports mTOR mutation as a mechanism of resistance, and underscores the importance of tumor molecular profiling, exemplifying precision medicine in action.",
"affiliations": "Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.;Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.;Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.;Khalifa Institute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX, USA.;Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA.;Abdominal Imaging Department, MD Anderson Cancer Center, Houston, TX, USA.;Khalifa Institute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX, USA.;Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.;Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA.;Khalifa Institute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX, USA.;Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX, 77030, USA. fmeric@mdanderson.org.",
"authors": "Coleman|Niamh|N|;Subbiah|Vivek|V|http://orcid.org/0000-0002-6064-6837;Pant|Shubham|S|;Patel|Keyur|K|;Roy-Chowdhuri|Sinchita|S|;Yedururi|Sireesha|S|http://orcid.org/0000-0001-6391-3446;Johnson|Amber|A|http://orcid.org/0000-0002-6202-6113;Yap|Timothy A|TA|;Rodon|Jordi|J|;Shaw|Kenna|K|;Meric-Bernstam|Funda|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1038/s41698-021-00240-w",
"fulltext": "\n==== Front\nNPJ Precis Oncol\nNPJ Precis Oncol\nNPJ Precision Oncology\n2397-768X\nNature Publishing Group UK London\n\n240\n10.1038/s41698-021-00240-w\nCase Report\nEmergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition\nColeman Niamh 1\nhttp://orcid.org/0000-0002-6064-6837\nSubbiah Vivek 1\nPant Shubham 1\nPatel Keyur 2\nRoy-Chowdhuri Sinchita 3\nhttp://orcid.org/0000-0001-6391-3446\nYedururi Sireesha 4\nhttp://orcid.org/0000-0002-6202-6113\nJohnson Amber 2\nYap Timothy A. 12\nRodon Jordi 1\nShaw Kenna 2\nMeric-Bernstam Funda fmeric@mdanderson.org\n\n125\n1 grid.240145.6 0000 0001 2291 4776 Department of Investigational Cancer Therapeutics (Phase I Program), The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030 USA\n2 grid.240145.6 0000 0001 2291 4776 Khalifa Institute for Personalized Cancer Therapy, MD Anderson Cancer Center, Houston, TX USA\n3 grid.240145.6 0000 0001 2291 4776 Department of Pathology, MD Anderson Cancer Center, Houston, TX USA\n4 grid.240145.6 0000 0001 2291 4776 Abdominal Imaging Department, MD Anderson Cancer Center, Houston, TX USA\n5 grid.240145.6 0000 0001 2291 4776 Department of Surgical Oncology, MD Anderson Cancer Center, Houston, TX USA\n1 12 2021\n1 12 2021\n2021\n5 9918 6 2021\n9 11 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/.\nAcquired resistance to molecular targeted therapy is a significant challenge of the precision medicine era. The ability to understand these mechanisms of resistance may improve patient selection and allow for the development of rationally designed next-line or combination treatment strategies and improved patient outcomes. AKT is a critical effector of the phosphoinositide 3-kinase signaling cascade, one of the most commonly activated pathways in human cancer. Deregulation of signaling pathways, such as RAF/MEK/ERK are previously described mechanisms of resistance to AKT/PI3K inhibitors. Mutations in the mTOR gene, however, are exceedingly rare. We present a case of acquired mTOR resistance, following targeted AKT inhibition, and subsequent response to mTOR1/2 inhibitor in a patient with metastatic endometrial cancer, the first documented response to ATP-competitive mTOR inhibition in this setting. This case supports mTOR mutation as a mechanism of resistance, and underscores the importance of tumor molecular profiling, exemplifying precision medicine in action.\n\nSubject terms\n\nTumour biomarkers\nOncogenes\nhttps://doi.org/10.13039/100006108 U.S. Department of Health & Human Services | NIH | National Center for Advancing Translational Sciences (NCATS) 1UL1TR003167-01 Meric-Bernstam Funda https://doi.org/10.13039/100000054 U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) CA-16672 Meric-Bernstam Funda This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.This study was funded in part by Takeda Pharmaceutical company, a subsidiary of Merck & Co., Inc., Kenilworth NJ, USA, the Once Upon a Time Foundation, The MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.issue-copyright-statement© The Author(s) 2021\n==== Body\npmcIntroduction\n\nThe serine/threonine kinase, AKT, is a critical effector of the phosphoinositide 3-kinase (PI3K) signaling cascade and is one of the most commonly activated pathways in human cancer1. Dysregulation of AKT-dependent pathways is associated with the development and maintenance of various solid tumors, such as those of the endometrium, cervix, lung, prostate, skin, and breast2–4. Thus, AKT remains an intensely pursued therapeutic target in the era of precision medicine. Indeed, there are a number of small-molecule inhibitors targeting various components of the PI3K/AKT pathway currently at various stages of clinical development, in multiple solid tumors, including prostate, gastric, and breast cancer5–7.\n\nThere are several AKT inhibitors in clinical development, which predominantly fall into two separate classes: ATP-competitive inhibitors of AKT, which bind to the active site of AKT, blocking ATP binding (e.g., ipatasertib and capivasertib) and allosteric inhibitors of the AKT PH-domain which prevent localization of AKT to the plasma membrane, thereby blocking AKT phosphorylation and activation (e.g., ARQ 751 (ArQule) and MK-2206). Capivasertib (AZD5363) is an oral, potent, selective ATP-competitive pan-AKT kinase inhibitor, which has demonstrated clinical activity in patients with heavily pretreated AKT1 E17K mutant solid tumors, with confirmed partial responses reported in ER- endometrial, breast, cervical, and lung cancer8. Furthermore, capivasertib demonstrated a 28.6% ORR in the National Cancer Institute MATCH subprotocol (EAY131-Y) in patients with AKT1 E17K mutant tumors9. Capivasertib plus fulvestrant has also shown antitumor activity in heavily pretreated patients with PTEN-mutated ER + metastatic breast cancer (MBC), including those with prior progression on fulvestrant9.\n\nIpatasertib (GDC-0068), another ATP-competitive pan-AKT kinase inhibitor, has also shown clinical activity in combination with fulvestrant in patients with AKT1 E17K mutant MBC10,11, and has been explored in this population. Although in a Phase III trial, ipatasertib in combination with paclitaxel has not enhanced PFS compared to paclitaxel in MBC, in the Phase III IPATential150 trial12, ipatasertib improved radiographic progression-free survival in metastatic castration-resistant prostate cancer (mCRPC) and patients whose tumors had PTEN loss13. Previously, we have shown that ARQ 751 demonstrated a manageable safety profile, and four patients achieved the best response of stable disease, including one with MBC treated for 42+ weeks; the dose escalation is currently ongoing14.\n\nAcquired resistance is a major challenge for molecularly targeted therapies, and understanding these mechanisms of resistance may improve patient selection and allow the development of rationally designed next-line or combination treatment strategies. Here, we present a case of acquired mTOR resistance, following targeted AKT inhibition, and subsequent response to mTOR1/2 inhibitor in a patient with metastatic endometrial carcinoma. To our knowledge, this is the first documented case of mTOR mutation as an acquired mechanism of resistance in the setting of AKT inhibition, and subsequent documented response to mTOR-based targeted therapy.\n\nResults\n\nCase\n\nA 60-year-old female patient, with a prior history of breast cancer, presented with abnormal vaginal bleeding, and biopsy-confirmed grade II endometrial adenocarcinoma with squamous metaplasia. Following her diagnosis, she initially underwent total laparoscopic hysterectomy with pelvic/aortic lymph node dissection, and pathology confirmed IB grade II endometrial adenocarcinoma with squamous metaplasia, and lymphovascular space invasion. Following this, the patient received adjuvant cisplatin and radiotherapy, with pelvic external beam radiotherapy and vaginal brachytherapy (Fig. 1).Fig. 1 Treatment timeline.\n\nTimeline summarizing treatment course of the patient, including all systemic treatments that the patient received.\n\nOne year later, she developed persistent back pain, and imaging revealed a single T12 lesion with epidural impingement, and subsequent tumor biopsy confirmed metastatic adenocarcinoma consistent with endometrial cancer. Systemic restaging studies revealed a small but suspicious left-sided para-aortic lymph node at the levels of L2-L3. The patient underwent stereotactic radiosurgery and thermal ablation for cord compression, and she received carboplatin and liposomal doxorubicin for three cycles, followed by focal radiotherapy to persistent para-aortic lymphadenopathy.\n\nComputed tomography (CT) restaging imaging 7 months later revealed disease progression in the lungs, and the patient commenced cisplatin and gemcitabine chemotherapy. However, post cycle 3, imaging revealed T12 metastasis showing a new region of FDG-avidity, compatible with progression and stable pulmonary nodules. MRI spine showed suspected progression of epidural soft tissue metastasis at T12 resulting in mild-to-moderate spinal canal stenosis but no definite cord signal abnormality. She received definitive treatment for her cancer in the spine, with thermal ablation of the T12 region, followed by vertebrectomy and reconstruction with cement stabilization T9-L3, and zolendronic acid therapy was commenced.\n\nFollowing the further progression of cancer on positron emission tomography (PET) CT, with the increase in size and number of pulmonary metastases and new mesenteric disease, the patient was referred to for consideration of a phase I trial Department of Investigational Cancer Therapeutics at the University of Texas MD Anderson Cancer Center. Next-generation sequencing (NGS)– analysis for the detection of somatic mutations in the coding sequence of 50 genes15 (Ion Ampliseq 50-Gene Assay; Thermo Fisher) of retroperitoneal lymph node revealed an AKT1 E17K activating mutation and no other co-occurring alterations of functional significance (Supplementary Table 1). The patient was enrolled on a phase I study of an allosteric pan-AKT inhibitor ARQ751 (NCT02761694). The patient received 25 mg daily orally initially and tolerated treatment without significant toxicity. As the protocol allowed intra-patient dose-escalation, the dose was escalated to 50 mg daily and subsequently increased to 75 mg daily. Treatment was relatively well-tolerated, requiring no dose reductions or interruptions of treatment. She experienced stability of disease (4% reduction by RECIST criteria version 1.1)16 lasting 27 months.\n\nFollowing 27 months of AKT inhibition, RECISTv1.1 progressive disease was confirmed on restaging PET-CT imaging, showing an increase in the size of multifocal pulmonary metastases and increase in left axillary nodal metastatic disease. The patient underwent a CT-guided lung biopsy which confirmed adenocarcinoma consistent with the endometrial primary. NGS analysis (Oncomine®, Thermo Fisher) for the detection of somatic mutations in the coding sequence of 143 cancer-related genes17 was conducted, on this occasion on the DNA extracted from the patients’ metastatic pulmonary lesion, which confirmed the persistence of AKT1 E17K mutation, and an mTOR mutation, mTOR A1459D, annotated to be an activating mTOR mutation. Sequencing on the lung metastasis demonstrated a CTNNB1 G34R mutation which was also noted on the 50 gene panel of the initial sample. There were no other co-occurring alterations identified. Although the original 50 gene hotspot panel did not sequence mTOR, it was hypothesized that the mTOR mutation may be an acquired resistance mutation, thus, the original pre-treatment sample was re-sequenced on the Oncomine platform, confirming that the AKT1 E17K mutation, and but not the mTOR A1459D mutation was detected (Supplementary Table 1).\n\nThe patient was subsequently enrolled on a phase I study of the mTORC1/2 inhibitor sapanisertib (TAK-228) given 4 mg daily with metformin 500 mg twice daily (NCT03017833). The patient achieved a confirmed partial response (PR) by RECIST criteria version 1.116 post-6 cycles of therapy (maximum reduction 30% from baseline) (Fig. 2). The patient remains on trial at 14 months with good tolerability.Fig. 2 Serial axial CT and fused PET/CT images from contrast enhanced PET/CT examinations at baseline, 4.5 months and 8.5 months illustrate disease response.\n\nSerial axial CT (A–C) and fused PET/CT (D–F) images of the abdomen in soft tissue window show response in the mesenteric implant with decreased size (white arrows in A–F) and significantly decreased FDG uptake with a maximum SUV of 10.5 at baseline, 3.6 at 4.5 months follow up and 4.8 at 8.5 months follow up. Serial axial CT (G-I), and fused PET/CT (J-L) images in lung windows showed a response in the lung metastases. The largest metastasis in the lingua remained grossly stable in size (white arrows in G-I) but showed decreased uptake with a maximum SUV of 20.1 at baseline, 8.8 at 4.5 months follow up and 8.6 at 8.5 months follow up. Multiple other smaller lung metastases (black arrows in G-L) also showed decreased size and decreased uptake.\n\nDiscussion\n\nAKT/PI3K/mTOR signaling is commonly disrupted in human cancers, with AKT being a central component of the pathway, influencing multiple processes which are directly involved in tumorigenesis. AKT is a family of serine/threonine kinases consisting of three isoforms (AKT1, AKT2, and AKT3), regulated upstream by the activation of PI3K, following growth factor stimulation. Several downstream substrates of activated AKT play a major role in the regulation of cell size, cell cycle progression, glucose metabolism, genome stability, transcription, protein synthesis, and inhibition of pro-apoptotic proteins18–20. Targeting this pathway has, therefore, been a highly attractive anti-cancer strategy and significant efforts have been made to target this kinase for many years.\n\nAcquired resistance to molecular targeted therapy represents a significant challenge for the effective treatment of cancer. Deregulation of signaling pathways, including alterations in Raf/Mek/ERK are previously described determinants of tumor resistance to AKT/PI3K inhibitors21,22. We report, to the best of our knowledge, the first clinical case of acquired resistance following targeted therapy with AKT inhibition due to the development of an activating mTOR mutation, and following subsequent detection of this lesion, the first clinical case of documented response to mTOR inhibition in this setting.\n\nThe AKT mutation described in our patient, E17K, is found in the PH domain of AKT1 where a glutamic acid is substituted with a lysine residue at amino acid 17 (E17K), results in enhanced activity of the kinase, leading to constitutive membrane localization of the kinase and increased phosphorylation on T308 and S473 in a PI3K-independent manner23,24. Upregulation of AKT3 has been suggested as a potential mechanism of resistance to allosteric AKT inhibitor MK2206, using preclinical breast cancer models25. Target engagement can, however, be significantly influenced by drug-specific and drug-class-specific differences in isoform and conformation selectivity, and also by the effects of mutation on the accessibility to drug binding sites. For instance, activating AKT mutations such as AKT1-E17K, can destabilize the PH-in conformation and therefore confer resistance to allosteric AKT inhibitors but sensitivity to ATP-competitive inhibitors26. Therefore, the mechanisms of resistance to different AKT inhibitors may be different.\n\nmTOR is a serine-threonine kinase that forms two physically and functionally distinct protein signaling complexes, mTORC1 and mTORC2, which are distinct in their regulation, susceptibility to different classes of inhibitors, and downstream substrates27. Multiple independent studies in cellular and mouse models have demonstrated that sustained, or incompletely inhibited, mTORC1 signaling can contribute to TKI resistance in EGFR-mutant NSCLC and BRAF-mutant melanoma28. Moreover, pre-clinical data are implicating mTORC signaling in resistance to PI3K inhibitors: PIK3CA-mutant breast cancer models resistant to PI3K inhibitors have been shown to exhibit sustained mTORC1 signaling29, and treatment with a rapalog was sufficient to sensitize resistant cells to PI3Kα inhibitor alpelisib29. Indeed, activation of mTORC1 has been shown to be a key event in resistance to PI3K inhibitors in a number of tumors types, perhaps because of its role downstream of PI3K28. In addition to this, the concomitant inhibition of PI3K and mTORC1 has been proven to sensitize resistant cell lines in breast and head and neck cancer, suggesting that mTORC1 may play a role in limiting the sensitivity to PI3K30.\n\nMutations in the mTOR gene are rare, and on the interrogation of the Institute for Personalized Cancer Therapy (IPCT) database in MD Anderson Cancer Center, we noted a frequency of 1.35% of 20,150 patients screened (platforms included CMS400, STGAv1, STGA DNA2018, and LBPv1) (Fig. 3). The mTOR A1459D alteration found in our patient is located within the FAT domain of MTOR (amino acids 1382-1982, UniProt) and TPR repeat 4 (amino acids 1443-1473, UniProt) and has been reported as a recurrent mutation (Fig. 3). This alteration has been reported in a patient with hemimegalencephaly a disorder caused by mutations that result in activation of the PI3K pathway31. Analysis of resected brain tissue from the patient revealed hyper-phosphorylation of mTOR’s downstream targets. Additionally, another study identified this mutation in focal cortical dysplasia type IIb32. In this study, the researchers also observed increased phosphorylation of the mTOR target, 4EBP, compared with cells expressing wild-type mTOR. Another variation of this codon, A1459P, was experimentally shown to also confer a gain-of-function through reduced interaction with the negative regulator, DEPTOR33. Thus, we conclude that this alteration leads to a gain-of-function.Fig. 3 Frequency of mTOR mutations.\n\nA Interrogation of IPCT database in MDACC found that of 20,150 patients sequenced, 273 cases of mTOR mutation were identified; cbioportal was used to identify the frequency in other datasets, including Metastatic Solid Cancers (UMich, Nature 2017) and the MSK-IMPACT Clinical Sequencing Cohort (MSKCC, Nat Med 2017)46,47. B Lollipop plot showing the distribution of mTOR mutations, including the mTOR A1459D mutation, detected in this case46,47.\n\nSome activating mTOR mutations are sensitive to rapamycin treatment34, and while genomic studies have linked mTORC1 pathway–activating mutations with exceptional response to treatment with rapalogs, preclinical studies have also shown that some mTOR mutations can increase mTORC2 activities35,36. Notably, Wagle et al. reported the emergence of an mTOR F2108L mutation in patient with anaplastic thyroid cancer bearing an inactivating TSC2 mutation, after 18 months of treatment on everolimus. Similarly, we have also preclinically identified an acquired resistance mutation in mTOR (mTOR S2035F) with continuous in vitro rapalog treatment and demonstrated that cancer cells with this mutation are resistant to everolimus but are still sensitive to mTOR catalytic inhibitor TAK228 in vitro and in vivo37. Altogether, these data suggest that mTOR mutations may indeed be a mechanism of resistance to allosteric mTOR inhibitors, with a potential role for catalytic inhibitors38. However, this mechanism of resistance is likely to be rare, and in Phase II trials sapanisertib showed only modest clinical benefit in breast cancer patients previously treated with everolimus39.\n\nCells expressing another variant of this codon, mTOR A1459P, were found to be still sensitive to mTOR inhibition with rapamycin33. Thus, it is unclear whether mTOR_A1459D selectively benefitted from catalytic mTOR inhibition or whether it would also have been sensitive to rapamycin analogs. In our previous preclinical work, we have shown that combination of allosteric AKT inhibitor MK2206 and allosteric mTOR inhibitor rapamycin are synergistic in vitro, with greater pathway inhibition as well as greater induction of apoptosis, and the combination leads to a greater enhancement of antitumor activity in vivo40. Thus, the combination of Akt/mTOR inhibition may be another strategy worth exploring to achieve deeper responses but may be limited due to tolerability concerns.\n\nOur case report has a few limitations. Our patient had her tumor sequenced on two occasions using different metastatic disease sites (Supplementary Table 1), and NGS data-guided therapeutic strategy development. The first biopsy was obtained from retroperitoneal nodes that were progressing at that time; the second biopsy was obtained from the lung metastases, the site of progression post-AKT inhibitor treatment. Tumor heterogeneity is a veritable challenge and not only can the molecular profile of cancer change over time, the molecular profile(s) of different metastatic sites can be incongruent41. Admittedly, it is possible that different metastatic sites may harbor heterogeneous gene alterations, which could include the possibility of the pre-existence of mTOR A1459D clones in the non-biopsied metastatic site. Another limitation is that the mTOR A1459D mutation was not evaluated functionally in our study for confirmation of the gain of function. However, there are data published which suggest that this is an activating mutation; in addition, another variant in the same site, A1459P, has already been shown to be activating experimentally. We, thus, felt that this alteration was actionable in the context of clinical trial enrollment. This report is significant for both reporting of mTOR as a potential resistance mechanism for AKT inhibition as well as the clinical response to a mTORC1/2 inhibitor post AKT inhibitor resistance.\n\nOur patient demonstrated impressive disease stability with allosteric AKT inhibition for 27 months, and on the progression of disease genomic profiling revealed downstream activating mTOR mutation A1459D, as well as the persistence of AKT1 E17K. Of note, the allosteric inhibitor AKT inhibitor ARQ751, used in this patient inhibits AKT E17K in preclinical models42. Treatment with dual mTOR inhibitor sapanisertib (TAK228) in combination with metformin achieved a PR on imaging: potentially even a superior response (PR rather than SD), due to more potent ATP-competitive inhibition, and the downstream inhibition of the two oncogenic lesions. In this trial, metformin was used in combination with sapanisertib as metformin activating AMP-dependent kinase (AMPK) causes phosphorylation and activation of the tumor suppressor gene TSC2, which exerts an inhibitory effect on mTOR43; pre-clinically, metformin-induced activation of AMPK has been shown to inhibit cell proliferation, reduce colony formation, and inhibit MAP kinase, AKT, and mTOR44, therefore use of metformin in this patient may have also contributed to the enhanced anti-tumor effect.\n\nTo our knowledge, we report the first clinical case of acquired resistance following ATP-competitive AKT inhibition due to the development of activating mTOR A1459D, and the first documented response to ATP-competitive mTOR inhibition in this setting. Our case exemplifies precision medicine in action from the ability to rapidly identify a patients’ oncogenic driver, to allow physicians to precisely target drivers of disease in real-time. Furthermore, our case underscores the importance of longitudinal genomic profiling in modern cancer care, to guide management, allowing for the rapid identification of molecular mechanisms of resistance and identifying approaches to overcome resistance.\n\nMethods\n\nParticipant\n\nThe patient was treated with allosteric pan-AKT inhibitor ARQ751 following enrollment to phase I study of ARQ751 (NCT02761694) after the collection of the written informed consent. The patient was subsequently treated with mTORC1/2 inhibitor sapanisertib (TAK-228) following enrollment to a phase I study of sapanisertib (TAK-2280) with metformin 500 mg twice daily (NCT03017833) and collection of written informed consent.\n\nMaterials\n\nTumor samples were obtained by core biopsy performed by an interventional radiologist. FFPE specimens derived from fresh tumor biopsies were reviewed by an MD Anderson pathologist to ensure adequate tumor cellularity (≥ 20%) for analysis. Tumor samples were evaluated using hematoxylin and eosin staining for tumor cellularity. DNA was extracted, purified, and quantified. All procedures were performed in a CLIA-compliant environment. For genomic analysis, the pre-treatment sample was sequenced and subsequently analysed in the MD Anderson CLIA molecular diagnostic laboratory using the Ion Ampliseq 50-Gene Assay for the detection of mutations in the coding sequence of 50 genes (Thermo Fisher Scientific, MA, USA). DNA extracted from the lung metastasis biopsy after progression on the Akt inhibitor was sequenced along with matched normal DNA from blood, in the MD Anderson CLIA molecular diagnostic laboratory utilizing the Oncomine® platform (Thermo Fisher) for the detection of somatic mutations in the coding sequence of 143 cancer-related genes, as previously described45. The pre-treatment DNA sample was sequenced using the Ion Ampliseq 50-Gene Assay and was subsequently re-sequenced on the Oncomine platform to confirm the presence of AKT1 E17K mutation, but not mTOR A1459D mutation. All alterations detected were listed in Supplementary Table 1. The radiologic response was assessed according to RECISTv1.1.\n\nReporting Summary\n\nFurther information on research design is available in the Nature Research Reporting Summary linked to this article.\n\nSupplementary information\n\nReporting Summary\n\nSupplementary Information\n\nSupplementary information\n\nThe online version contains supplementary material available at 10.1038/s41698-021-00240-w.\n\nAcknowledgements\n\nThis study was funded in part by Takeda Pharmaceutical company, Merck (ArQule), the Once Upon a Time Foundation, the MD Anderson Cancer Center Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, the Center for Clinical and Translational Sciences (CTSA-Informatics) # 1UL1TR003167-01, and the Cancer Prevention Institute of Texas Grant RP150535: Precision Oncology Decision Support Core, MD Anderson Cancer Center Support Grant (CCSG) funded by National Cancer Institute (NCI) # CA-16672.\n\nAuthor contributions\n\nAll authors contributed equally to the following: conception or design of the work, drafting the article, critical revision of the article, and final approval of the version to be published.\n\nData availability\n\nSamples were sequenced and analysed in a CLIA-compliant MD Anderson laboratory as described above. The raw sequencing data are not publicly available due to data privacy regulations and restrictions for use of such data, as stated in the study protocol and patient consent form. The alterations identified on the targeted panels are available in Supplementary Table 1.\n\nCompeting interests\n\nThe Precision Oncology Decision Support (PODS) team at MD Anderson Cancer Center is receiving funding and technology support from Royal Philips. N.C., K.P., S.R-C., S.Y., A.J., and K.S. report no conflicts of interest. V.S. reports receiving Research funding/Grant support for clinical trials from Roche/ Genentech, Novartis, Bayer, GlaxoSmithKline, Nanocarrier, Vegenics, Celgene, Northwest Biotherapeutics, Berghealth, Incyte, Fujifilm, Pharmamar, D3, Pfizer, Multivir, Amgen, Abbvie, Alfa-sigma, Agensys, Boston Biomedical, Idera Pharma, Inhibrx, Exelixis, Blueprint medicines, Loxo oncology, Medimmune, Altum, Dragonfly Therapeutics, Takeda, and National Comprehensive Cancer Network, NCI-CTEP and UT MD Anderson Cancer Center, Turning point therapeutics, Boston Pharmaceuticals; Travel support from Novartis, Pharmamar, ASCO, ESMO, Helsinn, Incyte and has served on Consultancy/Advisory boards for Helsinn, LOXO Oncology/Eli Lilly, R-Pharma US, INCYTE, QED pharma, Medimmune, Novartis, Relay Therapeutics, Roche; Other: Medscape. S.P. reports receiving Research/Grant Funding through the institution from the following sources: AbbVie, Argule, Bristol-Myers Squibb, Eli Lilly, Five Prime Therapeutics, Glaxo Smith Kline, Holy Stone Healthcare Co., InnoPharmax Inc., Ipsen, Mirati Therapeutics, Inc., Novartis, Onco Response, Parexel International LLC, Red Hill Biopharma Ltd., Rgenix, Sanofi US Services Inc., Sanofi-Aventis, Xencor and Financial Relationship/Speakers Bureau Consultancy from Tyme Inc. and 4D-Pharma. T.Y. reports receiving research support (to institution) from Artios, AstraZeneca, Bayer, Clovis, Constellation, Cyteir, Eli Lilly, EMD Serono, Forbius, F-Star, GlaxoSmithKline, Genentech, ImmuneSensor, Ipsen, Jounce, Karyopharm, Kyowa, Merck, Novartis, Pfizer, Ribon Therapeutics, Regeneron, Repare, Sanofi, Scholar Rock, Seattle Genetics, Tesaro, and Vertex Pharmaceuticals and consultancies from Almac, Aduro, AstraZeneca, Atrin, Axiom, Bayer, Bristol Myers Squibb, Calithera, Clovis, Cybrexa, EMD Serono, F-Star, Guidepoint, Ignyta, I-Mab, Jansen, Merck, Pfizer, Repare, Roche, Rubius, Schrodinger, Seattle Genetics, Varian and Zai Labs. J.R. reports non financial support and reasonable reimbursement for travel from European Journal of Cancer, Vall d’Hebron Institut of Oncology, Chinese University of Hong Kong, SOLTI, Elsevier, GLAXOSMITHKLINE,; receiving consulting and travel fees from Novartis, Eli Lilly, Orion Pharmaceuticals, Servier Pharmaceuticals, Peptomyc, Merck Sharp & Dohme, Kelun Pharmaceutical/Klus Pharma, Spectrum Pharmaceuticals Inc, Pfizer, Roche Pharmaceuticals, Ellipses Pharma, NovellusDx, Ionctura and Molecular Partners (including serving on the scientific advisory board from 2015-present), receiving research funding from Blueprint Pharmaceuticals, Bayer and Novartis, and serving as investigator in clinical trials with Spectrum Pharmaceuticals, Tocagen, Symphogen, BioAtla, Pfizer, GenMab, CytomX, KELUN-BIOTECH, Takeda-Millenium, GLAXOSMITHKLINE, IPSEN and travel fees from ESMO, US Department of Defense, Louissiana State University, Hunstman Cancer Institute, Cancer Core Europe, Karolinska Cancer Institute and King Abdullah International Medical Research Center (KAIMRC), Molecular Partners. F.M-B. reports Consulting from AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tyra Biosciences, Xencor, Zymeworks. Advisory Committee from Black Diamond, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Mersana Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, Zentalis. Sponsored Research from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical (formerly Millennium Pharmaceutical), Novartis, Puma Biotechnology Inc., Taiho Pharmaceutical Co.Honoraria from Chugai Biopharmaceuticals, Mayo Clinic, Rutgers Cancer Institute of New Jersey. Other (Travel Related) from Beth Israel Deaconess Medical Center.\n\nEthical approval\n\nEthical approval/Institutional review board approval for the above clinical trials were obtained by MD Anderson Cancer Center. Consent to participate was obtained.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Lawrence, M. S. et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature. 10.1038/nature12912 (2002).\n2. Clark, A. S., West, K., Streicher, S. & Dennis, P. A. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol. Cancer Ther. 10.1158/1535-7163.MCT-11-0712 (2002).\n3. Mundi, P. S., Sachdev, J., McCourt, C. & Kalinsky, K. AKT in cancer: new molecular insights and advances in drug development. British Journal of Clinical Pharmacology. 10.1111/bcp.13021 (2016).\n4. Hinz, N. & Jücker, M. Distinct functions of AKT isoforms in breast cancer: a comprehensive review. Cell Commun. Signal. 10.1186/s12964-019-0450-3 (2019).\n5. Bang, Y. J. et al. A phase II, randomised study of mFOLFOX6 with or without the Akt inhibitor ipatasertib in patients with locally advanced or metastatic gastric or gastroesophageal junction cancer. Eur. J. Cancer. 10.1016/j.ejca.2018.11.017 (2019).\n6. De Bono, J. S. et al. Randomized phase II study evaluating AKT blockade with ipatasertib, in combination with abiraterone, in patients with metastatic prostate cancer with and without PTEN loss. Clin. Cancer Res. 10.1158/1078-0432.CCR-18-0981 (2019).\n7. Zhu, R. et al. Exposure–response-based product profile–driven clinical utility index for Ipatasertib dose selection in prostate cancer. CPT Pharmacometrics Syst. Pharmacol. 10.1002/psp4.12394 (2019).\n8. Hyman, D. M. et al. AKT inhibition in solid tumors with AKT1 mutations. J. Clin. Oncol. 10.1200/JCO.2017.73.0143 (2017).\n9. Kalinsky, K. et al. Effect of capivasertib in patients with an AKT1 E17K-mutated tumor: NCI-MATCH subprotocol EAY131-Y nonrandomized trial. JAMA Oncol. 10.1001/jamaoncol.2020.6741 (2021).\n10. Bose, S. & Kalinsky, K. Durable clinical activity to the AKT inhibitor Ipatasertib in a heavily pretreated patient with an AKT1 E17K mutant metastatic breast cancer. Clin. Breast Cancer. 10.1016/j.clbc.2020.10.002 (2020).\n11. Saura, C. et al. A first-in-human phase I study of the ATP-competitive AKT inhibitor Ipatasertib demonstrates robust and safe targeting of AKT in patients with solid tumors. Cancer Discov. 10.1158/2159-8290.CD-16-0512 (2017).\n12. Dent, R. et al. Abstract GS3-04: double-blind placebo (PBO)-controlled randomized phase III trial evaluating first-line ipatasertib (IPAT) combined with paclitaxel (PAC) for PIK3CA/AKT1/PTEN-altered locally advanced unresectable or metastatic triple-negative breast cancer (aTNBC): primary results from IPATunity130 Cohort A. Cancer Res. 81, GS3-04 LP-GS3-04 (2021).\n13. de Bono, J. S. et al. LBA4 IPATential150: Phase III study of ipatasertib (ipat) plus abiraterone (abi) vs placebo (pbo) plus abi in metastatic castration-resistant prostate cancer (mCRPC). Ann. Oncol. 10.1016/j.annonc.2020.08.2250 (2020).\n14. Pant, S. et al. Abstract CT024: results of a phase I dose escalation study of ARQ 751 in adult subjects with advanced solid tumors with AKT1, 2, 3 genetic alterations, activating PI3K mutations, PTEN-null, or other known actionable PTEN mutations. Cancer Res.10.1158/1538-7445.am2018-ct024 (2018).\n15. Meric-Bernstam, F. et al. 1 Feasibility of large-scale genomic testing to facilitate enrollment on genomically-matched clinical trials. Eur. J. Cancer. 10.1016/s0959-8049(14)70127-3 (2014).\n16. Schwartz, L. H. et al. RECIST 1.1 - Update and clarification: From the RECIST committee. Eur. J. Cancer. 10.1016/j.ejca.2016.03.081 (2016).\n17. Williams, H. L., Walsh, K., Diamond, A., Oniscu, A. & Deans, Z. C. Validation of the OncomineTM focus panel for next-generation sequencing of clinical tumour samples. Virchows Arch. 10.1007/s00428-018-2411-4 (2018).\n18. Bellacosa, A., Kumar, C. C., Cristofano, A. D. & Testa, J. R. Activation of AKT kinases in cancer: Implications for therapeutic targeting. Adv. Cancer Res. 10.1016/S0065-230X(05)94002-5 (2005).\n19. Vivanco, I. & Sawyers, C. L. The phosphatidylinositol 3-kinase-AKT pathway in humancancer. Nat. Rev. Cancer.10.1038/nrc839 (2002).\n20. Duronio V The life of a cell: apoptosis regulation by the PI3K/PKB pathway Biochem. J. 2008 415 333 344 10.1042/BJ20081056 18842113\n21. Janku, F., Yap, T. A. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway? Nat. Rev. Clin. Oncol.10.1038/nrclinonc.2018.28 (2018).\n22. Yap, T. A. et al. Targeting the PI3K-AKT-mTOR pathway: progress, pitfalls, and promises. Curr. Opin. Pharmacol. 10.1016/j.coph.2008.08.004 (2008).\n23. Carpten, J. D. et al. A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature.10.1038/nature05933 (2007).\n24. Kumar, A. & Purohit, R. Cancer associated E17K mutation causes rapid conformational drift in AKT1 pleckstrin homology (PH) domain. PLoS One. 10.1371/journal.pone.0064364 (2013).\n25. Stottrup, C., Tsang, T. & Chin, Y. R. Upregulation of AKT3 confers resistance to the AKT Inhibitor MK2206 in breast cancer. Mol. Cancer Ther. 10.1158/1535-7163.MCT-15-0748 (2016).\n26. Lazaro, G., Kostaras, E. & Vivanco, I. Inhibitors in AKTion: ATP-competitive vs allosteric. Biochem. Soc. Trans.10.1042/BST20190777 (2020).\n27. Wullschleger, S., Loewith, R. & Hall, M. N. TOR signaling in growth and metabolism. Cell. 10.1016/j.cell.2006.01.016 (2006).\n28. Ilagan, E. & Manning, B. D. Emerging Role of mTOR in the Response to Cancer Therapeutics. Trends Cancer. 10.1016/j.trecan.2016.03.008 (2016).\n29. Elkabets, M. et al. MTORC1 inhibition is required for sensitivity to PI3K p110α inhibitors in PIK3CA-mutant breast cancer. Sci. Transl. Med. 10.1126/scitranslmed.3005747 (2013).\n30. Elkabets, M. et al. AXL mediates resistance to PI3Kα inhibition by activating the EGFR/PKC/mTOR Axis in Head and neck and esophageal squamous cell carcinomas. Cancer Cell. 10.1016/j.ccell.2015.03.010 (2015).\n31. Hanai, S. et al. Pathologic active mTOR mutation in brain malformation with intractable epilepsy leads to cell-autonomous migration delay. Am. J. Pathol. 10.1016/j.ajpath.2017.01.015 (2017).\n32. Nakashima, M. et al. Somatic mutations in the MTOR gene cause focal cortical dysplasia type IIb. Ann. Neurol. 10.1002/ana.24444 (2015).\n33. Grabiner, B. C. et al. A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity. Cancer Discov. 10.1158/2159-8290.CD-13-0929 (2014).\n34. Kwiatkowski, D. J. et al. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma. Clin. Cancer Res. 10.1158/1078-0432.CCR-15-2631 (2016).\n35. Xu, J. et al. Mechanistically distinct cancer-associated mTOR activation clusters predict sensitivity to rapamycin. J. Clin. Invest. 10.1172/JCI86120 (2016).\n36. Ghosh, A. P. et al. Point mutations of the mTOR-RHEB pathway in renal cell carcinoma. Oncotarget. 10.18632/oncotarget.4963 (2015).\n37. Hassan, B. et al. Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors. Oncotarget. 10.18632/oncotarget.2337 (2014).\n38. Wagle, N. et al. Response and acquired resistance to everolimus in anaplastic thyroid cancer. N. Engl. J. Med. 10.1056/nejmoa1403352 (2014).\n39. Diamond, J. R. et al. Abstract PD1-09: Phase 2 safety and efficacy results of TAK-228 in combination with exemestane or fulvestrant in postmenopausal women with ER-positive/HER2-negative metastatic breast cancer previously treated with everolimus. Cancer Res. 79, PD1-09 LP–PD1-09 (2019).\n40. Woo, S. U. et al. Vertical inhibition of the PI3K/Akt/mTOR pathway is synergistic in breast cancer. Oncogenesis.10.1038/oncsis.2017.86 (2017).\n41. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N. Engl. J. Med. 10.1056/nejmoa1113205 (2012).\n42. Yu, Y. et al. Targeting AKT1-E17K and the PI3K/AKT pathway with an allosteric AKT inhibitor, ARQ 092. PLoS One. 10.1371/journal.pone.0140479 (2015).\n43. Zakikhani, M., Blouin, M. J., Piura, E. & Pollak, M. N. Metformin and rapamycin have distinct effects on the AKT pathway and proliferation in breast cancer cells. Breast Cancer Res. Treat. 10.1007/s10549-010-0763-9 (2010).\n44. Alimova, I. N. et al. Metformin inhibits breast cancer cell growth, colony formation and induces cell cycle arrest in vitro. Cell Cycle.10.4161/cc.8.6.7933 (2009).\n45. Luthra, R. et al. A targeted high-throughput next-generation sequencing panel for clinical screening of mutations, gene amplifications, and fusions in solid tumors. J. Mol. Diagnostics.10.1016/j.jmoldx.2016.09.011 (2017).\n46. Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 10.1158/2159-8290.CD-12-0095 (2012).\n47. Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 10.1126/scisignal.2004088 (2013).\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2397-768X",
"issue": "5(1)",
"journal": "NPJ precision oncology",
"keywords": null,
"medline_ta": "NPJ Precis Oncol",
"mesh_terms": null,
"nlm_unique_id": "101708166",
"other_id": null,
"pages": "99",
"pmc": null,
"pmid": "34853384",
"pubdate": "2021-12-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Emergence of mTOR mutation as an acquired resistance mechanism to AKT inhibition, and subsequent response to mTORC1/2 inhibition.",
"title_normalized": "emergence of mtor mutation as an acquired resistance mechanism to akt inhibition and subsequent response to mtorc1 2 inhibition"
} | [
{
"companynumb": "US-MYLANLABS-2022M1027048",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "IgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.\n\n\n\nA 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.\n\n\n\nThe corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.",
"affiliations": "Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.;Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.;Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.;Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.;Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.;Department of Imaging, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.;Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.;Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.;Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.;Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China. wangnn@njmu.edu.cn.;Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.",
"authors": "Xu|Yili|Y|;Yang|Guang|G|;Xu|Xueqiang|X|;Huang|Yaoyu|Y|;Liu|Kang|K|;Yu|Tongfu|T|;Qian|Jun|J|;Zhao|Xiufen|X|;Zhu|Jingfeng|J|;Wang|Ningning|N|;Xing|Changying|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12882-020-02223-8",
"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369 BioMed Central London \n\n2223\n10.1186/s12882-020-02223-8\nCase Report\nIgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report\nXu Yili 1 Yang Guang 1 Xu Xueqiang 1 Huang Yaoyu 1 Liu Kang 1 Yu Tongfu 2 Qian Jun 1 Zhao Xiufen 1 Zhu Jingfeng 1 Wang Ningning wangnn@njmu.edu.cn 1 Xing Changying 1 1 grid.412676.00000 0004 1799 0784Department of Nephrology, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China \n2 grid.412676.00000 0004 1799 0784Department of Imaging, the First Affiliated Hospital with Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China \n11 1 2021 \n11 1 2021 \n2021 \n22 2227 8 2020 23 12 2020 © The Author(s) 2021Open 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.Background\nIgG4-related kidney disease (IgG4-RKD) can affect multiple organs, which was first reported as a complication or extra-organ manifestation of autoimmune pancreatitis in 2004. It is characterized by abundant IgG4-positive plasma cells infiltration in tissues involved.\n\nCase presentation\nA 69-year-old man presented with cough and renal dysfunction with medical history of hypertension and diabetes. Pathological findings revealed interstitial nephritis and he was initially diagnosed with IgG4-RKD. Prednisone helped the patient to get a remission of cough and an obvious decrease of IgG4 level. However, he developed invasive pulmonary fungal infection while steroid theatment. Anti-fungal therapy was initiated after lung puncture (around cavitary lung lesion). Hemodialysis had been conducted because of renal failure and he got rid of it 2 months later. Methylprednisolone was decreased to 8 mg/day for maintenance therapy. Anti-fungal infection continued for 4 months after discharge home. On the 4th month of follow-up, Chest CT revealed no progression of lung lesions.\n\nConclusions\nThe corticosteroids are the first-line therapy of IgG4-RD and a rapid response helps to confirm the diagnosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control.\n\nKeywords\nIgG4-Related nephritisIgG4-Related lung diseaseCorticosteroidInvasive pulmonary fungal infectionCase reportthe National Natural Science Foundation of China81570666International Society of Nephrology (ISN) Clinical Research Program18-01-0247Jiangsu Province Key Medical Personnel Project ZDRCA2016002issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nIgG4-related disease (IgG4-RD) is an inflammatory and fibrotic disease which was first described in the pancreas and was called autoimmune pancreatitis (AIP) in 2001 [1]. Its concept has been recognized worldwide since then that this systemic disease involved multiple organs or tissues characterized by elevated serum IgG4 level and IgG4 positive plasma cells infiltration in the affected tissues, leading to fibrosis eventually [2–6]. The prevalence of IgG4-RD in Japan was estimated as 0.28–1.08/100,000 people in 2012 [7].\n\nIgG4-related tubulointerstitial nephritis (IgG4-TIN), is one of the frequent pathological changes of IgG4-related kidney disease (IgG4-RKD), accounting for about 15–25% of all IgG-RD [4, 8]. IgG4-related TIN shows a range of histologic appearances including (A) acute interstitial nephritis with minimal fibrosis; (B) a more cellular inflammatory pattern in the setting of expansile fibrosis; and (C) a very fibrotic, pauci-cellular pattern [7]. The diagnosis criteria of IgG4-RKD were proposed by the Japanese Society of Nephrology [9] and a work group of North America [7], respectively. IgG4-related kidney lesions were often associated with extrarenal disease, such as chronic sclerosing inflammation of the lacrimal gland, salivary gland [10] and lung [11].\n\nPatients with IgG4-RKD have an increased risk of infection than general population. IgG4-TIN can be accompanied by eosinophilic lung disease [12] and pneumonia [13]. Here, we present a case of IgG4-RKD and lung interstitial lesions who developed invasive pulmonary fungal infection (IPFI) during treatment of glucocorticoid combined with immunosuppressive agents.\n\nCase presentation\nA 69-year-old male was admitted to the hospital in 2019 January 5th because of gradually aggravated edema and cough. His medical history included hypertension, arrhythmia and diabetes. On 2019 May 8th, he had experienced cough and phlegm with temperature around 38 ~ 39 °C. Laboratory tests were presented in Table 1. 18F-FDG-PET/CT showed interstitial pneumonia in both lungs. There was also elevated uptake abnormality in the upper kidney observed. Cefperazone-Sulbactam, doxycycline hydrochloride, imipenem, and linezolid were given. Because of no improvement, he took oral prednisone 24 mg per day. The body temperature recovered to normal and lower limb edema was alleviated after one week. On 2019 June 13th ,serum creatinine 157.7 umol/L (Fig. 1); and serum albumin, 24.9 g/L. Chest computed tomography (CT) scan showed that honeycomb-like changes considering interstitial inflammation and bilateral pleural effusion (Fig. 1A).\nTable 1 Laboratory data performed before and after treatment\n\nITEMS\tBeforetherapy\tSteroidtherapyfor 1month\tSteroid therapy for2 months\tSteroid therapy for3 months\tSteroid therapy for4 months\t\nWhite blood cell count(*10^9/L)\t15.4\t21.11\t8.24\t11.66\t13.28\t\nHemoglobin(g/L)\t129\t108\t84\t98\t101\t\nPlatelet count(*10^9/L)\t323\t285\t100\t273\t176\t\nC-reaction protein (CRP)(mg/L)\t90\t58.1\t32\t79.8\t18.9\t\nErythrocyte sedimentation rate(mm/H)\t120\t60\t/\t/\t/\t\nSerum nitrogen (mmol/L)\t10.2\t24.71\t24.18\t30.33\t14.5\t\nSerum creatinine (umol/L)\t64.6\t232.8\t212.4\t187.2\t100.7\t\nSerum albumin(g/L)\t24.2\t32\t30\t27.6\t21.2\t\nUrine RBC(/ul)\t/\t42.6\t10.9\t\t3\t\nUrine protein creatine ratio(mg/g)\t\t48.5\t\t\t\t\n24 h urine protein (g)\t0.721\t0.62\t0.61\t0.45\t0.49\t\nANCA-MPO (RU/ml)\t\t35.1\t12.7\t8.6\t\t\nANCA-PR3 (RU/ml)\t\t6.7\t4.9\t4.7\t\t\nCD4+ / CD8 + lymphocyte\t0.81\t/\t/\t/\t1.9\t\nABG\tBefore therapy\tSteroid therapy for 2 months\t\nPH\t7.201\t7.498\t\nPCO2(mmHg)\t20\t31.6\t\nPO2(mmHg)\t117\t49\t\nSpO2 (%)\t98\t88\t\nK(mmol/L)\t5.4\t4.1\t\nHCO3-(mmol/L)\t7.8\t24.5\t\nBE(mmol/L)\t-20\t1\t\nANCA-MPO Myeloperoxidase-antineutrophil cytoplasmic antibody, ANCA-PR3 proteinase 3, ABG Arterial Blood Gas, / not available\n\nFig. 1 Chest CT showed interstitial inflammation and bilateral pleural effusion before therapy (a). After glucocorticoids admission, obvious absorption of interstitial inflammation and pleural effusion on both sides were found (b). Infection of both lungs with a left lower lobe cavity before anti-infection therapy (c). After anti-infection therapy, no increase boarder of lung lesions (d)\n\n\n\nHe went to Nephrology Department on 2019 July 2nd for further treatment. Laboratory results were presented in Table 1. Urine RBC 42.6/ul; Urine protein: creatine ratio (uPCR) 48.5 mg/g; Serum IgG4 level was elevated at 3.42 g/L (Normal range: 0.03–2.10 g/L). Anti-myeloperoxidase anti-neutrophil cytoplasmic antibody level was elevated at 35.1Ru/ml (Normal range:<20 Ru/ml). However, serum immunoglobulin A(IgA), IgG and IgM level were normal. Furthermore, the patient was negative for anti-double-stranded antibody, antinuclear antibody, anti-Sjogren’s syndrome A antibody, anti-Sjogren’s syndrome B antibody and anti-proteinase 3. Ultrasound displayed large-sized kidneys with uniform echo frequency and clear corticomedullary boundaries. Chest CT revealed obvious absorption of interstitial inflammation and pleural effusion on both sides, there were also multiple nodules in both lungs (Fig. 1b).\n\nHistopathology of the kidney biopsy shows proliferation of glomerular mesangial cells, diffuse and irregular thickening of basement membrane (Fig. 2a). The tubulointerstitium shows marked injury. Patchy foci fibrosis and inflammatory cells infiltration were prominent in the interstitium (Fig. 2b, c). Immunofluorescence staining shows that IgG, IgM, IgA, C1q, C3 and C4 were negative in the granular mesangial area. Immunohistological analysis revealed numerous CD20-positive B cells ((D), × 400) and dense infiltration of CD138-positive plasma cells ((E), × 400), with an IgG4+/IgG+ plasma cell ratio being > 40% ((F), × 400). Electron microscopy demonstrated that there were no electron-dense deposits in the glomeruli (Fig. 3).\nFig. 2 Renal histopathological result showed almost normal glomeruli, massively infiltrating cells, and abundant interstitial fibrosis under the light microscopy. a The glomerulus showed glomerular mesangial cells proliferation and diffuse and irregular thickening of basement membrane (HE staining, × 200). b, c A mass of plasma cells and fibrotic fibers (HE staining, × 400) can be observed in the interstitium. d, e Immunohistological analysis revealed mostly CD20-positive B cells (× 400) and CD138-positive plasma cells (× 400) in the interstitium. f Immunohistochemistry for IgG4 shows abundant positive plasma cells (coloured brown) (× 400)\n\nFig. 3 No electron-dense deposits are observed under electron microscopy. a Abundant plasma cells (× 2000) infiltrated in renal interstitium. b Detachment and partial atrophy of the microvilli of renal tubular epithelial cells as well as edema, infiltration of lymphocytes/monocytes, and fibrosis in renal interstitium. There are no electron-dense deposits in the glomeruli (× 2000). c Proliferation of glomerular mesangial cells and interstitial cells (× 2000). d Diffuse and irregular thickening of basement membrane (× 12,000)\n\n\n\nBased on these findings, he had been diagnosed as IgG4-related renal disease. Oral prednisone (40 mg/day) and cyclophosphamide (CTX, 0.4 g) were prescribed by intravenous infusion. The patient had been followed up every month after the treatment (Table 1). He presented with intermittent fever for more than 20 days and acute onset of left pleuritic chest pain with dry cough for 10 days. Negative results were found in aerobic or anaerobic blood culture. Chest CT showed recent infection of both lungs with left upper lung cavity (Fig. 1c). At June 28th he developed hemoptysis and type 1 respiratory failure (Table 2). The results of relevant tests are shown in Table 1. In order to differentiate between IgG4-RLD and IPFI, left upper lung puncture was conducted and showed that interstitial collagen fibrosis with acute and chronic inflammatory cell infiltration, focal fibrous necrosis and exudation, and small alveolar cell response. Fungal spores were also found in lung puncture specimen. Filamentous fungi can be seen in sputum culture. Immunohistochemistry test revealed that most plasma cells in the lung interstitium were positive for CD38 (+), CD138 (+), IgG (+) (Fig. 4). IgG positive plasma cells < 40%, IgG4 positive plasma cells < 10/HPF, which does not meet the pathological diagnostic criteria of IgG4 related diseases. The diagnosis of IPFI was definite. After then, the patient was initiated on voriconazole and caspofungin to anti-fungal infection, and prednisolone was decreased to 30 mg per day.\nTable 2 Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ [2, 14, 15]\n\nCriterion\t\t\nHistology\t(i)The specimen pathology shows the dense lymphoplasmacytic infiltrate, storiform fibrosis or obliterative phlebitis, the infiltration of IgG4-positive cells, and IgG cells more than IgG4 cells ratio of 40%;\t\nImaging\t(ii)clinical/radiological examination showing characteristic diffuse or localized swelling or masses in single or multiple organs;\t\nSerology\t(iii) serum IgG4 concentration > 135 mg/dL;\n\n(iv)Inflammatory markers such as white blood cells count and C-reactive protein concentrations are not elevated, despite the degree of lesions, their spread on imaging analysis and massive cellular infiltration on pathological examination;\n\n\t\nOther organ involvement\t(v)Characteristic findings of IgG4-RD in other organs, including autoimmune pancreatitis, lung involvement, et al.\t\nTreatment\t(vi)response to steroids.\t\nAll 3 criteria (i + ii + iii) are needed for definite diagnosis of IgG4-RD\n\nFig. 4 Histopathological findings of the pulmonary tissue (light microscopy: HE). a Pulmonary tissue shows fibrotic changes of the interstitium (× 100) in the lung. b Cell and tissue reactions and cellulosic exudation were observed in alveoli (× 200). c, d Giant cell, interstitial edema, collagen fiber hyperplasia and masson body were observed in the specimen (× 200). e, f Immunohistological analysis revealed CD38-positive plasmacyte (coloured brown) (E × 400) and CD138-positive plasmacyte (coloured brown) infiltration (F × 400). g IgG immunostaining shows IgG-positive plasmacyte (coloured brown) infiltration (× 400). h IgG4 immunostaining shows IgG4-positive plasmacyte (coloured brown) infiltration in the lung (× 400)\n\n\n\nWith anti-infection and immunosuppressive treatment for 2 weeks, serum CRP and IgG4 level had been considerably decreased to 2.94 mg/L and 1.57 g/L, respectively. Voriconazole 200 mg bid and Methylprednisolone 30 mg/day were continued after discharge home. After treatment for one month, a repeat CT scan showed no progression of lung lesions (Fig. 1D). CD4+/CD8+ lymphocyte: 1.9. The patient had been followed up for 4 months. In the most recent follow-up examination, the serum creatinine level decreased to 101 umol/L and he got rid of hemodialysis (Fig. 5). He is currently undergoing tapered prednisolone treatment.\nFig. 5 Dynamic changes of renal function before and after treatment in the patient with IgG4-RKD\n\n\n\nDiscussion and conclusions\nThis patient is characterized by serum IgG4 elevation, positive MPO-ANCA, which suggested the possibility of co-occurrence/concurrence of AAV and IgG4‐RD on his first visit from his serological presentation. Diagnosis of IgG4-RD requires particular pathological, serological and clinical features [2, 14, 15] (listed in Table 2). This patient presented with serum IgG4 elevation, hematuria, proteinuria, elevated uptake abnormality of the upper kidney observed in 18F-FDG-PET/CT, progressive kidney failure and interstitial lung disease. Histopathology of kidney biopsy showing typical lymphoplasmacytic infiltration and fibrosis enriched in IgG4-positive plasma cells, and infiltration of IgG4 + plasma cells with IgG4+/IgG+ plasma cells ratio greater than 40% and a total of ≥ 10 IgG4 + plasma cells per high-power field (HPF) indicated the diagnosis of IgG4-RKD.\n\nGiven the elevated MPO-ANCA and CRP, AAV related nephritis was a possible differential diagnosis (Proposed diagnostic criteria for kidney involvement in AAV listed in Table 3 [16]). In this case, pathological findings did not show renal crescentic glomerulonephritis or vasculitis, thus, anti-neutrophil cytoplasmic antibody associated vasculitis (ANCA-AAV) was not firstly considered according to the Chapel Hill Consensus Conference nomenclature criteria for AAV [16]; However, Some ANCA positive patients may present with interstitial nephritis without severe glomerulopathy, and whether his initial interstitial lung disease was related to IgG4 or AAV or both was not determined. Some reports suggested a possible pathogenic effect of ANCA-IgG4 [17, 18]. Serum IgG4 increase and IgG4-positive cell infiltration in the organ can also be seen in AAV [19, 20]. Distinguishing between these diseases is essential for treatment planning [20], because IgG4-RD responds well to steroid therapy alone, while AAV often requires concomitant immunosuppressant use. His initial interstitial lung disease was improved (Fig. 1) with prednisone therapy alone for one month favored the diagnosis of IgG4-RLD. Kim et al. [21] described that a steroid trial was useful for differentiating and response to steroid therapy is recommended to be added to the diagnostic criteria. Proposed diagnostic criteria for IgG4-RD according to ‘Comprehensive diagnostic criteria for IgG4-related disease’ listed in Table 2. Therefore, we preferred his diagnosis of IgG4-RD.\nTable 3 Proposed diagnostic criteria for kidney involvement in AAV [16]\n\nclinical manifestations\ta rapidly progressive GN with a decline in kidney function accompanied by sub–nephrotic-range proteinuria, microscopic hematuria, and hypertension over days to a few months\t\nSerology\tAnti-MPO antibody or anti-PR3 antibody positive\t\nPathological findings\tpauci-immune focal necrotizing crescentic GN\n\nRare patients with AAV have a prominent tubulointerstitial nephritis, which can be associated with vasculitis of the vasa recta\n\n\t\nA diagnosis of AAV incorporates the integration of clinical features, ANCA serology, and tissue pathology as needed\n\n\n\nSince kidney involvement was firstly reported in a patient with IgG4-RD in 2004 [22], many similar cases have been described [23–25]. A cross-sectional study reported in 2010 revealed all kidney lesions were associated with extrarenal disease among 114 patients with IgG4-related disease [26]. Several clinicopathologic studies reported IgG4-RD with both kidney and lung involvement [5, 14, 27–30]. In kidney its characteristic manifestation is TIN with multiple extrarenal tissue damage [14, 31], which is easily apparent with a chronic or rapid progressive renal function decline [23]. In lung, this may present as nodules with spiculated margins mimicking primary pulmonary malignancy [28, 32], multiple ground glass opacities (GGO) mimicking interstitial lung disease [14], alveolar interstitial type, and bronchovascular type [33].\n\nHowever, he developed intermittent fever, acute onset of left pleuritic chest pain and an emerging lung lesion after steroid use for one month. IgG4-RLD has been classified into four categories based on CT. Our case was the GGO type. This also was the primary feature of IPFI [34] of which most common chest CT signs are nodules, consolidation and GGO. This patient had several high-risk factors of IPFI such as old age, long-term use of glucocorticoids, repeated hospitalization, etc. [35]. However,it is difficult to distinguish between IgG4-related lung disease (IgG4-RLD) and IPFI (Table 3). Lung puncture pathology is key standard. Thus, sputum culture and pathogenic examination were repeated and infiltration of IgG4-positive plasma cells was not found. The lung tissue specimen showed fungal spores which supported the diagnosis of IPFI. The differential diagnosis of IgG4-RLD and IPFI were listed in Table 4 [34, 36, 37].\nTable 4 Differences between IgG4-RLD and IPFI [34, 36, 37]\n\nItems\tIgG4-RLD\tIPFI\t\nClinical manifestations\tmulti-system injuries\tdry cough and fever,no specific\t\nLaboratory tests\tSerum IgG4 elevation\tCRP and (or) PCT elevation,G/GM positive\t\nImaging\tnodules, multiple ground glass opacities (GGO),alveolar interstitial type, and bronchovascular type\tnodules, consolidation and ground-glass opacity(GGO)\t\nPathology\tMainly IgG4\n\nWith plasma cell infiltration and often with interstitial damage\n\n\tfungal spores with hyphae can be observed, pulmonary fibrosis and inflammatory cell infiltration\t\nTreatment protocol\tSystemic glucocorticoids\tanti-infection\t\n\n\nSystemic glucocorticoids are recommended as the first-line approach of renal injury in untreated IgG4-RD [31]. A moderate initial dose of oral prednisolone for induction is 0.6 mg/kg daily for 2–4 weeks. The maintenance dose of steroid therapy is given after remission as 2.5-5 mg daily over a period of 2–3 months [2]. However, treatment with exogenous glucocorticoids comes with a number of risks such as avascular necrosis, osteoporosis, glaucoma, cardiovascular disease, worse glucose tolerance and diabetes. The risk of infection is of utmost concern and is well-documented [36, 38]. A Japanese study including 459 AIP patients reported pneumonia occurred in 3 patients treated with steroid [13]. Optimizing the nutritional state of patients, reducing its dose, duration and number of immunosuppressants are recommended to help prevent infection. In the present case, we have to decrease the dosage of immunosuppressive drugs after then, nevertheless, IgG4-RLD were aggravated and renal failure developed during dosage decrease.\n\nSince not every patient can be recover from renal disfunction, maintenance hemodialysis become necessary in patients with irreversible renal failure due to IgG4-RKD [4, 39]. And in this case, the patient experienced a short-time hemodialysis because of azotemia, which partly due to deteriorating renal function, steroids use or (and) infection. Improvements in pulmonary lesions and kidney function were observed after 4 months and were maintained with a dose of 8.0 mg/day prednisone. Thus, the dosage of steroid and immunosuppressant should be reduced for the therapy of the elderly patients with IgG4 related diseases. In addition, it has been reported that relapse of IgG4-related lesions, including kidney damage, occurred in 20% of treated patients with IgG4-RKD during maintenance treatment [39]. Thus, long-term follow-up for this patient are required and a well prognosis is expected.\n\nTaken together, IgG4-RKD is an immune-mediated condition that can affect not only kidney but also several other organs, leading to a dense lymphoplasmacytic infiltration dominant in IgG4-positive plasma cells with fibrosis. This case should inspire clinicians to identify IgG4-related lung disease and secondary pulmonary infection, pay attention to the complications during immunosuppressive therapy for primary disease control (Fig. 6).\nFig. 6 Flow diagram of the patient’s disease progression and treatment\n\n\n\nAbbreviations\nIgG4-RKDIgG4-related kidney disease\n\nAIPAutoimmune pancreatitis\n\nIgG4-TINIgG4-related tubulointerstitial nephritis\n\nIPFIInvasive pulmonary fungal infection\n\nCTChest computed tomography\n\nuPCRUrine protein: creatine ratio\n\nIgGSerum immunoglobulin G\n\nCTXCyclophosphamide\n\nMPO-ANCAAnti-myeloperoxidase anti-neutrophil cytoplasmic antibody\n\nANCA-AAVAnti-neutrophil cytoplasmic antibody associated vasculitis\n\nGGOMultiple ground glass opacities\n\nIgG4-RLDIgG4-related lung disease\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe sincerely thank the Department of Pathology, Jiangsu province Hospital, for pulmonary pathology.\n\nAuthors’ contributions\nYLX reviewed the patient’s clinical data, performed the literature search, and wrote the initial draft of the manuscript. YYH and KL assisted in the preparation of the manuscript contributed to data collection and interpretation and critically reviewed the manuscript. JQ, and JFZ provide the pathology of renal biopsy. XFZ performed the immunohistochemical studies. TFY conducted pulmonary puncture and provide the possibility of lung pathology. GY and XQX carried out analysis of patient’s clinical course, outcomes and interpretation of findings, and provided critical review comments for the manuscript. NNW and CYX had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, and provided critical review comments for the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe research was financially supported by the National Natural Science Foundation of China (81570666), International Society of Nephrology (ISN) Clinical Research Program (18-01-0247), Jiangsu Province Key Medical Personnel Project (ZDRCA2016002). The funders had the idea for this case report, and carried out analysis of patient’s clinical course, outcomes, and interpretation of findings, provided critical review comments and also submission for the manuscript.\n\nAvailability of data and materials\nThe datasets used during the current study available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Hamano H High serum IgG4 concentrations in patients with sclerosing pancreatitis N Engl J Med 2001 344 10 732 8 11236777 \n2. Kamisawa T Okazaki K Diagnosis and Treatment of IgG4-Related Disease Curr Top Microbiol Immunol 2017 401 19 33 28197739 \n3. Morales AT An update on IgG4-related lung disease Eur J Intern Med 2019 66 18 24 31227290 \n4. Saeki T Clinicopathological characteristics of patients with IgG4-related tubulointerstitial nephritis Kidney Int 2010 78 10 1016 23 20720530 \n5. Dhobale S IgG4 related sclerosing disease with multiple organ involvements and response to corticosteroid treatment J Clin Rheumatol 2009 15 7 354 7 20009972 \n6. Higashioka K A Case of Immunoglobulin G4-Related Disease with Extensive Multiorgan Involvements Case Rep Rheumatol. 2015 2015 392893 26101684 \n7. Raissian Y Diagnosis of IgG4-related tubulointerstitial nephritis J Am Soc Nephrol 2011 22 7 1343 52 21719792 \n8. Lin W Clinical characteristics of immunoglobulin G4-related disease: a prospective study of 118 Chinese patients Rheumatology 2015 54 11 1982 90 26106212 \n9. Kawano M Proposal for diagnostic criteria for IgG4-related kidney disease Clin Exp Nephrol 2011 15 5 615 26 21898030 \n10. Shoji S Nakano M Usui Y IgG4-related inflammatory pseudotumor of the kidney Int J Urol 2010 17 4 389 90 20409237 \n11. Surintrspanont J IgG4-related pseudo-tumor of the kidney and multiple organ involvement mimicked malignancy Urol Case Rep 2019 26 100953 31309039 \n12. Adachi H A case of IgG4-related kidney disease complicated by eosinophilic lung disease CEN Case Rep 2015 4 2 162 8 28509093 \n13. Kamisawa T Standard steroid treatment for autoimmune pancreatitis Gut 2009 58 11 1504 7 19398440 \n14. Saravanan M Immunoglobulin G4-related tubulointerstitial nephritis associated with interstitial pulmonary disease: Report of a case with review of literature Indian J Nephrol 2015 25 2 113 6 25838652 \n15. Umehara H Comprehensive diagnostic criteria for IgG4-related disease (IgG4-RD), 2011 Mod Rheumatol 2012 22 1 21 30 22218969 \n16. Jennette JC 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides Arthritis Rheum. 2013 65 1 1 11 23045170 \n17. Holland M Anti-neutrophil cytoplasm antibody IgG subclasses in Wegener’s granulomatosis: a possible pathogenic role for the IgG4 subclass Clin Exp Immunol 2004 138 1 183 92 15373923 \n18. Liu LJ IgG subclass distribution, affinity of anti-myeloperoxidase antibodies in sera from patients with Wegener’s granulomatosis and microscopic polyangiitis Nephrology (Carlton) 2008 13 7 629 35 18775059 \n19. Li ZY An overlap of antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis and IgG4-related kidney disease Clin Chim Acta 2020 501 12 9 31805271 \n20. Kawashima H Consideration concerning similarities and differences between ANCA-associated vasculitis and IgG-4-related diseases: case series and review of literature Immunol Res 2019 67 1 99 107 30734199 \n21. Kim KP Diagnostic criteria for autoimmune chronic pancreatitis revisited World J Gastroenterol 2006 12 16 2487 96 16688792 \n22. Uchiyama-Tanaka Y Acute tubulointerstitial nephritis associated with autoimmune-related pancreatitis Am J Kidney Dis 2004 43 3 e18 25 14981637 \n23. Wakabayashi K Progressive Renal Dysfunction due to IgG4-Related Kidney Disease Refractory to Steroid Therapy: A Case Report Case Rep Nephrol Dial 2019 9 1 1 7 31616671 \n24. Zhang NN IgG4-related kidney disease (IgG4-RKD) with membranous nephropathy as its initial manifestation: report of one case and literature review BMC Nephrol 2019 20 1 263 31311519 \n25. Evans R Clinical Manifestations and Long-term Outcomes of IgG4-Related Kidney and Retroperitoneal Involvement in a United Kingdom IgG4-Related Disease Cohort Kidney Int Rep 2019 4 1 48 58 30596168 \n26. Zen Y Nakanuma Y IgG4-related disease: a cross-sectional study of 114 cases Am J Surg Pathol 2010 34 12 1812 9 21107087 \n27. Cravedi P Membranous nephropathy associated with IgG4-related disease Am J Kidney Dis 2011 58 2 272 5 21658826 \n28. Omokawa A Membranous nephropathy with monoclonal IgG4 deposits and associated IgG4-related lung disease Clin Kidney J 2014 7 5 475 8 25878779 \n29. Yamasue M Corticosteroid Therapy for a Patient with Relapsing Polychondritis Complicated by IgG4-Related Disease Tohoku J Exp Med 2016 239 3 223 30 27396510 \n30. Horita S A case of IgG4-related tubulointerstitial nephritis and membranous glomerulonephritis during the clinical course of gastric cancer: Imaging features of IgG4-related kidney disease Mod Rheumatol 2019 29 3 542 6 27785920 \n31. Saeki T Kawano M IgG4-related kidney disease Kidney Int 2014 85 2 251 7 24107849 \n32. Pandita A Wong J IgG4-related disease in lung: a diagnostic challenge Pathology 2020 52 3 390 2 32107075 \n33. Ishikawa H IgG4-related disease in the differential diagnosis of lung nodules Respirol Case Rep 2020 8 4 e00550 32180984 \n34. Wang J Clinical diagnostic value of spiral CT in invasive pulmonary fungal infection Exp Ther Med 2019 17 5 4149 53 30988792 \n35. Mu FG He HL Li J [Risk factors for invasive pulmonary fungal infection in children] Zhongguo Dang Dai Er Ke Za Zhi 2014 16 8 779 82 25140766 \n36. Lionakis MS Kontoyiannis DP Glucocorticoids and invasive fungal infections Lancet 2003 362 9398 1828 38 14654323 \n37. Sanguinetti M Diagnosis and treatment of invasive fungal infections: looking ahead J Antimicrob Chemother 2019 74 Suppl 2 ii27 37 31222314 \n38. Youssef J, Novosad SA, Winthrop KL. Infection Risk and Safety of Corticosteroid Use. Rheum Dis Clin North Am. 2016. 42(1):157 – 76, ix-x.\n39. Saeki T The clinical course of patients with IgG4-related kidney disease Kidney Int 2013 84 4 826 33 23698232\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "22(1)",
"journal": "BMC nephrology",
"keywords": "Case report; Corticosteroid; IgG4-Related lung disease; IgG4-Related nephritis; Invasive pulmonary fungal infection",
"medline_ta": "BMC Nephrol",
"mesh_terms": null,
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "22",
"pmc": null,
"pmid": "33430791",
"pubdate": "2021-01-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "31222314;14654323;31227290;30734199;25140766;22218969;21898030;31616671;26101684;23045170;21719792;20009972;21107087;20720530;26611557;31311519;14981637;25838652;31805271;32180984;25878779;30596168;28509093;24107849;26106212;16688792;18775059;28197739;23698232;20409237;30988792;31309039;11236777;15373923;19398440;32107075;27396510;27785920;21658826",
"title": "IgG4-related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection: a case report.",
"title_normalized": "igg4 related nephritis and interstitial pulmonary disease complicated by invasive pulmonary fungal infection a case report"
} | [
{
"companynumb": "CN-GYP-000059",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "Solid organ transplant (SOT) recipients may be at risk for severe COVID-19. Data on the clinical course of COVID-19 in immunosuppressed patients are limited, and the effective treatment strategy for these patients is unknown. We describe our institutional experience with COVID-19 in SOT. Demographic, clinical, and treatment data were extracted from the electronic patient files. A total of 23 SOT transplant recipients suffering from COVID-19 were identified (n = 3 heart; n = 15 kidney; n = 1 kidney-after-heart; n = 3 lung, and n = 1 liver transplant recipient). The presenting symptoms were similar to nonimmunocompromised patients. Eighty-three percent (19/23) of the patients required hospitalization, but only two of these were transferred to the intensive care unit. Five patients died from COVID-19; all had high Clinical Frailty Scores. In four of these patients, mechanical ventilation was deemed futile. In 57% of patients, the immunosuppressive therapy was not changed and only three patients were treated with chloroquine. Most patients recovered without experimental antiviral therapy. Modification of the immunosuppressive regimen alone could be a therapeutic option for SOT recipients suffering from moderate to severe COVID-19. Pre-existent frailty is associated with death from COVID-19.",
"affiliations": "Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Cardiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Pulmonary Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Viroscience, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Cardiology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.;Department of Nephrology and Transplantation, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.",
"authors": "Hoek|Rogier A S|RAS|0000-0003-2165-3222;Manintveld|Olivier C|OC|;Betjes|Michiel G H|MGH|0000-0001-9435-6208;Hellemons|Merel E|ME|;Seghers|Leonard|L|;Van Kampen|Jeroen A A|JAA|;Caliskan|Kadir|K|;van de Wetering|Jacqueline|J|;van den Hoogen|Martijn|M|;Metselaar|Herold J|HJ|0000-0002-7203-8126;Hesselink|Dennis A|DA|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/tri.13662",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-0874",
"issue": "33(9)",
"journal": "Transplant international : official journal of the European Society for Organ Transplantation",
"keywords": "COVID-19; SARS-CoV-2; organ transplantation; solid organ transplantation",
"medline_ta": "Transpl Int",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000086382:COVID-19; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D016377:Organ Transplantation; D058873:Pandemics; D000086402:SARS-CoV-2; D066027:Transplant Recipients; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "8908516",
"other_id": null,
"pages": "1099-1105",
"pmc": null,
"pmid": "32460390",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "COVID-19 in solid organ transplant recipients: a single-center experience.",
"title_normalized": "covid 19 in solid organ transplant recipients a single center experience"
} | [
{
"companynumb": "NL-TEVA-2020-NL-1846155",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3"... |
{
"abstract": "Sofosbuvir-based direct-acting antiviral therapy revolutionized the treatment of hepatitis C virus (HCV) infection. However, sofosbuvir use is not approved for patients with severe renal insufficiency (estimated glomerular filtration (eGFR) rate below 30 ml/min) or end-stage renal disease (ESRD) based on concerns raised during premarket animal testing over hepatobiliary and cardiovascular toxicity in this population. We report the first published data on use of sofosbuvir-based regimens in patients with severe renal insufficiency and ESRD, focusing on clinical efficacy and safety. Six patients were treated with full dose sofosbuvir; three received sofosbuvir and simeprevir, two received sofosbuvir and ribavirin, and one received sofosbuvir, ribavirin, and interferon. Three of the patients had cirrhosis. On-treatment viral suppression was 100% and sustained virological response (SVR) rate at 12 weeks was 67%. One patient had to discontinue antiviral therapy early due to side effects. No hepatobiliary or cardiovascular toxicity was reported.",
"affiliations": "a From the Department of Medicine , Massachusetts General Hospital , Boston , MA , USA.;b Division of Nephrology, Massachusetts General Hospital , Boston , MA , USA.;c Gastrointestinal Unit, Massachusetts General Hospital , Boston , MA , USA.;a From the Department of Medicine , Massachusetts General Hospital , Boston , MA , USA.;d Department of Medicine , Newton-Wellesley Hospital , Newton , MA , USA.;c Gastrointestinal Unit, Massachusetts General Hospital , Boston , MA , USA.;c Gastrointestinal Unit, Massachusetts General Hospital , Boston , MA , USA.",
"authors": "Hundemer|Gregory L|GL|;Sise|Meghan E|ME|;Wisocky|Jessica|J|;Ufere|Nneka|N|;Friedman|Lawrence S|LS|;Corey|Kathleen E|KE|;Chung|Raymond T|RT|",
"chemical_list": "D000998:Antiviral Agents; D016898:Interferon-alpha; C571406:PEG-IFN-SA; D012367:RNA, Viral; D011092:Polyethylene Glycols; D012254:Ribavirin; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": "10.3109/23744235.2015.1078908",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2374-4243",
"issue": "47(12)",
"journal": "Infectious diseases (London, England)",
"keywords": "Hepatitis C; chronic kidney disease; end-stage renal disease; sofosbuvir",
"medline_ta": "Infect Dis (Lond)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D006526:Hepatitis C; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha; D007676:Kidney Failure, Chronic; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D012367:RNA, Viral; D012189:Retrospective Studies; D012254:Ribavirin; D000069474:Sofosbuvir; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101650235",
"other_id": null,
"pages": "924-9",
"pmc": null,
"pmid": "26365684",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "26111063;26456905;14520615;23281974;15149347;18215704;18382440;21056689;22863263;23746377;24297189;9862875",
"title": "Use of sofosbuvir-based direct-acting antiviral therapy for hepatitis C viral infection in patients with severe renal insufficiency.",
"title_normalized": "use of sofosbuvir based direct acting antiviral therapy for hepatitis c viral infection in patients with severe renal insufficiency"
} | [
{
"companynumb": "US-KADMON PHARMACEUTICALS, LLC-KAD201604-001332",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ERYTHROPOIETIN"
},
"dr... |
{
"abstract": "We report a case in which placental abruption occurred at 16 weeks following first trimester diagnosis and treatment for typhoid fever. Unexpectedly Salmonella enterica serovar Typhi (S. Typhi) was found in fetal tissues at autopsy. Using information from the murine model of typhoid fever in pregnancy, we draw parallels between S. Typhi and L. monocytogenes to develop a plausible hypothesis to explain how this organism was able to cross the placenta in the first trimester to cause abruption, inflammation, and expulsion of the fetus and placenta. We hope that this model for understanding placental infections by the hematogenous route helps to raise awareness that organisms not typically associated with TORCH infection can nevertheless cause placental infection and pregnancy loss.",
"affiliations": "Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, East Providence, RI 02914-5300, USA.;Department of Pediatrics, Microbial Pathogenesis and Host Defense Program, University of California, San Francisco, CA 94143-0654, USA.",
"authors": "Vigliani|Marguerite B|MB|;Bakardjiev|Anna I|AI|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2013/973297",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIM.MEDICINECase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2013/973297Case ReportFirst Trimester Typhoid Fever with Vertical Transmission of Salmonella Typhi, an Intracellular Organism Vigliani Marguerite B. \n1\n*Bakardjiev Anna I. \n2\n1Department of Obstetrics and Gynecology, Warren Alpert Medical School of Brown University, East Providence, RI 02914-5300, USA2Department of Pediatrics, Microbial Pathogenesis and Host Defense Program, University of California, San Francisco, CA 94143-0654, USA*Marguerite B. Vigliani: mbvmd@fullchannel.netAcademic Editor: Florian Thalhammer\n\n2013 29 12 2013 2013 97329720 10 2013 19 11 2013 Copyright © 2013 M. B. Vigliani and A. I. Bakardjiev.2013This 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.We report a case in which placental abruption occurred at 16 weeks following first trimester diagnosis and treatment for typhoid fever. Unexpectedly Salmonella enterica serovar Typhi (S. Typhi) was found in fetal tissues at autopsy. Using information from the murine model of typhoid fever in pregnancy, we draw parallels between S. Typhi and L. monocytogenes to develop a plausible hypothesis to explain how this organism was able to cross the placenta in the first trimester to cause abruption, inflammation, and expulsion of the fetus and placenta. We hope that this model for understanding placental infections by the hematogenous route helps to raise awareness that organisms not typically associated with TORCH infection can nevertheless cause placental infection and pregnancy loss.\n\nhttp://dx.doi.org/10.13039/100000002 National Institutes of HealthR01AI084928http://dx.doi.org/10.13039/100000861 Burroughs Wellcome Fund41259\n==== Body\n1. Introduction\nA recent case of typhoid fever in the first trimester of pregnancy stimulated our curiosity about organisms that can cross the placenta in pregnancy. Despite early diagnosis and prompt treatment with appropriate antibiotic therapy, fetal loss occurred at 16 weeks with Salmonella enterica serovar Typhi (S. Typhi), found in the fetus at autopsy. No one caring for the patient had considered that S. Typhi could be one of the “other” pathogens on the TORCH (Toxoplasma gondii, other, Rubellavirus, Cytomegalovirus, Herpes Simplex virus) list of pathogens. Other microbes not on the TORCH list can also infect the human placenta and affect the fetus (Table 1) [1]. Interestingly many of these same microbes cause abortion in cattle, sheep, goats, and camelids [2]. These microbes disseminate via the hematogenous route and have at least partially intracellular life cycles [3]. It is important to consider these pathogens as a cause for septic abortion or preterm labor in addition to the pathogens that cause chorioamnionitis via the ascending route (e.g., Escherichia coli and Streptococcus agalactiae) [4].\n\n2. Case\nA 23-year-old married HIV-negative Cambodian female developed fevers, chills, nausea, vomiting, headache, and vague abdominal pain while travelling home from Cambodia where she had been visiting relatives. She was admitted to an outside hospital for presumed pyelonephritis because of hematuria. After having received two doses of intravenous antibiotics, it was found that she was pregnant and bleeding, so she was transferred to our institution with a tentative diagnosis of septic abortion.\n\nOn admission, she was febrile to 103°F and had vaginal bleeding. A pelvic ultrasound showed a viable intrauterine pregnancy of 11 weeks and 6 days. Her blood pressure was 98/60 and her pulse was 90, but both nurse and lab tech had difficulty drawing blood. A finger stick CBC showed Hb 9.8 g/dL (nl 11.7–16.0) and wbc 7.8 (nl 4.0–11.0). A manual differential on 100 cells showed 17 bands and 20 lymphocytes. The platelets were estimated to be low. Her bilirubin was normal, but albumin was 2.0 gm/dL (nl 3.8–5.0), and transaminases were elevated, SGOT 57 U/L (nl 12–30); SGPT 37 U/L (nl 5–32).\n\nShortly after admission, she became increasingly weak and obtunded with blood pressures of 70/40. She was transferred to the ICU where she was treated empirically for sepsis with Zosyn and Azithromycin. Her condition stabilized. Within 24 hours, both aerobic and anaerobic blood cultures grew S. Typhi, and her antibiotics were switched to Ceftriaxone. She continued to spike fevers to 103°F for seven days while on antibiotics, but ultimately she defervesced and was discharged where she completed a 14-day course of IV Ceftriaxone in accordance with CDC recommendations.\n\nShe developed recurrent vaginal bleeding and lower abdominal pain after the antibiotics were completed, but there was good fetal growth by ultrasound and the cervical os remained closed. Followup blood cultures and stool cultures were negative for S. Typhi and her blood counts were unremarkable, but vaginal bleeding and lower abdominal pain persisted. At 16 weeks she delivered an 86 gm female fetus in the ER. The heart rate was present at delivery, but absent at 15 minutes.\n\nThe products of conception were sent for postmortem examination. Cultures of the placenta were not ordered by the emergency physician. The fetus did not have any congenital anomalies or growth retardation and all measurements were consistent with 16 weeks gestational age. Widespread petechial hemorrhages in many organs were suggestive of recent acute intrauterine stress and hypoxia. Although fetal blood cultures were negative, S. Typhi was isolated by culture from the fetal lung, consistent with vertical transmission. The placenta was large for gestational age, consistent with transplacental infection. There was mild acute chorioamnionitis and an adherent blood clot associated with placental infarct, with intra- and intervillous hemorrhage involving 70% of the maternal surface.\n\n3. Comment\nThis case is notable because Salmonellae are usually not considered TORCH organisms, making it inscrutable that S. Typhi found its way into the fetus despite minimal pathological evidence of chorioamnionitis and despite two weeks of treatment with an antibiotic known to cross the placenta. Regrettably, the emergency physician did not order Gram stains or cultures of the placenta, but it begs the question because S. Typhi was found in the fetal lung proving not only that the organism could cross the placenta, but also that it had found a way to evade both maternal immune responses and intravenous antibiotics.\n\n\nSalmonellae are facultative intracellular Gram-negative bacteria that cause disease in a wide range of host species [19]. S. Typhi affects only humans and is the causative agent of typhoid fever. Typhoid fever is contracted by drinking water tainted by the feces of infected individuals. Every year, an estimated 21.7 million cases occur, resulting in approximately 217,000 deaths [20]. The highest incidence is in Southeast Asia where poor sanitation and unclean water are rampant. In the United States 450 cases are reported annually, and most have travelled internationally within 6 weeks of the onset of the disease.\n\nBefore the antibiotic era, typhoid fever in pregnancy was a well-known and dreaded disease, associated with a 60–80% risk of abortion and premature labor and a maternal mortality of 15% [21]. Since the introduction of antibiotics there have been a few case reports and case series describing typhoid fever in pregnancy [5–18, 22]. The conventional wisdom and the CDC recommendations for treatment are based on a case-control study by Sulaiman which shows that typhoid fever does not affect the outcome of the pregnancy [22]. However, our review of the literature supports the contention by Carles et al. [18] that infection early in pregnancy carries a worse prognosis for the fetus, based on studies that address gestational age at the time of infection (Table 2). Certainly, our anecdotal experience is consistent with this observation.\n\nMost of the information we have about the pathogenesis typhoid fever in pregnancy is derived from experiments with S. typhimurium, a serovar that causes gastroenteritis in humans but produces a disseminated disease similar to typhoid fever in mice [23]. Infections of pregnant mice with S. typhimurium result in 100% fetal loss and 60% maternal mortality. S. typhimurium proliferates in the infected placenta and causes widespread placental necrosis and inflammation leading to fetal death and maternal disease [24, 25]. Interestingly, the inflammatory response triggered by the bacterium appears to be more important for the clinical outcome than the bacterial burden. To wit, infection of the placenta with a mutant strain of S. typhimurium that is unable to cause inflammation does not induce fetal or maternal mortality despite bacterial burdens similar to wild-type infection [25].\n\nThe murine model of S. typhimurium thus explains the relationship between bacteria in the placenta, inflammation, placental necrosis, and fetal loss, but it does not explain how the organism breaches the placental barrier. To answer that question, we invite the reader to consider the analogy to Listeria monocytogenes, a well-studied enteric organism, which bears similarities to Salmonella. \n\n\n\nListeria monocytogenes has provided a prototype for understanding placental infection by intracellular organisms via the hematogenous route [3]. L. monocytogenes is a ubiquitous facultative intracellular Gram-positive bacterium that causes food-borne disease in humans and other mammals [26]. Infection in pregnancy can result in spontaneous second trimester abortion, preterm labor, and neonatal sepsis or meningitis with mortality rates as high as 50% [27]. The pregnant guinea pig model of listeriosis has shown that the placenta is generally resistant to infection [28]. A mere fraction of the maternal load manages to colonize the placenta, but once infected, even by a single founder bacterium, a clonal infection can start. The placenta becomes a nidus of infection, causing continuous seeding of bacteria to the fetus and to maternal organs. Antibiotics that kill extracellular but not intracellular L. monocytogenes demonstrate that the majority of bacteria in the placenta, maternal organs, and blood are inside of host cells.\n\nThe decidua is the initial site of placental colonization in experimental models for L. monocytogenes, T. gondii, Chlamydia psittaci, Coxiella burnetii, Fusobacterium nucleatum, and Brucella abortus [3]. Since there is no physical barrier between invasive fetal trophoblasts and maternal decidual cells it is not surprising that L. monocytogenes can spread from maternal macrophages to invasive fetal trophoblasts. In contrast, syncytiotrophoblasts are very resistant to infection by viral [29, 30], bacterial [31], and protozoan pathogens [32] and are underlain by a continuous basement membrane which acts as an additional physical barrier against pathogen invasion.\n\n\nSalmonellae are a well-known cause of abortion in livestock, resulting in significant economic damages. In humans nontyphoidal Salmonellae have been associated with sepsis and early second trimester pregnancy loss, similar to S. Typhi in our patient [33–35]. Since Salmonellae are intracellular organisms, it is reasonable to speculate that decidual infection might have occurred early in the illness, prior to diagnosis or treatment, during an episode of bacteremia. Our hypothesis is that an abruption occurred at 16 weeks as the result of a delayed but robust host inflammatory response to the continuing presence of the pathogen in the placenta. We know that the organism crossed over into the fetal compartment, and we surmise that the most likely mechanism might have been via infection of fetal invasive trophoblasts in the maternal decidua. There was only minimal chorioamnionitis in the placenta suggestive of hematogenous infection leading primarily to placentitis. Consistent with this hypothesis is that our patient had placental abruption involving 70% of the maternal surface, a finding that parallels the placental necrosis seen in the murine model of pregnancy-associated typhoid fever [24, 25].\n\nBy this case report we hope to challenge the prevailing TORCH paradigm. We propose that researchers and clinicians alike consider the hypothesis that any organism with even a partially intracellular lifecycle may potentially infect the placenta via the hematogenous route. There is ample evidence in the literature that various intracellular organisms can travel inside of the immune cells, and that maternal immune cells can be recruited to the fetal implantation site, where extravillous trophoblasts with immune modifications are juxtaposed to maternal decidual cells. Given sufficient invasive and evasive strategies, some intracellular organisms, like S. Typhi, may be able to take advantage of these opportunities to cause significant damage to the mother or the fetus.\n\nConflict of Interests\nNone of the authors have any conflict of interests.\n\nAcknowledgments\nThe authors would like to acknowledge Monique Depaepe, M.D., Staff Pathologist, Division of Perinatal and Pediatric Pathology at Women and Infants' Hospital, for her autopsy of the fetus and for stimulating the authors thinking about S. Typhi crossing the placenta. Anna I. Bakardjiev. is supported by the US National Institutes of Health (R01AI084928) and a Burroughs Wellcome Fund Investigator in the Pathogenesis of Infectious Disease Award (41259).\n\nTable 1 Organisms that invade the placenta to cause fetal damage and maternal complications are all intracellular for a portion of their lifecycles.\n\nBacteria\tParasites\tViruses*\t\n\nBrucella spp. (F)\t\nLeishmania spp. (O)\tCytomegalovirus (O)\t\n\nCoxiella burnetii (F)\t\nPlasmodium falciparum (O)\tLymphocytic choriomeningitis virus (O)\t\n\nListeria monocytogenes (F)\t\nToxoplasma gondii (O)\tParvovirus B19 (O)\t\n\nMycobacterium tuberculosis (F)\t\nTrypanosoma cruzi (F)\tRubella virus (O)\t\n\nTreponema pallidum (E)\t \tVaricella zoster virus (O)\t\n\nSalmonellae (F)\t \t \t\n\nO: obligate intracellular. F: facultative intracellular. E: mainly extracellular, but intracellular is documented.\n\nMany other intracellular organisms including Babesia spp., Coxsackie B virus, Japanese Encephalovirus, Leptospira spp., Wuchereria bancrofti, Candida spp., Pasteurella, Shigella, Campylobacter, nontyphoidal Salmonella spp. and many gingival bacteria including Fusobacterium nucleatum merit further study because of human case reports and/or animal studies.\n\n*Epstein-Barr virus, Hepatitis B virus, HIV, and HSV are transmitted perinatally, but rarely cross the placenta.\n\nTable 2 Typhoid Fever in Pregnancy (adapted from Carles with permission).\n\nAuthor, date\tNo. of patients\t<16 weeks\tFetal losses <16 weeks\tInfection >16 weeks\tIntrauterine fetal deaths >16 weeks\tNeonatal sepsis\tNeonatal deaths\tPerinatal deaths >16 weeks\t\n\nRiggall et al., 1974 [5]\t7\t1\t1\t6\t0\t0\t0\t0\t\n\nAwadalla et al., 1985 [6]\t1\t0\t0\t1\t1\t0\t0\t1\t\n\nAmster et al., 1985 [7]\t1\t1\t1\t0\t0\t0\t0\t0\t\n\nSadan et al., 1986 [8]\t2\t1\t1\t1\t0\t0\t0\t0\t\n\nChin et al., 1986 [9]\t3\t0\t0\t3\t0\t3\t0\t0\t\n\nSeoud et al., 1988 [10]\t14\t2\t1\t12\t0\t3\t0\t0\t\n\nDildy et al., 1990 [11]\t1\t1\t0\t0\t0\t0\t0\t0\t\n\nFigueroa, 1994 [12]\n\t5\t2\t1\t3\t0\t0\t1\t1\t\n\nGluck et al., 1994 [13]\t1\t0\t0\t1\t0\t0\t0\t0\t\n\nHedriana et al., 1995 [14]\t1\t1\t1\t0\t0\t0\t0\t0\t\n\nKoul et al., 1995 [15]\t7\t0\t0\t7\t0\t0\t0\t0\t\n\nLeung et al., 1995 [16]\t3\t0\t0\t3\t0\t0\t0\t0\t\nZenilman, 1997 [17]\t1\t0\t0\t1\t0\t0\t0\t0\t\n\nCarles et al., 2002 [18]\t25\t3\t1\t22\t6\t2\t0\t6\t\n\n\n\t\nTotal\t72\t12\t7\t60\t7\t8\t1\t8\t\n \t \t(58%)\t \t \t \t \t(13%)\n==== Refs\n1 Zeldovich VB Bakardjiev AI Host defense and tolerance: unique challenges in the placenta PLoS Pathogens 2012 8 8 e1002804 \n2 Daniel Givens M Marley MS Infectious causes of embryonic and fetal mortality Theriogenology 2008 70 3 270 285 2-s2.0-45649083335 18502494 \n3 Robbins JR Bakardjiev AI Pathogens and the placental fortress Current Opinion in Microbiology 2012 15 1 36 43 2-s2.0-84856093366 22169833 \n4 Queiros da Mota V Prodhom G Yan P Hohlfheld P Greub G Rouleau C Correlation between placental bacterial culture results and histological chorioamnionitis: a prospective study on 376 placentas Journal of Clinical Pathology 2013 66 3 243 248 23268318 \n5 Riggall F Salkind G Spellacy W Typhoid fever complicating pregnancy Obstetrics and Gynecology 1974 44 1 117 121 2-s2.0-0016193284 4834804 \n6 Awadalla SG Mercer LJ Brown LG Pregnancy complicated by intraamniotic infection by Salmonella typhi Obstetrics and Gynecology 1985 65 3, supplement 2-s2.0-0021922573 \n7 Amster R Lessing JB Jaffa AJ Peyser MR Typhoid fever complicating pregnancy Acta Obstetricia et Gynecologica Scandinavica 1985 64 8 685 686 2-s2.0-0022312171 3832761 \n8 Sadan O Matthews LH Koller AB White RG Typhoid fever in pregnancy. Case report and review of the literature Acta Obstetricia et Gynecologica Scandinavica 1986 65 7 807 809 2-s2.0-0023007637 3811857 \n9 Chin KC Simmonds EJ Tarlow MJ Neonatal typhoid fever Archives of Disease in Childhood 1986 61 12 1228 1230 2-s2.0-0023013445 3813617 \n10 Seoud M Saade G Uwaydah M Azoury R Typhoid fever in pregnancy Obstetrics and Gynecology 1988 71 5 711 714 2-s2.0-0023944934 3357660 \n11 Dildy GA III Martens MG Faro S Lee W Typhoid fever in pregnancy. A case report Journal of Reproductive Medicine for the Obstetrician and Gynecologist 1990 35 3 273 276 2-s2.0-0025236553 2325041 \n12 Figueroa DR Segura CE García AT de la Cruz BR Typhoid fever in pregnancy. Clinical course, treatment and perinatal repercussions Ginecología Y Obstetricia De México 1994 62 362 367 7821835 \n13 Gluck B Ramin KD Ramin SM Salmonella typhi and pregnancy: a case report Infectious Diseases in Obstetrics and Gynecology 19941994 2 4 186 189 \n14 Hedriana HL Mitchell JL Williams SB Salmonella typhi chorioamnionitis in a human immunodeficiency virus- infected pregnant woman: a case report Journal of Reproductive Medicine for the Obstetrician and Gynecologist 1995 40 2 157 159 2-s2.0-0028959468 7738931 \n15 Koul PA Wani JI Wahid A Ciprofloxacin for multiresistant enteric fever in pregnancy The Lancet 1995 346 8970 307 308 2-s2.0-0029149287 \n16 Leung D Venkatesan P Boswell T Innes JA Wood MJ Treatment of typhoid in pregnancy The Lancet 1995 346 8975 p. 648 2-s2.0-0029102941 \n17 Zenilman JM Typhoid fever The Journal of the American Medical Association 1997 278 10 847 850 2-s2.0-0030804390 9293994 \n18 Carles G Montoya Y Seve B Rakotofananina T Largeaud M Mignot V Typhoid fever and pregnancy Journal de Gynecologie Obstetrique et Biologie de la Reproduction 2002 31 5 495 499 2-s2.0-0036715023 \n19 de Jong HK Parry CM van der Poll T Wiersinga WJ Host-pathogen interaction in invasive Salmonellosis PLoS Pathogens 2012 8 10 e100293 \n20 Crump JA Luby SP Mintz ED The global burden of typhoid fever Bulletin of the World Health Organization 2004 82 5 346 353 2-s2.0-2642571836 15298225 \n21 Villarama A Galang JS Typhoid fever in pregnancy Phillippine Islands Medical Association 1930 10 311 315 \n22 Sulaiman K Sarwari AR Culture-confirmed typhoid fever and pregnancy International Journal of Infectious Diseases 2007 11 4 337 341 2-s2.0-34250792350 17321180 \n23 Carter PB Collins FM The route of enteric infection in normal mice Journal of Experimental Medicine 1974 139 5 1189 1203 2-s2.0-0016064933 4596512 \n24 Pejcic-Karapetrovic B Gurnani K Russell MS Finlay BB Sad S Krishnan L Pregnancy impairs the innate immune resistance to Salmonella typhimurium leading to rapid fatal infection Journal of Immunology 2007 179 9 6088 6096 2-s2.0-38449097276 \n25 Chattopadhyay A Robinson N Sandhu JK Finlay B Sad S Krishnan L Salmonella enterica serovar typhimurium-induced placental inflammation and not bacterial burden correlates with pathology and fatal maternal disease Infection and Immunity 2010 78 5 2292 2301 2-s2.0-77951230714 20194592 \n26 Linnan MJ Mascola L Xiao Dong Lou XDL Epidemic listeriosis associated with Mexican-style cheese The New England Journal of Medicine 1988 319 13 823 828 2-s2.0-0023681508 3137471 \n27 Lamont RF Sobel J Mazaki-Tovi S Listeriosis in human pregnancy: a systematic review Journal of Perinatal Medicine 2011 39 3 227 236 2-s2.0-79959950593 21517700 \n28 Bakardjiev AI Theriot JA Portnoy DA Listeria monocytogenes traffics from maternal organs to the placenta and back PLoS Pathogens 2006 2 6 p. e66 2-s2.0-33746539047 \n29 Koi H Zhang J Makrigiannakis A Syncytiotrophoblast is a barrier to maternal-fetal transmission of herpes simplex virus Biology of Reproduction 2002 67 5 1572 1579 2-s2.0-0036839306 12390890 \n30 Delorme-Axford E Donker RB Mouillet JF Human placental trophoblasts confer viral resistance to recipient cells Proceedings of the National Academy of Sciences of the United States of America 2013 110 29 12048 12053 23818581 \n31 Robbins JR Skrzypczynska KM Zeldovich VB Kapidzic M Bakardjiev AI Placental syncytiotrophoblast constitutes a major barrier to vertical transmission of Listeria monocytogenes PLoS Pathogens 2010 6 1 2-s2.0-77649214077 e1000732 \n32 Robbins JR Zeldovich VB Poukchanski A Boothroyd JC Bakardjiev AI Tissue barriers of the human placenta to infection with Toxoplasma gondii \n Infection and Immunity 2012 80 1 418 428 2-s2.0-84857075243 22083708 \n33 Dalaker K Andersen BM Lovslett K Revhaug A Berdal B Septic abortion caused by Salmonella enteritidis Acta Obstetricia et Gynecologica Scandinavica 1988 67 2 185 186 2-s2.0-0023715831 3051872 \n34 Zettell L Jelsema RD Isada NB First-trimester septic abortion due to Salmonella enteritidis oranienburg Infectious Diseases in Obstetrics and Gynecology 1995 2 5 239 241 18475401 \n35 Coughlin LB McGuigan J Haddad NG Mannion P Salmonella sepsis and miscarriage Clinical Microbiology and Infection 2003 9 8 866 868 2-s2.0-0141516239 14616710\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2013()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
"mesh_terms": null,
"nlm_unique_id": "101512910",
"other_id": null,
"pages": "973297",
"pmc": null,
"pmid": "24459469",
"pubdate": "2013",
"publication_types": "D016428:Journal Article",
"references": "12390890;3811857;3137471;3871929;14616710;17321180;18475401;23055923;22169833;4834804;3357660;20107601;22912572;22083708;18502494;7738931;7630260;23818581;4596512;15298225;3813617;7651044;3051872;16846254;12379834;17947683;3832761;20194592;21517700;7821835;2325041;18475390;23268318;9293994",
"title": "First trimester typhoid Fever with vertical transmission of salmonella typhi, an intracellular organism.",
"title_normalized": "first trimester typhoid fever with vertical transmission of salmonella typhi an intracellular organism"
} | [
{
"companynumb": "PHHY2017US177950",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
"dru... |
{
"abstract": "Drug-induced liver injury (DILI) with features of autoimmunity (AI) represents an important category of hepatotoxicity due to medication exposure. Drugs repeatedly associated with AI-DILI include diclofenac, α-methyl DOPA, hydralazine, nitrofurantoin, minocycline, and more recently statins and anti-TNF-α agents. Usually, symptoms of acute liver injury occur within a few months after initiation of a culprit medication, but a longer latency period is possible. Like idiopathic autoimmune hepatitis, circulating autoantibodies and a hypergammaglobulinemia are frequently present in sera from patients with AI-DILI. If performed, a liver biopsy should demonstrate interface hepatitis with a prominent plasma cell infiltrate. The severity of AI-DILI is variable, but a complete resolution after withdrawal of the offending medication is the expectation. A response to corticosteroid therapy supports the diagnosis, whereas a lack of recurrence of symptoms or signs following corticosteroid cessation distinguishes AI-DILI from idiopathic autoimmune hepatitis.",
"affiliations": "Department of Medicine, Center for Liver Diseases and Transplantation, Carolinas Medical Center, Charlotte, North Carolina.;Immune Monitoring Core Laboratory, Carolinas Medical Center, Charlotte, North Carolina.;Department of Pathology, Carolinas Medical Center, Charlotte, North Carolina.;Department of Pathology, Carolinas Medical Center, Charlotte, North Carolina.;Department of Medicine, Center for Liver Diseases and Transplantation, Carolinas Medical Center, Charlotte, North Carolina.;Department of Medicine, Center for Liver Diseases and Transplantation, Carolinas Medical Center, Charlotte, North Carolina.",
"authors": "deLemos|Andrew S|AS|;Foureau|David M|DM|;Jacobs|Carl|C|;Ahrens|Will|W|;Russo|Mark W|MW|;Bonkovsky|Herbert L|HL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000892:Anti-Infective Agents, Urinary; D000959:Antihypertensive Agents; D001323:Autoantibodies; D016207:Cytokines; D006680:HLA Antigens; D006830:Hydralazine; D008750:Methyldopa; D009582:Nitrofurantoin; D008911:Minocycline",
"country": "United States",
"delete": false,
"doi": "10.1055/s-0034-1375959",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-8087",
"issue": "34(2)",
"journal": "Seminars in liver disease",
"keywords": null,
"medline_ta": "Semin Liver Dis",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D000892:Anti-Infective Agents, Urinary; D000959:Antihypertensive Agents; D001323:Autoantibodies; D015551:Autoimmunity; D056486:Chemical and Drug Induced Liver Injury; D016207:Cytokines; D003937:Diagnosis, Differential; D004342:Drug Hypersensitivity; D005260:Female; D006680:HLA Antigens; D019693:Hepatitis, Autoimmune; D006801:Humans; D006830:Hydralazine; D006942:Hypergammaglobulinemia; D008099:Liver; D008111:Liver Function Tests; D008297:Male; D008750:Methyldopa; D008911:Minocycline; D009582:Nitrofurantoin; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "8110297",
"other_id": null,
"pages": "194-204",
"pmc": null,
"pmid": "24879983",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D016454:Review",
"references": null,
"title": "Drug-induced liver injury with autoimmune features.",
"title_normalized": "drug induced liver injury with autoimmune features"
} | [
{
"companynumb": "US-TEVA-606802USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDRALAZINE HYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "A vulnerable elderly man with prednisone-induced delirium Background Delirium always has an underlying cause, for example, medication. This article describes the case of a man with severe delirium caused by prednisone. Case description A 91-year-old vulnerable man developed severe delirium with agitation, verbal and physical aggression and visual hallucinations 3 days after starting treatment with low-dose prednisone. The delirium disappeared completely after prednisone was stopped. The delirium led to a long hospital stay of 36 days, weight loss of 10 kg due to undernourishment and extension of home care on discharge. Conclusion This case illustrates that delirium is always lurking around the corner in patients with multiple vulnerabilities. The provoking factor can be slight, for example 15 or 5 mg of prednisone. So be careful when starting prednisone in vulnerable elderly patients.",
"affiliations": "Deventer Ziekenhuis, afd. Geriatrie.;Deventer Ziekenhuis, afd. Geriatrie.;Deventer Ziekenhuis, afd. Geriatrie.",
"authors": "Otten|Rosali I|RI|;Jansen|Inge H M|IHM|;Zeeman|Marieke|M|",
"chemical_list": "D005938:Glucocorticoids; D011241:Prednisone",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "163()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000369:Aged, 80 and over; D003693:Delirium; D005938:Glucocorticoids; D006212:Hallucinations; D006801:Humans; D008297:Male; D011241:Prednisone",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31120224",
"pubdate": "2019-05-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A vulnerable elderly man with prednisone-induced delirium.",
"title_normalized": "a vulnerable elderly man with prednisone induced delirium"
} | [
{
"companynumb": "NL-TEVA-2019-NL-1105218",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Although imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), 25-30% patients do not respond or relapse after initial response. Imatinib uptake into targeted cells is crucial for its molecular response and clinical effectiveness. The organic cation transporter 1 (OCT1) has been proposed to be responsible for this process, but its relevance has been discussed controversially in recent times. Here we found that the multidrug and toxin extrusion protein 1 (MATE1) transports imatinib with a manifold higher affinity. MATE1 mainly mediates the cellular uptake of imatinib into targeted cells and thereby controls the intracellular effectiveness of imatinib. Importantly, MATE1 but not OCT1 expression is reduced in total bone marrow cells of imatinib-non-responding CML patients compared with imatinib-responding patients, indicating that MATE1 but not OCT1 determines the therapeutic success of imatinib. We thus propose that imatinib non-responders could be identified early before starting therapy by measuring MATE1 expression levels.",
"affiliations": "Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany.;Experimental Nephrology, Medizinische Klinik D, University Hospital Münster, Münster, Germany.;Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany.;Molecular Nephrology, Department of Internal Medicine D, University Hospital Münster, Münster, Germany.;Experimental Nephrology, Medizinische Klinik D, University Hospital Münster, Münster, Germany.;Department of Medicine A, University Hospital Münster, Münster, Germany.;Department of Medicine A, University Hospital Münster, Münster, Germany.;Molecular Nephrology, Department of Internal Medicine D, University Hospital Münster, Münster, Germany.;Clinic and Polyclinic of Internal Medicine IV, Hematology and Oncology, University Hospital Halle, Halle (Saale), Germany.;MLL Munich Leukemia Laboratory, München, Germany.;MLL Munich Leukemia Laboratory, München, Germany.;Experimental Nephrology, Medizinische Klinik D, University Hospital Münster, Münster, Germany.;Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany.",
"authors": "Harrach|S|S|;Schmidt-Lauber|C|C|;Pap|T|T|;Pavenstädt|H|H|;Schlatter|E|E|;Schmidt|E|E|;Berdel|W E|WE|;Schulze|U|U|;Edemir|B|B|;Jeromin|S|S|;Haferlach|T|T|;Ciarimboli|G|G|;Bertrand|J|J|",
"chemical_list": "D000970:Antineoplastic Agents; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D047428:Protein Kinase Inhibitors; C521869:SLC47A1 protein, human; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl",
"country": "United States",
"delete": false,
"doi": "10.1038/bcj.2016.79",
"fulltext": "\n==== Front\nBlood Cancer JBlood Cancer JBlood Cancer Journal2044-5385Nature Publishing Group bcj20167910.1038/bcj.2016.7927635733Original ArticleMATE1 regulates cellular uptake and sensitivity to imatinib in CML patients MATE1 regulates imatinib uptake and sensitivityHarrach S 18Schmidt-Lauber C 28Pap T 1Pavenstädt H 3Schlatter E 2Schmidt E 4Berdel W E 4Schulze U 3Edemir B 5Jeromin S 6Haferlach T 6Ciarimboli G 2*8Bertrand J 1781 Institute of Experimental Musculoskeletal Medicine, University Hospital Münster, Münster, Germany2 Experimental Nephrology, Medizinische Klinik D, University Hospital Münster, Münster, Germany3 Molecular Nephrology, Department of Internal Medicine D, University Hospital Münster, Münster, Germany4 Department of Medicine A, University Hospital Münster, Münster, Germany5 Clinic and Polyclinic of Internal Medicine IV, Hematology and Oncology, University Hospital Halle, Halle (Saale), Germany6 MLL Munich Leukemia Laboratory, München, Germany7 Department of Orthopedic Surgery, Otto-von-Guericke University Magdeburg, Magdeburg, Germany* Experimentelle Nephrologie, Medizinische Klinik D, Universitätsklinikum Münster, Albert-Schweitzer-Campus 1 (A14), Münster 48149 Germany. E-mail: gciari@uni-muenster.de8 These authors contributed equally to this work.\n\n09 2016 16 09 2016 1 9 2016 6 9 e470 04 08 2016 11 08 2016 Copyright © 2016 The Author(s)2016The Author(s)This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/Although imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), 25–30% patients do not respond or relapse after initial response. Imatinib uptake into targeted cells is crucial for its molecular response and clinical effectiveness. The organic cation transporter 1 (OCT1) has been proposed to be responsible for this process, but its relevance has been discussed controversially in recent times. Here we found that the multidrug and toxin extrusion protein 1 (MATE1) transports imatinib with a manifold higher affinity. MATE1 mainly mediates the cellular uptake of imatinib into targeted cells and thereby controls the intracellular effectiveness of imatinib. Importantly, MATE1 but not OCT1 expression is reduced in total bone marrow cells of imatinib-non-responding CML patients compared with imatinib-responding patients, indicating that MATE1 but not OCT1 determines the therapeutic success of imatinib. We thus propose that imatinib non-responders could be identified early before starting therapy by measuring MATE1 expression levels.\n==== Body\nIntroduction\nAlthough the tyrosine kinase inhibitor imatinib is highly effective in the treatment of chronic myeloid leukemia (CML), some patients do not respond to imatinib or relapse after initial response.1, 2 In all, 25–30% of CML patients treated with imatinib as a first-line therapy experience treatment failure leading to an increased risk of progression to accelerated or blast phase. The response rate varies within different stages of the disease.3 Besides other mechanisms of resistance such as mutations in the BCR-ABL1 fusion gene,4 the transport of imatinib into its targeted cells has been proposed to be crucial for the clinical effectiveness.5, 6, 7 As an organic cation, imatinib has to be actively translocated across the cell membrane. Several clinical trials as well as in vitro studies investigated the role of the organic cation transporter 1 (OCT1) in this process. Although some studies suggested a critical role of OCT1 in regulating imatinib efficacy,5, 6, 7 other studies could not confirm these findings.8, 9 The role of OCT1 for imatinib uptake has mostly been inferred from inhibition studies with prazosin and amantadine. This approach has been criticized recently, as these substances do not specifically inhibit OCT1 but are potential inhibitors of other imatinib uptake pathways distinct from OCT1.10 Although OCT1 is generally capable to transport imatinib, it might have minor relevance for a transport under clinical conditions. Indeed, in vitro studies have shown a moderate affinity of OCT1 to imatinib11, 12 as well as low expression levels in mononuclear and CD34+ cells.8, 13 OCT1 belongs to the SLC22A family of polyspecific organic cation transporters that also includes OCT2 and OCT3, which have an overlapping spectrum of substrates.14 Experiments on model cells have shown that other members of this group also transport imatinib.11, 12, 15 Others and our group recently demonstrated that the multidrug and toxin extrusion protein 1 (MATE1), also belonging to the group of organic cation transporters, accepts imatinib as a substrate.11, 12\n\nTransporters other than OCT1, especially MATE1, have not been investigated regarding their role for imatinib accumulation in targeted cells for CML treatment yet. Here we investigate transporters that might be relevant for imatinib uptake, and regarding their role in mediating cellular imatinib uptake, regulating molecular response and their correlation to the clinical therapeutic response to imatinib of CML patients.\n\nMaterials and methods\nCells\nPeripheral blood mononuclear cells (PBMCs) were isolated from buffy coats of six healthy volunteers (German Red Cross) with a Ficoll density gradient assay (GE Healthcare, Freiburg, Germany) and used for experiments within 6 h. The ethics committee of the University of Münster approved these experiments. K562 cells were kindly provided by Prof. Müller-Tidow (University of Halle, Halle (Saale), Germany) and cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 2 mm glutamine at 37 °C in 5% CO2. HEK293 cells were stably transfected with single OCT11, 16 and cultured as described.11 Overexpression of the single OCT was verified via real-time reverse transcription polymerase chain reaction (qRT-PCR).11\n\nmRNA expression analysis\nRNA isolation and reverse transcription were performed with Qiagen RNeasy Midikit (Qiagen, Hilden, Germany) and Invitrogen Super Script III (Invitrogen, Carlsbad, CA, USA), respectively. For amplification of the respective transporters and the analyzed housekeeping genes, the following specific primer pairs were used: OCT1 S, 5′-CATCATAATCATGTGTGTTGGCC-3′ and OCT1 AS, 5′-CAAACAAAATGAGGGGCAAGGCTT-3′ OCT2 S, 5′-CATTGAACTAAGAAGAGAGACCG-3′ and OCT2 AS, 5′-CCACAGTGTACAATAGACTCCA-3′ OCT3 S, 5′-GACAAGAGAAGCCCCCAACCTGAT-3′ and OCT3 AS, 5′-CACTAAAGGAGAGCCAAAAATGTC-3′ MATE1 S, 5′-GCAACCACACTTGGAGTGATGG-3′ and MATE1 AS, 5′-GAGCAGAATTCCCACTCCGAG-3′ GAPDH S, 5′-CAAGCTCATTTCCTGGTATGAC-3′ GAPDH AS, 5′-GTGTGGTGGGGGACTGAGTGTGG-3′. Quantitative real-time PCR was then carried out with ABI PRISM 7900 Sequence Detection System (Applied Biosystems, Foster City, CA, USA) using SYBR Green PCR Master Mix (Fischer Scientific, Portsmouth, NH, USA).\n\nAffinity of imatinib to single OCT\nTo elucidate whether a transport is relevant under clinically used concentrations, peak plasma levels of imatinib were compared with apparent affinities of single OCT to imatinib as recommended by the International Transporter Consortium.17 Imatinib plasma levels and the unbound fraction were obtained from the literature.18, 19 The half-maximal inhibitory drug concentration (IC50) was taken from previously published data, where IC50 values were obtained by inhibition of the well-known model substrate 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP+).11 Similar IC50 values were obtained when inhibiting the uptake of 1-methyl-4-phenylpyridinium iodide (MPP+) by imatinib underlining the stability of this method.12\n\nCellular imatinib uptake and specific OCT inhibition\nHEK293, PMBC or K562 cells were incubated with 5 μm imatinib (LC Laboratories, Woburn, MA, USA) for 10 min at 4 °C, where mainly passive diffusion of imatinib through the cell membrane is possible, and at 37 °C, where active transporter-mediated uptake occurs. The transport process of the investigated transporters was specifically inhibited by chemical substances at concentrations that are known to inhibit specifically the distinct transporters (Supplementary Table 1). MATE1-mediated transport was inhibited by 200 nm pyrimethamine (Sigma-Aldrich, Steinheim, Germany),20 whereas 80 μm MPP+ (Sigma-Aldrich) was used for OCT1 and OCT2 coinhibition.14, 20, 21, 22, 23 Cells were then lysed and intracellular imatinib accumulation was quantified with high-performance liquid chromatography with UV detector as described previously.11\n\nMATE1 knockdown and effects on BCR-ABL1 activation or cytokinesis\nMATE1 knockdown in K562 cells was performed with Hyperfect transfection reagent (Qiagen) according to the manufacturer's instructions using either 40 nM MATE1 small interfering RNA (siRNA) (Sigma-Aldrich; 5′-GACAAUUUACUGUGAGUUA-3′) or control siRNA (Invitrogen; nonsilencing mock siRNA). The transfection efficiency was verified by PCR and western blot analysis for MATE1 as described earlier.11 To assess the influence of MATE1 expression on imatinib-dependent biologic effects, transfected K562 cells were incubated with imatinib at different concentrations (5 or 10 μM) for 10 min and the activity of BCR-ABL1 protein was then detected by western blot analysis using anti-phospho-ABL (Cell signaling, Frankfurt, Germany) and GAPDH antibody (Sigma-Aldrich). Further, we evaluated the clonal growth of K562 cells stably transduced with lentiviral vectors (plKO.1-GFP) delivering a short hairpin RNA against MATE1 (shMATE1, 5′-GACAAUUUACUGUGAGUUA-3′) or control mRNA (shscramble). Thereon, short hairpin-transduced K562 cells (3 × 103 cells) were plated in 1 ml of methylcellulose medium (M3234 MethoCult; Stem Cell Technologies, Cologne, Germany) without cytokines in quadruplicates, supplemented with imatinib (0–1000 nM) and the colonies were counted on day 7.\n\nPatient analysis\nIn total, 30 patients with BCR-ABL1 major transcript (p210)-positive CML were included in this study after written informed consent was obtained (Ethik-Kommission der Bayerischen Landesärztekammer; Ethik-Kommission No. 05117). BCR-ABL1 diagnostic procedures were performed in the Munich Leukemia Laboratory (MLL, München, Germany) and data were kindly provided by S Jeromin and T Haferlach. Upon diagnosis, MATE1-mRNA expression was quantified by qRT-PCR in total bone marrow (BM) cells as described above. All patients were treated with imatinib and MATE1 expression was compared between imatinib-responding and -refractory patients defined by major molecular response. BCR-ABL1/ABL1 ⩽10% (International Scale) after 3 months of imatinib therapy was defined as optimal response, whereas poor response was defined by a BCR-ABL1/ABL1 >1% after 6 months of therapy (warning and failure according to the ELN 2013 guidelines24). Detailed patient characteristics are given in Table 1.\n\nStatistical analysis\nData were analyzed with GraphPad Prism, V4.0 (GraphPad Software, San Diego, CA, USA). One-way analysis of variance with Tukey's post hoc test or unpaired Student's t-test were used for statistical analysis as indicated. Values are mean±s.e.m. with the following statistical significance levels: *P<0.05, **P<0.01, ***P<0.005 and NS=not significant.\n\nResults\nTo investigate the transport capacity of OCT1 and other potential imatinib transporters, such as OCT2, OCT3 and MATE1, we measured the imatinib uptake in HEK293 cells overexpressing the respective OCTs. Imatinib uptake as detected by HPLC was significantly increased in OCT1- (1.16±0.16 nmol/mg protein; P=0.0013), OCT2- (1.30±0.13 nmol/mg protein; P=0.0001) and MATE1-overexpressing HEK cells (1.16±0.15 nmol/mg protein; P=0.0002), but not in OCT3-HEK cells (0.84±0.10 nmol/mg protein; P=0.2105) compared with wild-type HEK cells (0.53±0.03 nmol/mg protein) (Figure 1a). This indicates that OCT1, OCT2 and MATE1 but not OCT3 can generally function as imatinib transporters.\n\nTo elucidate whether this transport is relevant under clinically used concentrations, we compared imatinib plasma levels to apparent affinities of the transporters according to the recommendations of the International Transporter Consortium.17 Along with these guidelines, transporters with a quotient of unbound plasma drug concentration (Cunbound) divided by IC50 >0.1 are defined as clinically relevant. Imatinib plasma levels for therapy regimens of 400 and 600 mg daily, the unbound fraction and the half-maximal inhibitory imatinib concentration to the respective OCTs (IC50) were obtained from the literature (Supplementary Table 2).11, 18, 19 For OCT1, the quotient of the unbound imatinib plasma concentration for therapy regimens of 400 or 600 mg daily divided by the apparent affinity to imatinib was 0.03 and 0.1, respectively. A relevant interaction of OCT1 with imatinib under clinically used concentration is thus unlikely. However, we found remarkably high quotients for MATE1 with 1.7 (for 400 mg imatinib daily) and 5.8 (for 600 mg imatinib daily), suggesting a possible interaction at clinically used concentrations. Quotients for OCT2 were manifold lower compared with that for MATE1, but in contrast to those of OCT1 still in the range of a potential contribution under clinically relevant concentrations (0.2 for 400 mg and 0.6 for 600 mg imatinib daily).\n\nBesides the affinities of an OCT to imatinib, their expression level in targeted cells is important for a relevant cellular uptake of imatinib in patients. In a first step, we thus measured mRNA expression levels of the potential imatinib transporters in PBMCs of healthy volunteers as well as in the immortalized CML cell line K562, derived from a BCR-ABL-positive CML patient in blast crisis.25 In both cell types mRNA for OCT1 (1/ΔCt= 0.07 and 0.07, NS), OCT2 (0.08 and 0.07, NS), and MATE1 (0.09 and 0.07, NS) in PBMC and K562 cells, respectively, were expressed at similar levels (Figure 1c).\n\nTo elucidate whether the imatinib uptake in these cells is mediated by transporters in general and not only due to passive diffusion through the cell membrane, we measured the uptake at 37 °C and 4 °C, where transporter-mediated uptake is strongly reduced. For PBMC and K562 cells, the uptake was significantly higher at 37 °C (PBMC: 1.56±0.22 nmol/mg protein, P=0.0027; K562: 1.83±0.14 nmol/mg protein, P=0.0001) than at 4 °C (PBMC: 0.62±0.10 nmol/mg protein; K562: 0.64±0.01 nmol/mg protein). This suggests a transporter-mediated process as the main mechanism of imatinib uptake (Figure 1d). In an attempt to identify the responsible transporters, we performed uptake experiments in the presence of specific transporter inhibitors and confirmed our finding using a gene-knockdown approach. Specific inhibitors were chosen from the literature (Supplementary Table 1).14, 20, 21, 22, 23, 26, 27 The selective inhibition of MATE1 with pyrimethamine significantly reduced the imatinib uptake in PBMCs by 34±8% (P=0.0262), whereas coinhibition of OCT1 and OCT2 with MPP+ had no significant effect (P=0.6051) (Figure 1e). Most of the studies showing that OCT1 is important for imatinib uptake and molecular response in CML patients used prazosin and amantadine as OCT1 inhibitors.5, 28 However, in accordance with recently published data,10 prazosin and amantadine are not specific inhibitors for OCT1 but have similar or even higher affinities to MATE1 than to OCT1 (Supplementary Table 1). The experiments with pyrimethamine show that this substance at the concentration used did not inhibit the imatinib uptake completely. We did not increase the pyrimethamine concentration to reach a complete suppression of imatinib cellular accumulation, to avoid additional inhibition of other OCT. To unequivocally confirm the role of MATE1 in the process of imatinib uptake, we performed a gene knockdown of MATE1 in K562 cells using specific siRNA. The knockdown of MATE1, as confirmed by western blot analysis, led to an almost complete inhibition of the imatinib uptake compared with mock siRNA-transfected cells (−80±12%, P=0.0005) (Figure 2a). Consequently, we found that imatinib-induced inhibition of c-ABL phosphorylation was remarkably reduced in siMATE1-transfected cells compared with mock-transfected cells (Figure 2b). These results clearly show that MATE1 is the major transporter for imatinib uptake in K562 cells and is probably crucial for its intracellular therapeutic effects.\n\nTo further prove that MATE1 has an important role in regulating imatinib sensitivity in CML patients, we analyzed the transporter profile of total BM samples obtained from CML patients by qRT-PCR and correlated the expression levels with the major molecular response to imatinib treatment (Figures 2c and d). As some patients fail to respond to imatinib therapy because of BCR-ABL1 mutations,4 patients with these mutations were excluded from the analysis. OCT2 mRNA was not expressed at detectable levels in the BM of all patients. The expression of mRNA for OCT1 was low (1/ΔCt=0.07±0.002 and 1/ΔCt=0.08±0.003 for imatinib responders and non-responders, respectively) and did not differ significantly between responders and non-responders.\n\nHowever, MATE1-mRNA was expressed at higher levels and furthermore significantly decreased in imatinib non-responders (1/ΔCt=0.07±0.001) compared with imatinib responders (1/ΔCt=0.11±0.04, P<0.0001) (Figure 2c). We found a correlation (r2=0.60 and r2=0.57 for responder and non-responder, respectively) between MATE1 transporter mRNA expression and clinical response to imatinib treatment, suggesting that MATE1 levels might enable to predict whether CML patients are likely to respond to imatinib therapy (Figure 2d). In contrast, we did not find a correlation (r2=0.01 and r2=0.15 for responder and non-responder, respectively) between OCT1 transporter expression and major molecular response (Figure 2d).\n\nTo underline the hypothesis that MATE1 expression is crucial for the response to imatinib, we examined the role of MATE1 for the reductive effect of imatinib on colony formation. Therapeutically used imatinib concentrations reduced colony growth in shscramble-transduced K562 cells concentration dependently. Imatinib (250 nm) led to a colony reduction of 58% (1280 colonies without and 532 colonies with 250 nM imatinib) and 1 μm nearly totally inhibited colony growth (74 colonies, reduction of 94%). In contrast, the effects of imatinib were reduced when MATE1 was knocked down. Thus, there was no significant reduction of colony growth by imatinib in shMATE1-transduced K562 cells until a concentration of 1 μm was used (1266 colonies without and 560 colonies with 1 μm imatinib, reduction of 56% Figures 2e and f).\n\nDiscussion\nBesides other mechanisms of resistance, the transport of imatinib into target cells was proposed to regulate the effectiveness of imatinib treatment. The role of OCT1 in this process has been discussed controversially.5, 8, 9, 28 Most studies showing that OCT1 mediates the cellular uptake and regulates the response to imatinib rely on inhibition experiments with prazosin or amantadine.5, 6, 7, 28 This approach has been criticized recently and might explain the dichotomic results as both, the inhibition with prazosin and amantadine, are not specific for OCT1.10 We here show that although OCT1 can potentially transport imatinib, the affinity to imatinib is too low to allow a significant interaction at therapeutically reached plasma levels. Indeed, inhibition of OCT1 and OCT2, which we also identified as a potential imatinib transporter, by MPP+ had no significant effect of the uptake in PMBC. In contrast, MATE1 transports imatinib with a manifold higher affinity as shown in model experiments permitting an uptake at clinically observed plasma levels. Indeed, prazosin and amantadine have similar or even higher inhibitory affinities to MATE1 than to OCT1.21, 22, 26, 27 The observed inhibitory effects of prazosin and amantadine on imatinib uptake and its effectiveness might thus be rather because of MATE1 than OCT1 inhibition.\n\nSpecific inhibition of single OCT is difficult as these transporters share various substrates.14 To further prove the role of MATE1 for the cellular uptake and effectiveness of imatinib, we thus confirm the observed results of our model experiments with both specific inhibition of MATE1 by pyrimethamine and a MATE1 gene knockdown. Pyrimethamine was used at low concentrations, which significantly but not completely reduced imatinib uptake. However, we did not increase the pyrimethamine concentration to reach a total inhibition of MATE1 to guarantee specificity. This may explain the different degree of reduction in inhibition and knockdown experiment.\n\nThe importance of MATE1-mediated imatinib uptake for therapeutic effects is supported by our transduction experiments, where MATE1 knockdown markedly reduced the effects of imatinib on c-ABL phosphorylation and colony formation. Both effects are essential in the pathogenesis of CML, and c-ABL phosphorylation has been shown to be a good predictor for the molecular response of CML patients to imatinib.29\n\nDeep and early molecular response is suggested to be predictive of improved long-term outcomes in CML therapy. We therefore correlated MATE1-mRNA expression levels in CML patients with the molecular response to elucidate whether MATE1 can influence the response of CML patients to imatinib. There was a significant reduction of MATE1-mRNA expression in patients who did not respond to imatinib and a strong correlation of MATE1-mRNA levels in total BM cells with the molecular response of CML patients. Interestingly, this correlation was not observed for OCT1. Measuring MATE1-mRNA levels might therefore enable to predict whether CML patients are likely to respond to imatinib therapy. Clinical trials showed evidence that dasatinib and nilotinib generate faster and deeper short-term responses in first-line CML therapy compared with imatinib.30, 31 However, imatinib is the most cost-effective tyrosine kinase inhibitor therapy for CML and, in contrast to dasatinib and nilotinib, is associated with less severe side effects. Screening tools such as a MATE1 expression analysis or detection of MATE1 mutations, which have been shown to rigorously change the functionality of MATE1,32 might thus help to individually choose the best, safest and economically reasonable therapy.\n\nIn conclusion, we demonstrate that MATE1 is the major transporter for the cellular uptake of imatinib and crucial for the therapeutic success in CML patients. We suggest that the detailed analysis of MATE1 expression levels and mutations could be a predictor for the response to imatinib therapy.\n\nWe thank the funding organization IMF of the Medical Faculty of Münster University (BE-121009) and the DFG (CI-107/4-123).\n\nAuthor contributions\n\nSH and CSL designed the study, performed all experiments and prepared the initial draft of the manuscript; TP, HP and EbS participated in data analysis interpretation and manuscript revisions; EvS, SJ and WB designed the patient study and analyzed the patient data; SJ and TH provided the patient data; US supported the S2 experiments and viral transduction; BE supported the PCR primers; JB and GC supervised the project and drafted/revised the manuscript.\n\nSupplementary Information accompanies this paper on Blood Cancer Journal website (http://www.nature.com/bcj)\n\nTH partly owns MLL Munich Leukemia Laboratory. SJ is employed by MLL Munich Leukemia Laboratory. The other authors declare no conflict of interest and nothing to disclose.\n\nSupplementary Material\nSupplementary Table 1 Click here for additional data file.\n\n Supplementary Table 2 Click here for additional data file.\n\n Figure 1 MATE1 transports imatinib with a high affinity and is the main transporter mediating imatinib uptake. (a) Imatinib accumulation in HEK cells overexpressing single OCTs indicates a significant transport via OCT1, OCT2 and MATE1, but not via OCT3 (n=4–12). Imatinib was used at 5 μM. One-way analysis of variance (ANOVA) with Tukey's post hoc test was used for statistical analysis. (b) Potential interaction of OCTs with imatinib at clinically relevant plasma levels for therapy regimens of 400 and 600 mg daily. A quotient of the unbound imatinib plasma level divided by the apparent affinities of single OCT to imatinib >0.1 indicates a possible interaction (detailed calculation see Supplementary Table 2). In contrast to OCT1 (0.03 for 400 mg and 0.1 for 600 mg imatinib daily), the quotients for MATE1 (1.7 and 5.8) and OCT2 (0.2 and 0.6) are above 0.1. (c) mRNA expression levels of OCT1, OCT2 and MATE1 detected by qRT-PCR in PBMCs from six healthy volunteers and in the CML cell line K562 (n=3–7). One-way ANOVA with Tukey's post hoc test was used for statistical analysis. (d) Temperature-dependent imatinib uptake as quantified by HPLC in PBMCs from six healthy volunteers and K562 (n=3–7). The significant higher uptake at 37 °C (P=0.0027 for PBMC; P=0.0001 for K562) suggests a transporter-mediated uptake. Imatinib was used at 5 μM and unpaired Student's t-test was used for statistical analysis. (e) Imatinib uptake detected by HPLC in PBMC of healthy volunteers (n=3–5) is reduced by specific inhibition of MATE1 with 200 nM pyrimethamine but not by OCT1 and two coinhibition with 80 μM MPP+. Imatinib was used at 5 μM and one-way ANOVA with Tukey's post hoc test was used for statistical analysis.\n\n*P<0.05; **P<0.01; ***P<0.005.\n\nFigure 2 MATE1 mediates imatinib uptake in target cells and MATE1 expression levels correlate with sensitivity of CML patients to imatinib. (a) MATE1 knockdown in K562 cells with specific siRNA reduces the imatinib uptake compared with mock siRNA-transfected cells detected by HPLC (n=4). MATE1 knockdown was confirmed by RT-PCR and western blot analysis (lower panel). Imatinib was used at 5 μM and unpaired Student's t-test was used for statistical analysis. (b) Concentration-dependent effects of imatinib (5 and 10 μM) on c-ABL phosphorylation in MATE1- and mock siRNA-transfected K562 cells as quantified by western blot analysis in relation to the housekeeping gene GAPDH. (c) MATE1 and OCT1 mRNA expression in relation to the housekeeping gene. (d) OCT expression levels were analyzed in total BM cells of CML patients by qRT-PCR and correlated with the molecular response to imatinib treatment. MATE1 (1/ΔCt=0.11±0.04, P<0.0001 for responders and 1/ΔCt=0.07±0.001 for non-responders, P<0.0001) but not OCT1 (1/ΔCt=0.07±0.002 for responders and 1/ΔCt=0.08±0.003 for non-responders, P=0.4102) expression is lower in imatinib non-responders compared with responders (c) and correlates with the BCR-ABL1/ABL1. Thirty patients with BCR-ABL1 major transcript (p210)-positive CML were included in this study and unpaired Student's t-test was used for statistical analysis. (e and f) MATE1 knockdown in K562 cells with specific siRNA reduces the concentration-dependent effects of imatinib on colony growth compared with shscramble-transduced K562 cells (n=4). Unpaired Student's t-test was used for statistical analysis. *P<0.05; ***P<0.005.\n\nTable 1 Patient characteristics\nPat. no.\tResponsea\tWBCb/μl\tHb (g/dl)\tPLTc/μl\tMaterial\tRatiod\nMonth 3\tRatio Month 6\tRatio 12 months\tGendere\tAge (years)\t\n1\tGood\t13 000\t13.9\t442 000\tBM\t0.213\t0.001\t \t1\t28.9\t\n2\tGood\t7,200\t13.7\t1 130 000\tBM\t0.399\t0.316\t \t2\t76.6\t\n3\tGood\t57 700\t11.6\t515 000\tBM\t0.742\t0.055\t \t1\t52.8\t\n4\tGood\t23 900\t15\t649 000\tBM\t0.15\t0.05\t0.004\t2\t64.8\t\n5\tGood\t132 500\t10\t689 000\tBM\t0.739\t0.383\t \t2\t57.1\t\n6\tGood\t80 400\t12\t212 000\tBM\t0.109\t \t0.000\t1\t47.6\t\n7\tGood\t49 000\t14\t173 000\tBM\t0.322\t \t0.083\t2\t56.8\t\n8\tGood\t28 360\t13.7\t665 000\tBM\t0.1\t0.025\t0.014\t1\t77.2\t\n9\tGood\t27 500\t8.8\t1 710 000\tBM\t0.361\t0.008\t0.035\t1\t40.9\t\n10\tGood\t \t \t \tBM\t0.112\t \t0.009\t1\t26.3\t\n11\tGood\t49 020\t11.6\t335 000\tBM\t0.915\t \t0.003\t1\t38.8\t\n12\tGood\t35 600\t9.2\t169000\tBM\t0.318\t0.554\t0.001\t1\t73.2\t\n13\tGood\t13 700\t10.8\t639 000\tBM\t0.02\t0.031\t0.102\t1\t58.9\t\n14\tGood\t \t \t \tBM\t0.351\t0.094\t0.050\t1\t75.4\t\n15\tGood\t \t \t \tBM\t0.446\t \t \t1\t57.2\t\n16\tPoor\t60 000\t17\t101 000\tBM\t \t7.25\t \t2\t43.2\t\n17\tPoor\t \t10.5\t580 000\tBM\t47.411\t35.246\t \t2\t46\t\n18\tPoor\t344 800\t11.9\t300 000\tBM\t \t48.413\t \t1\t74.4\t\n19\tPoor\t126 000\t12.9\t539 000\tBM\t \t13.157\t2.370\t2\t35.8\t\n20\tPoor\t196 900\t7.8\t192 000\tBM\t \t7.035\t6.849\t2\t60.6\t\n21\tPoor\t108 000\t11.6\t744 000\tBM\t \t8.448\t \t1\t54.5\t\n22\tPoor\t526 400\t7.3\t430 000\tBM\t \t23.422\t6.095\t2\t52.1\t\n23\tPoor\t157 200\t15\t352 000\tBM\t4.556\t36.021\t0.448\t2\t62.4\t\n24\tPoor\t160 710\t7.3\t74 000\tBM\t \t13.473\t \t2\t46.5\t\n25\tPoor\t186.000\t12.4\t843 000\tBM\t \t9.968\t10.410\t1\t58.8\t\n26\tPoor\t249 000\t11.2\t540 000\tBM\t45.473\t35.46\t \t1\t70.8\t\n27\tPoor\t \t \t \tBM\t \t5.45\t \t2\t38.3\t\n28\tPoor\t128 400\t10.2\t621 000\tBM\t \t11.172\t2.819\t1\t69.9\t\n29\tPoor\t51 200\t9\t891 000\tBM\t \t7.446\t \t2\t64\t\n30\tPoor\t26 700\t10.8\t1 200 000\tBM\t \t29.86\t0.755\t1\t79.5\t\nAbbreviations: BM, bone marrow; IS, International Scale; PLT, platelets; WBC, white blood cell count in peripheral blood (cells/μl).\n\na Response to imatinib therapy: good=3 months after the start of imatinib therapy BCR-ABL1/ABL1 ⩽10% poor=6 months after the start of imatinib therapy BCR-ABL1/ABL1 >1%.\n\nb WBC in peripheral blood (cells per μl).\n\nc PLT per μl peripheral blood.\n\nd BCR-ABL1/ABL1—ratio according to IS in %.\n\ne 1=female; 2=male.\n==== Refs\nKalmanti L, Saussele S, Lauseker M, Müller MC, Dietz CT, Heinrich L et al. Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV . Leukemia \n2015 ; 29 : 1123 –1132.25676422 \nCastagnetti F, Gugliotta G, Breccia M, Stagno F, Iurlo A, Albano F et al. Long-term outcome of chronic myeloid leukemia patients treated frontline with imatinib . Leukemia \n2015 ; 29 : 1823 –1831.26088952 \nTalpaz M, Silver RT, Druker BJ, Goldman JM, Gambacorti-Passerini C, Guilhot F et al. Imatinib induces durable hematologic and cytogenetic responses in patients with accelerated phase chronic myeloid leukemia: results of a phase 2 study . Blood \n2002 ; 99 : 1928 –1937.11877262 \nGorre ME, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao PN et al. Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification . Science (New York, NY) \n2001 ; 293 : 876 –880.\nEngler JR, Frede A, Saunders VA, Zannettino ACW, Hughes TP, White DL. Chronic myeloid leukemia CD34+ cells have reduced uptake of imatinib due to low OCT-1 activity . Leukemia \n2010 ; 24 : 765 –770.20147974 \nWhite DL, Dang P, Engler J, Frede A, Zrim S, Osborn M et al. Functional activity of the OCT-1 protein is predictive of long-term outcome in patients with chronic-phase chronic myeloid leukemia treated with imatinib . J Clin Oncol \n2010 ; 28 : 2761 –2767.20421539 \nGiannoudis A, Wang L, Jorgensen AL, Xinarianos G, Davies A, Pushpakom S et al. The hOCT1 SNPs M420del and M408V alter imatinib uptake and M420del modifies clinical outcome in imatinib-treated chronic myeloid leukemia . Blood \n2013 ; 121 : 628 –637.23223357 \nNies AT, Schaeffeler E, van der Kuip H, Cascorbi I, Bruhn O, Kneba M et al. Cellular uptake of imatinib into leukemic cells is independent of human organic cation transporter 1 (OCT1) . Clin Cancer Res \n2013 ; 20 : 985 –994.24352644 \nTzvetkov MV, Seitz T, Bokelmann K, Mueller T, Brockmöller J, Koepsell H. Does the haplotype Met408-Del420, which was apparently predictive for imatinib efficacy, really exist and how strongly may it affect OCT1 activity ? Blood \n2014 ; 123 : 1427 –1429.24578499 \nBurger H, Mathijssen RHJ, Sparreboom A, Wiemer EAC. Can ‘specific' OCT1 inhibitors be used to determine OCT1 transporter activity toward imatinib ? Blood \n2013 ; 121 : 4965 –4966.23766461 \nSchmidt-Lauber C, Harrach S, Pap T, Fischer M, Victor M, Heitzmann M et al. Transport mechanisms and their pathology-induced regulation govern tyrosine kinase inhibitor delivery in rheumatoid arthritis . PLoS One \n2012 ; 7 : e52247 .23284953 \nMinematsu T, Giacomini KM. Interactions of tyrosine kinase inhibitors with organic cation transporters and multidrug and toxic compound extrusion proteins . Mol Cancer Ther \n2011 ; 10 : 531 –539.21252289 \nMinuesa G, Purcet S, Erkizia I, Molina-Arcas M, Bofill M, Izquierdo-Useros N et al. Expression and functionality of anti-human immunodeficiency virus and anticancer drug uptake transporters in immune cells . J Pharmacol Exp Ther \n2008 ; 324 : 558 –567.18042828 \nKoepsell H, Lips K, Volk C. Polyspecific organic cation transporters: structure, function, physiological roles, and biopharmaceutical implications . Pharm Res \n2007 ; 24 : 1227 –1251.17473959 \nHu S, Franke RM, Filipski KK, Hu C, Orwick SJ, de Bruijn EA et al. Interaction of imatinib with human organic ion carriers . Clin Cancer Res \n2008 ; 14 : 3141 –3148.18483382 \nLee W-K, Reichold M, Edemir B, Ciarimboli G, Warth R, Koepsell H et al. Organic cation transporters OCT1, 2, and 3 mediate high-affinity transport of the mutagenic vital dye ethidium in the kidney proximal tubule . Am J Physiol Renal Physiol \n2009 ; 296 : F1504 –F1513.19357179 \nInternational Transporter Consortium, Giacomini KM, Huang S-M, Tweedie DJ, Benet LZ, KLR Brouwer et al. Membrane transporters in drug development . Nat Rev Drug Discov \n2010 ; 9 : 215 –236.20190787 \nle Coutre P, Kreuzer K-A, Pursche S, Bonin MV, Leopold T, Baskaynak G et al. Pharmacokinetics and cellular uptake of imatinib and its main metabolite CGP74588 . Cancer Chemother Pharmacol \n2004 ; 53 : 313 –323.14658008 \nvan Erp NP, Gelderblom H, Guchelaar H-J. Clinical pharmacokinetics of tyrosine kinase inhibitors . Cancer Treatment Reviews \n2009 ; 35 : 692 –706.19733976 \nIto S, Kusuhara H, Kuroiwa Y, Wu C, Moriyama Y, Inoue K et al. Potent and specific inhibition of mMate1-mediated efflux of type I organic cations in the liver and kidney by pyrimethamine . J Pharmacol Exp Ther \n2010 ; 333 : 341 –350.20065018 \nHayer Zillgen M, Brüss M, Bönisch H. Expression and pharmacological profile of the human organic cation transporters hOCT1, hOCT2 and hOCT3 . Br J Pharmacol \n2002 ; 136 : 829 –836.12110607 \nWittwer MB, Zur AA, Khuri N, Kido Y, Kosaka A, Zhang X et al. Discovery of potent, selective multidrug and toxin extrusion transporter 1 (MATE1, SLC47A1) inhibitors through prescription drug profiling and computational modeling . J Med Chem \n2013 ; 56 : 781 –795.23241029 \nUmehara K-I, Iwatsubo T, Noguchi K, Kamimura H. Comparison of the kinetic characteristics of inhibitory effects exerted by biguanides and H2-blockers on human and rat organic cation transporter-mediated transport: insight into the development of drug candidates . Xenobiotica \n2007 ; 37 : 618 –634.17614008 \nBaccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia . Blood \n2013 ; 122 : 872 –884.23803709 \nKlein E, Ben-Bassat H, Neumann H, Ralph P, Zeuthen J, Polliack A et al. Properties of the K562 cell line, derived from a patient with chronic myeloid leukemia . Int J Cancer \n1976 ; 18 : 421 –431.789258 \nAmphoux A, Vialou V, Drescher E, Brüss M, Mannoury la Cour C, Rochat C et al. Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain . Neuropharmacology \n2006 ; 50 : 941 –952.16581093 \nSuhre WM, Ekins S, Chang C, Swaan PW, Wright SH. Molecular determinants of substrate/inhibitor binding to the human and rabbit renal organic cation transporters hOCT2 and rbOCT2 . Mol Pharmacol \n2005 ; 67 : 1067 –1077.15630081 \nWhite DL, Saunders VA, Dang P, Engler J, Venables A, Zrim S et al. Most CML patients who have a suboptimal response to imatinib have low OCT-1 activity: higher doses of imatinib may overcome the negative impact of low OCT-1 activity . Blood \n2007 ; 110 : 4064 –4072.17761829 \nWhite D, Saunders V, Lyons AB, Branford S, Grigg A, To LB et al. In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML . Blood \n2005 ; 106 : 2520 –2526.15956284 \nJabbour E, Kantarjian HM, Saglio G, Steegmann J-L, Shah NP, Boqué C et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION) . Blood \n2014 ; 123 : 494 –500.24311723 \nSaglio G, Kim D-W, Issaragrisil S, le Coutre P, Etienne G, Lobo C et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia . N Engl J Med \n2010 ; 362 : 2251 –2259.20525993 \nChen Y, Teranishi K, Li S, Yee SW, Hesselson S, Stryke D et al. Genetic variants in multidrug and toxic compound extrusion-1, hMATE1, alter transport function . Pharmacogenomics J \n2009 ; 9 : 127 –136.19172157\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2044-5385",
"issue": "6()",
"journal": "Blood cancer journal",
"keywords": null,
"medline_ta": "Blood Cancer J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D005260:Female; D016044:Fusion Proteins, bcr-abl; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D047428:Protein Kinase Inhibitors; D034622:RNA Interference",
"nlm_unique_id": "101568469",
"other_id": null,
"pages": "e470",
"pmc": null,
"pmid": "27635733",
"pubdate": "2016-09-16",
"publication_types": "D016428:Journal Article",
"references": "19357179;14658008;20525993;20190787;23241029;20147974;17614008;17761829;24578499;21252289;23223357;17473959;16581093;20065018;26088952;23284953;25676422;18483382;12110607;11877262;24311723;23803709;15630081;20421539;19733976;11423618;24352644;789258;19172157;15956284;18042828;23766461",
"title": "MATE1 regulates cellular uptake and sensitivity to imatinib in CML patients.",
"title_normalized": "mate1 regulates cellular uptake and sensitivity to imatinib in cml patients"
} | [
{
"companynumb": "DE-MYLANLABS-2018M1034069",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": "3",
... |
{
"abstract": "This case report evaluates the potential benefit of pitolisant in a 15-year-old female with Prader-Willi syndrome, obsessive-compulsive disorder, autism spectrum disorder, and mild intellectual disability. Due to its action on the H3 receptor, it enhances central activity of histaminergic neurons resulting in increased alertness, irrespective of the loss of orexin neurons seen in narcolepsy. Additionally, it is thought to modulate various other neurotransmitter systems including acetylcholine, norepinephrine, and dopamine. Pitolisant has the potential to improve many symptoms in patients with Prader-Willi syndrome and it appears to be well tolerated with minimal side effects observed. Therefore, the use of pitolisant should be considered in patients with Prader-Willi syndrome who fail a psychostimulant trial.",
"affiliations": null,
"authors": "Pennington|Stephanie|S|;Stutzman|Danielle|D|;Sannar|Elise|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-26.4.405",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "26(4)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "Prader-Willi syndrome; case report; histamine-H3 receptor antagonist; pediatric; pitolisant",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "405-410",
"pmc": null,
"pmid": "34035686",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "3993694;21671379;10517055;24854887;28490912;26062517;24636456;18201664;27363923;12617696;24107292;26282120;28129985;22758607;22550944;23109919;31019411;12203850;27438291;21503198;23965896;11869927;22356925;26584571;28449891;22237428",
"title": "Pitolisant in an Adolescent with Prader-Willi Syndrome.",
"title_normalized": "pitolisant in an adolescent with prader willi syndrome"
} | [
{
"companynumb": "US-APOTEX-2022AP002380",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Epstein-Barr virus (EBV)-associated lymphoid proliferations are a well-recognized complication of congenital or acquired systemic immunosuppression. The CNS is a frequent site for development of such lymphoid proliferations. We describe the clinical, imaging, and pathologic observations of a CNS disorder histologically similar to posttransplantation lymphoproliferative disorder that occurred in four patients with autoimmune disease treated with mycophenolate mofetil (MM). Two patients had polymorphous lymphoplasmacytic infiltration of brain parenchyma, and two had monomorphous infiltrations consistent with diffuse large B-cell lymphoma. In situ hybridization for EBV-encoded RNA was positive in all four patients. All patients improved after MM withdrawal and the use of rituximab. Because of a favorable toxicity profile, MM is now being used as steroid-sparing immunomodulatory therapy in autoimmune disorders. Based on our experience presented herein, we recommend caution in patient selection for MM and strict surveillance of those patients with autoimmune disorders who receive MM.",
"affiliations": "Department of Neurology, Mayo Clinic and Foundation and the Mayo Clinic Cancer Center, Rochester, MN 55905, USA.",
"authors": "O'Neill|Brian Patrick|BP|;Vernino|Steven|S|;Dogan|Ahmet|A|;Giannini|Caterina|C|",
"chemical_list": "D007166:Immunosuppressive Agents; D012367:RNA, Viral; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1215/15228517-2007-004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-8517",
"issue": "9(3)",
"journal": "Neuro-oncology",
"keywords": null,
"medline_ta": "Neuro Oncol",
"mesh_terms": "D000368:Aged; D001327:Autoimmune Diseases; D001927:Brain Diseases; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D017403:In Situ Hybridization; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D012367:RNA, Viral",
"nlm_unique_id": "100887420",
"other_id": null,
"pages": "364-9",
"pmc": null,
"pmid": "17522336",
"pubdate": "2007-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15660500;9762190;11265232;11328549;11578286;16251851;16216037;16314791;16335585;16427492;16503851;16611303;16700819;12165547;12742411;14508356;14628072;14993405;15280831;6603477;2017655;8298139;8536794;8946604;9125261;9238621;16116136",
"title": "EBV-associated lymphoproliferative disorder of CNS associated with the use of mycophenolate mofetil.",
"title_normalized": "ebv associated lymphoproliferative disorder of cns associated with the use of mycophenolate mofetil"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2022-02272",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
... |
{
"abstract": "After 4 months of therapy with secukinumab, a 67-year-old man with moderate psoriasis developed generalized hypertrichosis, along with PASI 90. The patient denied any drug intake, apart from secukinumab, nor applications of any creams. Moreover, this event did not really bother the patient, thus the therapy was not discontinued and the hypertrichosis is persisting as psoriasis' control.",
"affiliations": "Division of Dermatology, Department of Specialized, Clinical and Experimental Medicine, University of Bologna, Bologna, Italy.;Division of Dermatology, Department of Specialized, Clinical and Experimental Medicine, University of Bologna, Bologna, Italy.;Division of Dermatology, Department of Specialized, Clinical and Experimental Medicine, University of Bologna, Bologna, Italy.;Division of Dermatology, Department of Specialized, Clinical and Experimental Medicine, University of Bologna, Bologna, Italy.",
"authors": "Sacchelli|Lidia|L|0000-0003-4388-4523;Magnano|Michela|M|0000-0001-9429-9004;Patrizi|Annalisa|A|;Bardazzi|Federico|F|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C555450:secukinumab",
"country": "United States",
"delete": false,
"doi": "10.1111/dth.12894",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1396-0296",
"issue": "32(3)",
"journal": "Dermatologic therapy",
"keywords": "alopecia areata; anti-IL17; drug adverse events; hypertrichosis; psoriasis",
"medline_ta": "Dermatol Ther",
"mesh_terms": "D000368:Aged; D000506:Alopecia Areata; D061067:Antibodies, Monoclonal, Humanized; D006801:Humans; D006983:Hypertrichosis; D008297:Male; D011565:Psoriasis",
"nlm_unique_id": "9700070",
"other_id": null,
"pages": "e12894",
"pmc": null,
"pmid": "30963671",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Generalized hypertrichosis due to secukinumab in a patient with moderate psoriasis: A case of serendipity or zemblanity?",
"title_normalized": "generalized hypertrichosis due to secukinumab in a patient with moderate psoriasis a case of serendipity or zemblanity"
} | [
{
"companynumb": "PHHY2019IT084455",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SECUKINUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "BACKGROUND\nLiver injury associated with antiepileptic drugs accounts for a large proportion of drug-induced liver injuries (DILI) in children. Although withdrawal of the causative agent is the only proved treatment for DILI, in some clinical situations it is not possible. Recent studies have reported promising results of using hepatoprotective drugs with antioxidant actions for the management of DILI. This study aimed to evaluate the efficacy of folic acid versus silymarin treatment in relation to decreasing liver enzymes in patients with DILI due to antiepileptic therapy.\n\n\nMETHODS\nThis randomized, open-label, clinical trial evaluated 55 children with epilepsy who were on antiepileptic treatment and experienced DILI. The children were randomized to receive either silymarin (5 mg/kg per day) or folic acid (1 mg per day) for one month and were followed up for three months.\n\n\nRESULTS\nLiver enzymes significantly decreased in both groups. The decrease trend in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were stronger in the folic acid group compared to silymarin group (P=0.04 and P=0.007, respectively). At the end of the study patients in the folic acid group had significantly lower ALT (P=0.04), AST (P=0.02), and gamma-glutamyl transferase (GGT) (P<0.001) levels and also higher percentage of normal ALT (30.7% vs 3.4%, P=0.009) and AST (42.3% vs 0%, P<0.001), and GGT (23.1% vs 0%, P=0.008) values compared to the patients in the silymarin group. No rebound elevations in ALT, AST and GGT levels or adverse reactions were noted in neither of the study groups.\n\n\nCONCLUSIONS\nAlthough both treatments were safe and effective in decreasing liver enzymes, folic acid seems to be superior to silymarin in the management of DILI.",
"affiliations": "Maternal, Fetal and Neonatal Research Center, Tehran University of Medical Sciences, Tehran, Iran. mahdisheikh@gmail.com.",
"authors": "Asgarshirazi|Masoumeh|M|;Shariat|Mamak|M|;Sheikh|Mahdi|M|",
"chemical_list": "D000927:Anticonvulsants; D015415:Biomarkers; D020011:Protective Agents; D012838:Silymarin; D005492:Folic Acid; D005723:gamma-Glutamyltransferase; C554782:gamma-glutamyltransferase, human; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D000469:Alkaline Phosphatase",
"country": "Singapore",
"delete": false,
"doi": "10.1016/s1499-3872(16)60142-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "16(3)",
"journal": "Hepatobiliary & pancreatic diseases international : HBPD INT",
"keywords": null,
"medline_ta": "Hepatobiliary Pancreat Dis Int",
"mesh_terms": "D000410:Alanine Transaminase; D000469:Alkaline Phosphatase; D000927:Anticonvulsants; D001219:Aspartate Aminotransferases; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D002675:Child, Preschool; D004796:Clinical Enzyme Tests; D019610:Cytoprotection; D004334:Drug Administration Schedule; D005260:Female; D005492:Folic Acid; D006801:Humans; D007223:Infant; D007492:Iran; D008099:Liver; D008111:Liver Function Tests; D008297:Male; D011446:Prospective Studies; D020011:Protective Agents; D012838:Silymarin; D013997:Time Factors; D016896:Treatment Outcome; D005723:gamma-Glutamyltransferase",
"nlm_unique_id": "101151457",
"other_id": null,
"pages": "296-302",
"pmc": null,
"pmid": "28603098",
"pubdate": "2017-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Comparison of efficacy of folic acid and silymarin in the management of antiepileptic drug induced liver injury: a randomized clinical trial.",
"title_normalized": "comparison of efficacy of folic acid and silymarin in the management of antiepileptic drug induced liver injury a randomized clinical trial"
} | [
{
"companynumb": "IR-UCBSA-2017027982",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "Mitochondrial disorders refer to the complex group of conditions affecting energy metabolism. A number of mitochondrial disorders can lead to the development of diabetes mellitus, and mitochondrial diabetes is thought to account for up to 3% of all diabetes mellitus cases. Depending on the degree of preservation of beta cell secretory capacity and peripheral muscle insulin sensitivity, the phenotype of mitochondrial diabetes may resemble that of type 1 or type 2 diabetes. Additionally, mitochondrial diabetes may rarely present with diabetic ketoacidosis, and can be distinguished from other forms of monogenic diabetes including maturity onset diabetes of the young by the presence of multi-organ involvement, particularly pre-senile sensorineural hearing loss, maternal transmission, and later-onset diagnosis, typically affecting adults over 35 years. Various guidelines on diabetes care do not address this important subset of cases, and this diagnosis is easily missed. Additionally, there is paucity of data on tailored diabetes therapies for mitochondrial diabetes, particularly in the era of novel therapies including glucagon-like peptide-1 receptor agonist and sodium glucose co-transporter-2 inhibitors. Here, we report three patients with mitochondrial diabetes who responded well to the addition of these novel agents and propose a new treatment algorithm for this condition.",
"affiliations": "Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Canada. Electronic address: ryeung@ualberta.ca.;Section on Endocrinology & Genetics (SEGEN), National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.;Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, MD 20892, USA.;1st Department of Pediatrics, Aghia Sofia Children's Hospital, National and Kapodistrian University of Athens, School of Medicine, Athens, Greece.;Division of Endocrinology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.;Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada.;Section on Endocrinology & Genetics (SEGEN), National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, USA.",
"authors": "Yeung|Roseanne O|RO|;Al Jundi|Mohammad|M|;Gubbi|Sriram|S|;Bompu|Maria E|ME|;Sirrs|Sandra|S|;Tarnopolsky|Mark|M|;Hannah-Shmouni|Fady|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jdiacomp.2020.107584",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1056-8727",
"issue": "35(1)",
"journal": "Journal of diabetes and its complications",
"keywords": "Glucagon-like peptide receptor agonists; MELAS; MIDD; Mitochondrial diabetes; Mitochondrial disorders; Sodium-glucose cotransporter 2 inhibitors",
"medline_ta": "J Diabetes Complications",
"mesh_terms": null,
"nlm_unique_id": "9204583",
"other_id": null,
"pages": "107584",
"pmc": null,
"pmid": "32331977",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D052060:Research Support, N.I.H., Intramural",
"references": "25375397;16109014;30122305;11080250;22325939;28749475;25652200;17300999;20650404;26378978;26404827;21525453;27042263;19188683;25503498;27647878;12351431;15389892;27299675;30114489;31611148;31877117;29549796;25330715;28450048;28244632;12086967;29777474;11514398;24847880;29328405;27716753;19118289;29956047;19470628;31321014;29569427;30447687;24719357;27212224;14749274;28003053;23846908;27979887;20167576;19515413;31779619;23769710;25008908;15728297;27860132;17653689;29666206",
"title": "Management of mitochondrial diabetes in the era of novel therapies.",
"title_normalized": "management of mitochondrial diabetes in the era of novel therapies"
} | [
{
"companynumb": "CA-BAUSCH-BL-2020-036739",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Hematological malignancies with a BCR-JAK2 rearrangement have been described only sporadically in the literature over the last three decades. Although most patients suffer from a chronic myeloid neoplasm with marked eosinophilia, the clinical presentation varies significantly and can even manifest as a lymphoid malignancy. In this case report, we present a patient with a therapy-related BCR-JAK2 myeloid neoplasm with extensive extramedullary disease localizing in the lymph nodes. While treatment with a JAK2 inhibitor (ruxolitinib) was not able to stop disease progression, combination treatment with inhibitors of both JAK2 and BCL2 (venetoclax) resulted in disease control for over 1.5 years. Combining these two inhibitors might be strategic in these patients, not only because BCL2 is a downstream target of JAK/STAT signaling but also because BCL2 is crucial for JAK2 inhibitor resistance. The recent inclusion of JAK2-rearranged malignancies in major classification systems and guidelines emphasizes the importance of not only getting a better understanding of the clinical phenotype of these rare disorders but also of identifying alternative treatment options for patients ineligible for allogeneic stem cell transplantation. Considering the low toxicity of combination treatment with these two small molecule inhibitors, this regimen could be further explored in future studies.",
"affiliations": "The George Washington University Medical Faculty Associates, Washington, DC, USA.;The George Washington University Medical Faculty Associates, Washington, DC, USA.;Washington DC Veterans Affairs Medical Center, Washington, DC, USA.;Washington DC Veterans Affairs Medical Center, Washington, DC, USA.;The George Washington University Medical Faculty Associates, Washington, DC, USA.",
"authors": "Lap|Coen J|CJ|https://orcid.org/0000-0001-6815-0695;Nassereddine|Samah|S|;Liu|Min-Ling|ML|;Nava|Victor E|VE|;Aggarwal|Anita|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/2348977",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560\n2090-6579\nHindawi\n\n10.1155/2021/2348977\nCase Report\nCombined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm\nhttps://orcid.org/0000-0001-6815-0695\nLap Coen J. clap@mfa.gwu.edu\n1\nNassereddine Samah 1\nLiu Min-Ling 2\nNava Victor E. 2\nAggarwal Anita 1 2\n1The George Washington University Medical Faculty Associates, Washington, DC, USA\n2Washington DC Veterans Affairs Medical Center, Washington, DC, USA\nAcademic Editor: Håkon Reikvam\n\n2021\n28 7 2021\n2021 234897722 5 2021\n12 7 2021\n17 7 2021\nCopyright © 2021 Coen J. Lap et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nHematological malignancies with a BCR-JAK2 rearrangement have been described only sporadically in the literature over the last three decades. Although most patients suffer from a chronic myeloid neoplasm with marked eosinophilia, the clinical presentation varies significantly and can even manifest as a lymphoid malignancy. In this case report, we present a patient with a therapy-related BCR-JAK2+ myeloid neoplasm with extensive extramedullary disease localizing in the lymph nodes. While treatment with a JAK2 inhibitor (ruxolitinib) was not able to stop disease progression, combination treatment with inhibitors of both JAK2 and BCL2 (venetoclax) resulted in disease control for over 1.5 years. Combining these two inhibitors might be strategic in these patients, not only because BCL2 is a downstream target of JAK/STAT signaling but also because BCL2 is crucial for JAK2 inhibitor resistance. The recent inclusion of JAK2-rearranged malignancies in major classification systems and guidelines emphasizes the importance of not only getting a better understanding of the clinical phenotype of these rare disorders but also of identifying alternative treatment options for patients ineligible for allogeneic stem cell transplantation. Considering the low toxicity of combination treatment with these two small molecule inhibitors, this regimen could be further explored in future studies.\n==== Body\n1. Introduction\n\nActivating mutations in Janus kinase 2 (JAK2), which include JAK2 V617F and mutations in exon 12, are found in a high proportion of patients diagnosed with chronic myeloproliferative neoplasms (MPN), including >95% of patients with polycythemia vera and approximately 55–65% of patients with essential thrombocytosis and primary myelofibrosis [1]. While these mutations are considered crucial molecular events in the pathogenesis of these disorders, rare chromosomal translocations involving JAK2 have been described in patients suffering from both myeloid and lymphoid malignancies [2, 3]. The t(9; 22) (p24.1; q11.2) is a recurrent rearrangement that juxtaposes the Breakpoint Cluster Region gene (BCR; 22q11.2) to the JAK2 gene (9p24.1), which leads to the formation of a BCR-JAK2 fusion [4]. While this translocation has been identified in patients diagnosed with acute myeloid leukemia (AML) and B-cell acute lymphoblastic leukemia (B-ALL), most case reports have described it as the sole genetic abnormality observed in patients suffering from a clinical disease that resembles myeloid neoplasms, including MPN, myelodysplastic syndrome (MDS), or MPN/MDS overlap syndromes and is often associated with significant extramedullary hematopoiesis and/or bone marrow failure [2, 3, 5–8]. In most patients, the disease is highly therapy-resistant with rapid progression occurring within the first couple of months after diagnosis [9]. While JAK2 inhibitors have been suggested to be of some benefit in controlling disease, so far, long-term remissions have only been achieved after allogeneic stem cell transplantation (allo-SCT) [10, 11]. Here, we describe a case of a patient suffering from a therapy-related BCR-JAK2+ myeloid neoplasm with significant disease localized in his lymph nodes. While monotherapy with a JAK2 inhibitor (ruxolitinib) was not able to control disease, combined treatment with inhibitors of JAK2 and BCL2 (venetoclax) resulted in disease control for over 1.5 years. A rationale for combining these two small molecule inhibitors is provided as an additional option, which could be further explored for patients with this rare hematological malignancy, especially when allo-SCT is not feasible.\n\n2. Case Presentation\n\nA 54-year-old male presented initially in February 2013 with left axillary lymphadenopathy. He was diagnosed with stage IIA nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) and received two cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) before he became lost to follow-up. In March 2014, he presented again with biopsy-proven relapsing NLPHL. A bone marrow aspirate was performed at that time, revealing an unremarkable flow analysis and a normal karyotype (46XY [12]). He received three cycles of R-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) with additional radiation therapy to the left axillary region for residual disease. He remained in complete remission until May 2018, when he presented with fatigue, a 25 kg weight loss over three months and was found to be anemic with a hemoglobin (Hgb) of 7.2 g/dL, platelet count (Plt) of 159 × 103/µL, and a white blood cell count (WBC) of 6.1 × 103/µL. Peripheral blood smear revealed a neutrophilic left-shift with 3% myelocytes, 2% metamyelocytes, and 6% eosinophils. Evaluation of the red blood cells (RBC) revealed marked anisopoikilocytosis, teardrop cells, and 2% nucleated RBC. No circulating blasts were seen. FDG-PET/CT displayed extensive FDG-avid lymphadenopathy (SUVmax∼10) with splenomegaly measuring 18.4 cm. Bone marrow (BM) biopsy demonstrated a hypercellular BM with left-shifted myeloid hyperplasia but less than 1% blasts (Figure 1(a)), an increased myeloid to erythroid ratio (>5 : 1) and diffuse grade 3 reticulin fibrosis (Figure 1(b)). Cytogenetics revealed a 46XY, del(6) (p21.2p24), t(22; 9; 11) (q11.2, p24, p11.2) [11]/46XY, del(9) [9] karyotype with fluorescent in situ hybridization (FISH) analysis showing absence of a BCR-ABL1 rearrangement, but three copies of BCR (Figure 2). The third copy of BCR was identified to be on the short arm terminus of chromosome 9 resulting in a BCR-JAK2 fusion as suggested with an additional JAK2 (9p24.1) probe (not shown). The rearrangement was confirmed with RNA sequencing, which revealed a break in exon 1 of BCR (nucleotide 1107 and codon 369) and a break in exon 17 of JAK2 (nucleotide 2171 and codon 724) leading to an in-frame fusion. The resulting product included the coiled-coil oligodimerization domain of BCR as well as the area distal to the pseudokinase domain (JH2) of JAK2, thereby maintaining the active tyrosine kinase domain (JH1) in exon 19. Additional mutation analysis was negative for JAK2 V617 F or alterations in CALR, PDGFRA, PDGFRB, or FGFR1 but did reveal an alteration in CD36 (c.157_158AA > G_p.N53 fs ∗ 24). Excisional biopsy of a lymph node ruled out lymphoma, but revealed extensive extramedullary involvement of the same myeloid malignancy with prominent erythroid precursors, atypical megakaryocytes, and left-shifted myeloid cells without increase of blasts (Figure 3). Importantly, the same BCR-JAK2 translocation was identified in the biopsy and confirmed with RNA sequencing.\n\nPending the results of the molecular analysis, the patient was started on the BCR-ABL1 tyrosine kinase inhibitor (TKI) imatinib mesylate 400 mg once daily due to an initial concern of CML. Because of limited response and upon identification of the BCR-JAK2 translocation, treatment was switched to ruxolitinib and uptitrated to 20 mg twice daily. An early referral for allo-SCT was discussed, but the patient decided to postpone this. While initially an improvement in blood counts was observed (Hgb, 10.8 g/dL; Plt, 180 × 103/µL; WBC, 8.1 × 103/µL) with a reduced need for transfusions, he developed worsening anemia (Hgb, 7.8 g/dL), thrombocytopenia (Plt, 30 × 103/µL), and leukocytosis (WBC, 17.6 × 103/µL) with an elevated LDH (680 U/L) in January 2019. A peripheral smear revealed 6% promyelocytes, 3% metamyelocytes, 6% eosinophils, and 2% blasts, but repeated bone marrow evaluation only showed diffuse fibrosis and the previously identified BCR-JAK2 translocation. The spleen remained enlarged at 19 cm on imaging. Ruxolitinib was continued, and because of disease progression, venetoclax was initiated and uptitrated to 400 mg daily. At that point, he was evaluated for allo-SCT but was found ineligible due to diminished pulmonary function. After several weeks, blood counts improved, and the patient became transfusion-independent and EPO support was discontinued. Over time, his blood counts normalized (Hgb, 12.4 g/dl; Plt, 167 × 103/µL; WBC, 5.7 × 103/µL with 2% eosinophils) with repeat imaging, six months after the start of venetoclax, revealing a significant decrease in lymphadenopathy and a reduction in the spleen size to 13.1 cm. A new BM biopsy showed stable disease with extensive fibrosis, no increase in blasts, but persistence of the BCR-JAK2 fusion and the CD36 alteration, as well as a new TET2 mutation (c.3782 G > A_p.R1261H). During this time, the patient tolerated the combination regimen well without development of infections, need for blood product support, or hospitalizations. Although no cytogenetic response was observed, the treatment significantly improved his quality of life. He remained stable under this combination treatment until May 2020, at which point he presented with abdominal complaints and renal failure as a result of bulky lymphadenopathy and splenomegaly due to disease progression. Ruxolitinib and venetoclax were discontinued. Blood counts revealed Hgb, 11 g/dL; Plt, 170 × 103/µL; and WBC, 12.1 × 103/µL with a peripheral smear showing left-shifted hematopoiesis with 4% eosinophils and 1% blasts. Renewed bone marrow analysis only revealed fibrosis without a significant increase in blasts. The patient was started on azacytidine and re-evaluated for allo-SCT. However, allo-SCT was further postponed as a result of the patient contracting COVID-19. During that period, azacytidine was continued, and ruxolitinib was restarted. Unfortunately, the disease progressed with worsening bone marrow failure, without signs of transformation, and he passed away several months later.\n\n3. Discussion\n\nThe 2017 revision of the World Health Organization (WHO) Classification of Myeloid Neoplasms and Acute Leukemia included a new provisional entity “Myeloid Neoplasm with PCM1-JAK2 Rearrangement” in the category of “Myeloid/Lymphoid Neoplasms Associated with Eosinophilia and Rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2” [12]. While the patient described here does not have a hematological malignancy with a PCM1-JAK2 rearrangement, many experts in the field advocate to classify those rare cases with a JAK2 rearrangement, including gene partners other than PCM1, in the same category because of similar clinical features [13]. This is also highlighted by the inclusion of patients with a BCR-JAK2 rearrangement in the latest version of the U.S. National Comprehensive Cancer Network (NCCN) guidelines for “Myeloid/Lymphoid Neoplasms with Eosinophilia and Tyrosine Kinase Fusion Genes” (version 3.2021). Regardless of the classification, the presence of a BCR-JAK2 translocation has not been linked to a specific clinical phenotype although most patients present as a chronic myeloid neoplasm with marked eosinophilia (∼50–70%) (Table 1). However, eosinophilia can be notably absent and is not a requirement for the diagnosis. Additionally, BCR-JAK2 rearrangements are sometimes identified in the new provisional entity of Philadelphia chromosome-like ALL, which are characterized by activated tyrosine kinase signaling as well as JAK/STAT signaling but lack the presence of a BCR-ABL1 rearrangement [19]. The clinical heterogeneity may be the result of both disease factors (additional mutations and subclones) as well as existing host factors (germline allele diversity). Our patient presented with symptoms of a myeloid malignancy with a newly acquired BCR-JAK2 rearrangement, four years after treatment for relapsing NLPHL. Considering that the patient had a normal bone marrow evaluation at the time of his relapsing NLHPL and was subsequently exposed to cytotoxic chemotherapy, including etoposide and cyclophosphamide, it supports a diagnosis of a therapy-related malignancy. It is likely that clonal evolution and expansion over time have resulted in a secondary myeloid neoplasm. Although the clinical significance of a CD36 N53 fs∗24 mutation is not clear at the moment, it is important to mention that it has been identified in patients with mixed phenotype acute leukemia's (MPAL) [20]. More importantly, the R1261H missense mutation in the epigenetic modifier TET2 is a recurrent abnormality identified in (therapy-related) myeloid malignancies and is considered a driver of clonal hematopoiesis [21].\n\nAs a result of the t(9; 22) (p24.1; q11.2), a fusion gene is formed in which the oligodimerization domain of BCR is juxtaposed to the JAK2 tyrosine kinase domain resulting in constitutive activation of the JAK/STAT signaling pathway, which promotes cellular proliferation, differentiation, and growth [4, 22]. JAK inhibitors such as ruxolitinib (JAK1/2) have been used successfully in patients with JAK2-mutated MPN and, as such, have been proposed as a possible treatment for patients with a BCR-JAK2+ myeloid malignancy [10, 11]. Unfortunately, responses seen in the handful of patients treated to date have been mixed with some progressing rapidly and others obtaining a complete cytogenetic response. However, even cytogenetic responses are usually short-lived due to the development of JAK2 inhibitor resistance. Although our patient had an initial response after the start of ruxolitinib, he progressed five months later, prompting initiation of the BCL2 inhibitor venetoclax. Combining these two inhibitors may be strategic since downstream transcriptional targets of JAK/STAT signaling include antiapoptotic members of the BCL2 family, such as BCL2 and BCL-xl [23–25]. Several preclinical studies have suggested a beneficial synergistic effect of combining these two inhibitors in patients with JAK2-mutated hematological malignancies [25–27]. Moreover, resistance to JAK2 inhibitors has been attributed to overexpression of both BCL2 and BCL-xl. Although our patient did not develop a cytogenetic remission, the combination treatment stabilized the disease for over 1.5 years, achieving normal blood counts and significant reduction in splenomegaly and lymphadenopathy before final progression.\n\nEven with combination treatment, our patient eventually developed progressive disease and succumbed before he was able to undergo allo-SCT. Although combined treatment might be able to control disease for a significant period of time, even when monotherapy with a JAK2 inhibitor fails, only allo-SCT results in long-term disease control, affirming the need for early referral. It needs to be emphasized that TKIs used for the treatment of BCR-ABL1+ CML have not shown to be of any benefit and should be avoided in the treatment of these patients [11]. Considering the rarity of hematological malignancies with a BCR-JAK2 translocation, it remains important to report cases to disseminate clinical experience, which may allow better characterization of the clinical phenotype and provide beneficial insights regarding targeted therapy regimens for patients who are not eligible for allo-SCT.\n\n4. Conclusion\n\nBCR-JAK2-rearranged hematological malignancies are rare disorders that can have a variable clinical presentation but should be classified as a “Myeloid/Lymphoid Neoplasms with Eosinophilia and Gene Rearrangement.” Because eosinophilia can be discrete, or even absent, it highlights the importance of cytogenetic analysis in all patients that are presenting with a myeloid neoplasm. Combination treatment with inhibitors of JAK2 and BCL2 has minimal toxicity and can be beneficial in controlling disease.\n\nData Availability\n\nThe data used to support the findings of this study are available from the corresponding author upon request.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nAuthors' Contributions\n\nAll authors contributed equally to this work.\n\nFigure 1 Bone marrow biopsy showing a hypercellular marrow with marked myeloid hyperplasia with left shift ((a) hematoxylin and eosin stain, 400x) and grade 3 fibrosis ((b) reticulin stain, 200x).\n\nFigure 2 Fluorescent in situ hybridization with probes for BCR (22q11.2, green signal) and ABL1 (9q34.1, red signal) was negative for a BCR-ABL1 rearrangement. However, a third signal for the BCR probe (green signal, arrow) was observed, suggesting partial or complete gain of chromosome 22 or a translocation that involves BCR with a partner gene other than ABL1. Additional testing with a probe for JAK2 (9p24.1, not shown) suggested the presence of a BCR-JAK2 fusion, which was confirmed with RNA sequencing.\n\nFigure 3 Lymph node showing extensive extramedullary involvement by a myeloproliferative neoplasm with numerous megakaryocytes ((a) hematoxylin and eosin stain, 400x), no increase in blasts ((b) CD34 immunostain, 400x), or significant myeloid cells ((c) MPO immunostain, 400x) but with prominent erythroid precursors ((d) CD71 immunostain, 400x).\n\nTable 1 Summary of the literature regarding described phenotype, treatment, and response duration of patients with a BCR-JAK2 fusion.\n\nReference\tAge\tSex\tDisease\tTreatment\tFollow-up\t\nGriesinger et al. [2]\t63\tF\tCML-like MPD, myeloid blast crisis\tImatinib, hydroxyurea, interferon-alpha\tComplete hematological response. 20 months after diagnosis, she developed myeloid blast crisis and died.\t\nKantarcioglu et al. [3]\t64\tF\tMDS\tNot described\tDied 3 months after diagnosis\t\nCuesta-Domínguez et al. [4]\t58\tM\tB-ALL\tNot described\tNot described\t\nCirmena et al. [5]\t67\tF\tAML\tNot described\tNot described\t\nTirado et al. [6]\t14\tM\tB-ALL\tNot described\tNot described\t\nSnider et al. [7]\t59\tM\tMPN with eosinophilia, MPAL\tHydroxyurea, chemotherapy, allo-SCT\tTransformation to MPAL 12 months after diagnosis. No evidence of disease 30 days after allo-SCT.\t\nElnaggar et al. [8]\t84\tM\tCML-like MPD\tImatinib\tLost to follow-up\t\nSchwaab et al. [10]\tn/a\tn/a\tMyeloid neoplasm\tRuxolitinib 20 mg BID, allo-SCT\tComplete hematological and cytogenetic remission on ruxolitinib. Relapsed after 18 months upon which referred for allo-SCT.\t\nSchwaab et al. [11]\t69\tM\tMDS/MPN\tRuxolitinib 20 mg BID, allo-SCT\tComplete hematological, cytogenetic, and molecular response. AlloSCT while in remission\t\nHe et al. [14]\t36\tF\tMPN with eosinophilia\tDasatinib, allo-SCT\tNo response of dasatinib. No evidence of disease 18 months after allo-SCT.\t\nBellesso et al. [15]\t54\tM\tBCR-ABL - CML\tImatinib, dasatinib, allo-SCT\tNo response of imatinib or dasatinib. Died of aGvHD 53 days after allo-SCT\t\nImpera et al. [16]\t49\tF\tMPN-unclassifiable\tImatinib, dasatinib peg-interferon\tNo initial response with imatinib or dasatinib. Partial hematological response with peg-interferon\t\nLane et al. [17]\t44\tM\tAtypical CML with leukemia cutis\tNot described\tNot described\t\nThakral et al. [18]\t31\tM\tMPN with eosinophilia\tHydroxyurea, allo-SCT\tNo evidence of disease three months posttransplantation\t\nCML, chronic myeloid leukemia; MPD, myeloproliferative disorder; MDS, myelodysplastic syndrome; B-ALL, B-cell acute lymphoblastic leukemia; AML, acute myeloid leukemia; MPN, myeloproliferative neoplasm; MPAL, mixed phenotype acute leukemia; allo-SCT, allogeneic stem cell transplantation; BID, twice a day; aGvHD, acute graft-versus-host disease; F, female; M, male.\n==== Refs\n1 Tefferi A. Novel mutations and their functional and clinical relevance in myeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1 Leukemia 2010 24 6 1128 1138 10.1038/leu.2010.69 2-s2.0-77954581139 20428194\n2 Griesinger F. Hennig H. Hillmer F. ABCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11.2) translocation in a patient with a clinically typical chronic myeloid leukemia Genes, Chromosomes and Cancer 2005 44 3 329 333 10.1002/gcc.20235 2-s2.0-25844469587 16001431\n3 Kantarcioglu B. Kaygusuz-Atagunduz I. Uzay A. Toptas T. Tuglular T. F. Bayik M. Myelodysplastic syndrome with t(9;22)(p24;q11.2), a BCR-JAK2 fusion: case report and review of the literature International Journal of Hematology 2015 102 3 383 387 10.1007/s12185-015-1792-2 2-s2.0-84941426666 25833723\n4 Cuesta-Domínguez Á. Ortega M. Ormazábal C. Transforming and tumorigenic activity of JAK2 by fusion to BCR: molecular mechanisms of action of a novel BCR-JAK2 tyrosine-kinase PLoS One 2012 7 2 e32451 10.1371/journal.pone.0032451 2-s2.0-84857558600\n5 Cirmena G. Aliano S. Fugazza G. A BCR-JAK2 fusion gene as the result of a t(9;22)(p24;q11) in a patient with acute myeloid leukemia Cancer Genetics and Cytogenetics 2008 183 2 105 108 10.1016/j.cancergencyto.2008.02.005 2-s2.0-43949133894 18503828\n6 Tirado C. A. Chen W. Huang L. J.-s. Novel JAK2 rearrangement resulting from a t(9;22)(p24;q11.2) in B-acute lymphoblastic leukemia Leukemia Research 2010 34 12 1674 1676 10.1016/j.leukres.2010.05.031 2-s2.0-78149358109 20594592\n7 Snider J. S. Znoyko I. Lindsey K. G. Integrated genomic analysis using chromosomal microarray, fluorescence in situ hybridization and mate pair analyses: characterization of a cryptic t(9;22)(p24.1;q11.2)/BCR-JAK2 in myeloid/lymphoid neoplasm with eosinophilia Cancer Genetics 2020 247 44 47 10.1016/j.cancergen.2020.08.004\n8 Elnaggar M. M. Agersborg S. Sahoo T. BCR-JAK2 fusion as a result of a translocation (9;22)(p24;q11.2) in a patient with CML-like myeloproliferative disease Molecular Cytogenetics 2012 5 1 p. 23 10.1186/1755-8166-5-23 2-s2.0-84862200795\n9 Smith C. A. Fan G. The saga of JAK2 mutations and translocations in hematologic disorders: pathogenesis, diagnostic and therapeutic prospects, and revised World Health Organization diagnostic criteria for myeloproliferative neoplasms Human Pathology 2008 39 6 795 810 10.1016/j.humpath.2008.02.004 2-s2.0-44449118424 18538168\n10 Schwaab J. Knut M. Haferlach C. Limited duration of complete remission on ruxolitinib in myeloid neoplasms with PCM1-JAK2 and BCR-JAK2 fusion genes Annals of Hematology 2015 94 2 233 238 10.1007/s00277-014-2221-y 2-s2.0-84926627909 25260694\n11 Schwaab J. Naumann N. Luebke J. Response to tyrosine kinase inhibitors in myeloid neoplasms associated with PCM1 ‐ JAK2 , BCR‐JAK2 and ETV6‐ABL1 fusion genes American Journal of Hematology 2020 95 7 824 833 10.1002/ajh.25825 32279331\n12 Swerdlow S. Campo E. Harris N WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2017 4th Lyon, France iARC Press\n13 Reiter A. Gotlib J. Myeloid neoplasms with eosinophilia Blood 2017 129 6 704 714 10.1182/blood-2016-10-695973 2-s2.0-85015294920 28028030\n14 He R. Greipp P. T. Rangan A. BCR-JAK2 fusion in a myeloproliferative neoplasm with associated eosinophilia Cancer Genetics 2016 209 5 223 228 10.1016/j.cancergen.2016.03.002 2-s2.0-84964587156 27134074\n15 Bellesso M. Santucci R. Dias D. F. Centrone R. Elias R. C. Atypical chronic myeloid leukemia with t(9; 22)(p24, 11.2), a BCR-JAK2 fusion gene Revista Brasileira de Hematologia e Hemoterapia 2013 35 218 219 10.5581/1516-8484.20130044 2-s2.0-84881531298 23904814\n16 Impera L. Lonoce A. Fanfulla D. A. Two alternatively spliced 5′BCR/3′JAK2 fusion transcripts in a myeloproliferative neoplasm with a three-way t(9; 18; 22)(p23; p11.3; q11.2) translocation Cancer Genetics 2011 204 9 512 515 10.1016/j.cancergen.2011.08.016 2-s2.0-84856007547 22018274\n17 Lane S. W. Fairbairn D. J. McCarthy C. Nandini A. Perry-Keene J. Kennedy G. A. Leukaemia cutis in atypical chronic myeloid leukaemia with a t(9; 22) (p24; q11.2) leading to BCR-JAK2 fusion British Journal of Haematology 2008 142 4 p. 503 10.1111/j.1365-2141.2008.07164.x 2-s2.0-47649133542\n18 Thakral B. Muzzafar T. Wang S. A. Medeiros L. J. Myeloid neoplasm with eosinophilia and BCR-JAK2/t(9; 22)(p24; q11.2) morphologically mimicking chronic myeloid leukemia Annals of Diagnostic Pathology 2020 44 151405 10.1016/j.anndiagpath.2019.151405\n19 Jain S. Abraham A. BCR-ABL1-like B-acute lymphoblastic leukemia/lymphoma: a comprehensive review Archives of Pathology & Laboratory Medicine 2020 144 2 150 155 10.5858/arpa.2019-0194-RA 31644323\n20 Getta B. M. Roshal M. Zheng J. Allogeneic hematopoietic stem cell transplantation with myeloablative conditioning is associated with favorable outcomes in mixed phenotype acute leukemia Biology of Blood and Marrow Transplantation 2017 23 11 1879 1886 10.1016/j.bbmt.2017.06.026 2-s2.0-85026856336 28694182\n21 Bowman R. L. Busque L. Levine R. L. Clonal hematopoiesis and evolution to hematopoietic malignancies Cell Stem Cell 2018 22 2 157 170 10.1016/j.stem.2018.01.011 2-s2.0-85045375164 29395053\n22 Bousoik E. Montazeri Aliabadi H. Do we know Jack” about JAK? A closer look at JAK/STAT signaling pathway Frontiers in Oncology 2018 8 p. 287 10.3389/fonc.2018.00287\n23 Sepúlveda P. Encabo A. Carbonell-Uberos F. Miñana M. D. BCL-2 expression is mainly regulated by JAK/STAT3 pathway in human CD34+ hematopoietic cells Cell Death & Differentiation 2007 14 2 378 380 10.1038/sj.cdd.4402007 2-s2.0-33846240367 16841088\n24 Sakai I. Kraft A. S. The kinase domain of Jak2 mediates induction of bcl-2 and delays cell death in hematopoietic cells Journal of Biological Chemistry 1997 272 19 12350 12358 10.1074/jbc.272.19.12350 2-s2.0-0030953788\n25 Zeuner A. Pedini F. Francescangeli F. Activity of the BH3 mimetic ABT-737 on polycythemia vera erythroid precursor cells Blood 2009 113 7 1522 1525 10.1182/blood-2008-03-143321 2-s2.0-61849143248 19060244\n26 Will B. Siddiqi T. Jordà M. A. Apoptosis induced by JAK2 inhibition is mediated by Bim and enhanced by the BH3 mimetic ABT-737 in JAK2 mutant human erythroid cells Blood 2010 115 14 2901 2909 10.1182/blood-2009-03-209544 2-s2.0-77951041842 20160166\n27 Waibel M. Solomon V. S. Knight D. A. Combined targeting of JAK2 and BCL-2/BCL-XL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors Cell Reports 2013 5 4 1047 1059 10.1016/j.celrep.2013.10.038 2-s2.0-84888430616 24268771\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6579",
"issue": "2021()",
"journal": "Case reports in hematology",
"keywords": null,
"medline_ta": "Case Rep Hematol",
"mesh_terms": null,
"nlm_unique_id": "101576456",
"other_id": null,
"pages": "2348977",
"pmc": null,
"pmid": "34367701",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "22018274;27134074;20160166;22549126;32827877;16841088;24268771;31865248;29395053;30109213;9139679;19060244;25833723;32279331;31644323;20594592;23904814;22384256;18538168;18503828;20428194;28694182;16001431;28028030;25260694;18537978",
"title": "Combined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm.",
"title_normalized": "combined ruxolitinib and venetoclax treatment in a patient with a bcr jak2 rearranged myeloid neoplasm"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2022-022687",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Uterine myoma, the most common form of uterine tumor, occurs in approximately 25% of reproductive-aged women. Parasitic myoma, which outgrows its uterine blood supply and obtains a secondary blood supply from another organ such as the omentum, is rare. It is extremely rare if it is on the peritoneum of the right pelvic wall. Only a few cases have been found in this location so far. Here, the authors report an interesting case of parasitic myoma on the peritoneum of the right pelvic wall. They conclude with seven key points, which should be paid more attention to avoid iatrogenic parasitic myoma.",
"affiliations": null,
"authors": "Yang|Xi|X|;Ma|Ke|K|;Zhang|Shuang|S|;Wang|He|H|;Bai|Wenpei|W|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6663",
"issue": "43(5)",
"journal": "Clinical and experimental obstetrics & gynecology",
"keywords": null,
"medline_ta": "Clin Exp Obstet Gynecol",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007049:Iatrogenic Disease; D009214:Myoma; D010534:Peritoneal Neoplasms",
"nlm_unique_id": "7802110",
"other_id": null,
"pages": "769-773",
"pmc": null,
"pmid": "30074337",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Iatrogenic parasitic myoma on the peritoneum of the right pelvic wall.",
"title_normalized": "iatrogenic parasitic myoma on the peritoneum of the right pelvic wall"
} | [
{
"companynumb": "CN-TEVA-725599USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugadditional": null,
... |
{
"abstract": "Burkitt lymphoma is an aggressive B-cell lymphoma curable with dose-intensive chemotherapy derived from pediatric leukemia regimens. Treatment is acutely toxic with late sequelae. We hypothesized that dose-adjusted etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone, and rituximab (DA-EPOCH-R) may obviate the need for highly dose-intensive chemotherapy in adults with Burkitt lymphoma.\n\n\n\nWe conducted a multicenter risk-adapted study of DA-EPOCH-R in untreated adult Burkitt lymphoma. Low-risk patients received three cycles without CNS prophylaxis, and high-risk patients received six cycles with intrathecal CNS prophylaxis or extended intrathecal treatment if leptomeninges were involved. The primary endpoint was event-free survival (EFS), and secondary endpoints were toxicity and predictors of EFS and overall survival (OS).\n\n\n\nBetween 2010 and 2017, 113 patients were enrolled across 22 centers, and 98 (87%) were high risk. The median age was 49 (range, 18-86) years, and 62% were ≥ 40 years. Bone marrow and/or CSF was involved in 29 (26%) of patients, and 28 (25%) were HIV positive. At a median follow-up of 58.7 months, EFS and OS were 84.5% and 87.0%, respectively, and EFS was 100% and 82.1% in low- and high-risk patients. Therapy was equally effective across age groups, HIV status, and International Prognostic Index risk groups. Involvement of the CSF identified the group at greatest risk for early toxicity-related death or treatment failure. Five treatment-related deaths (4%) occurred during therapy. Febrile neutropenia occurred in 16% of cycles, and tumor lysis syndrome was rare.\n\n\n\nRisk-adapted DA-EPOCH-R therapy is effective in adult Burkitt lymphoma regardless of age or HIV status and was well tolerated. Improved therapeutic strategies for adults with CSF involvement are needed (funded by the National Cancer Institute; ClinicalTrials.gov identifier: NCT01092182).",
"affiliations": "Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD.;George Washington University Cancer Center, Washington, DC.;Massachusetts General Hospital Cancer Center, Boston, MA.;Comprehensive Cancer Center of Wake Forest Baptist Health, Winston-Salem, NC.;University of Iowa Hospital and Clinics, Iowa City, IA.;University of Texas Southwestern, Dallas, TX.;University of Nebraska Medical Center, Omaha, NE.;Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.;University of California Los Angeles Clinical AIDS Research and Education Center, Los Angeles, CA.;University of Illinois, Chicago, IL.;Kinston Medical Specialists, Kinston, NC.;University of Tennessee Medical Center, Knoxville, TN.;Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD.;Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD.;Biostatistics and Data Management Section, Center for Cancer Research, National Cancer Institute, Bethesda, MD.;Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD.;Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, MD.;Montefiore Medical Center, Bronx, NY.;Washington University School of Medicine, St. Louis, MO.;Division of Cancer Therapy and Diagnosis, National Cancer Institute, Bethesda, MD.;Washington University School of Medicine, St. Louis, MO.;MD Anderson Cancer Center, Houston, TX, and Seattle Genetics, Seattle, WA.;Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY.;Lymphoid Malignancies Branch, National Cancer Institute, Bethesda, MD.",
"authors": "Roschewski|Mark|M|;Dunleavy|Kieron|K|;Abramson|Jeremy S|JS|;Powell|Bayard L|BL|;Link|Brian K|BK|;Patel|Prapti|P|;Bierman|Philip J|PJ|;Jagadeesh|Deepa|D|;Mitsuyasu|Ronald T|RT|;Peace|David|D|;Watson|Peter R|PR|;Hanna|Wahid T|WT|;Melani|Christopher|C|;Lucas|Andrea N|AN|;Steinberg|Seth M|SM|;Pittaluga|Stefania|S|;Jaffe|Elaine S|ES|;Friedberg|Jonathan W|JW|;Kahl|Brad S|BS|;Little|Richard F|RF|;Bartlett|Nancy L|NL|;Fanale|Michelle A|MA|;Noy|Ariela|A|;Wilson|Wyndham H|WH|",
"chemical_list": "D000069283:Rituximab; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.20.00303",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "38(22)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002051:Burkitt Lymphoma; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D011379:Prognosis; D012307:Risk Factors; D000069283:Rituximab; D015996:Survival Rate; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2519-2529",
"pmc": null,
"pmid": "32453640",
"pubdate": "2020-08-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D052060:Research Support, N.I.H., Intramural",
"references": "15160953;16150940;11309438;6961453;25066629;12181251;18378569;31864677;17242396;11369626;27080498;21030984;19717381;19087093;24428673;1742728;22885699;15042678;8622041;23641015;3525767;25957391;24224624;26980727;25359988;24146219;15837965;30939090;3491184;22098541;15358629;5536703;16502413;17132719;16284057;17138821",
"title": "Multicenter Study of Risk-Adapted Therapy With Dose-Adjusted EPOCH-R in Adults With Untreated Burkitt Lymphoma.",
"title_normalized": "multicenter study of risk adapted therapy with dose adjusted epoch r in adults with untreated burkitt lymphoma"
} | [
{
"companynumb": "US-PFIZER INC-2018047267",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "Posthypoxic and postencephalitic myoclonus is often poorly controlled with current treatments. The authors successfully treated three patients with posthypoxic and postencephalitic myoclonus by using levetiracetam, a new antiepileptic drug. Levetiracetam appears to be a promising agent for treating action myoclonus caused by hypoxic and encephalitic brain injury-the degree of functional improvement may depend on the severity of associated motor dysfunction.",
"affiliations": "Department of Neurology, Johns Hopkins University, Baltimore, MD, USA. gkrauss@jhmi.edu",
"authors": "Krauss|G L|GL|;Bergin|A|A|;Kramer|R E|RE|;Cho|Y W|YW|;Reich|S G|SG|",
"chemical_list": "D000077287:Levetiracetam; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1212/wnl.56.3.411",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "56(3)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000328:Adult; D000368:Aged; D005260:Female; D006801:Humans; D002534:Hypoxia, Brain; D000077287:Levetiracetam; D008297:Male; D008875:Middle Aged; D009207:Myoclonus; D010889:Piracetam; D013997:Time Factors",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "411-2",
"pmc": null,
"pmid": "11171914",
"pubdate": "2001-02-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Suppression of post-hypoxic and post-encephalitic myoclonus with levetiracetam.",
"title_normalized": "suppression of post hypoxic and post encephalitic myoclonus with levetiracetam"
} | [
{
"companynumb": "US-UCBSA-2016038517",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
... |
{
"abstract": "Cryptococcus spp. other than Cryptococcus neoformans or Cryptococcus gattii were previously considered saprophytes and thought to be non-pathogenic to humans. However, opportunistic infections associated with non-neoformans and non-gattii species, such as Cryptococcus laurentii and Cryptococcus albidus, have increased over the past four decades. We experienced a case of cryptococcosis caused by non-neoformans and non-gattii spp. in a 47-year-old female with refractory acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. The patient underwent salvage chemotherapy with fluconazole prophylaxis and subsequently developed neutropenic fever with multiple erythematous umbilicated papules. A skin biopsy revealed fungal hyphae and repetitive blood cultures showed yeast microorganisms that were identified later as C. laurentii by Vitek-II®. Skin lesions and fever began to improve with conventional amphotericin B therapy. The treatment regimen was continued for 21 days until the disseminated cryptococcosis was completely controlled.",
"affiliations": "Department of Internal Medicine, National Cancer Center, Goyang, Korea.;Hematologic Oncology Clinic, National Cancer Center, Goyang, Korea.;Department of Pathology, National Cancer Center, Goyang, Korea.;Department of Laboratory Medicine, National Cancer Center, Goyang, Korea.;Department of Internal Medicine, National Cancer Center, Goyang, Korea.;Department of Internal Medicine, National Cancer Center, Goyang, Korea.;Department of Internal Medicine, National Cancer Center, Goyang, Korea.;Department of Internal Medicine, National Cancer Center, Goyang, Korea.;Infectious Disease Clinic, National Cancer Center, Goyang, Korea.;Hematologic Oncology Clinic, National Cancer Center, Goyang, Korea. hseom@ncc.re.kr.",
"authors": "Park|Sun Seob|SS|https://orcid.org/0000-0001-6091-4873;Lee|Hyewon|H|;Park|Weon Seo|WS|;Hwang|Sang Hyun|SH|;Choi|Sang Il|SI|;Choi|Mi Hong|MH|;Lee|Si Won|SW|;Ko|Eun Jung|EJ|;Choi|Young Ju|YJ|;Eom|Hyeon Seok|HS|https://orcid.org/0000-0002-0484-2067",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.3947/ic.2017.49.2.142",
"fulltext": "\n==== Front\nInfect ChemotherInfect ChemotherICInfection & Chemotherapy2093-23402092-6448The Korean Society of Infectious Diseases and Korean Society for Chemotherapy 10.3947/ic.2017.49.2.142Case ReportA Case of Disseminated Infection with Skin Manifestation due to Non-neoformans and Non-gattii\nCryptococcus in a Patient with Refractory Acute Myeloid Leukemia https://orcid.org/0000-0001-6091-4873Park Sun Seob 1Lee Hyewon 2Park Weon Seo 3Hwang Sang Hyun 4Choi Sang Il 1Choi Mi Hong 1Lee Si Won 1Ko Eun Jung 1Choi Young Ju 5https://orcid.org/0000-0002-0484-2067Eom Hyeon-Seok 21 Department of Internal Medicine, National Cancer Center, Goyang, Korea.2 Hematologic Oncology Clinic, National Cancer Center, Goyang, Korea.3 Department of Pathology, National Cancer Center, Goyang, Korea.4 Department of Laboratory Medicine, National Cancer Center, Goyang, Korea.5 Infectious Disease Clinic, National Cancer Center, Goyang, Korea.Corresponding author: Hyeon-Seok Eom, MD, PhD. Department of Internal Medicine, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea. Tel: +82-31-920-2402, Fax: +82-31-920-1163, hseom@ncc.re.kr6 2017 16 1 2017 49 2 142 145 16 3 2015 13 7 2015 Copyright © 2017 by The Korean Society of Infectious Diseases and Korean Society for Chemotherapy2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Cryptococcus spp. other than Cryptococcus neoformans or Cryptococcus gattii were previously considered saprophytes and thought to be non-pathogenic to humans. However, opportunistic infections associated with non-neoformans and non-gattii species, such as Cryptococcus laurentii and Cryptococcus albidus, have increased over the past four decades. We experienced a case of cryptococcosis caused by non-neoformans and non-gattii spp. in a 47-year-old female with refractory acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation. The patient underwent salvage chemotherapy with fluconazole prophylaxis and subsequently developed neutropenic fever with multiple erythematous umbilicated papules. A skin biopsy revealed fungal hyphae and repetitive blood cultures showed yeast microorganisms that were identified later as C. laurentii by Vitek-II®. Skin lesions and fever began to improve with conventional amphotericin B therapy. The treatment regimen was continued for 21 days until the disseminated cryptococcosis was completely controlled.\n\nCryptococcosisCryptococcus laurentiinon-neoformansnon-gattii cryptococci\n==== Body\nINTRODUCTION\nCryptococcosis is a systemic and local fungal infection caused by Cryptococcus spp. It is generally agreed that most cryptococcal infections are acquired by the inhalation of infectious propagules [1].\n\nCryptococcosis, which is usually due to Cryptococcus neoformans and Cryptococcus gattii, is considered to be one of the most serious fungal infections in immunocompromised patients [2]. Cryptococcus spp. other than C. neoformans and C. gattii were previously considered to be saprophytes and nonpathogenic to humans; however, opportunistic infections associated with rare Cryptococcus spp., such as Cryptococcus laurentii and Cryptococcus albidus, have increased over the past four decades [1, 3].\n\nDespite changing trends in opportunistic infections, infections caused by non-neoformans and non-gattii Cryptococcus are rare. We recently experienced an immunocompromised patient with refractory acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (HSCT) who presented with fungemia and a disseminated cutaneous infection caused by non-neoformans and non-gattii Cryptococcus.\n\nCASE REPORT\nA 47-year-old female diagnosed with AML underwent induction and consolidation chemotherapy. Allogeneic HSCT was subsequently performed after achieving complete remission in February 2009. Over the next 3 years, the patient showed no evidence of relapse. Then, the patient developed extramedullary relapse in the breast which was diagnosed by breast tissue biopsy.\n\nReinduction chemotherapy with a total of 40 Gy of radiation was administered to treat the breast mass. However, the mass increased in size after radiation therapy and a subsequent bone marrow biopsy showed the full-blown hematologic recurrence of AML. Therefore, salvage chemotherapy with fludarabine, cytarabine, and idarubicin was started for progressive AML.\n\nDuring salvage chemotherapy, the patient took 250 mg of ciprofloxacin twice daily and 100 mg of fluconazole per day for prophylaxis. On day 4 after starting chemotherapy, the patient developed a fever of 38.4°C. It subsided over the course of a day following empirical antibiotic treatment with 4.5 g of piperacillin/tazobactam four times per day.\n\nOn day 18, the patient again developed a high fever (38.8°C) and she exhibited multiple erythematous papules on her back, right thigh, and both arms. All other vital signs were stable, with a blood pressure of 120/80 mmHg, pulse rate of 104/min, and a breathing rate of 20/min. At this point, the patient did not have any other symptoms or signs except for an itching sensation, pain, and multiple pinhead- to matchhead-sized erythematous papules and vesicles with erythema on her back, right thigh, and extremities. Laboratory studies revealed a white blood cell count of 30/µL (neutrophils, 0%; lymphocytes, 80%; and monocytes, 20%), absolute neutrophil count (ANC) of 0/mm3, hemoglobin level of 7.5 g/dL, platelet count of 32 ⨯ 10³/mm3, and total bilirubin level of 1.3 mg/dL. Chest and abdominal X-rays did not reveal any specific abnormalities.\n\nEmpirical antibiotic therapy was changed to cefepime (2 g, three times per day) and vancomycin (1 g, twice daily) because of the patient’s persistent fever. Blood cultures, fungal cultures, and viral serologic tests were negative at this time.\n\nThough the administered antibiotics had been modified, the patient’s fever and skin lesions worsened. The cutaneous lesions changed to bullae with hemorrhagic patches (Fig. 1A) and edematous plaques (Fig. 1B). Repeated culture studies were performed; then, on day 21 after salvage chemotherapy, one set of blood culture from peripheral vein in four sets of them showed round to oval budding encapsulated yeast cells that were confirmed to be C. laurentii. In repeated blood culture on day 24, two sets of peripheral blood culture in four sets of blood culture examinations showed C. laurentii again. Biochemical identification of the culture was conducted by automated Vitek-II® (bioMérieux, Durham, NC, USA). A skin biopsy was also performed on day 26, and it revealed the presence of fungal hyphae (Fig. 2A and B).\n\nFigure 1 A skin lesion observed on day 18 after salvage chemotherapy. Multiple pinhead- to matchhead-sized papules and vesicles with erythema were observed initially, followed by 1cm-sized bullae with hemorrhagic patches (A) and 2cm-sized erythematous and edematous plaques with central bullous changes (B).\n\nFigure 2 Pathologic findings from a skin biopsy. Fungal hyphae were observed using Grocott’s methenamine silver stain (A, ×400) and Periodic acid-Schiff staining (B, ×400).\n\nThe patient was administered conventional amphotericin B (1 mg/kg, daily) beginning on day 27, immediately after the cryptococcosis was documented. The patient’s cutaneous lesions started to improve and her fever subsided after 2 days of treatment. Follow-up blood cultures became negative within 4 days. On day 29 after salvage chemotherapy, the ANC was recovered to 1,500/mm3. Amphotericin B was given for 3 weeks (cumulative dose, 1,284 mg), after which the disseminated cryptococcosis was deemed completely controlled.\n\nDISCUSSION\nCryptococcus spp. are encapsulated, basidiomycetous yeasts that are present in the environment worldwide. Cryptococcus spp. generally occur in soil contaminated with pigeon feces and are often transmitted to humans through inhaled fomites [4, 5]. There have been increasing reports of non-neoformans and non-gattii cryptococcosis over the past four decades [1, 6].\n\nCryptoccus spp. other than C. neoformans or C. gatii is extremely rare and includes C. laurentii and C. albidus. We identified C. laurentii from presented case by automated Vitek-II® (bioMérieux, USA), and it has high probability to be C. laurentii. Although we tried to perform DNA sequencing with paraffin-embedded skin block, we failed to amplify fungal DNA.\n\nAlthough non-neoformans and non-gattii cryptococcosis has been reported as occurring worldwide, its natural habitat or clinical characteristics have not been thoroughly established because of a lack of cases [1, 2]. Bloodstream and central nervous system infections are the most common forms of non-neoformans and non-gattii cryptococcosis. In the current case, the patient had a disseminated infection that presented with early skin manifestations. The patient had a refractory hematologic malignancy after allogeneic HSCT and was treated with multi-agent chemotherapy.\n\nCryptococcus spp. is capable of assuming different morphotypes: yeast, pseudohyphae, and hyphae. The yeast form is the most common cell type observed clinically [7]. The hyphal and pseudohyphal forms are rarely observed in the clinical setting and are considered attenuated in virulence during cryptococcosis in a mammalian host [7, 8]. The regulation of Ace2 and morphogenesis (RAM) pathway and the transcription factor ZNF2 is the master activator of the yeast transformation [7]. Any mutations of RAM pathway in Cryptococcus render cells constitutively in the pseudohyphal form and elevated expression of ZNF2 drives hyphal growth [7, 9].\n\nThe existing antifungal options and duration of treatment for cryptococcosis have been established largely for C. neoformans infections. The mainstay of treatment for cryptococcosis is combination therapy with amphotericin B and 5-flucytosine or monotherapy with amphotericin B [1, 10]. According to the case reports published thus far, the initial treatment for a rare Cryptococcus spp. infection is removal of the infection source either through the combined use of amphotericin B and 5-flucytosine or monotherapy with amphotericin B or fluconazole [1, 3]. Monotherapy with fluconazole or itraconazole can be used for patients that have only regional symptoms without a central nervous system or systemic infection [11, 12]. In patients with fungemia, combined treatment with amphotericin B and 5-flucytosine for the first 10–14 days followed by monotherapy with fluconazole or itraconazole for several weeks has been reported [1, 11]. However, there is no validated standard treatment for rare Cryptococcus spp. infections because of the lack of cases. In the presented case, the infection occurred during fluconazole prophylaxis, indicating the possibility of an azole-resistant pathogen. Therefore, we switched to amphotericin B, which showed good efficacy.\n\nNon-neoformans and non-gattii cryptococcosis, especially disseminated infections with a cutaneous manifestation, are rare; However these rare Cryptococcus spp. Infections have increased in recent years. In severely immunocompromised patients with persistent febrile neutropenia, non-neoformans and non-gattii cryptococcosis should be considered, especially when an azole-resistant fungal infection is suspected.\n\nCONFLICT OF INTEREST: No conflict of interest.\n==== Refs\n1 Khawcharoenporn T Apisarnthanarak A Mundy LM Non-neoformans cryptococcal infections: a systematic review Infection 2007 35 51 58 17401707 \n2 Shankar EM Kumarasamy N Bella D Renuka S Kownhar H Suniti S Rajan R Rao UA Pneumonia and pleural effusion due to Cryptococcus laurentii in a clinically proven case of AIDS Can Respir J 2006 13 275 278 16896431 \n3 Cheng MF Chiou CC Liu YC Wang HZ Hsieh KS \nCryptococcus laurentii fungemia in a premature neonate J Clin Microbiol 2001 39 1608 1611 11283097 \n4 Gupta RK Khan ZU Nampoory MR Mikhail MM Johny KV Cutaneous cryptococcosis in a diabetic renal transplant recipient J Med Microbiol 2004 53 445 449 15096556 \n5 Chand-Goyal T Spotts RA Enumeration of bacterial and yeast colonists of apple fruits and identification of epiphytic yeasts on pear fruits in the Pacific Northwest United States Microbiol Res 1996 151 427 432 9022303 \n6 Johnson LB Bradley SF Kauffman CA Fungaemia due to Cryptococcus laurentii and a review of non-neoformans cryptococcaemia Mycoses 1998 41 277 280 9861831 \n7 Lin J Idnurm A Lin X Morphology and its underlying genetic regulation impact the interaction between Cryptococcus neoformans and its hosts Med Mycol 2015 53 493 504 25841056 \n8 Magditch DA Liu TB Xue C Idnurm A DNA mutations mediate microevolution between host-adapted forms of the pathogenic fungus Cryptococcus neoformans \n PLoS Pathog 2012 8 e1002936 23055925 \n9 Walton FJ Heitman J Idnurm A Conserved elements of the RAM signaling pathway establish cell polarity in the basidiomycete Cryptococcus neoformans in a divergent fashion from other fungi Mol Biol Cell 2006 17 3768 3780 16775005 \n10 Kulkarni A Sinha M Anandh U Primary cutaneous cryptococcosis due to Cryptococcous laurentii in a renal transplant recipient Saudi J Kidney Dis Transpl 2012 23 102 105 22237228 \n11 Saag MS Graybill RJ Larsen RA Pappas PG Perfect JR Powderly WG Sobel JD Dismukes WE Practice guidelines for the management of cryptococcal disease Clin Infect Dis 2000 30 710 718 10770733 \n12 Husain S Wagener MM Singh N \nCryptococcus neoformans infection in organ transplant recipients: variables influencing clinical characteristics and outcome Emerg Infect Dis 2001 7 375 381 11384512\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-8112",
"issue": "49(2)",
"journal": "Infection & chemotherapy",
"keywords": "Cryptococcosis; Cryptococcus laurentii; non-gattii cryptococci; non-neoformans",
"medline_ta": "Infect Chemother",
"mesh_terms": null,
"nlm_unique_id": "101531537",
"other_id": null,
"pages": "142-145",
"pmc": null,
"pmid": "28271644",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports",
"references": "9861831;17401707;11384512;23055925;15096556;25841056;22237228;11283097;10770733;16775005;16896431;9022303",
"title": "A Case of Disseminated Infection with Skin Manifestation due to Non-neoformans and Non-gattii Cryptococcus in a Patient with Refractory Acute Myeloid Leukemia.",
"title_normalized": "a case of disseminated infection with skin manifestation due to non neoformans and non gattii cryptococcus in a patient with refractory acute myeloid leukemia"
} | [
{
"companynumb": "KR-SA-2017SA126704",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "3",
... |
{
"abstract": "Toxic epidermal necrolysis (NET) and Steven Johnson syndrome (SJS) are infrequent mucocutaneous hypersensitivity reactions with systemic involvement. They are predominantly caused by drugs. We report the case of a patient over 60 years of age who presented with extensive mucocutaneous and ophthalmic injury with hemodynamic failure, associated with the rapid onset of lamotrigine in a short period of time. Although the incidence is low, the mortality rate is high. It requires early suspicious and diagnosis in addition to an interdisciplinary therapeutic approach.",
"affiliations": "Servicio de Clínica Médica, Instituto de Investigaciones Médicas \"Alfredo Lanari\". Ciudad Autónoma de Buenos Aires, Argentina. E-mail: rotondarojuliocesar@gmail.com.;Servicio de Clínica Médica, Instituto de Investigaciones Médicas \"Alfredo Lanari\". Ciudad Autónoma de Buenos Aires, Argentina.;Servicio de Clínica Médica, Instituto de Investigaciones Médicas \"Alfredo Lanari\". Ciudad Autónoma de Buenos Aires, Argentina.;Servicio de Dermatología, Instituto de Investigaciones Médicas \"Alfredo Lanari\". Ciudad Autónoma de Buenos Aires, Argentina.;Servicio de Patología, Instituto de Investigaciones Médicas \"Alfredo Lanari\". Ciudad Autónoma de Buenos Aires, Argentina.;Unidad de Cuidados Intensivos, Instituto de Investigaciones Médicas \"Alfredo Lanari\". Ciudad Autónoma de Buenos Aires, Argentina.;Servicio de Salud Mental, Instituto de Investigaciones Médicas \"Alfredo Lanari\". Ciudad Autónoma de Buenos Aires, Argentina.;Servicio de Salud Mental, Instituto de Investigaciones Médicas \"Alfredo Lanari\". Ciudad Autónoma de Buenos Aires, Argentina.",
"authors": "Rotondaro|Julio César|JC|;Kim|Aaron Cristian|AC|;Monti|Paula|P|;Pazos|Mónica|M|;Gazzi|Carla|C|;López|Rodolfo|R|;Riccioppo|Fernando|F|;Fadel|Daniel|D|",
"chemical_list": "D000927:Anticonvulsants; D004364:Pharmaceutical Preparations",
"country": "Argentina",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0327-6139",
"issue": "XXXII(152)",
"journal": "Vertex (Buenos Aires, Argentina)",
"keywords": null,
"medline_ta": "Vertex",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D004364:Pharmaceutical Preparations; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "9440528",
"other_id": null,
"pages": "20-23",
"pmc": null,
"pmid": "34783791",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Toxic epidermal necrolysis: idiosyncratic reaction to drugs.",
"title_normalized": "toxic epidermal necrolysis idiosyncratic reaction to drugs"
} | [
{
"companynumb": "AR-TEVA-2022-AR-2007112",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nFunctioning farnesoid X receptor (FXR; encoded by NR1H4) is key to normal bile acid homeostasis. Biallelic mutations in NR1H4 are reported in a few children with intrahepatic cholestasis. We describe a boy with progressive familial intrahepatic cholestasis and homozygous mutation in NR1H4.\n\n\nMETHODS\nA boy had severe neonatal cholestasis with moderate hypercholanemia and persistently elevated alpha-fetoprotein. Despite medical treatment, coagulopathy was uncontrollable, prompting liver transplantation at age 8 mo with incidental splenectomy. The patient experienced catch-up growth with good liver function and did not develop allograft steatosis. However, 1 year after transplant, he died from an acute infection, considered secondary to immunosuppression and asplenia. A homozygous protein-truncating mutation, c.547C > T, p.(Arg183Ter), was subsequently identified in NR1H4, and both parents were shown to be heterozygous carriers. Absence of FXR and of bile salt export pump expression was confirmed by immunostaining of explanted liver.\n\n\nCONCLUSIONS\nSevere cholestasis with persistently high alpha-fetoprotein and modest elevation of serum bile acid levels may suggest FXR deficiency. Some patients with FXR deficiency may not develop allograft steatosis and may respond well to liver transplantation.",
"affiliations": "Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw 04-730, Poland. p.czubkowski@ipczd.pl.;Institute of Liver Studies, King's College London Hospital, London SE5 9RS, United Kingdom.;Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw 04-730, Poland.;Institut für Pathologie, Medizinische Universität Graz, Graz 8010, Austria.;Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, United States.;Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, United States.;Department of Pathology, The Children's Memorial Health Institute, Warsaw 04-730, Poland.;Institute of Liver Studies, King's College London Hospital, London SE5 9RS, United Kingdom.;Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children's Memorial Health Institute, Warsaw 04-730, Poland.;Department of Medicine and Institute for Human Genetics, UCSF Liver Center Laboratory, University of California San Francisco, San Francisco, CA 94143, United States.",
"authors": "Czubkowski|Piotr|P|;Thompson|Richard J|RJ|;Jankowska|Irena|I|;Knisely|A S|AS|;Finegold|Milton|M|;Parsons|Pamela|P|;Cielecka-Kuszyk|Joanna|J|;Strautnieks|Sandra|S|;Pawłowska|Joanna|J|;Bull|Laura N|LN|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v9.i15.3631",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i15.pg3631\n10.12998/wjcc.v9.i15.3631\nCase Report\nProgressive familial intrahepatic cholestasis — farnesoid X receptor deficiency due to NR1H4 mutation: A case report\nCzubkowski P et al. Cholestasis due to FXR deficiency\nCzubkowski Piotr Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw 04-730, Poland. p.czubkowski@ipczd.pl\n\nThompson Richard J Institute of Liver Studies, King's College London Hospital, London SE5 9RS, United Kingdom\n\nJankowska Irena Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw 04-730, Poland\n\nKnisely A S Institut für Pathologie, Medizinische Universität Graz, Graz 8010, Austria\n\nFinegold Milton Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, United States\n\nParsons Pamela Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, United States\nTexas Children’s Hospital, Houston, TX 77030, United States\n\nCielecka-Kuszyk Joanna Department of Pathology, The Children’s Memorial Health Institute, Warsaw 04-730, Poland\n\nStrautnieks Sandra Institute of Liver Studies, King's College London Hospital, London SE5 9RS, United Kingdom\n\nPawłowska Joanna Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Warsaw 04-730, Poland\n\nBull Laura N Department of Medicine and Institute for Human Genetics, UCSF Liver Center Laboratory, University of California San Francisco, San Francisco, CA 94143, United States\n\nAuthor contributions: All authors contributed significantly to the preparation of the manuscript; Czubkowski P, Bull LN, Thompson RJ, Knisely AS, Jankowska I and Pawłowska J contributed to conception and design of the case presentation, acquisition of data and case description; Bull LN, Strautnieks S and Thompson RJ contributed to genetic studies; Knisely AS, Finegold M, Parsons P and Cielecka-Kuszyk J contributed to histopathological assessment; Czubkowski P, Bull LN, Thompson RJ and Knisely AS contributed to drafting the article and making critical revisions related to the content of the manuscript; All authors have read and approve the final manuscript.\n\nSupported by National Institutes of Health, No. R01DK094828 ; and National Human Genome Research Institute, No. UM1 HG006493 and No. U24 HG008956 .\n\nCorresponding author: Piotr Czubkowski, MD, PhD, Associate Professor, Department of Gastroenterology, Hepatology, Nutritional Disorders and Pediatrics, The Children’s Memorial Health Institute, Al. Dzieci Polskich 20, Warsaw 04-730, Poland. p.czubkowski@ipczd.pl\n\n26 5 2021\n26 5 2021\n9 15 36313636\n17 10 2020\n16 12 2020\n24 2 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 which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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.\nBACKGROUND\n\nFunctioning farnesoid X receptor (FXR; encoded by NR1H4) is key to normal bile acid homeostasis. Biallelic mutations in NR1H4 are reported in a few children with intrahepatic cholestasis. We describe a boy with progressive familial intrahepatic cholestasis and homozygous mutation in NR1H4.\n\nCASE SUMMARY\n\nA boy had severe neonatal cholestasis with moderate hypercholanemia and persistently elevated alpha-fetoprotein. Despite medical treatment, coagulopathy was uncontrollable, prompting liver transplantation at age 8 mo with incidental splenectomy. The patient experienced catch-up growth with good liver function and did not develop allograft steatosis. However, 1 year after transplant, he died from an acute infection, considered secondary to immunosuppression and asplenia. A homozygous protein-truncating mutation, c.547C > T, p.(Arg183Ter), was subsequently identified in NR1H4, and both parents were shown to be heterozygous carriers. Absence of FXR and of bile salt export pump expression was confirmed by immunostaining of explanted liver.\n\nCONCLUSION\n\nSevere cholestasis with persistently high alpha-fetoprotein and modest elevation of serum bile acid levels may suggest FXR deficiency. Some patients with FXR deficiency may not develop allograft steatosis and may respond well to liver transplantation.\n\nNeonatal cholestasis\nProgressive familial intrahepatic cholestasis\nBile salt export pump\nLiver transplantation\nAlpha-fetoprotein\nCase report\n==== Body\nCore Tip: Despite the central role farnesoid X receptor (FXR) plays in bile acid metabolism, only a few children with cholestasis and biallelic FXR deficiency have been reported, and that only recently. Using banked DNA from patients without previous successful genetic diagnosis, we have identified a child with a homozygous mutation predicted to truncate FXR prematurely. We describe his disease course before and after liver transplantation, accompanied by immunohistochemical studies. This report adds meaningfully to the available information regarding disease course and outcomes in patients with severe FXR deficiency. It highlights biochemical findings that may be characteristic of FXR deficiency.\n\nINTRODUCTION\n\nA key function of the farnesoid X receptor (FXR) is maintenance of physiologic bile acid (BA) pool size. FXR activation by BA within terminal-ileum enterocytes triggers production of fibroblast growth factor 19, which in turn suppresses hepatocellular synthesis of BA. In addition, FXR protects against intrahepatocytic BA accumulation by increasing bile salt export pump (BSEP) expression and by suppressing both uptake of BA from plasma via Na+-taurocholate cotransporting polypeptide and synthesis of BA via sterol-27 hydroxylase[1].\n\nNR1H4 encodes FXR. Biallelic mutation in NR1H4 is a rare cause of intrahepatic cholestasis. Eight such children have been reported, three of whom underwent liver transplantation (LT)[2-4]. We describe a patient with FXR deficiency, due to biallelic mutation in NR1H4, who presented with neonatal cholestasis that progressed to end-stage liver disease successfully treated by LT.\n\nCASE PRESENTATION\n\nChief complaints\n\nNeonate presented with rapidly progressing cholestatic jaundice.\n\nHistory of present illness\n\nJaundice was observed from the second postnatal day. Phototherapy was given. At age 5 wk, deepening jaundice and pale stools were noted. He was hospitalized at age 6 wk and transferred to Children’s Memorial Health Institute at age 7 wk.\n\nHistory of past illness\n\nThe patient had an otherwise unremarkable medical history.\n\nPersonal and family history\n\nA boy was born at term, weighing 4.1 kg (93rd percentile), to parents without known consanguinity. Pregnancy and spontaneous vaginal delivery were uncomplicated. A brother aged 5 years was healthy; however, two maternal uncles had died as neonates for unknown reasons.\n\nPhysical examination\n\nAt transfer, he was jaundiced but otherwise well [5.8 kg (77th percentile)]. Motor development was normal. Stools varied from pale to bright yellow. The liver and spleen were palpable, respectively 3 cm and 2 cm below the costal margin. A left iridial coloboma and a right inguinal hernia were found.\n\nLaboratory examinations\n\nConjugated hyperbilirubinemia accompanied elevated serum transaminase activity (Table 1). Serum BA and alpha-fetoprotein (AFP) levels were elevated. Serum gamma-glutamyl transpeptidase activity was normal. Hypocoagulability did not respond to vitamin K. Persistent hypoglycemia required intravenous glucose. Investigation for metabolic disorders yielded no diagnosis.\n\nTable 1 Summary of laboratory data\n\nSerum analyte\tReference range\tAge 7 wk (presentation)\tAge 22 wk (before liver transplantation)\t\nHematocrit (%)\t33.0-39.0\t29.2\t29.6\t\nHemoglobin (g/dL)\t10.5-13.5\t10.1\t10.1\t\nWhite-cell count (per mm3)\t6.0-17.5\t9.1\t11.4\t\nPlatelet count (per mm3)\t150-400\t184\t154\t\nTotal bilirubin (mg/dL)\t0.0-1.0\t9.4\t23.8\t\nDirect bilirubin (mg/dL)\t0.0-0.4\t7.3\t14.0\t\nALT (U/L)\t10-55\t170\t224\t\nAST (U/L)\t10-55\t260\t456\t\nGGT (U/L)\t10-80\t35\t41\t\nAlkaline phosphatase (U/L)\t15-350\t331\t356\t\nBile acids (mol/L)\t0-11\t69\t157\t\nCholesterol (mg/dL)\t80-170\t228\t220\t\nTriglycerides (mg/dL)\t50-150\t136\t137\t\nCreatine kinase (U/L)\t60-400\t30\t\t\nActivated partial-thromboplastin time (s)\t21-33\t49\t59\t\nProthrombin time (s)\t10-13\t17\t20\t\nInternational normalized ratio\t< 1.2\t1.50\t2.03\t\nD-dimer\t< 500\t138\t274\t\nFibrinogen\t150-400\t200\t174\t\nFactor V (%)\t70-140\t70.4\t-\t\nFactor VII (%)\t70-120\t36.9\t-\t\nAmmonia (g/dL)\t12-48\t178\t243\t\nGlucose (mg%)\t70-110\t55\t30\t\nCreatinine (mg/dL)\t0.3-1.0\t0.2\t0.2\t\nProtein (g/L)\t60-83\t45\t55\t\nAlbumin (g/L)\t33-50\t25\t34\t\nGlobulin (g/L)\t26-41\t7\t14\t\nImmunoglobulin G (mg/dL)\t231-1411\t713\t-\t\nImmunoglobulin A (mg/dL)\t0-83\t21\t-\t\nImmunoglobulin M (mg/dL)\t0-145\t79\t-\t\n1Alpha-fetoprotein (IU/mL)\t\t358000\t230000\t\nVitamin A (ng/mL)\t200-800\t165\t-\t\nVitamin E (g/mL)\t3.8-16.0\t8.4\t-\t\n25OHD3 (ng/mL)\t11-54\t26\t-\t\n1 Alpha-fetoprotein normal values according to age: Premature 95000-175000; term newborn 13000-83000; 2 wk-1 mo 20-19000; 3 mo 10-180; 8 mo 0-10.\n\nALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase.\n\nImaging examinations\n\nA normal gallbladder and non-dilated bile ducts were visible on sonography; the left lobe of the liver was enlarged. Splenomegaly was confirmed. After 3 d of phenobarbital, hepatobiliary scintigraphy found decreased and patchy isotope uptake by the liver and substantially decreased, but detectable, excretion into the bowel. A type 2 atrial septal defect (assessed as clinically unimportant) and a butterfly vertebra were noted.\n\nFurther diagnostic work-up\n\nPercutaneous liver-biopsy (age 9 wk) found moderate fibrosis, mild inflammation and ductular proliferation; immunostaining for BSEP was unavailable. At age 12 wk, open cholangiography was performed and found a normal biliary tree; wedge liver biopsy revealed changes like those seen previously.\n\nFINAL DIAGNOSIS\n\nArchived patient DNA underwent sequencing of a panel of cholestasis-associated genes (ATP8B1, ABCB11, ABCB4, TJP2, JAG1, NOTCH2, BAAT) with no diagnostic variants found. These results were confirmed when patient DNA then underwent whole-exome sequencing. However, homozygosity was found for c.547C > T, p.(Arg183Ter), a nonsense mutation in NR1H4. Sanger sequencing confirmed homozygosity for this variant in the patient and heterozygosity in each parent. Immunostaining revealed absence of BSEP (Figure 1B) and of nuclear marking for FXR (Figure 1C). Gamma-glutamyl transpeptidase expression was present but very abnormal (Figure 1D).\n\nFigure 1 Histopathologic findings, explanted liver and controls. A: Fibrosis and nodularity with steatosis and substantial lobular disarray, explanted liver. Pronounced cholestasis spares portal tracts. Hematoxylin & eosin; main image 100 ×, inset 200 × original magnifications; B: Bile salt export pump expression in normal liver (“control”) and explanted liver. No expression in explanted liver (main image); the pigment seen is bile. Control (inset), crisp expression along an unremarkable bile-canaliculus network. Anti-bile salt export pump antibody (Santa Cruz Biotechnology, Dallas, TX, United States; sc-74500)/hematoxylin; both main image and inset 200 × original magnifications; C: Farnesoid X receptor expression in normal liver (“control”) and explanted liver. No expression in explanted liver (main image); the pigment seen is bile. Control (inset), nuclear expression evident in most hepatocytes. Anti-farnesoid X receptor antibody (Santa Cruz Biotechnology; sc-25309)/hematoxylin; both main image and inset 400 × original magnifications; D: Gamma-glutamyl transpeptidase expression in normal liver (“control”) and explanted liver. Control (main image), crisp expression at apices of cholangiocytes (arrow) and along an unremarkable bile-canaliculus network, with faint perisinusoidal staining. Explanted liver (inset), blurred marking at severely distorted canalicular network with pronounced cytoplasmic and basolateral staining, abnormalities that reflect the extent of hepatocellular injury and disarray. Anti-gamma-glutamyl transpeptidase 1 (Abnova, Taipei, Taiwan; H00002678-M01)/hematoxylin; both main image and inset 200 × original magnifications.\n\nTREATMENT\n\nVitamin supplementation and ursodeoxycholic acid (20 mg/kg per d) were initiated. Icterus and hypercholanemia worsened and the patient required repeated intravenous vitamin K. At age 8 mo [8.4 kg (40th percentile)], uncontrollable coagulopathy prompted maternal-donor LT, with splenectomy due to substantial splenomegaly. Histopathologic evaluation revealed marked hepatocellular and canalicular cholestasis with steatosis and micronodular cirrhosis (Figure 1A). Dysplasia and malignancy were not found.\n\nOUTCOME AND FOLLOW-UP\n\nThere were no surgical issues after LT. Immunosuppression included tacrolimus and corticosteroids, with trimethoprim/sulfamethoxazole prophylaxis. Vaccination against meningococcus infection was unavailable. His course after LT was unremarkable for 12 mo, apart from transaminitis (cytomegalovirus infection, resolved with ganciclovir). His weight recovered [75th percentile (age 19 mo) 11 mo after LT]. At age 20 mo, vomiting and fever required hospital admission elsewhere. He was assessed as in good condition, but within 12 h he died with disseminated intravascular coagulation and multiorgan failure. No micro-organisms were cultured. Necropsy found hemorrhagic adrenal necrosis. The liver was unremarkable. The heart contained a few foci of remote intramyocardial arterial thrombosis, with dystrophic mineralization.\n\nDISCUSSION\n\nThe fundamental role of FXR in BA homeostasis is consistent with the severity of liver disease associated with its absence. Our patient had substantially impaired liver function from presentation at Children’s Memorial Health Institute onward (hypoglycemia; coagulopathy unresponsive to parenteral vitamin K). These disease manifestations overlap with those in the children in whom FXR deficiency was first reported[2]. Coagulopathy is common in cholestasis. Initially, however, it usually responds to vitamin K. In FXR deficiency, vitamin K does not correct the clotting, which seems disproportionate to the severity of liver disease. This may reflect direct involvement of FXR in regulating-clotting factor production[5]. Serum BA elevations in our patient and in one previously described FXR-deficient patient for whom serum BA were reported[2] were modest compared with those in patients with similarly severe cholestasis and BSEP deficiency. This difference may reflect failure of FXR-mediated down-regulation of Na+-taurocholate cotransporting polypeptide in FXR deficiency, with consequent unabated hepatocellular uptake of BA[6].\n\nHigh AFP levels are found in hepatocellular carcinoma and, during early infancy, in severe early-onset cholestasis. As seen in our patient and others, persistently elevated AFP values in the absence of hepatocellular carcinoma may be a feature of NR1H4 disease[2-4]. This may complicate monitoring for hepatocellular carcinoma development.\n\nTwo siblings who underwent LT for FXR deficiency developed mild allograft steatosis, ascribed provisionally to disrupted ileal control of enterohepatic BA homeostasis[2]. The third transplanted patient had stable graft function, and no steatosis in post-transplant liver biopsies in the first 2 years. Our patient had no allograft steatosis, good graft function and no evidence of gastrointestinal disease. These observations suggest heterogeneity in compensation for extrahepatic FXR deficiency. We consider our patient’s death (sepsis, adrenal haemorrhage; predisposed by immunosuppression and lack of spleen) to be independent of NR1H4 mutation.\n\nCONCLUSION\n\nFXR deficiency due to NR1H4 mutation is a rare cause of neonatal cholestasis. Severe cholestasis with persistently high AFP and modestly elevated serum BA levels may suggest FXR deficiency.\n\nInformed consent statement: Parental consent was obtained for hospitalizations and all the procedures described in the manuscript.\n\nConflict-of-interest statement: Dr. Thompson consults for Albireo, Mirum, GenerationBio, Alnylam, Qing Bile, Horizon, Sana, and Retrophin and has share options in Qing Bile and GenerationBio. Other authors report no conflicts 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\nCorresponding Author's Membership in Professional Societies: Polish Society of Gastroenterology.\n\nPeer-review started: October 17, 2020\n\nFirst decision: November 3, 2020\n\nArticle in press: February 24, 2021\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: Poland\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C, C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Mrzljak A S-Editor: Gao CC L-Editor: Filipodia P-Editor: Li JH\n==== Refs\n1 Claudel T Sturm E Kuipers F Staels B The farnesoid X receptor: a novel drug target? Expert Opin Investig Drugs 2004 13 1135 1148\n2 Gomez-Ospina N Potter CJ Xiao R Manickam K Kim MS Kim KH Shneider BL Picarsic JL Jacobson TA Zhang J He W Liu P Knisely AS Finegold MJ Muzny DM Boerwinkle E Lupski JR Plon SE Gibbs RA Eng CM Yang Y Washington GC Porteus MH Berquist WE Kambham N Singh RJ Xia F Enns GM Moore DD Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis Nat Commun 2016 7 10713 26888176\n3 Chen HL Li HY Wu JF Wu SH Chen HL Yang YH Hsu YH Liou BY Chang MH Ni YH Panel-Based Next-Generation Sequencing for the Diagnosis of Cholestatic Genetic Liver Diseases: Clinical Utility and Challenges. J Pediatr 2019; 205: 153-159 e6\n4 Himes RW Mojarrad M Eslahi A Finegold MJ Maroofian R Moore DD NR1H4-related Progressive Familial Intrahepatic Cholestasis 5: Further Evidence for Rapidly Progressive Liver Failure J Pediatr Gastroenterol Nutr 2020 70 e111 e113 32443034\n5 Zhao A Lew JL Huang L Yu J Zhang T Hrywna Y Thompson JR de Pedro N Blevins RA Peláez F Wright SD Cui J Human kininogen gene is transactivated by the farnesoid X receptor J Biol Chem 2003 278 28765 28770 12761213\n6 Denson LA Sturm E Echevarria W Zimmerman TL Makishima M Mangelsdorf DJ Karpen SJ The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp Gastroenterology 2001 121 140 147 11438503\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "9(15)",
"journal": "World journal of clinical cases",
"keywords": "Alpha-fetoprotein; Bile salt export pump; Case report; Liver transplantation; Neonatal cholestasis; Progressive familial intrahepatic cholestasis",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "3631-3636",
"pmc": null,
"pmid": "34046462",
"pubdate": "2021-05-26",
"publication_types": "D002363:Case Reports",
"references": "26888176;12761213;11438503;15330745;32443034;30366773",
"title": "Progressive familial intrahepatic cholestasis - farnesoid X receptor deficiency due to NR1H4 mutation: A case report.",
"title_normalized": "progressive familial intrahepatic cholestasis farnesoid x receptor deficiency due to nr1h4 mutation a case report"
} | [
{
"companynumb": "PL-NOVARTISPH-NVSC2022PL099433",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "4",
... |
{
"abstract": "Autoimmune adverse events are the most relevant risks of alemtuzumab therapy. We present a patient with relapsing-remitting multiple sclerosis, who developed adult-onset Still's disease (AOSD) following alemtuzumab treatment.\n\n\n\nThe patient suffered from sore throat, swallowing difficulties, high spiking quotidian fever, generalized skin rash, arthritis, and myalgia 2 months after the second course of alemtuzumab. Laboratory tests revealed elevated acute-phase reactants, anemia, neutrophilic leukocytosis, and thrombocytosis. Serum calprotectin, interleukin-2, and interleukin-6 levels were strongly increased. Autoimmune, rheumatic, neoplastic, infectious, and granulomatous disorders were excluded. The NLRP1 and NLRP3 gene test, which was performed under the presumption of a cryopyrin-associated autoinflammatory syndrome, was negative. Based on the Yamaguchi and Fautrel criteria, and supported by the histological findings from a skin biopsy of the rash, the diagnosis of AOSD was established. Therapy with the anti-IL-1 agent (anakinra) led to a significant improvement of symptoms and blood parameters. However, anakinra had to be converted to rituximab due to generalized drug eruption. Following therapy with rituximab, the patient has fully recovered.\n\n\n\nThe current case highlights AOSD as another rare and potentially life-threatening secondary autoinflammatory/autoimmune event following alemtuzumab treatment.",
"affiliations": "Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.;Department of Dermatology, Venerology, Allergology, and Phlebology, Johannes-Wesling-Hospital Minden, University Hospital Ruhr University of Bochum, Minden, Germany.;Department of Rheumatology and Physical Medicine, Johannes-Wesling-Hospital Minden, University Hospital Ruhr University of Bochum, Minden, Germany.;Department of Neurology and Neurogeriatrics, Johannes-Wesling-Hospital Minden, University Hospital Ruhr University of Bochum, Minden, Germany.;Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany.;Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany.;Department of Neurology and Neurogeriatrics, Johannes-Wesling-Hospital Minden, University Hospital Ruhr University of Bochum, Minden, Germany.",
"authors": "Krämer|Julia|J|;Krömer-Olbrisch|Tanja|T|;Lakomek|Heinz-Jürgen|HJ|;Schellinger|Peter D|PD|;Foell|Dirk|D|;Meuth|Sven G|SG|;Straeten|Vera|V|",
"chemical_list": "D000074323:Alemtuzumab",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2020.02099",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224 Frontiers Media S.A. \n\n10.3389/fimmu.2020.02099\nImmunology\nCase Report\nCase Report: Adult Still’s Disease in an Alemtuzumab-Treated Multiple Sclerosis Patient\nKrämer Julia 1* Krömer-Olbrisch Tanja 2 Lakomek Heinz-Jürgen 3 Schellinger Peter D. 4 Foell Dirk 5 Meuth Sven G. 1† Straeten Vera 4† 1Department of Neurology with Institute of Translational Neurology, University Hospital Münster, Münster, Germany\n2Department of Dermatology, Venerology, Allergology, and Phlebology, Johannes-Wesling-Hospital Minden, University Hospital Ruhr University of Bochum, Minden, Germany\n3Department of Rheumatology and Physical Medicine, Johannes-Wesling-Hospital Minden, University Hospital Ruhr University of Bochum, Minden, Germany\n4Department of Neurology and Neurogeriatrics, Johannes-Wesling-Hospital Minden, University Hospital Ruhr University of Bochum, Minden, Germany\n5Department of Pediatric Rheumatology and Immunology, University Hospital Münster, Münster, Germany\nEdited by: Philipp Albrecht, Heinrich Heine University, Germany\n\nReviewed by: Jörg Kraus, Paracelsus Medical University, Austria; Bonaventura Casanova, La Fe Hospital, Spain\n\n*Correspondence: Julia Krämer, julia.kraemer@ukmuenster.de†These authors have contributed equally to this work\n\nThis article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Immunology\n\n\n28 8 2020 \n2020 \n11 209914 6 2020 03 8 2020 Copyright © 2020 Krämer, Krömer-Olbrisch, Lakomek, Schellinger, Foell, Meuth and Straeten.2020Krämer, Krömer-Olbrisch, Lakomek, Schellinger, Foell, Meuth and StraetenThis 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\nAutoimmune adverse events are the most relevant risks of alemtuzumab therapy. We present a patient with relapsing-remitting multiple sclerosis, who developed adult-onset Still’s disease (AOSD) following alemtuzumab treatment.\n\nCase Presentation\nThe patient suffered from sore throat, swallowing difficulties, high spiking quotidian fever, generalized skin rash, arthritis, and myalgia 2 months after the second course of alemtuzumab. Laboratory tests revealed elevated acute-phase reactants, anemia, neutrophilic leukocytosis, and thrombocytosis. Serum calprotectin, interleukin-2, and interleukin-6 levels were strongly increased. Autoimmune, rheumatic, neoplastic, infectious, and granulomatous disorders were excluded. The NLRP1 and NLRP3 gene test, which was performed under the presumption of a cryopyrin-associated autoinflammatory syndrome, was negative. Based on the Yamaguchi and Fautrel criteria, and supported by the histological findings from a skin biopsy of the rash, the diagnosis of AOSD was established. Therapy with the anti-IL-1 agent (anakinra) led to a significant improvement of symptoms and blood parameters. However, anakinra had to be converted to rituximab due to generalized drug eruption. Following therapy with rituximab, the patient has fully recovered.\n\nConclusion\nThe current case highlights AOSD as another rare and potentially life-threatening secondary autoinflammatory/autoimmune event following alemtuzumab treatment.\n\nmultiple sclerosisAdult onset still diseasesecondary autoimmunityalemtuzumabrituximabanakinracase report\n==== Body\nIntroduction\nThe use of alemtuzumab as therapy for active relapsing-remitting multiple sclerosis was recently restricted due to safety concerns. The potential development of secondary autoimmunity represents the most relevant risk of this therapy (1). In the last 2 years, previously unknown autoimmune phenomena, such as sarcoidosis, vitiligo, autoimmune hepatitis, hemophagocytic lymphohistiocytosis, and idiopathic multicentric Castleman’s disease were described in real-world cohorts (2–4). Here, we present for the first time a case of adult-onset Still’s disease (AOSD) following alemtuzumab treatment.\n\nAOSD\nAdult-onset Still’s disease is a rare, multigenic, clinically highly variable, multi-systemic inflammatory disease of unknown etiology, and pathogenesis usually affecting young adults. It is typically characterized by high spiking fever, arthralgia or arthritis, and transient maculopapular salmon-pink evanescent skin rash. Other manifestations are sore throat or pharyngitis, dynophagia, myalgia or myositis, generalized lymphadenopathy, hepatosplenomegaly, serositis, and cardiopulmonary or kidney involvement (5, 6). Common laboratory abnormalities include neutrophilic leukocytosis, elevated acute-phase reactants, inflammatory anemia, and thrombocytosis accompanied by liver abnormalities. The diagnosis is primarily clinical, necessitates the exclusion of a wide range of mimicking disorders, and still lacks specific diagnostic testing (5, 6). Different diagnostic criteria have been proposed for AOSD diagnosis (Supplementary Table S1). Therapy remains essentially empirical comprising traditionally non-steroidal anti-inflammatory drugs, corticosteroids, and immunosuppressants. Recently biological therapies such as tumor necrosis factor-α inhibitors, and IL-1, -18, and -6 antagonists (5, 6) were introduced as potential therapies for AOSD patients.\n\nCase Report\nPatient Information\nA 26-year-old, previously completely healthy, female Caucasian was first diagnosed with relapsing-remitting multiple sclerosis in August 2016. Family history of neurological and autoimmune diseases was negative. Due to high clinical disease activity (three relapses in 2016), she received two courses of alemtuzumab (10/2016 and 10/2017) as first-line therapy. Urticaria after the first course of alemtuzumab had to be treated with antihistamines. In February 2017, the patient suffered from varicella-zoster virus-induced left ophthalmic zoster (Figure 1A), which was treated with intravenous aciclovir. She developed pronounced postherpetic neuralgia, which was treated with pregabalin, opiods, and amitriptyline. The patient also developed Hashimoto’s disease 11 months after alemtuzumab initiation. Disease activity stabilized clinically over time, but cranial magnetic resonance imaging from April and October 2017 showed three new, non-enhancing T2 hyperintense lesions in the left operculum and periventricular (Figure 1B). 2 months after the second course of alemtuzumab, the patient presented to her local ear, nose, and throat (ENT) clinic with a sore throat and swallowing difficulties.\n\nFIGURE 1 Diagnostic work-up and treatment regimes in an alemtuzumab-treated patient with relapsing-remitting multiple sclerosis developing AOSD. (A) Varicella-zoster virus-induced left ophthalmic zoster. (B) Sagittal fluid-attenuated inversion recovery of the brain demonstrating multiple non-enhancing T2 hyperintense lesions. One new, non-enhancing lesion is indicated by an arrow. (C) Evanescent maculopapular, salmon-pink skin rash on the right arm. Charts show the course of white blood cell counts and neutrophils (D), CRP (E), platelets (F), ferritin (G), and amyloid (H). Time points and length of different treatment regimens are outlined : single administration of IVMPS; : three doses of IVMPS on three consecutive days; : three doses of intravenous immunoglobulins on three consecutive days; arrows indicate the duration of therapies with anakinra (A) and rituximab (R). (I) FDG-PET/CT showing significant hypermetabolism in bone marrow and spleen. Hematoxylin and eosin staining of skin biopsy displaying periadnexal and perivascular infiltrates of inflammatory cells, surrounding superficial blood vessels, hair follicles, and the interstitium (in between the vessels and adnexal structures). Original magnification at 200 μm (J). Hematoxylin and eosin stain showing perivascular inflammatory infiltration of lymphocytes, neutrophils, and eosinophils. Original magnification at 50 μm (K). Generalized drug eruption on the back, chest area, arms, and legs due to therapy with anakinra (L).\n\nClinical Findings\nThe patient further suffered from high spiking quotidian fever of up to 40 degrees occurring in the evenings, and a generalized itching, evanescent maculopapular, salmon-pink skin rash (Figure 1C) that accompanied the fever. Pharyngitis was diagnosed and treated with antibiotics. Under single dose of intravenous methylprednisolone (IVMPS, Figures 1D,E) and antihistamines, the rash improved only temporarily. However, the patient developed arthritis and myalgia. She was referred to her local clinic of neurology, rheumatology, and dermatology.\n\nDiagnostic Assessment\nRepeated dermatological examinations (radioallergosorbent test and total IgE) were not indicative. She developed anemia, neutrophilic leukocytosis, and thrombocytosis, and showed elevated acute-phase reactants (Figures 1D–F) including amyloid, interleukin-2 (1654 U/ml; reference value < 623 U/ml), and interleukin-6 levels (61.8 pg/ml; reference value < 7 pg/ml). Autoimmune, rheumatic, neoplastic, infectious, and granulomatous disorders were excluded as possible causes by repeated serological testing, blood and urine cultures, and imaging tests (chest x-ray, abdomen sonography, and transesophageal echocardiography). The NLRP1 and NLRP3 gene test, which was performed under the presumption of a cryopyrin-associated autoinflammatory syndrome, was negative.\n\nTreatment and Outcome\nFollowing a probatory IVMPS therapy (three doses; Figures 1D,E) and subsequent oral prednisolone with slow dose tapering, symptoms improved, and inflammatory blood parameters decreased. When trying to reduce oral prednisolone, the symptoms came back, and inflammatory blood parameters and platelets immediately increased (Figures 1D–G). Serum calprotectin (157100 ng/ml; reference value < 2940 ng/ml) (7) and interleukin-2 levels (2129 U/ml; reference value < 623 U/ml) were strongly increased.\n\nBased on the Yamaguchi and Fautrel criteria, and supported by the histological findings from a skin biopsy of the rash (Figures 1J,K) the diagnosis of AOSD was established (8, 9).\n\nTherapy with the anti-IL-1 agent (anakinra), initiated in April 2018, led to a significant improvement of symptoms and blood parameters (Figures 1D–H). Besides anakinra, the patient was treated with oral prednisolone. However, anakinra had to be discontinued after 4 weeks due to generalized itching and follicular drug eruption (Figure 1L). Treatment was symptomatic, consisting of anti-H1 antihistamines. Whole-body 18F-FDG-PET/CT demonstrated significant hypermetabolism in bone marrow and spleen (Figure 1I).\n\nTherapy termination led to a massive deterioration of symptoms and anemia, and an increase of acute-phase reactants, leukocytes, neutrophils, ferritin and amyloid (Figures 1D–H). Repeated IVMPS and oral prednisolone with slow dose tapering, intravenous immunoglobulins (Figures 1D–H,), and initiation of rituximab therapy (Figures 1D–H) induced ongoing remission. The patient fully recovered and continues to receive a small dose of oral prednisolone and, every 6 months, rituximab. Therapy with hydroxychloroquine sulfate had to be discontinued due to hair loss. This adverse event disappeared immediately after termination of therapy. The patient is regularly examined at her neurological and rheumatological clinic. Serological testing is performed regularly. Since January 2019, the patient is working works fulltime again. However, 24 months after the second course of alemtuzumab, she developed a steroid-induced cataract of the left eye, which required an surgical intervention.\n\nDiscussion\nA strict risk management strategy and several tools implemented in real-world clinical settings, were developed for early detection and management of autoimmune events in patients treated with alemtuzumab (10). However, a variety of new rare autoimmune entities have been described in the past 2 years (2–4). The current case highlights AOSD as another rare and potentially life-threatening secondary autoinflammatory/autoimmune event following alemtuzumab treatment. The European Medicines Agency (EMA) has recently restricted the use of alemtuzumab as therapy for active relapsing-remitting MS due to reports of rare but serious and partially fatal side effects. Alemtuzumab should only be started in adults with relapsing-remitting MS that is highly active despite treatment with at least one disease-modifying therapy or if the disease is rapidly worsening (11). These safety issues, in the context of the increasing number of highly effective alternative disease-modifying therapies, makes alemtuzumab a less likely early treatment option to consider (12).\n\nEven if the pathogenesis of the disease has not been elucidated in its entirety, activation of macrophages and neutrophils and subsequent proinflammatory cytokine storms triggered by activated immune cells play a pivotal role (6, 13). In terms of genetic susceptibility, several human leukocyte antigens (HLAs) have been reported to be associated with AOSD including HLA-Bw35, -DRw6, HLA-DR4, HLA-B17, HLA-B18, HLA-B35, and HLA-DRB1 (6, 13). Interestingly, our patient expressed the HLA-DRB1 allele that both increase the risk for MS and AOSD (6, 13). Moreover, the current case demonstrates a compatible response of AOSD to two different biological therapies: first, the anti-IL-1 agent anakinra (used for treating inflammatory diseases) and second, the monoclonal anti-CD20 antibody rituximab (used for treating autoimmune diseases). While anakinra is the standard therapy for AOSD, particularly in prednisone-refractory disease courses, rituximab was shown to be effective in treating AOSD, and also juvenile idiopathic arthritis, in numerous case studies (14, 15). This applies especially to patients in whom a strong activation of the adaptive immune system is essential for disease progress.\n\nWe consider the cutaneous adverse reaction after therapy with anakinra (Figure 1L) rather as generalized drug eruption than as drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. DRESS syndrome is a rare, severe multiorgan and potentially fatal systemic hypersensitivity reaction mostly caused by a limited number of eliciting drugs, especially anti-convulsants and antibiotics (16–20). A DRESS syndrome was also described in a child following treatment with anakinra (20). In our case several facts speak against a DRESS syndrome: after initiation of anakinra our patient did not suffer from systemic symptoms (fever, rigors, and hypotension), lymphadenopathy, facial swelling or hematological abnormalities such as atypical lymphocytosis, thrombocytopenia, agranulocytosis, or eosinophilia. Involvement of visceral organs was excluded by whole-body 18F-FDG-PET/CT (Figure 1I). Infectious disorders (HHV-6, HHV-7, CMV, EBV, and VZV) were formally excluded as further possible causes.\n\nAlthough an early and accurate diagnosis may lead to better outcomes, diagnosing AOSD is often difficult and typically delayed – as in our case – due to the presence of several non-specific symptoms and the absence of characteristic serological biomarkers. Thus, it took 4 months to establish the diagnosis of AOSD and initiate a suitable therapy with the anti-IL-1 blocker (anakinra).\n\nThe current case highlights AOSD as another potentially life-threatening secondary autoinflammatory/autoimmune event following alemtuzumab treatment. Thorough clinical follow-up and early intense interdisciplinary communication and intervention are necessary in suspicious cases after treatment with alemtuzumab.\n\nPatient Perspective\nWhile treatment with corticosteroids caused only a short-term improvement, initiation of rituximab therapy induced long-lasting remission. Now, i am feeling fine again, but these 4 months were the worst experiences of my life. I do not want anyone to go through what I had to. In the end I hope that physicians all over the world have learned something from reading my case.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nWritten informed consent to publish the present case details (clinical, histopathological, and imaging data and laboratory findings) was obtained from the patient. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nJK, SM, and VS conceived the study and defined the concept. JK, TK-O, H-JL, PS, DF, SM, and VS collected and interpreted the data. JK wrote the initial draft of the manuscript. TK-O prepared the histopathological images. JK, TK-O, H-JL, PS, DF, SM, and VS critically discussed the data, revised the manuscript for intellectual content, and approved the version to be published. All authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nConflict of Interest\nJK received honoraria for lecturing from Biogen, Novartis, Genzyme, Merck, Mylan, and Teva, and financial research support from Sanofi Genzyme and Novartis. TK-O, H-JL, and PS declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. DF received honoraria for lecturing and travel expenses for attending meetings from Chugai-Roche, Novartis, and SOBI, and financial research support from Novartis, Pfizer, and SOBI. SM received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Münster, German Foundation Neurology, and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. VS received honoraria for serving on Scientific Advisory Boards, lecturing and travel expenses for attending meetings from Novartis, Biogen, Merck Serono, Sanofi Genzyme, Roche, and Teva.\n\nFunding. This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nWe thank Zoe Hunter of the Department of Neurology with Institute of Translational Neurology, University Hospital Münster, for proofreading the manuscript.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fimmu.2020.02099/full#supplementary-material\n\nClick here for additional data file.\n\n Abbreviations\nAOSDadult-onset Still’s disease\n\nDRESSdrug rash with eosinophilia and systemic symptoms\n\nEMAEuropean Medicines Agency\n\nENTear, nose, and throat\n\nHLAhuman leukocyte antigen\n\nIVMPSintravenous methylprednisolone.\n==== Refs\nReferences\n1. Coles AJ Cohen JA Fox EJ Giovannoni G Hartung HP Havrdova E \nAlemtuzumab CARE-MS II 5-year follow-up: efficacy and safety findings.\n\nNeurology. (2017 ) 89 :1117 –26\n. 10.1212/WNL.0000000000004354 \n28835403 \n2. Pfeuffer S. \nSarcoidosis following alemtuzumab treatment: autoimmunity mediated by T cells and interferon-gamma.\n\nMult Scler. (2018 ) 24 :1783 –4\n. 10.1177/1352458518804124 \n30307361 \n3. Saarela M Senthil K Jones J Tienari PJ Soilu-Hänninen M Airaset L \nHemophagocytic lymphohistiocytosis in 2 patients with multiple sclerosis treated with alemtuzumab.\n\nNeurology. (2018 ) 90 :849 –51\n. 10.1212/WNL.0000000000005420 \n29602914 \n4. Rolfes L Pfeuffer S Ruck T Windhagen S Oschlies I Pavenstädt HJ \nA case of idiopathic multicentric Castleman disease in an alemtuzumab-treated patient with MS.\n\nNeurol Neuroimmunol Neuroinflamm. (2019 ) 7 :e657 . 10.1212/NXI.0000000000000657 \n31806686 \n5. Giacomelli R Ruscitti P Shoenfeld Y. \nA comprehensive review on adult onset Still’s disease.\n\nJ Autoimmun. (2018 ) 93 :24 –36\n. 10.1016/j.jaut.2018.07.018 \n30077425 \n6. Li S Zheng S Tang S Pan Y Zhang S Fanget H \nAutoinflammatory pathogenesis and targeted therapy for adult-onset still’s disease.\n\nClin Rev Allergy Immunol. (2019 ) 58 :71 –81\n. 10.1007/s12016-019-08747-8 \n31147820 \n7. Qian G Xicao Z Chun L Jia Y Zhu L Guo J \nSerum calprotectin—a promising diagnostic marker for adult-onset Still’s disease.\n\nClin Rheumatol. (2016 ) 35 :73 –9\n. 10.1007/s10067-015-3108-6 \n26547221 \n8. Yamagushi M Ohta A Tsunematsu T Kasukawa R Mizushima Y Kashiwagi H \nPreliminary criteria for classification of adult Still’s disease.\n\nJ Rheumatol. (1992 ) 19 :424 –30\n.1578458 \n9. Fautrel B Zing E Golmard JL Le Moel G Bissery A Rioux C \nProposal for a new set of classification criteria for adult-onset still disease.\n\nMedicine (Baltimore). (2002 ) 81 :194 –200\n. 10.1097/00005792-200205000-00003 \n11997716 \n10. Barclay K Carruthers R Traboulsee A Bass AD LaGanke C Bertolotto A \nBest practices for long-term monitoring and follow-up of alemtuzumab-treated ms patients in real-world clinical settings.\n\nFront Neurol. (2019 ) 10 :253 . 10.3389/fneur.2019.00253 \n30967831 \n11. EMA. \nMeasures to Minimise Risk of Serious Side Effects of Multiple Sclerosis Medicine Lemtrada. (2019). Available online at: https://www.ema.europa.eu/en/documents/press-release/measures-minimise-risk-serious-side-effects-multiple-sclerosis-medicine-lemtrada_en.pdf (accessed July 24, 2020).\n12. Killestein J van Oosten B. \nEmerging safety issues in alemtuzumab- treated MS patients.\n\nMult Scler. (2019 ) 25 :1206 –8\n. 10.1177/1352458519851219 \n31368417 \n13. Jung JY Suh CH Kim HA. \nThe role of damage-associated molecular pattern for pathogenesis and biomarkers in adult-onset Still’s disease.\n\nExpert Rev Mol Diagn. (2019 ) 19 :459 –68\n. 10.1080/14737159.2019.1615449 \n31055973 \n14. Kaegi C Wuest B Schreiner J Steiner UC Vultaggio A Matucci A \nSystematic review of safety and efficacy of rituximab in treating immune-mediated disorders.\n\nFront Immunol. (2019 ) 10 :1990 . 10.3389/fimmu.2019.01990 \n31555262 \n15. Kearsley-Fleet L Sampath S McCann LJ Baildam E Beresford MW Davieset R \nUse and effectiveness of rituximab in children and young people with juvenile idiopathic arthritis in a cohort study in the United Kingdom.\n\nRheumatology. (2019 ) 58 :331 –5\n. 10.1093/rheumatology/key306 \n30358861 \n16. Behera SK Das S Xavier AS Selvarajan S. \nDRESS syndrome: a detailed insight.\n\nHosp Pract. (2018 ) 46 :152 –62\n. 10.1080/21548331.2018.1451205 \n29519170 \n17. Pichler WJ Wendland T Hausmann O Schnyder B Fricker M Pichler C \nDRESS (Drug Rash with Eosinophilia and Systemic Symptoms) – Eine schwere, oft verkannte Medikamentenallergie.\n\nSchweiz Med Forum. (2011 ) 11 :879 –84\n. 10.4414/fms.2011.07693 \n31760237 \n18. Cho YT Yang CW Chu CY. \nDrug reaction with eosinophilia and systemic symptoms (DRESS): an interplay among drugs, viruses, and immune system.\n\nInt J Mol Sci. (2017 ) 18 :1243 . 10.3390/ijms18061243 \n28598363 \n19. Shiohara T Mizukawa J. \nDrug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS): an update in 2019.\n\nAllergol Int. (2019 ) 68 :301 –8\n. 10.1016/j.alit.2019.03.006 \n31000444 \n20. Mori F Caffarelli C Caimmi S Bottau P Liotti L Franceschini F \nDrug reaction with eosinophilia and systemic symptoms (DRESS) in children.\n\nActa Biomed. (2019 ) 90 :66 –79\n.30830064\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "11()",
"journal": "Frontiers in immunology",
"keywords": "Adult onset still disease; alemtuzumab; anakinra; case report; multiple sclerosis; rituximab; secondary autoimmunity",
"medline_ta": "Front Immunol",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D005260:Female; D006801:Humans; D009103:Multiple Sclerosis; D016706:Still's Disease, Adult-Onset",
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "2099",
"pmc": null,
"pmid": "33013884",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29519170;31555262;30077425;31000444;31704887;30830064;28598363;26547221;28835403;31055973;30358861;30967831;31368417;30307361;29602914;31147820;1578458;11997716",
"title": "Case Report: Adult Still's Disease in an Alemtuzumab-Treated Multiple Sclerosis Patient.",
"title_normalized": "case report adult still s disease in an alemtuzumab treated multiple sclerosis patient"
} | [
{
"companynumb": "DE-HIKMA PHARMACEUTICALS USA INC.-DE-H14001-20-04528",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"... |
{
"abstract": "Disseminated fusariosis (DF) is a rare life threatening fungal infection in immunocompromised hosts. We herein report a case of a fatal DF mimicking varicella zoster virus (VZV) infection that was emerged from a localized genital infection during cord blood transplantation (CBT) in a patient with severe aplastic anemia (SAA). The patient developed an ulcer following small painful vesicles mimics herpes simplex virus infection (HSV) on the glans penis before CBT, but a Fusarium species was identified. Despite administration of voriconazole, liposomal amphotericin B and granulocyte transfusion, the lesion was extended to extensive skin looked like VZV infection and the patients died after CBT. Massive fusarium infiltration was detected in multiple organs at autopsy. A genetic analysis of the mold identified Fusarium solani after his death. It should be noted that in patients with fusarium infection, localized and disseminated lesions of fusarium infection sometimes mimic HSV and VZV infections, which hampers an early diagnosis.",
"affiliations": "Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan. Electronic address: okada@med.hokudai.ac.jp.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Medical Mycology Research Center, Chiba University, Chiba, Japan.;Department of Dermatology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Department of Cancer Pathology, Hokkaido University Faculty of Medicine, Sapporo, Japan.;Medical Mycology Research Center, Chiba University, Chiba, Japan.;Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan.",
"authors": "Okada|Kohei|K|;Endo|Tomoyuki|T|;Hashimoto|Daigo|D|;Saga|Tomoyuki|T|;Ara|Takahide|T|;Ogasawara|Reiki|R|;Yasumoto|Atsushi|A|;Ibata|Makoto|M|;Takahata|Mutsumi|M|;Shigematsu|Akio|A|;Kondo|Takeshi|T|;Muraosa|Yasunori|Y|;Nomura|Toshifumi|T|;Kanno-Okada|Hiromi|H|;Hashino|Satoshi|S|;Tanaka|Shinya|S|;Kamei|Katsuhiko|K|;Teshima|Takanori|T|",
"chemical_list": "D000935:Antifungal Agents; D000998:Antiviral Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2017.12.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "24(8)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Disseminated fusarium infection; Fusarium solani; Genital herpes; Hematopoietic stem cell transplantation; Herpes simplex virus; Varicella zoster virus",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000328:Adult; D000741:Anemia, Aplastic; D000935:Antifungal Agents; D000998:Antiviral Agents; D036101:Cord Blood Stem Cell Transplantation; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005312:Fetal Blood; D060585:Fusariosis; D005670:Fusarium; D014645:Herpesvirus 3, Human; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D010413:Penis; D013997:Time Factors; D014184:Transplantation, Homologous; D000073618:Varicella Zoster Virus Infection",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "660-663",
"pmc": null,
"pmid": "29373264",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated fusariosis emerged from prolonged local genital infection after cord blood transplantation.",
"title_normalized": "disseminated fusariosis emerged from prolonged local genital infection after cord blood transplantation"
} | [
{
"companynumb": "PHHY2018JP044750",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": null,
... |
{
"abstract": "An 87-year-old man was hospitalized due to dyspnea and leg edema. He was diagnosed with heart failure due to anemia with a hemoglobin (Hb) concentration of 6.0 g/dL. Chest X-ray on admission revealed pleural effusion. He was transfused with 400 mL packed red blood cells, which elevated the Hb concentration to 8.6 g/dL. Spironolactone (25 mg/day) and furosemide (20 mg/day, intravenously) were initiated. Despite the negative fluid balance, the patient's dyspnea worsened. Chest X-ray on day 8 revealed pulmonary edema despite decreased pleural effusion. Transthoracic echocardiography (TTE) revealed a sigmoid-shaped interventricular septum and systolic anterior motion of the mitral valve, causing left ventricular outflow tract obstruction (LVOTO; peak pressure gradient, 96 mmHg). Pilsicainide (75 mg/day) was administered to reduce the LVOTO. In addition, furosemide administration was changed to continuous infusion with increased dose of 48 mg/day (2 mg/h). The patient's dyspnea finally abated, with X-ray on day 12 revealing marked reduction in pulmonary congestion. TTE on day 17 revealed marked reduction in LVOTO (peak pressure gradient, 21 mmHg). Hemodynamic change by diuretics in the setting of right-sided heart failure due to anemia and in the presence of LVOTO due to sigmoid septum could be the cause of pulmonary edema.",
"affiliations": "Department of General Internal Medicine, Tokai University School of Medicine, Hachioji Hospital, 1838 Ishikawa-machi, Hachioji, Tokyo 192-0032, Japan. kmiyazaki@tsc.u-tokai.ac.jp.",
"authors": "Miyazaki|Koji|K|;Onuma|Yuki|Y|;Komatsu|Rena|R|;Kamono|Masahiro|M|",
"chemical_list": "D004232:Diuretics; D005665:Furosemide; D008012:Lidocaine; C042288:pilsicainide",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0005",
"issue": "45(1)",
"journal": "The Tokai journal of experimental and clinical medicine",
"keywords": null,
"medline_ta": "Tokai J Exp Clin Med",
"mesh_terms": "D000369:Aged, 80 and over; D004232:Diuretics; D005665:Furosemide; D006333:Heart Failure; D006801:Humans; D008012:Lidocaine; D008297:Male; D011654:Pulmonary Edema; D014694:Ventricular Outflow Obstruction; D054088:Ventricular Septum",
"nlm_unique_id": "7704186",
"other_id": null,
"pages": "31-36",
"pmc": null,
"pmid": "32219807",
"pubdate": "2020-04-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Development of Pulmonary Edema Despite Negative Fluid Balance with Diuretics in a Patient with Heart Failure and Sigmoid Septum.",
"title_normalized": "development of pulmonary edema despite negative fluid balance with diuretics in a patient with heart failure and sigmoid septum"
} | [
{
"companynumb": "JP-ACCORD-179157",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "1",
"druga... |
{
"abstract": "We present the case of a 6-year-old boy diagnosed with stage III mediastinal Non Hodgkin Lymphoblastic T cell Lymphoma who suffered from catheter-related bloodstream infection (CRBI) due to Mycobacterium fortuitum whilst receiving chemotherapy. Isolation of this rare pathogen was done directly from blood culture and identification was made rapidly within 48 h using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectro-metry as well as specific polymerase chain reaction (PCR)-reverse hybridization method. This allowed prompt directed antibiotic therapy apart from central venous catheter removal and resulted in an excellent clinical response. This case highlights the potential benefit of using MALDI-TOF mass spectrometry, a fast, cost-effective and precise methodology, in the diagnosis and subsequent management of invasive bacterial infection.",
"affiliations": "Department of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocio, Sevilla, Spain.;Paediatric Infectious Diseases and Immunopathology Unit, University -Hospital Virgen del Rocio, Sevilla, Spain.;Department of Paediatric Oncology, University Hospital Virgen del Rocio, Sevilla, Spain.;Department of Paediatrics, University Hospital Virgen del Rocio, Sevilla, Spain.;Department of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocio, Sevilla, Spain.;Paediatric Infectious Diseases and Immunopathology Unit, University -Hospital Virgen del Rocio, Sevilla, Spain.;Department of Infectious Diseases, Microbiology and Preventive Medicine, University Hospital Virgen del Rocio, Sevilla, Spain.",
"authors": "Artacho-Reinoso|M J|MJ|;Olbrich|P|P|;Solano-Paéz|P|P|;Ybot-Gonzalez|P|P|;Lepe|J A|JA|;Neth|O|O|;Aznar|J|J|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0033-1363959",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8630",
"issue": "226(2)",
"journal": "Klinische Padiatrie",
"keywords": null,
"medline_ta": "Klin Padiatr",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D016470:Bacteremia; D055499:Catheter-Related Infections; D002405:Catheterization, Central Venous; D002648:Child; D020878:Device Removal; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009165:Mycobacterium Infections, Nontuberculous; D019907:Mycobacterium fortuitum; D009367:Neoplasm Staging; D009894:Opportunistic Infections; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014945:Wound Healing",
"nlm_unique_id": "0326144",
"other_id": null,
"pages": "68-71",
"pmc": null,
"pmid": "24554588",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Catheter-related Mycobacterium fortuitum bloodstream infection: rapid identification using MALDI-TOF mass spectrometry.",
"title_normalized": "catheter related mycobacterium fortuitum bloodstream infection rapid identification using maldi tof mass spectrometry"
} | [
{
"companynumb": "ES-TEVA-539587ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"d... |
{
"abstract": "Pure erythroid leukemia (PEL) is rare hematopoietic neoplasm characterized by uncontrolled proliferation of immature erythroid precursors - mainly abnormal proery-throblasts - comprising at least 80% of bone marrow cells. In this paper, I present a case of 48 years old patient, who presented with pancytopenia and circulating erythroblast in peripheral blood after long history of alcohol abuse. Bone marrow examination revealed hypercellular marrow which is markedly infiltrated with immature erythroid precursors. An expanded panel of immunophenotyping markers has confirmed the diagnosis of PEL. Cytogenetics analysis detected a complex karyotype with multiple chromosomal abnormalities and a novel translocation, t(8;9) (p11.2;q12), which has not been reported in acute myeloid leukemia (AML) in the past. The patient was treated with standard AML chemotherapy but he did not show an optimal response and passed away. An updated and short review about various aspects of PEL has been made with special focus on immunophenotyping and genetic studies.",
"affiliations": "Department of Pathology, King Khalid University Hospital, King Saud University , Riyadh, Saudi Arabia.",
"authors": "Aljabry|Mansour|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4081/hr.2015.5674",
"fulltext": "\n==== Front\nHematol RepHematol RepHRHematology Reports2038-83222038-8330PAGEPress Publications, Pavia, Italy hr-2015-1-567410.4081/hr.2015.5674ArticleComplex Karyotype with Novel Translocation in Pure Erythroid Leukemia Patient Aljabry Mansour Department of Pathology, King Khalid University Hospital, King Saud University, Riyadh, Saudi ArabiaHematology Unit, Pathology Department, King Khalid University Hospital, King Saud University, P.O Box 2925, Riyadh 11461, Kingdom of Saudi Arabia. +966.114.671812. m.aljabry4210@gmail.comConflict of interest: the authors declare no potential conflict of interest.\n\n16 3 2015 24 2 2015 7 1 567414 10 2014 20 2 2015 24 2 2015 ©Copyright M. Aljabry2015Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Pure erythroid leukemia (PEL) is rare hematopoietic neoplasm characterized by uncontrolled proliferation of immature erythroid precursors – mainly abnormal proery-throblasts – comprising at least 80% of bone marrow cells. In this paper, I present a case of 48 years old patient, who presented with pancytopenia and circulating erythroblast in peripheral blood after long history of alcohol abuse. Bone marrow examination revealed hypercellular marrow which is markedly infiltrated with immature erythroid precursors. An expanded panel of immunophenotyping markers has confirmed the diagnosis of PEL. Cytogenetics analysis detected a complex karyotype with multiple chromosomal abnormalities and a novel translocation, t(8;9) (p11.2;q12), which has not been reported in acute myeloid leukemia (AML) in the past. The patient was treated with standard AML chemotherapy but he did not show an optimal response and passed away. An updated and short review about various aspects of PEL has been made with special focus on immunophenotyping and genetic studies.\n\nKey words\npure erythroid leukemiaacute erythroid leukemiaacute myeloid leukemiaFunding: this paper has been funded by King Saud University, Deanship of Scientific Research, College of Medicine, Research Center.\n==== Body\nCase Report\nClinical history\nA 48 years old Saudi male presented to the emergency department with shortness of breath, persistent low grade fever and easy bruising for 3 days. The patient also complained of progressive weakness, loss of appetite for 2 months duration and had lost 7 kg of weight over the last 2 months. His family or medical history was unremarkable and was not receiving any medical treatment for any chronic illness. Social history revealed that he was unemployed with low economic status. He was a heavy smoker consuming two packs of cigarettes daily for several years and had long history of heavy alcohol abuse. He denied any drug abuse or toxin exposure. On physical examination; he was pale, had multiple bruises particularly on the lower limbs and his body temperature was 38.2°C. There was mild hepatosplenomegaly with no lymphadenopathy.\n\nMethods and investigations\nHematological investigation revealed hemoglobin of 51 g/L (120-160 g/L), red blood cells (RBC) 2.15×1012/L (4.2-5.5×1012/L), mean corpuscular volume 88 fl (78-97 fl) and mean corpuscular hemoglobin 28 pg (27-32 pg). Leukocytes were 2.01×109/L with 3% blasts, myelocytes 3%, neutrophils 19%, monocytes 8%, basophils 1% and 67% lymphocytes. Platelet count was 23×109/L (140-450×109/L). Biochemical markers revealed elevated serum levels of lactate dehydrogenase (LDH), uric acid and total bilirubin. Renal function and liver function tests were within normal limits. Peripheral smear showed marked anisopoikilocytosis with schistocytes, basophilic stippling, spherocytes, many nucleated RBC and rare circulating blasts. Erythroid precursors showed significant dysplastic changes with nuclear irregularities, budding and bi-nucleation while neutrophil morphology was essentially normal. The circulating blasts were medium to large blasts with round nuclei, fine chromatin, prominent nucleoli and deep blue a granular cytoplasm without Auer rods.\n\nThe bone marrow aspirate yielded a markedly hypercellular bone marrow essentially replaced by erythroid precursors, representing approximately 87% of the marrow cells. Of this, the proerythroblasts comprised 58%. The erythroid precursors displayed dysplastic morphology, including multi-nucleation, nuclear budding and megaloblastoid changes. Myeloblasts were about 3% and megakaryocytes were reduced without obvious dysplasia. Periodic Acid Schiff (PAS) stain revealed globular and block-like positivity in many abnormal erythroblasts. Perls Perl’s stain showed a few sideroblasts; however no ringed sideroblasts were observed.\n\nFlow cytometry analysis of the bone marrow aspirate revealed many immature cells which were positive for CD71, glycophorin A and partially positive for CD36, consistent with erythroid precursors. Staining for CD13, CD33, CD34, CD41, CD61 and all other myeloid and lymphoid makers was negative. Myeloblasts were not detected. The bone marrow biopsy revealed a hypercellular packed marrow with monotonous leukemic infiltrate composed of primitive looking blasts. The infiltrating blasts had scant cytoplasm, high nuclear to cytoplasmic ratio, round nucleus with fine chromatin and 1-2 prominent nucleoli (Figure 1).\n\nImmunohistochemistry revealed strong positivity to E-cadherin (ECH-6; Ventana Medical Systems, Inc., Roche, Basel, Switzerland), weak positivity for glycophorin A (GA-R2; Ventana Medical Systems, Inc.) and negative for CD34, MPO, vWF, CD3 and CD79a. These morphological and immunophenotypic findings supported the diagnosis of pure erythroid leukemia (PEL) FAB subtype M6b.\n\nCytogenetics analysis was performed on 20 metaphases and detected a complex karyotype with multiple chromosomal aberrations (Figure 2):\n 46-48,XY,add(4)(q?) [11]del(4)(p?)[17],del(5)(q23)[8],add(6)(p 23)[16],del(7)(q22)[12], t(8;9)(p11.2;q12)[20],+del(9)(q22)[17],de l(18)(q21)[13] \n\nHospital course\nThe patient was treated with a standard induction (7+3) chemotherapy regimen consisting of daunorubicin 45 mg/m2 daily for 3 days and cytarabine 100 mg/m2 daily continuous infusion for 7 days. Blood and platelet transfusions were administered during induction period. On post-induction day 28, the bone marrow biopsy showed hypercellular marrow with 38% residual erythroblasts. Cytogenetics showed persistent multiple chromosomal abnormalities. He was re-inducted again with FLAG regimen (fludarabine + high-dose cytarabine + G-CSF). He failed to tolerate the treatment and died after 10 days due to severe pulmonary infection.\n\nDiscussion\nPure erythroid leukemia is exceedingly rare type of AML representing <1% of all AML cases and 13% of acute erythroid leukemia cases.1 It is a neoplastic proliferation of immature cells committed exclusively to the erythroid lineage comprising at least 80% of bone marrow cells with no evidence of a significant myeloblastic component.2\n\nClinically, PEL patients present usually with profound anemia symptoms such as weakness and pallor, fever and hemorrhages.3 Presence of hepatosplenomegaly varies between 20 to 40% of the series.3,4 There are few reported cases of extramedullary pure erythroid leukemia involving lymph nodes or presenting as a hemangioma.5,6\n\nOur patient presented with PEL post heavy alcohol abuse over a prolonged time period that may indicate presence of some kind of causal relationship, an observation consistent with previous reports.7,8\n\nBecause of the extreme rarity of PEL, few studies have examined its pathogenesis and genetic features. There are no clear identifiable risk factors. However, rare cases of de novo familial PEL, being autosomal dominant, have been reported.9,10 A number of available studies have revealed complex karyotype with predominance of -5/del(5q), -7/del(7q) and +19p.1,7,8,11-13 In a study conducted by Liu et al., all PEL patients (n=16) showed an extremely complex karyotype, with a median of 12 abnormalities (range 3-37). These abnormalities most frequently involved chromosomes 5 (69%), 7 (56%), 17 (44%), and 19 (38%).1\n\nCytogenetic study for the present patient revealed an extreme complex karyotype with 8 chromosomal abnormalities. Beside the most commonly reported abnormalities, such as del(5q) and del(7q), our patient had a novel translocation t(8;9)(p11.2;q12) in all the examined metaphases. To the best of our knowledge, this translocation has never been reported in acute myeloid leukemia in the past. Unfortunately, we were not able to perform a higher molecular study in order to clarify the origin of this abnormality.\n\nDiagnosis of PEL requires multiparameter approach including detailed clinical history, peripheral blood and bone marrow examination, immunophenotyping and genetic studies as well.\n\nPeripheral blood smears reveal non specific findings in the majority of PEL cases. However, about one quarter of patients show circulating erythroblasts.1 Anemia and thrombocytopenia are frequently observed while neutrophil counts vary.2 The present case also showed pancytopenia with 3% circulating blasts in the peripheral blood.\n\nIn bone marrow aspirate, the majority of cells (>80%) are erythroid precursors with marked left shift and increased proerythroblasts. Proerythroblasts-the most immature recognizable erythroid precursors- are medium to large blasts with round nuclei, fine chromatin, occasional prominent nucleoli, deep blue agranular cytoplasm with variable cytoplasmic vacuolization and no Auer rods.14 Dyserythropoiesis is prominent, while myeloid and megakaryocytic dysplasia is not an obvious feature.5\n\nPeriodic Acid-Schiff (PAS) cytochemical staining is commonly positive, often in cytoplasmic vacuoles in a block-like pattern, while MPO, Sudan Black, and chloroacetate esterase are characteristically negative.15 Core biopsy is usually markedly hypercellular and shows erythroid predominance with sheets of immature cells clearly demonstrating a leukemic infiltrative pattern.1\n\nErythroblasts usually express CD71 (transferrin receptor), but occasionally CD71 expression can be aberrantly dim. These cells variably express hemoglobin A, glycophorin A, ABH blood group antigens, and HLA-DR. Erythroblasts are usually negative for myeloidassociated markers such as MPO. The Gerbich blood group (Gero) antibody, carbonic anhydrase1, and CD36 can be expressed by more immature erythroblast.16-19\n\nImmunophenotyping of the present case revealed many immature cells which were positive for CD71, glycophorin A and partially positive for CD36, consistent with erythroid precursors. Myeloblasts were not detected.\n\nVarious markers including glycophorin A, B, and C, hemoglobin, CD36, and spectrin have been used to identify immature erythroblasts in PEL; however, the results either lack consistency or specificity.20,21\n\nE-cadherin is a cell adhesion molecule involved in the morphogenesis of multicellular organisms and maintenance of solid tissues. It is a selective marker of immature erythroblasts and is down regulated during erythroid maturation. In the bone marrow, its expression appears to be limited to erythroid lineage, and mainly in immature erythroblasts.22-24\n\nIn the present patient, e-cadherin immunohistochemistry stain revealed strong positivity (≈80%) while glycophorine glycophorin A was weak positive (≈20) which was in agreement with the published data. The combination of Ecadherin with glycophorin A effectively distinguishes immature and mature erythroid precursors.\n\nDifferential diagnosis of PEL is broad, and includes both non-neoplastic and neoplastic conditions. Erythroid hyperplasia may result from ineffective erythropoiesis such as congenital dyserythropoietic anemia, hemolytic anemia, vitamin B12/folate deficiency, infection, or autoimmune hemolysis. Importantly, previous erythropoietin treatment can cause reactive erythropoiesis that mimics pure erythroid leukemia.25 Even marked dyserythropoiesis can be seen in floridly reactive conditions potentially mimicking a myeloid neoplasm.5\n\nPure erythroid leukemia needs also, to be distinguished from other forms of myeloid neoplasms with erythroid predominance namely therapy related (t-AML), acute myeloid leukemia with myelodysplasia related changes (AML-MRC), AML with recurrent cytogenetic abnormalities and myelodysplastic syndrome. Cases that do not fit into any of the above well-defined categories are classified as AMLNOS, further subcategorized by their morphologic and immunophenotypic characteristics. Thus, PEL is largely a diagnosis of exclusion.2 Pure erythroid leukemia without morphologic evidence of erythroid maturation may be difficult to be distinguished from other types of AML, particularly megakaryoblastic leukemia, and also from acute lymphoblastic leukemia and lymphoma.\n\nTreatment and prognosis\nPure erythroid leukemia is a very aggressive disease with dismal prognosis and poor outcome. The median survival is 3.6 months compared with 28 months in acute erythroid/myeloid leukemia.1,5 The standard induction for PEL is (7+3) chemotherapy regimen, consisting of daunorubicin 45 mg/m2 daily for 3 days and cytarabine 100 mg/m2 daily continuous infusion for 7 days; which offers a complete remission (CR) rate of approximately 10-40%; if CR is obtained, it is usually brief.\n\nThe response to chemotherapy and the length of survival is dependent on several factors such as cytogenetics and karyotype abnormality and patient comobidities.14,15-17\n\nFigure 1. Morphological and Immunohistochemistry findings of bone marrow. A) Bone marrow aspirate with erythroid precursors and many proerythroblasts (arrow). The erythroblasts are medium with scant cytoplasm, high nuclear to cytoplasmic ratio, round nuclei with fine chromatins and 1-2 prominent nucleoli. B) Bone marrow biopsy is hypercellular and packed with monotonous leukemic infiltrate composed of primitive looking blasts. (H&E,×100).C) Proerythroblasts are strongly positive for E-cadherin. D) Glycophorin A shows weak positivity.\n\nFigure 2. Complex karyotype with multiple chromosomal aberrations: 46-48,XY, add(4)(q?), del(4)(p?), del(5)(q23), add(6)(p23), del(7)(q22), t(8;9)(p11.2;q12), +del(9)(q22), del(18)(q21).\n==== Refs\nReferences\n1. Liu W Hasserjian RP Hu Y \nPure erythroid leukemia: a reassessment of the entity using the 2008 World Health Organization classification . Mod Pathol 2011 ;24 :375 -83 .21102413 \n2. Arber DA Brunning RD Orazi A \nAcute myeloid leukemia, not otherwise specified . Swerdlow SH Campo E Harris NL , Tumours of haematopoietic and lymphoid tissues . Lyon : IARC Press ; 2008 \n134 -136 .\n3. Olopade OI Thangavelu M Larson RA \nClinical, morphologic, and cytogenetic characteristics of 26 patients with acute erythroblastic leukemia . Blood 1992 ;80 :2873 -82 .1450412 \n4. Colita A Belhabri A Chelghoum Y \nPrognostic factors and treatment effects on survival in acute myeloid leukemia of M6 subtype: a retrospective study of 54 cases . Ann Oncol 2001 ;12 :451 -5 .11398875 \n5. Mihova D Zhang L. Acute erythroid leukemia: a review . N A J Med Sci 2012 ;5 :110 -8 .\n6. Keifer J Zaino R Ballard JO \nErythroleukemic infiltration of a lymph node: use of hemoglobin immunohisto-chemical techniques in diagnosis . Hum Pathol 1984 ;15 :1090 -3 .6386660 \n7. Latif N Salazar E Khan R \nThe pure erythroleukemia: a case report and literature review . Clin Adv Hematol Oncol 2010 ;4 :283 -8 .20505651 \n8. Suresh PK Rao PS Khalidkar UN \nErythroleukemia with complex cytogenetic abnormalities: a case report with review of literature . Indian J Appl Res 2013 :7 ;539 -40 .\n9. Haught EAS Johnson MC Witt PD \nCongenital erythroleukemia presenting as a congenital infantile hemangioma . Plast Reconstr Surg 2007 ;119 :e70 -2 .\n10. Novik Y Marino P Makower DF Wiernik PH \nFamilial erythroleukemia: a distinct clinical and genetic type of familial leukemias . Leuk Lymphoma 1998 ;30 :395 -401 .9713970 \n11. Bacher U Haferlach C Kern W \nPrognostic relevance of FLT3-TKD mutations in AML: the combination matters: an analysis of 3082 patients . Blood 2008 ;111 :2527 -37 .17965322 \n12. Marcucci G Maharry K Whitman SP \nHigh expression levels of the ETS-related gene, ERG, predict adverse outcome and improve molecular risk based classification of cytogenetically normal acute myeloid leukemia: a Cancer and Leukemia Group B study . J Clin Oncol 2007 ;25 :3337 -43 .17577018 \n13. Acquaviva C Gelsi-Boyer V Birnbaum D. Myelodysplastic syndromes: lost between two states? Leukemia 2010 ;24 :1 -5 .20068572 \n14. Hasserjian RP Zuo Z Garcia C \nAcute erythroid leukemia: a reassessment using criteria refined in the 2008 WHO classification . Blood 2010 ;115 :1985 -92 .20040759 \n15. Zuo Z Polski JM Kasyan A \nAcute erythroid leukemia . Arch Pathol Lab Med 2010 ;134 :1261 -70 .20807044 \n16. Bain BJ \nDi Guglielmo and his syndromes . Br J Haematol 2003 ;120 :939 -43 .12648062 \n17. Lowenberg B Downing JR Burnett A. Acute myeloid leukemia . N Engl J Med 1999 ;341 :1051 -62 .10502596 \n18. Kogawa K Sekine I Masuda T \nBone marrow transplantation for erythroleukemia: a case report . Acta Paediatr Jpn 1994 ;36 :693 -6 .7871985 \n19. Killick S Matutes E Powles RL \nAcute erythroid leukemia (M6): outcome of bone marrow transplantation . Leuk Lymphoma 1999 ;35 :99 -107 .10512167 \n20. Garand R Duchayne E Blanchard D \nMinimally differentiated erythroleukaemia (AML M6 variant): a rare subset of AML distinct from AML M6. Groupe Francais d’Hematologie Cellulaire . Br J Haematol 1995 ;90 :868 -75 .7669665 \n21. Sadahira Y Kanzaki A Wada H \nImmunohistochemical identification of erythroid precursors in paraffin embedded bone marrow sections: spectrin is a superior marker to glycophorin . J Clin Pathol 1999 ;52 :919 -21 .10711257 \n22. Acs G LiVolsi VA \nLoss of membrane expression of E-cadherin in leukemic erythroblasts . Arch Pathol Lab Med 2001 ;125 :198 -201 .11175634 \n23. Armeanu S Buhring HJ Reuss-Borst M \nE-cadherin is functionally involved in the maturation of the erythroid lineage . J Cell Biol 1995 ;131 :243 -9 .7559781 \n24. Buhring HJ Muller T Herbst R \nThe adhesion molecule E-cadherin and a surface antigen recognized by the antibody 9C4 are selectively expressed on erythroid cells of defined maturational stages . Leukemia 1996 ;10 :106 -16 .8558914 \n25. Moharram L Kamal N Sukhun SA Sughayer MA \nErythropoietin-induced acute erythroid leukemia-like picture: a potential pitfall . Hematol Oncol Stem Cell Ther 2014 ;7 :50 -2 .24239851\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2038-8322",
"issue": "7(1)",
"journal": "Hematology reports",
"keywords": "acute erythroid leukemia; acute myeloid leukemia; pure erythroid leukemia",
"medline_ta": "Hematol Rep",
"mesh_terms": null,
"nlm_unique_id": "101556723",
"other_id": null,
"pages": "5674",
"pmc": null,
"pmid": "25852849",
"pubdate": "2015-02-24",
"publication_types": "D016428:Journal Article",
"references": "17965322;20807044;11398875;7669665;8558914;9713970;7559781;20505651;20068572;10512167;6386660;11175634;17496582;10711257;24239851;1450412;7871985;10502596;17577018;21102413;12648062;20040759",
"title": "Complex karyotype with novel translocation in pure erythroid leukemia patient.",
"title_normalized": "complex karyotype with novel translocation in pure erythroid leukemia patient"
} | [
{
"companynumb": "SA-PFIZER INC-202200784964",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": "3",
... |
{
"abstract": "In the complex setting of obstetrics and reproductive medicine, the medication-related injuries leading to the most litigation involve some of the most commonly used drugs, rather than the newer, more complicated therapies. The authors present a number of cases illustrating how sophisticated treatment of high-risk pregnancies can be jeopardized by a simple negligent act.",
"affiliations": null,
"authors": "O'Donnell|James T|JT|;O'Donnell|James J|JJ|;Vogenberg|F Randy|FR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-1372",
"issue": "44(3)",
"journal": "P & T : a peer-reviewed journal for formulary management",
"keywords": "Drug injuries; OB-GYN; drug therapy; litigation; negligence; pharmacology; reproductive medicine",
"medline_ta": "P T",
"mesh_terms": null,
"nlm_unique_id": "9015516",
"other_id": null,
"pages": "118-121",
"pmc": null,
"pmid": "30828231",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": "24832366;24901312;25164435;26105228;28479842;28890645;3631562",
"title": "Forensic Analysis in Drug Litigation Finds Most Errors Occur with Commonly Used Therapies and Practices.",
"title_normalized": "forensic analysis in drug litigation finds most errors occur with commonly used therapies and practices"
} | [
{
"companynumb": "US-LEADING PHARMA, LLC-2076005",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TERBUTALINE SULFATE"
},
"drugadditional... |
{
"abstract": "BACKGROUND\nTemozolomide is an alkylating agent used along with concurrent radiation therapy in the treatment of glioblastoma. The primary adverse effect of temozolomide is bone marrow suppression with resulting cytopenias. There have been reported cases of temozolomide-induced hepatotoxicity, including fatal liver failure, associated with reactivation of the hepatitis virus or with concurrent use of other hepatotoxic drugs. In this report, we describe a unique mechanism of temozolomide-induced liver injury with supporting histopathology.\n\n\nMETHODS\nOur patient, a 58-year-old African american woman with glioblastoma, was treated with concurrent radiation and temozolomide therapy. After 6 weeks of treatment, she developed worsening transaminitis and bilirubinemia with liver biopsy results consistent with drug-induced cholestasis and ductopenia. After cessation of drug treatment, her hyperbilirubinemia progressed with a peak bilirubin of 36.8 mg/dl. A repeat liver biopsy revealed severe biliary ductopenia consistent with vanishing bile duct syndrome.\n\n\nCONCLUSIONS\nWe present a rare case of a patient with biliary ductopenia as an adverse effect of temozolomide. During radiation and temozolomide therapy, blood counts and liver enzymes should be carefully monitored for the development of cholestatic liver injury. We recommend monitoring with weekly liver function tests and minimizing drugs that are metabolized by the liver during chemoradiation for glioblastoma.",
"affiliations": "Department of Internal Medicine, University of South Florida, Tampa, FL, USA. ashab@health.usf.edu.;Department of Internal Medicine, University of South Florida, Tampa, FL, USA. rledford@health.usf.edu.;Department of Internal Medicine, University of South Florida, Tampa, FL, USA. michael.jaglal@moffitt.org.",
"authors": "Balakrishnan|Asha|A|;Ledford|Robert|R|;Jaglal|Michael|M|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D003606:Dacarbazine; D000077204:Temozolomide",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-016-0804-z",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 80410.1186/s13256-016-0804-zCase ReportTemozolomide-induced biliary ductopenia: a case report Balakrishnan Asha ashab@health.usf.edu Ledford Robert rledford@health.usf.edu Jaglal Michael michael.jaglal@moffitt.org Department of Internal Medicine, University of South Florida, Tampa, FL USA Department of Malignant Hematology, H. Lee Moffitt Cancer and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612 USA 5 2 2016 5 2 2016 2016 10 3328 10 2015 6 1 2016 © Balakrishnan et al. 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\nTemozolomide is an alkylating agent used along with concurrent radiation therapy in the treatment of glioblastoma. The primary adverse effect of temozolomide is bone marrow suppression with resulting cytopenias. There have been reported cases of temozolomide-induced hepatotoxicity, including fatal liver failure, associated with reactivation of the hepatitis virus or with concurrent use of other hepatotoxic drugs. In this report, we describe a unique mechanism of temozolomide-induced liver injury with supporting histopathology.\n\nCase presentation\nOur patient, a 58-year-old African american woman with glioblastoma, was treated with concurrent radiation and temozolomide therapy. After 6 weeks of treatment, she developed worsening transaminitis and bilirubinemia with liver biopsy results consistent with drug-induced cholestasis and ductopenia. After cessation of drug treatment, her hyperbilirubinemia progressed with a peak bilirubin of 36.8 mg/dl. A repeat liver biopsy revealed severe biliary ductopenia consistent with vanishing bile duct syndrome.\n\nConclusions\nWe present a rare case of a patient with biliary ductopenia as an adverse effect of temozolomide. During radiation and temozolomide therapy, blood counts and liver enzymes should be carefully monitored for the development of cholestatic liver injury. We recommend monitoring with weekly liver function tests and minimizing drugs that are metabolized by the liver during chemoradiation for glioblastoma.\n\nKeywords\nTemozolamideGlioblastomaHepatotoxicityBiliary ductopeniaVanishing bile duct syndromeno awardNo awardissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nGlioblastoma is the most common aggressive primary central nervous system tumor in adults. It accounts for 45.6 % of all malignant central nervous system tumors and has an incidence of 3.19 per 100,000 [1]. The current standard of care for the treatment of glioblastoma is surgical resection followed by adjuvant temozolomide and concurrent radiation therapy. The addition of temozolomide to radiotherapy significantly improves the median overall survival and progression-free survival compared with radiotherapy alone [2]. Temozolomide, an oral alkylating agent, enters the cerebrospinal fluid and does not require hepatic metabolism for activation [3]. The most common adverse effects of temozolomide include nausea, fatigue, and hematologic toxicities. In April 2014, Merck Canada released an announcement acknowledging the association of temozolomide use with liver injury, including fatal hepatic failure, which may present up to 16 weeks following drug initiation [4]. Various mechanisms of hepatotoxicity have been described in the literature, including the reactivation of hepatitis virus, the use of concomitant hepatotoxic medications, and cholestatic hepatitis [5–11]. We present a case of vanishing bile duct syndrome secondary to temozolomide use in the treatment of a patient with glioblastoma. To the best of our knowledge, we report only the second such case in the literature [12].\n\nCase presentation\nA 58-year-old previously healthy Caucasian woman initially presented to our institute with headaches, nausea, and photophobia. She was found to have a 4.7 × 4.2 × 3.6–cm hemorrhagic right temporal lobe mass. She underwent emergent right craniotomy and mass resection, and the tumor pathology was consistent with glioblastoma. In laboratory examinations to evaluate her baseline hepatic function before chemoradiation, the results were aspartate transaminase 22 IU/L (normal range 5–34 IU/L), alanine transaminase 14 IU/L (normal range 5–55 IU/L), alkaline phosphatase 90 U/L (normal range 40–150 U/L), and total bilirubin 0.4 mg/dl (normal range 0.2–1.2 mg/dl). The patient’s medications during chemoradiation were temozolomide, trimethoprim-sulfamethoxazole, and ondansetron, and no supplements (herbal or over-the-counter vitamins) were used during chemoradiation.\n\nSix weeks after initiation of temozolomide and radiation therapy, the patient was admitted to the hospital for rapidly increasing transaminitis (aspartate transaminase 425 IU/L, alanine transaminase 1028 IU/L), elevated alkaline phosphatase (291 U/L), and hyperbilirubinemia (total bilirubin 7.9 mg/dl) discovered in routine weekly blood work. She presented with jaundice and dark urine but otherwise was asymptomatic. The results of her infection workup (hepatitis panel, cytomegalovirus, herpes simplex virus, Epstein-Barr virus, HIV) and her autoimmune workup (antinuclear antibody, smooth muscle antibody, antimitochondrial antibody, immunoglobulins) were negative, and her liver ultrasound was unremarkable. She was not on any other hepatotoxic medications at the time of admission. Temozolomide was held on admission, and, although her aspartate transaminase and alanine transaminase levels improved, her total bilirubin continued to rise. Her initial liver biopsy pathology was consistent with a cholestatic pattern of injury with mild ductopenia and portal eosinophilia consistent with a drug-induced liver injury.\n\nThree weeks after admission, the patient’s total bilirubin rose to a peak of 36.8 mg/dl, and repeat liver biopsy revealed progression to severe biliary ductopenia, consistent with vanishing bile duct syndrome. She was started on a trial of ursodeoxycholic acid and zinc with gradual improvement of her transaminitis and hyperbilirubinemia over several months. After discontinuation of temozolomide, she completed radiation. She did not have any further therapy except radiation while her hepatic function normalized. She relapsed approximately 9 months later and was then treated with re-resection followed by reradiation. Since her reradiation, the patient has had no evidence of recurrence and undergoes follow-up magnetic resonance imaging every 3 months. She has been followed for a total of 2 years and is currently without evidence of disease.\n\nDiscussion\nThe association of liver injury with the use of temozolomide has become more established in recent years. The mechanism of temozolomide-induced hepatotoxicity is unclear, as the drug does not require hepatic metabolism for activation [3]. Vanishing bile duct syndrome is a rare manifestation of temozolomide-induced liver injury. In a recent case report, Mason et al. [12] described a 62-year-old Indian woman who developed signs of liver failure 17 days after initiation of temozolomide therapy, with a peak bilirubin of 289 mg/dl. A liver biopsy done at day 30 confirmed vanishing bile duct syndrome, and she was treated with ursodeoxycholic acid and cholestyramine with resolution of liver enzymes by day 129. Several triggers of vanishing bile duct syndrome have been described, including autoimmune disorders, infections, congenital diseases, malignancy, and medications [13]. Treatment of vanishing bile duct syndrome varies with the underlying cause, but strategies generally include supportive care, withdrawal of the offending medication, treatment of the underlying infection, ursodeoxycholic acid, and immunosuppressive agents.\n\nConclusions\nBiliary ductopenia is a rare manifestation of temozolomide-induced liver injury. Blood counts and liver enzymes should be monitored closely during concurrent temozolomide and radiation therapy for glioblastoma. We recommend monitoring with weekly liver function tests and minimizing drugs that are metabolized by the liver during chemoradiation for glioblastoma.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAB, RL, and MJ conceived and designed the case report, acquired and interpreted the data, and drafted the manuscript. All authors read and approved the final manuscript.\n\nThe authors acknowledge Rasa Hamilton for review of the manuscript.\n==== Refs\nReferences\n1. Ostrom QT Gittleman H Liao P Rouse C Chen Y Dowling J CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011 Neuro Oncol 2014 16 Suppl 4 iv1 63 10.1093/neuonc/nou223 25304271 \n2. Stupp R Mason WP van den Bent MJ Weller M Fisher B Taphoorn MJ Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma N Engl J Med 2005 352 10 987 96 10.1056/NEJMoa043330 15758009 \n3. Friedman HS Kerby T Calvert H Temozolomide and treatment of malignant glioma Clin Cancer Res 2000 6 7 2585 97 10914698 \n4. Merck Canada. Health Canada endorsed important safety information on TEMODAL® (temozolomide): association of TEMODAL® (temozolomide) with the risk of hepatic injury [news release]. 7 May 2014; http://www.merck.ca/Assets/News/TEMODAL%20HPC%20ENGLISH%20-%20FINAL.pdf. Accessed 15 January 2016.\n5. Becker F Hecht M Schmidtner J Semrau S Fietkau R Temozolomide-induced liver damage: a case report Strahlenther Onkol 2014 190 4 408 10 10.1007/s00066-013-0519-7 24452817 \n6. Chheda MG Drappatz J Greenberger NJ Kesari S Weiss SE Gigas DC Hepatitis B reactivation during glioblastoma treatment with temozolomide: a cautionary note Neurology 2007 68 12 955 6 10.1212/01.wnl.0000259430.48835.b5 17372135 \n7. Sarganas G Orzechowski HD Klimpel A Thomae M Kauffmann W Herbst H Severe sustained cholestatic hepatitis following temozolomide in a patient with glioblastoma multiforme: case study and review of data from the FDA adverse event reporting system Neuro Oncol 2012 14 5 541 6 10.1093/neuonc/nos056 22394496 \n8. Ohno M Narita Y Miyakita Y Ueno H Kayama T Shibui S Reactivation of hepatitis B virus after glioblastoma treatment with temozolomide: case report Neurol Med Chir (Tokyo) 2011 51 10 728 31 10.2176/nmc.51.728 22027252 \n9. Niewald M Berdel C Fleckenstein J Licht N Ketter R Rübe C Toxicity after radiochemotherapy for glioblastoma using temozolomide - a retrospective evaluation Radiat Oncol. 2011 6 141 10.1186/1748-717X-6-141 22017800 \n10. Grewal J Dellinger CA Yung WK Fatal reactivation of hepatitis B with temozolomide N Engl J Med 2007 356 15 1591 2 10.1056/NEJMc063696 17429098 \n11. Dixit S Hingorani M Afzal P Campbell AP Temozolomide induced liver injury Acta Neurol Belg 2011 111 3 249 51 22141295 \n12. Mason M, Adeyi O, Fung S, Millar BA. Vanishing bile duct syndrome in the context of concurrent temozolomide for glioblastoma. BMJ Case Rep. 2014. doi: 10.1136/bcr-2014-208117\n13. Reau NS Jensen DM Vanishing bile duct syndrome Clin Liver Dis 2008 12 1 203 17 10.1016/j.cld.2007.11.007 18242505\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1752-1947",
"issue": "10()",
"journal": "Journal of medical case reports",
"keywords": null,
"medline_ta": "J Med Case Rep",
"mesh_terms": "D018906:Antineoplastic Agents, Alkylating; D001649:Bile Duct Diseases; D001653:Bile Ducts, Intrahepatic; D059248:Chemoradiotherapy; D002779:Cholestasis; D003606:Dacarbazine; D005260:Female; D005909:Glioblastoma; D006801:Humans; D006932:Hyperbilirubinemia; D008875:Middle Aged; D000077204:Temozolomide",
"nlm_unique_id": "101293382",
"other_id": null,
"pages": "33",
"pmc": null,
"pmid": "26846183",
"pubdate": "2016-02-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10914698;15758009;17372135;17429098;18242505;25432915;22017800;22141295;22394496;24452817;25304271;22027252",
"title": "Temozolomide-induced biliary ductopenia: a case report.",
"title_normalized": "temozolomide induced biliary ductopenia a case report"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2016US-115189",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"dr... |
{
"abstract": "BACKGROUND\nA randomized, double-blind, multinational, phase 3 study was conducted comparing the efficacy and safety of peginterferon lambda-1a (Lambda)/ribavirin (RBV)/telaprevir (TVR) vs. peginterferon alfa-2a (Alfa)/RBV/TVR in patients with chronic hepatitis C virus (HCV) genotype-1 (GT-1) infection.\n\n\nMETHODS\nPatients (treatment-naïve or relapsers on prior Alfa/RBV treatment) were randomly assigned in a 2:1 ratio to receive Lambda/RBV/TVR or Alfa/RBV/TVR. Total duration of treatment was either 24 or 48 weeks (response-guided treatment), with TVR administered for the first 12 weeks. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post treatment week 12 (SVR12), which was tested for noninferiority of Lambda/RBV/TVR.\n\n\nRESULTS\nA total of 838 patients were enrolled, and 617 were treated; 411 and 206 patients received Lambda/RBV/TVR and Alfa/RBV/TVR, respectively. The majority of patients were treatment-naïve, with HCV GT-1b and a high baseline viral load (≥800,000 IU/mL). Less than 10% of patients had cirrhosis (Lambda, 7.5%; Alfa, 6.8%). Lambda/RBV/TVR did not meet the criterion for noninferiority (lower bound of the treatment difference interval was -12.3%); the SVR12 in all patients (modified intent-to-treat) was 76.2% in the Lambda arm and 82.0% in the Alfa arm. Overall, the frequency of adverse events in each arm was comparable (Lambda, 91.7%; Alfa, 97.1%). As expected based on the safety profile of the 2 interferons, there were more hepatobiliary events observed in the Lambda arm and more hematologic events in the Alfa arm.\n\n\nCONCLUSIONS\nIn this comparison of Lambda/RBV/TVR and Alfa/RBV/TVR in patients who were treatment-naïve or had relapsed on prior Alfa/RBV treatment, Lambda failed to demonstrate noninferiority based on SVR12 results. Treatment with Lambda/RBV/TVR was associated with a higher incidence of relapse. More patients discontinued Lambda/RBV/TVR treatment during the first 4 weeks of study treatment, mainly due to hepatobiliary-related events, and more Lambda patients were lost to follow-up.",
"affiliations": "Department of Infectious Diseases and Hepatology, Medical University of Bialystock, Bialystock, Poland.;Bon Secours Liver Institute of Virginia, Richmond, Virginia, United States of America.;Department of Gastroenterology and Hepatology, University Hospital Donostia, San Sebastián, Spain.;Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.;Department of Higher Level General Medicine, Russian State Medical University, Moscow, Russia.;Research and Development, Bristol-Myers Squibb, Inc., Wallingford, Connecticut, United States of America.;Research and Development, Bristol-Myers Squibb, Inc., Wallingford, Connecticut, United States of America.;Research and Development, Bristol-Myers Squibb, Inc., Wallingford, Connecticut, United States of America.",
"authors": "Flisiak|Robert|R|;Shiffman|Mitchell|M|;Arenas|Juan|J|;Cheinquer|Hugo|H|;Nikitin|Igor|I|;Dong|Yuping|Y|;Rana|Khurram|K|;Srinivasan|Subasree|S|",
"chemical_list": "D000998:Antiviral Agents; C471044:IFNL3 protein, human; D016898:Interferon-alpha; D007378:Interleukins; D009842:Oligopeptides; D012367:RNA, Viral; D011994:Recombinant Proteins; C000600496:peginterferon lambda-1a; D011092:Polyethylene Glycols; D012254:Ribavirin; C486464:telaprevir; D007372:Interferons; C100416:peginterferon alfa-2a",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0164563",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2774990010.1371/journal.pone.0164563PONE-D-16-12779Research ArticleBiology and life sciencesOrganismsVirusesRNA virusesFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensFlavivirusesHepacivirusHepatitis C virusBiology and life sciencesMicrobiologyMedical microbiologyMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusMedicine and health sciencesPathology and laboratory medicinePathogensMicrobial pathogensViral pathogensHepatitis virusesHepatitis C virusBiology and life sciencesOrganismsVirusesViral pathogensHepatitis virusesHepatitis C virusBiology and Life SciencesBiochemistryProteinsInterferonsMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesCirrhosisBiology and Life SciencesBiochemistryEnzymologyEnzymesTransferasesAminotransferasesBiology and Life SciencesBiochemistryProteinsEnzymesTransferasesAminotransferasesResearch and Analysis MethodsResearch DesignClinical Research DesignAdverse EventsMedicine and Health SciencesGastroenterology and HepatologyLiver DiseasesChronic Liver DiseaseChronic HepatitisBiology and Life SciencesToxicologyToxicityMedicine and Health SciencesPathology and Laboratory MedicineToxicologyToxicityBiology and Life SciencesVeterinary ScienceVeterinary DiseasesA Randomized Study of Peginterferon Lambda-1a Compared to Peginterferon Alfa-2a in Combination with Ribavirin and Telaprevir in Patients with Genotype-1 Chronic Hepatitis C Lambda/RBV/TVR vs Alfa/RBV/TVR in GT-1 Chronic HCVFlisiak Robert 1Shiffman Mitchell 2Arenas Juan 3Cheinquer Hugo 4Nikitin Igor 5Dong Yuping 6Rana Khurram 6Srinivasan Subasree 6*1 \nDepartment of Infectious Diseases and Hepatology, Medical University of Bialystock, Bialystock, Poland2 \nBon Secours Liver Institute of Virginia, Richmond, Virginia, United States of America3 \nDepartment of Gastroenterology and Hepatology, University Hospital Donostia, San Sebastián, Spain4 \nDepartment of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil5 \nDepartment of Higher Level General Medicine, Russian State Medical University, Moscow, Russia6 \nResearch and Development, Bristol-Myers Squibb, Inc., Wallingford, Connecticut, United States of AmericaSu Chien-Wei EditorTaipei Veterans General Hospital, TAIWANCompeting Interests: Grants were provided by Bristol-Myers Squib, Achillion, AbbVie, Gilead, Beckman-Colter, Beohringer-Ingelheim, Conatus, CymaBay, Galectin, Immuron, Intercept, Lumena, NGMBio. The authors of this manuscript are also employed by Bristol-Myers Squib (S. S., K. R., Y. D.).\n\nConceived and designed the experiments: SS YD.\n\nPerformed the experiments: RF MS JA HC IN.\n\nAnalyzed the data: RF MS JA HC IN KR SS.\n\nContributed reagents/materials/analysis tools: YD KR SS.\n\nWrote the paper: RF MS JA HC IN YD KR SS.\n\n\n\n\n* E-mail: subasree@sbcglobal.net17 10 2016 2016 11 10 e016456329 3 2016 2 9 2016 © 2016 Flisiak et al2016Flisiak 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.Background\nA randomized, double-blind, multinational, phase 3 study was conducted comparing the efficacy and safety of peginterferon lambda-1a (Lambda)/ribavirin (RBV)/telaprevir (TVR) vs. peginterferon alfa-2a (Alfa)/RBV/TVR in patients with chronic hepatitis C virus (HCV) genotype-1 (GT-1) infection.\n\nMethods\nPatients (treatment-naïve or relapsers on prior Alfa/RBV treatment) were randomly assigned in a 2:1 ratio to receive Lambda/RBV/TVR or Alfa/RBV/TVR. Total duration of treatment was either 24 or 48 weeks (response-guided treatment), with TVR administered for the first 12 weeks. The primary endpoint was the proportion of patients who achieved a sustained virologic response at post treatment week 12 (SVR12), which was tested for noninferiority of Lambda/RBV/TVR.\n\nResults\nA total of 838 patients were enrolled, and 617 were treated; 411 and 206 patients received Lambda/RBV/TVR and Alfa/RBV/TVR, respectively. The majority of patients were treatment-naïve, with HCV GT-1b and a high baseline viral load (≥800,000 IU/mL). Less than 10% of patients had cirrhosis (Lambda, 7.5%; Alfa, 6.8%). Lambda/RBV/TVR did not meet the criterion for noninferiority (lower bound of the treatment difference interval was -12.3%); the SVR12 in all patients (modified intent-to-treat) was 76.2% in the Lambda arm and 82.0% in the Alfa arm. Overall, the frequency of adverse events in each arm was comparable (Lambda, 91.7%; Alfa, 97.1%). As expected based on the safety profile of the 2 interferons, there were more hepatobiliary events observed in the Lambda arm and more hematologic events in the Alfa arm.\n\nConclusions\nIn this comparison of Lambda/RBV/TVR and Alfa/RBV/TVR in patients who were treatment-naïve or had relapsed on prior Alfa/RBV treatment, Lambda failed to demonstrate noninferiority based on SVR12 results. Treatment with Lambda/RBV/TVR was associated with a higher incidence of relapse. More patients discontinued Lambda/RBV/TVR treatment during the first 4 weeks of study treatment, mainly due to hepatobiliary-related events, and more Lambda patients were lost to follow-up.\n\nhttp://dx.doi.org/10.13039/100002491Bristol-Myers SquibbBristol-Myers Squibb (the sponsor) designed the study in collaboration with the academic investigators (Robert Flisiak, Mitchell Shiffman, Juan Arenas, Hugo Cheinquer, and Igor Nikitin), conducted the study, collected study data, and performed statistical analyses. The sponsor, together with all authors, interpreted the data and drafted the manuscript with the assistance of a medical writer funded by the sponsor. Authors employed by the sponsor (Yuping Dong, Khurram Rana, and Subasree Srinivasan), in concert with all other authors, approved the final manuscript and made the decision to submit the manuscript for publication. 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\nUntil recently, the basis of treatment for infection with chronic hepatitis C virus (HCV) involved the use of a type I interferon (IFN), peginterferon alfa-2a or -2b (Alfa), plus ribavirin (RBV); however, these regimens are associated with treatment-limiting hematologic and systemic toxicity [1], due largely to the expression of the type I IFN receptor complex on a wide variety of nonhepatic cell types [2,3]. In 2003, type III (lambda) IFNs were identified [4,5]. Lambda IFNs have antiviral activity similar to that of type I IFNs [2,4,6], however their receptor complexes are expressed on a more limited subset of host cells, suggesting treatment with IFN lambda may be associated with fewer systemic adverse events (AEs) [2,3]. Clinical trials assessing the efficacy and safety of peginterferon lambda-1a (Lambda)-based regimens for treatment of chronic HCV infection have shown improved overall tolerability, along with similar efficacy, compared to Alfa-based regimens [7].\n\nIn 2011, regulatory authorities in the United States and in many countries in Europe approved 2 direct-acting antivirals (DAAs), telaprevir (TVR) [8] and boceprevir (BOC) [9], for use in combination with Alfa plus RBV for the treatment of IFN/RBV-naïve and -experienced patients with genotype-1 (GT-1) chronic HCV infection. Response-guided treatment using TVR or BOC, each in combination with Alfa/RBV, was shown to reduce treatment duration and improve sustained virologic response (SVR) rates in treatment-naïve and -experienced patients [10–14]. Although these new combination regimens demonstrated improved efficacy, they were not without both tolerability and resistance challenges.\n\nAt the time this study was initiated, IFN-based alternatives to Alfa with the potential for improved tolerability and efficacy were being developed for use in combination with RBV with or without a DAA. Based on the improved safety profile of Lambda vs. Alfa and the improved efficacy of Alfa plus RBV when combined with a DAA [10–14], the combination of Lambda/RBV/DAA was of interest. To investigate this option, Lambda and Alfa, each administered in combination with RBV plus TVR (TVR selected because of its wider usage at the time), were evaluated in this study to compare their safety and efficacy profiles in patients with chronic HCV GT-1 infection.\n\nMaterials and Methods\nTrial design\nThis was a randomized, double-blind, multinational, phase 3 study in patients with GT-1 chronic HCV infection (treatment-naïve or relapsed following prior Alfa/RBV treatment) (supporting CONSORT checklist is available as supporting information; see S1 Checklist). Patients were randomly assigned 2:1 to receive Lambda (180 μg by subcutaneous [SC] injection once weekly) or Alfa (180 μg by SC injection once weekly), each administered in combination with RBV (1000 mg per day orally for patients weighing <75 kg and 1200 mg per day orally for patients weighing ≥75 kg) plus TVR (750 mg orally 3 times daily) during the first 12 weeks, followed by either Lambda/RBV or Alfa/RBV for a total treatment duration of 24 or 48 weeks depending on the achievement or not, respectively, of an extended rapid virologic response (eRVR; defined as undetectable HCV RNA at weeks 4 and 12 of treatment). Patients with cirrhosis completed a total of 48 weeks of treatment, regardless of their eRVR status. At the completion of treatment, all patients were to receive off-treatment follow-up for 48 weeks. Randomization was stratified according to interleukin-28B (IL28B) host GT (CC vs. non-CC), treatment-naïve versus prior relapse status, and HCV GT (1a vs. 1b), and was performed by a sponsor-designated center via an Interactive Voice Response System using a block size of 6. Both site and subjects were blinded to treatment for the entire study. A designated member of the study staff at each investigative site was unblinded and responsible for dispensing study medication.\n\nPatients\nThe study population was comprised of adults (aged ≥18) who were naïve to prior anti-HCV therapy (including IFN and DAA), or prior relapsers to Alfa/RBV, with GT-1a or -1b chronic HCV infection and HCV RNA ≥100,000 IU/mL. Patients with cirrhosis as determined by either liver biopsy indicating METAVIR score F4 or equivalent, or by FibroScan® score ≥14.6 kPa were eligible to participate. After the trial started, the protocol was amended to exclude patients with significant portal hypertension (eg, hepatic venous pressure gradient [HVPG] ≥10 mmHg, splenomegaly ≥12 cm (diameter), and a Fibroscan score >21 kPa) who could be at an increased risk of developing hepatic decompensation during treatment. Patients who were co-infected with hepatitis B virus or human immunodeficiency virus (HIV), had other medical conditions contributing to chronic liver disease, had current or prior evidence of portal hypertension, or had previous exposure to a DAA were excluded from participating.\n\nThe study was conducted in accordance with Good Clinical Practice (GCP), as defined by the International Conference on Harmonization (ICH) and in accordance with the ethical principles underlying the European Union Directive 2001/20/EC and the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50). The study protocol and any amendments were approved by the institutional review board/independent ethics committee at each site (Protocol and IRBs available as supporting information; see S1 Protocol and S1 IRBs), and all patients provided written informed consent. This study has been registered at ClinicalTrials.gov, identifier NCT01598090 (https://clinicaltrials.gov/ct2/show/NCT01598090?term=nct01598090&rank=1)\n\nEndpoints and assessments\nThe primary endpoint was the proportion of patients who achieved SVR at post treatment week 12 (SVR12). Secondary efficacy endpoints included: the proportion of patients who achieved rapid virologic response (RVR; defined as undetectable HCV RNA at week 4 of treatment); eRVR; end of treatment response (EOTR); and the proportion of treatment-naïve patients who achieved SVR12.\n\nSecondary safety endpoints included the proportion of patients with: rash-related dermatologic events reported during the first 12 weeks of treatment; treatment-emergent cytopenic abnormalities defined as hemoglobin <10 g/dL, absolute neutrophil count <750 x 106/L, and platelet count <50000 x 106/L; on-treatment flu-like symptoms; on-treatment musculoskeletal symptoms; serious adverse events (SAEs); discontinuation due to AEs; dose reductions throughout the study; and laboratory abnormalities. Laboratory abnormalities were measured and graded using the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events (grade 1–2, mild to moderate; grade 3–4, severe to potentially life-threatening).\n\nPlasma HCV RNA was assessed using the COBAS® TaqMan® HCV Test v2.0 (Roche Molecular Systems Inc., Pleasanton, California, USA) with a lower limit of quantification (LLOQ) of 25 IU/mL. HCV RNA was assessed at baseline, week 2, every 2 weeks through week 12, then at weeks 16, 20, 24, 36, and 48, and at post-treatment follow-up weeks 4, 12, 24, 36, and 48.\n\nTreatment was discontinued if any of the following futility criteria were met: (1) HCV RNA >1000 IU/mL at week 4 or 12; (2) confirmed HCV RNA detected at week 24; or (3) a virologic breakthrough, defined as a confirmed increase in HCV RNA >1 × log10 above nadir or HCV RNA ≥LLOQ after previously having HCV RNA <LLOQ while on treatment.\n\nStatistical analysis\nThe primary endpoint, SVR12, was tested for noninferiority between Lambda/RBV/TVR and Alfa/RBV/TVR treatment arms. Power calculations to determine appropriate sample sizes assumed a 79% response rate for both Lambda/RBV/TVR and Alfa/RBV/TVR and a −12% boundary for comparison with the lower limit of the two-sided 95% confidence interval (CI) for the treatment difference (Lambda/RBV/TVR—Alfa/RBV/TVR). Sample sizes of 406 patients treated with Lambda/RBV/TVR and 203 patients treated with Alfa/RBV/TVR, resulted in a 95% power to demonstrate noninferiority of Lambda/RBV/TVR to Alfa/RBV/TVR for the proportion of patients with SVR12.\n\nAnalyses were performed using the modified intent-to-treat (mITT) population, which includes all randomized patients who received at least one treatment dose. Patients with missing data for an endpoint were treated as nonresponders. Treatment differences in SVR12 rate and 95% CI were estimated using the stratum-adjusted Mantel-Haenszel approach. All testing was performed at a significance level of 0.05.\n\nResults\nPatient disposition and baseline characteristics\nA total of 838 patients were enrolled starting in March of 2013, and the last patient visit occurred in February of 2015. Following enrollment, 217 patients were excluded from randomization for reasons detailed in Fig 1. Of the 621 patients randomized (2:1), 617 were treated: 411 received Lambda/RBV/TVR, and 206 received Alfa/RBV/TVR. A similar proportion of patients completed treatment in both study arms (Lambda, 82.5%; Alfa, 83.0%). Because the clinical development of Lambda was discontinued while this study was in progress, the trial was terminated after all patients had received at least 12 weeks of post-treatment follow-up to determine SVR12 but not the initially planned 48 weeks of post-treatment follow-up assessments.\n\n10.1371/journal.pone.0164563.g001Fig 1 Patient disposition and reasons for discontinuation.\nRBV, ribavirin; TVR, telaprevir.\n\nPatient demographic and disease characteristics were comparable between the 2 study arms (Table 1). The majority of patients were white, HCV GT-1b, treatment-naïve, IL28B non-CC GT, with a high (≥800,000 IU/mL) baseline viral load. Less than 10% of patients had cirrhosis (Lambda, 7.5%; Alfa, 6.8%). Because more study sites were located in Europe than in North America, enrollment was mostly in Europe.\n\n10.1371/journal.pone.0164563.t001Table 1 Baseline demographic and disease characteristics.\nHCV, hepatitis C virus; IL28B, interleukin 28B; RBV, ribavirin; TVR, telaprevir.\n\nCharacteristic\tLambda/RBV/TVR (n = 411)\tAlfa/RBV/TVR (n = 206)\t\nAge (years), median (range)\t48.0 (19–77)\t46.0 (19–71)\t\nAge category, n (%)\t\t\t\n<21\t5 (1.2)\t2 (1.0)\t\n21–64 years\t392 (95.4)\t197 (95.6)\t\n≥65 years\t14 (3.4)\t7 (3.4)\t\nHepatitis C disease-related characteristics\t\t\t\nHCV RNA (log10 IU/mL)\t\t\t\nMedian\t6.6\t6.6\t\nHCV RNA distribution, n (%)\t\t\t\n<800,000 IU/mL\t57 (13.9)\t35 (17.0)\t\n≥800,000 IU/mL\t354 (86.1)\t171 (83.0)\t\nHCV genotype, n (%)\t\t\t\n1a\t171 (41.6)\t84 (40.8)\t\n1b\t240 (58.4)\t122 (59.2)\t\nPrior relapse to peginterferon Alfa/RBV, n (%)\t\t\t\nRelapser\t101 (24.6)\t50 (24.3)\t\nNaïve\t309 (75.2)\t156 (75.7)\t\nNot reported\t1 (0.2)\t0\t\nStage of fibrosis, n (%)\t\t\t\nNone or mild\t241 (58.6)\t122 (59.2)\t\nModerate or severe\t118 (28.7)\t63 (30.6)\t\nCirrhosis\t31 (7.5)\t14 (6.8)\t\nNot reported\t21 (5.1)\t7 (3.4)\t\nIL28B genotype, n (%)\t\t\t\nCC\t97 (23.6)\t48 (23.3)\t\nCT\t242 (58.9)\t125 (60.7)\t\nTT\t72 (17.5)\t33 (16.0)\t\nRegion, n (%)\t\t\t\nEurope\t239 (58.2)\t137 (66.5)\t\nNorth America\t115 (28.0)\t43 (20.9)\t\nSouth America\t39 (9.5)\t19 (9.2)\t\nAsia\t18 (4.4)\t7 (3.4)\t\nKey efficacy endpoints\nA summary of key efficacy endpoints is shown in Table 2. Lambda/RBV/TVR did not meet the goal of noninferiority; the SVR12 rates (mITT) were 76.2% in patients treated with Lambda and 82.0% in patients treated with Alfa. The lower limit of the two-sided 95% CI for the treatment difference (Lambda—Alfa) was −12.3%, which was less than the prespecified lower bound of −12.0%.\n\n10.1371/journal.pone.0164563.t002Table 2 Summary of key efficacy endpoints.\nCI, confidence interval; EOTR, end-of-treatment response; eRVR, extended rapid virologic response; mITT, modified intent-to-treat; RBV, ribavirin; RVR, rapid virologic response; SVR12, sustained virologic response at week 12 post-treatment follow-up; TVR, telaprevir.\n\n\tLambda/RBV/TVR (n = 411) Responder/Evaluable n/N (%; 95% CI)\tAlfa/RBV/TVR (n = 206) Responder/Evaluable n/N (%; 95% CI)\t\nmITT analyses\t\t\t\nSVR12 (all patients)\t313/411 (76.2; 72.0–80.3)\t169/206 (82.0; 76.8–87.3)\t\nSVR12 (naïve patients)\t229/311 (73.6; 68.7–78.5)\t127/155 (81.9; 75.9–88.0)\t\nRVR\t275/411 (66.9; 62.4–71.5)\t157/206 (76.2; 70.4–82.0)\t\neRVR\t263/411 (64.0; 59.3–68.6)\t146/206 (70.9; 64.7–77.1)\t\nEOTR\t368/411 (89.5; 86.6–92.5)\t187/206 (90.8; 86.8–94.7)\t\nThe subset of patients treated with Lambda/RBV/TVR who were treatment-naïve also did not achieve SVR12 noninferiority (Lambda, 73.6%; Alfa, 81.9%; lower bound of the treatment difference interval was -15.8%). The RVR and eRVR rates were both lower in the Lambda arm (Table 2), although the complete early virologic response (cEVR; defined as undetectable HCV RNA at week 12 of treatment) was slightly higher with Lambda (Lambda, 88.1%; Alfa, 85.4%). Based on the eRVR rates, more patients in the Lambda arm than in the Alfa arm had to be treated for 48 weeks. The EOTR was comparable for both groups (Lambda, 89.5%; Alfa, 90.8%). However, there were more relapsers in the Lambda arm than in the Alfa arm (Lambda, 6.0%; Alfa, 4.3%). Virologic breakthrough occurred in 15 patients (3.6%) treated with Lambda versus 4 patients (1.9%) treated with Alfa; most of these 15 patients did not complete treatment.\n\nThe SVR12 rates for various patient subgroups, including high (≥800,000 IU/mL), GT-1a, treatment-naïve, baseline cirrhosis, and IL28B CC, are shown in Table 3. The SVR12 was comparable or higher following treatment with Alfa than with Lambda in all subgroups except for prior relapsers to Alfa/RBV; in this group, a comparable proportion of patients achieved SVR12 with Lambda (84.2%) compared to Alfa (82.0%).\n\n10.1371/journal.pone.0164563.t003Table 3 Subgroup analysis for SVR12.\nCI, confidence interval; HCV, hepatitis C virus; IL28B, interleukin 28B; RBV, ribavirin; SVR12, sustained virologic response at week 12 post-treatment follow-up; TVR, telaprevir.\n\n\tLambda/RBV/TVR (n = 411) Responder/Evaluable n/N (%; 95% CI)\tAlfa/RBV/TVR (n = 206) Responder/Evaluable n/N (%; 95% CI)\t\nHCV RNA distribution\t\t\t\n<800,000 IU/mL\t54/57 (94.7; 88.9–100.0)\t33/35 (94.3; 86.6–100.0)\t\n≥800,000 IU/mL\t259/354 (73.2; 68.5–77.8)\t136/171 (79.5; 73.5–85.6)\t\nHCV genotype\t\t\t\n1a\t119/171 (69.6; 62.7–76.5)\t65/84 (77.4; 68.4–86.3)\t\n1b\t194/240 (80.8; 75.9–85.8)\t104/122 (85.2; 79.0–91.5)\t\nPrior relapse to peginterferon Alfa/RBV\t\t\t\nRelapser\t85/101 (84.2; 77.0–91.3)\t41/50 (82.0; 71.4–92.6)\t\nNaïve\t228/309 (73.8; 68.9–78.7)\t128/156 (82.1; 76.0–88.1)\t\nNot reported\t0/1 (0.0; 0.0–0.0)\tNA\t\nBaseline cirrhosis status\t\t\t\nPresent\t16/31 (51.6; 34.0–69.2)\t10/14 (71.4; 47.8–95.1)\t\nAbsent\t282/359 (78.6; 74.3–82.8)\t153/185 (82.7; 77.3–88.2)\t\nNot reported\t15/21 (71.4; 52.1–90.8)\t6/7 (85.7; 59.8–100.0)\t\nIL28B genotype\t\t\t\nCC\t77/97 (79.4; 71.3–87.4)\t39/48 (81.3; 70.2–92.3)\t\nNon-CC\t236/314 (75.2; 70.4–79.9)\t130/158 (82.3; 76.3–88.2)\t\nSafety\nOn-treatment safety data, including AEs (any grade) in ≥20% of patients in any treatment group and SAEs, are summarized in Table 4. The vast majority of patients experienced at least one AE (Lambda, 91.7%; Alfa, 97.1%).\n\n10.1371/journal.pone.0164563.t004Table 4 On-treatment safety.\nAE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; RBV, ribavirin; TVR, telaprevir.\n\n\tLambda/RBV/TVR (n = 411)\tAlfa/RBV/TVR (n = 206)\t\nTotal number of patients with an AE, n (%)\t377 (91.7)\t200 (97.1)\t\nAEs (any grade) in ≥20% patients in any treatment group, n (%)\t\t\t\nPruritus\t187 (45.5)\t100 (48.5)\t\nNausea\t172 (41.8)\t67 (32.5)\t\nFatigue\t143 (34.8)\t75 (36.4)\t\nRash\t124 (30.2)\t59 (28.6)\t\nInsomnia\t102 (24.8)\t56 (27.2)\t\nDecreased appetite\t85 (20.7)\t42 (20.4)\t\nAsthenia\t81 (19.7)\t61 (29.6)\t\nHeadache\t66 (16.1)\t42 (20.4)\t\nAnemia\t54 (13.1)\t100 (48.5)\t\nArthralgia\t49 (11.9)\t43 (20.9)\t\nMyalgia\t49 (11.9)\t43 (20.9)\t\nPyrexia\t31 (7.5)\t53 (25.7)\t\nGrade 3/4 laboratory abnormalities, n (%)\t\t\t\nALT\t30 (7.3)\t1 (0.5)\t\nAST\t48 (11.7)\t2 (1.0)\t\nTotal bilirubin\t75 (18.2)\t10 (4.9)\t\nHemoglobin\t11 (2.7)\t45 (21.8)\t\nNeutrophils\t7 (1.7)\t39 (18.9)\t\nPlatelets\t1 (0.2)\t2 (1.0)\t\nSide effects typically associated with Alfa were statistically significantly lower with Lambda than with Alfa, including: emergent laboratory cytopenic abnormalities (Lambda, 11.7%; Alfa, 55.8%; p < 0.0001); flu-like symptoms (Lambda, 14.4%; Alfa 36.4%; p < 0.0001); and musculoskeletal symptoms (Lambda, 21.4%; Alfa, 30.6%; p < 0.0139). However, there was no overall difference between treatment arms with respect to rash-related dermatologic events (Lambda, 36.3%; Alfa, 38.3%), likely due to the use of TVR in both treatment regimens.\n\nA comparable proportion of patients discontinued treatment due to AEs (Lambda, 8.0%; Alfa, 8.3%). However, more patients discontinued treatment due to AEs during the first 4 weeks of therapy with Lambda than with Alfa, which contributed to the lower RVR observed in the Lambda arm.\n\nSerious AE (SAE) rates were comparable across the 2 treatment arms (Lambda, 10.5%; Alfa, 9.7%), with the most common hepatobiliary-related AE, jaundice (considered an important medical event) occurring more frequently in the Lambda arm (Lambda, 2.7%; Alfa, 1.0%) and rash occurring more frequently in the Alfa arm (Lambda, 0.2%; Alfa, 2.4%).\n\nTwo deaths were reported, one due to pneumonia (Lambda arm at treatment week 24), which was considered not related to study treatment, and one due to hypoxia (Alfa arm at treatment week 40), which was considered related to study treatment. The latter patient had a long history of tobacco use and a medical history of interstitial lung disease.\n\nTreatment-emergent laboratory abnormalities were generally consistent with the AE profiles for Lambda and Alfa (Table 4). Grade 3/4 elevations of alanine aminotransferase, aspartate aminotransferase, and total bilirubin were more frequent in the Lambda arm, while grade 3/4 cytopenic abnormalities were more frequent in the Alfa arm.\n\nOverall, the proportion of dose reductions for the peginterferon component of the study regimen was comparable for both treatment arms (Lambda, 12.7%; Alfa, 14.1%) but generally occurred for different reasons. In the Lambda arm, dose reductions occurred most commonly as a result of elevated liver function tests (10.2%), while in the Alfa treatment arm, dose reductions occurred most commonly because of hematologic toxicity (12.1%). The majority of RBV dose reductions were for hematologic toxicity and were substantially higher in the Alfa arm (40.8%) compared with the Lambda arm (9.5%).\n\nDiscussion\nIn this comparison of Lambda/RBV/TVR and Alfa/RBV/TVR in patients with GT-1 chronic HCV infection, Lambda failed to demonstrate noninferiority to Alfa for the primary (SVR12 overall) efficacy endpoint. For the primary endpoint, the overall SVR12 rate for Lambda/RBV/TVR (76.2%) was lower than the SVR12 rate for Alfa/RBV/TVR (82.0%). SVR rates obtained in large, randomized, controlled trials with similar patient populations and similar regimens of Alfa/RBV/TVR have ranged from 72.0% to 83.0% [10–12] and the result from this study for the Alfa arm was in the upper end of this range.\n\nIn this study, patients from both treatment groups infected with HCV GT-1b responded with a higher SVR12 rate than those with HCV GT-1a. These results are consistent with published results on response of GT-1 subtypes to IFN/RBV/DAA combinations, including IFN/RBV/TVR [10]. Also consistent with prior observations [15], patients from both treatment groups who had lower baseline HCV RNA levels had higher response rates than those with higher HCV RNA levels. In this study, SVR12 in prior relapsers to Alfa/RBV following retreatment with Lambda/RBV/TVR (84.2%) was higher than in HCV treatment-naive patients and comparable to the rate observed in the Alfa/RBV/TVR treatment arm (82.0%). This observation is consistent with the findings from other studies of Alfa/RBV/TVR therapy in chronic HCV infection, which have shown that response rates are generally higher in patients who relapsed after prior Alfa/RBV therapy than in treatment-naïve patients [10,12]. This observation is not surprising, as prior relapsers represent a relatively homogeneous group of patients who have responded to treatment previously and who would be expected to respond favorably to a retreatment regimen that includes a DAA. Finally, comparable responses were observed in the CC genotype and non-CC genotype patients treated with Alfa/RBV/TVR. IL28B genotype is a predictor of treatment response to a non-DAA interferon regimen; therefore, typically higher response rates might have been expected in the CC genotype patients. However, the increasing potency of treatment regimens, which include one or more DAAs, including TVR, has led to a diminished role of IL28B status in the prediction of treatment response.\n\nA number of factors may explain the difference in response rates in patients receiving Lambda and Alfa in this study. Patients treated with Lambda experienced more relapses compared with patients treated with Alfa. Slightly more patients treated with Lambda were lost to follow-up during the study (patients lost to follow-up were considered treatment failures in the study analysis). In addition, although baseline disease characteristics were balanced in the study arms, slightly more patients had cirrhosis in the Lambda arm (7.5%) vs. the Alfa arm, (6.8%), and these patients appeared to have a lower SVR12 response.\n\nEven though more relapses may have been observed in the Lambda arm as compared with the Alfa arm in this study, the relapse rate for Lambda is consistent with relapse rates observed in another TVR study [10] and was lower than the relapse rates observed in the phase 2b EMERGE study of Lambda/RBV vs. Alfa/RBV in HCV GT-1 patients (19.6% with Lambda/RBV and 18.4% with Alfa/RBV) [7]. Like other studies with TVR, the addition of TVR reduced the relapse rate when compared with non-DAA interferon regimens.\n\nThe RVR with Lambda treatment was lower than with Alfa treatment, suggesting that Lambda was not as efficacious in suppressing HCV within the first 4 weeks of treatment. This finding is not consistent with the Lambda phase 2b EMERGE study, which demonstrated higher RVR rates for Lambda/RBV than for Alfa/RBV and comparable SVR rates [7]. During these first 4 weeks of treatment, discontinuations due to AEs were more frequent in the Lambda arm than in the Alfa arm and more patients in the Lambda arm discontinued due to hepatobiliary-related events, therefore limiting the opportunity for these subjects to achieve virologic control. Hence, the inability to complete the required treatment duration may have negatively impacted both the early viral suppression rates and SVR12 rates for patients receiving Lambda.\n\nIn terms of safety, the Lambda and Alfa behaved as expected based on the cellular distribution of their respective receptors: more hepatic-related events (including discontinuations due to AEs) were seen with Lambda, while more hematologic and systemic AEs were seen with Alfa. The frequency of grade 3/4 alanine aminotransferase and aspartate aminotransferase elevations were higher with Lambda (11.7% and 7.3%, respectively) than Alfa (1.0% and 0.5%, respectively) but were also higher than that previously observed with Lambda/RBV (3%) [7]. The reasons for these elevations are unclear.\n\nAlthough it might be expected that improved tolerability with Lambda would lead to higher response rates as compared with Alfa-based regimens, the goal of Lambda treatment was to provide a regimen that was comparable to Alfa treatment without the treatment-limiting side effects of Alfa, with higher response rates being an added benefit, if observed. In this study, side effects that are typically associated with Alfa treatment such as emergent cytopenic abnormalities, flu-like symptoms, and musculoskeletal symptoms were lower with Lambda treatment. However, higher hepatobiliary-related events occurred with Lambda treatment, which led to early discontinuation of therapy and may have negated any potential benefit of this treatment. The addition of TVR in both groups also contributed to the side effect profile and was consistent with effects as observed in other TVR studies. Regarding central nervous system (CNS) AEs related to IFN therapy, the mechanisms and the specific receptors involved are not well understood. Differences in CNS AEs between groups treated with Lambda and Alfa were not observed in the previous clinical phase 2b study with Lambda; therefore, in the present study, differences were not anticipated, nor were they observed.\n\nSince the development of this study, treatment for chronic HCV infection has substantially evolved, with the approval of next generation, all-oral, IFN-free, direct-acting regimens that achieve high SVR rates with improved tolerability. Due to the diminished role of IFN-based regimens for the treatment of chronic HCV infection, the Lambda clinical development program has been discontinued. However, Lambda may be investigated to treat other viral infections such as chronic hepatitis D virus (HDV) infection. Moreover, the results of this study broaden the safety and efficacy information for Lambda as a therapeutic agent and are important to understanding the biology and tolerability of type III IFNs and the potential clinical importance of Lambda beyond HCV treatment. Although type I IFNs (alfa and beta) and type III IFNs (lambda) activate the same intracellular signaling pathway and possess many of the same biological activities, alfa receptors are broadly expressed on most cell types, while lambda receptors outside of the liver are largely restricted to cells of epithelial origin and plasmacytoid dendritic cells [16]. As a result, treatment with Lambda was expected to provide improved tolerability with comparable SVR rates. However, results of the present study show that when Lambda and TVR are combined in a treatment regimen, any potential benefit based on biology may be offset by a more complicated safety profile. Although Lambda is no longer being evaluated as a therapeutic alternative to Alfa for the treatment of HCV infection, Lambda may be investigated for treatment of other diseases of infectious or noninfectious etiology.\n\nConclusions\nIn this comparison of Lambda/RBV/TVR and Alfa/RBV/TVR for SVR12 in patients who were treatment-naïve or relapsers on prior treatment with Alfa/RBV, Lambda failed to demonstrate noninferiority. The safety profiles, as anticipated, were hepatobiliary-related in the Lambda arm, while those receiving Alfa had more of hematologic and systemic toxicities that are commonly associated with Alfa treatment.\n\nSupporting Information\nS1 Checklist (DOC)\n\nClick here for additional data file.\n\n S1 Protocol (PDF)\n\nClick here for additional data file.\n\n S1 IRBs (DOC)\n\nClick here for additional data file.\n\n We would like to acknowledge Cynthia Schultz, PhD, for assistance with medical writing and Dena McWain for editorial support.\n==== Refs\nReferences\n1 Ghany MG , Nelson DR , Strader DB , Thomas DL , Seeff LB . An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases . Hepatology . 2011 ; 54 : 1433 –1444 . 10.1002/hep.24641 \n21898493 \n2 Zhou Z , Hamming OJ , Ank N , Paludan SR , Nielsen AL , Hartmann R . Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases . J Virol . 2007 ; 81 : 7749 –7758 . 10.1128/JVI.02438-06 \n17507495 \n3 Doyle SE , Schreckhise H , Khuu-Duong K , Henderson K , Rosler R , Storey H , et al\nInterleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes . Hepatology . 2006 ; 44 : 896 –906 . 10.1002/hep.21312 \n17006906 \n4 Kotenko SV , Gallagher G , Baurin VV , Lewis-Antes A , Shen M , Shah NK , et al\nIFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex . Nat Immunol . 2003 ; 4 : 69 –77 . 10.1038/ni875 \n12483210 \n5 Sheppard P , Kindsvogel W , Xu W , Henderson K , Schlutsmeyer S , Whitmore TE , et al\nIL-28, IL-29 and their class II cytokine receptor IL-28R . Nat Immunol . 2003 ; 4 : 63 –68 . 10.1038/ni873 \n12469119 \n6 Dumoutier L , Tounsi A , Michiels T , Sommereyns C , Kotenko SV , Renauld JC . Role of the interleukin (IL)-28 receptor tyrosine residues for antiviral and antiproliferative activity of IL-29/interferon-lambda 1: similarities with type I interferon signaling . J Biol Chem . 2004 ; 279 : 32269 –32274 . 10.1074/jbc.M404789200 \n15166220 \n7 Muir AJ , Arora S , Everson G , Flisiak R , George J , Ghalib R , et al\nA randomized phase 2b study of peginterferon lambda-1a for the treatment of chronic HCV infection . J Hepatol . 2014 ; 61 : 1238 –1246 . 10.1016/j.jhep.2014.07.022 \n25064437 \n8 INCIVEK™ (telaprevir) [prescribing information]. Cambridge, MA; Vertex Pharmaceuticals Inc.; October 2013.\n9 VICTRELIS® (boceprevir) [prescribing information]. Whitehouse Station, NJ; Merck & Co., Inc.; August 2015.\n10 Jacobson IM , McHutchison JG , Dusheiko G , Di Bisceglie AM , Reddy KR , Bzowej NH , et al\nTelaprevir for previously untreated chronic hepatitis C virus infection . N Engl J Med . 2011 ; 364 : 2405 –2416 . 10.1056/NEJMoa1012912 \n21696307 \n11 Sherman KE , Flamm SL , Afdhal NH , Nelson DR , Sulkowski MS , Everson GT , et al\nResponse-guided telaprevir combination treatment for hepatitis c virus infection . N Engl J Med . 2011 ; 365 : 1014 –1024 . 10.1056/NEJMoa1014463 \n21916639 \n12 Zeuzem S , Andreone P , Pol S , Lawitz E , Diago M , Roberts S , et al\nTelaprevir for retreatment of HCV infection . N Engl J Med . 2011 ; 364 : 2417 –2428 . 10.1056/NEJMoa1013086 \n21696308 \n13 Poordad F , McCone J Jr, Bacon BR , Bruno S , Manns MP , Sulkowski MS , et al\nBoceprevir for untreated chronic HCV genotype 1 infection . N Engl J Med . 2011 ; 364 : 1195 –1206 . 10.1056/NEJMoa1010494 \n21449783 \n14 Bacon BR , Gordon SC , Lawitz E , Marcellin P , Vierling JM , Zeuzem S , et al\nBoceprevir for previously treated chronic HCV genotype 1 infection . N Engl J Med . 2011 ; 364 : 1207 –1217 . 10.1056/NEJMoa1009482 \n21449784 \n15 Zhu Y , Chen S . Antiviral treatment of hepatitis C virus infection and factors affecting efficacy . World J Gastroenterol . 2013 ; 19 : 8963 –8673 . 10.3748/wjg.v19.i47.8963 \n24379621 \n16 Donnelly RP , Kotenko SV . Interferon-lambda: a new addition to an old family . J Interferon Cytokine Res . 2010 ; 30 : 555 –564 . 10.1089/jir.2010.0078 \n20712453\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "11(10)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D006402:Hematologic Diseases; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; D016896:Treatment Outcome; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0164563",
"pmc": null,
"pmid": "27749900",
"pubdate": "2016",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": "12469119;21898493;17507495;25064437;24379621;17006906;21916639;12483210;21449784;15166220;21449783;21696308;21696307;20712453",
"title": "A Randomized Study of Peginterferon Lambda-1a Compared to Peginterferon Alfa-2a in Combination with Ribavirin and Telaprevir in Patients with Genotype-1 Chronic Hepatitis C.",
"title_normalized": "a randomized study of peginterferon lambda 1a compared to peginterferon alfa 2a in combination with ribavirin and telaprevir in patients with genotype 1 chronic hepatitis c"
} | [
{
"companynumb": "PL-ROCHE-1860327",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEGINTERFERON ALFA-2A"
},
"drugadditional": "3",
... |
{
"abstract": "Psoriasis is a systemic immune-inflammatory disease characterized by chronic or recurrent skin symptoms, psoriatic arthritis, enthesopathy, and uveitis. Psoriasis has recently been published to appear with various autoimmune disorders, but the coexistence has been systematically reviewed by only few studies until now. In the present study, charts and electronic database of 4344 patients with various systemic autoimmune disorders, under regular medical control at our department, were reviewed retrospectively searching for association with psoriasis. Hereby, we demonstrate 25 psoriatic patients coinciding with various systemic autoimmune diseases. The coexistence of psoriasis and autoimmune diseases resulted in the worsening of the clinical outcome of the autoimmune diseases as indicated by higher frequency and dosages of glucocorticoid use, need for biologicals, and other comorbidities. These results suggest common environmental and genetic background as well as therapeutic possibilities in the future.",
"affiliations": "National Institute of Rheumatology and Physiotherapy, Frankel Leó Utca 38-40, Budapest 1023, Hungary.;Institute of Immunology, Rikshospitalet, Oslo University Hospital, 0027 Oslo, Norway.;National Institute of Rheumatology and Physiotherapy, Frankel Leó Utca 38-40, Budapest 1023, Hungary.;National Institute of Rheumatology and Physiotherapy, Frankel Leó Utca 38-40, Budapest 1023, Hungary.;National Institute of Rheumatology and Physiotherapy, Frankel Leó Utca 38-40, Budapest 1023, Hungary.;National Institute of Rheumatology and Physiotherapy, Frankel Leó Utca 38-40, Budapest 1023, Hungary.;National Institute of Rheumatology and Physiotherapy, Frankel Leó Utca 38-40, Budapest 1023, Hungary.",
"authors": "Bazsó|Anna|A|;Szodoray|Péter|P|;Szappanos|Ágnes|Á|;Korda|Judit|J|;Pálfi|Patrícia|P|;Kiss|Emese|E|;Poór|Gyula|G|",
"chemical_list": "D005938:Glucocorticoids",
"country": "United States",
"delete": false,
"doi": "10.1155/2015/657907",
"fulltext": "\n==== Front\nMediators InflammMediators InflammMIMediators of Inflammation0962-93511466-1861Hindawi Publishing Corporation 10.1155/2015/657907Clinical StudySystemic Autoimmune, Rheumatic Diseases and Coinciding Psoriasis: Data from a Large Single-Centre Registry and Review of the Literature Bazsó Anna \n1\n\n*\nSzodoray Péter \n2\nSzappanos Ágnes \n1\nKorda Judit \n1\nPálfi Patrícia \n1\nhttp://orcid.org/0000-0002-5399-2379Kiss Emese \n1\nPoór Gyula \n1\n1National Institute of Rheumatology and Physiotherapy, Frankel Leó Utca 38-40, Budapest 1023, Hungary2Institute of Immunology, Rikshospitalet, Oslo University Hospital, 0027 Oslo, Norway*Anna Bazsó: bazsoanna@yahoo.comAcademic Editor: Yrjö Konttinen\n\n2015 3 8 2015 2015 65790714 9 2014 10 11 2014 Copyright © 2015 Anna Bazsó et al.2015This 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.Psoriasis is a systemic immune-inflammatory disease characterized by chronic or recurrent skin symptoms, psoriatic arthritis, enthesopathy, and uveitis. Psoriasis has recently been published to appear with various autoimmune disorders, but the coexistence has been systematically reviewed by only few studies until now. In the present study, charts and electronic database of 4344 patients with various systemic autoimmune disorders, under regular medical control at our department, were reviewed retrospectively searching for association with psoriasis. Hereby, we demonstrate 25 psoriatic patients coinciding with various systemic autoimmune diseases. The coexistence of psoriasis and autoimmune diseases resulted in the worsening of the clinical outcome of the autoimmune diseases as indicated by higher frequency and dosages of glucocorticoid use, need for biologicals, and other comorbidities. These results suggest common environmental and genetic background as well as therapeutic possibilities in the future.\n==== Body\n1. Introduction\nAutoimmunity is characterized by the breakdown of self-tolerance leading to a state of abnormal humoral and cell-mediated responses agaissnst self-components. Psoriasis is an immune-inflammatory skin disease affecting 2-3% of the general population which can be associated with psoriatic arthritis (PsA), enthesopathy, uveitis, and an increased prevalence of cardiovascular morbidity [1]. The association between psoriasis and systemic autoimmune, rheumatic diseases is rare and little is known about its exact incidence. The pathogenesis of both disease entities involves genetic background and environmental triggers. A potential role of molecular mimicry has previously been described in the pathogenesis not only of autoimmune disease but also of psoriasis [2]. Several autoantigens have been implicated in psoriasis, amongst which are keratin 13 (K13), heterogeneous nuclear ribonucleoprotein-A1 (hnRNP-A1), and Rab coupling protein isoform 3 (FLJ00294) (RAB11FIP1), although the epidermal autoantigens have not been conclusively identified [3]. Underlying the importance of genetic associations, previously a clear correlation has been shown between psoriasis and risk of the development of diseases with autoimmune background, such as rheumatoid arthritis (RA), type 1 diabetes, celiac disease, or Crohn's disease, based on the single nucleotide polymorphism (SNP) analysis of the TNFAIP3 gene [4].\n\nIn this work, we demonstrate 25 patients with psoriasis and various systemic autoimmune diseases. Among the patients with autoimmune diseases included in our database we selected those who were associated with psoriasis. Our survey aimed to determine the prevalence of coinciding psoriasis in autoimmune conditions and whether psoriasis has an impact on the outcome of associated autoimmune diseases.\n\n2. Materials and Methods\nIn this retrospective study medical charts and electronic database of patients, regularly followed at the National Institute of Rheumatology and Physiotherapy, were systematically reviewed searching for psoriasis as comorbidity. As psoriasis associated with the highest frequency to RA and SLE the same number of patients with and without psoriasis was selected and matched according to gender and age at onset, and as such case-control study could be performed. Patients in these subgroups were compared regarding the onset of the autoimmune diseases, clinical symptoms, and disease duration, as well as dose of corticosteroid and response to conventional and biological immunosuppressive therapies. In case of other autoimmune diseases only few patients belonged to subgroups with psoriasis; therefore a case-control study would not have been informative by statistical respect. Patients with psoriatic arthritis fulfilled the diagnostic criteria by laboratory markers, symptoms, and radiographic images and were distinguished from the joint manifestations of the coexisting autoimmune diseases.\n\n2.1. Study Population\nOut of the 4344 investigated patients (1450 with RA, 835 with Sjögren's syndrome, 807 with SLE, 486 with Raynaud's syndrome, 113 with undifferentiated connective diseases (UCTD), 313 with primary antiphospholipid syndrome (PAPS), 144 with polymyositis (PM), 127 with primary systemic vasculitis, 85 with systemic sclerosis, and 69 with mixed connective tissue diseases (MCTD)), 25 had coinciding psoriasis. Psoriatic arthritis was present in 14 cases. All patients fulfilled the corresponding classification criteria of the above-mentioned autoimmune diseases [1, 5–16]. Psoriasis coexisted with SLE (n = 8), rheumatoid arthritis (n = 5), primary Sjögren's syndrome (n = 5), primary Raynaud's syndrome (n = 4), primary systemic vasculitis (n = 3), APS (n = 2), systemic sclerosis (n = 2), UCTD (n = 1), polymyositis (n = 1), and MCTD (n = 1). Various other comorbidities also associate with different autoimmune diseases, such as hypertension, crystal arthritis, interstitial lung disease, ischemic heart disease, cataract, and glaucoma.\n\n2.2. Data Collection\nThe clinical and laboratory data were collected from the institute's electronic patient databases from inpatient and outpatient visits. The following diseases were investigated: SLE, primary systemic vasculitis, PAPS, UCTD, primary Raynaud's syndrome, PM, systemic sclerosis, MCTD, primary Sjögren's disease, and RA. Each specific disease was treated as an outcome variable. All diagnoses for these conditions were recorded from September 2007 to November 2013. In our database the following data were detected: age at the onset of the autoimmune diseases, clinical symptoms, immune serology, associated diseases, disease duration, coexistence of psoriatic arthritis, actual clinical state, and average dose of corticosteroid, immune suppressive therapy, and response to the therapy.\n\n2.3. Statistical Analysis\nAll statistical analyses were performed using IBM SPSS 20 software. Fisher's exact test was utilized to assess the average age of appearance of psoriasis and psoriatic arthritis and Mann-Whitney U test was performed to measure the average of corticosteroid usage.\n\n3. Results\nWe determined the frequency of psoriasis in various autoimmune diseases and also assessed the rate of the psoriatic arthritis. We also aimed to compare demographic and disease-specific characteristics of RA and SLE with and without associating psoriasis.\n\nThere were 25 eligible individuals who fulfilled the criteria for psoriasis in the study population. The frequency of coinciding psoriasis was 0.99% in RA, 0.34% in SLE, 0.59% in Sjögren's syndrome, 0.82% in Raynaud's syndrome, 3.29% in systemic vasculitis, 6.3% in PAPS, 0.69% in PM, 2.35% in systemic sclerosis, 1.17% in UCTD, and 1.44% in MCTD. Out of the psoriatic cases 62.5% (n = 15) had psoriatic arthritis. Compared to the estimated vary of the population from 0.3% to 1% [15]. Psoriatic arthritis was diagnosed and distinguished from the musculoskeletal manifestations of the autoimmune diseases by the CASPAR criteria [16]. The median (min-max) age at autoimmune disease onset was 48 (24–68) years. Of those with psoriasis 12% were male and 88% were female. In 18 patients psoriasis developed first. In psoriatic patients who also suffered from different kinds of autoimmune diseases an increased rate of comorbidities was observed.\n\nThe second goal was to analyze demographic characteristics and the outcome of clinical symptoms in RA and SLE. In the case-control study the same number of patients with and without psoriasis was selected and matched out of our entire RA and SLE population. Demographic and disease-specific and treatment-associated data were compared in psoriatic and nonpsoriatic SLE and RA groups. The average age of appearance of psoriasis was 48 (24–68) years. The female to male ratio was 3 : 22 (12% and 88%). The appearance of psoriasis before and after the age of 40 years was similar (13/11 or 54% and 46%); however the frequency of psoriatic arthritis was significantly higher after 40 years of age (1/14 or 7% and 93%). Significantly higher doses of glucocorticoid (GC) were required in the SLE with psoriasis group (16.88 (10–30)) compared to SLE without psoriasis (11.4 (7.5–20)) (Tables 3 and 4). On the contrary in RA patients with psoriasis both the number of patients on GC and both the used GC doses were lower as compared to those with RA patients without associating psoriasis (Tables 1 and 2). The fact can be explained by differences in the usage of biological therapies, as all patients from the RA + psoriasis group were on TNF-alpha inhibitors, while in the control group only 1 patient received biological therapy. Both the SLE- and RA-associated psoriasis groups required intensified immune suppressive therapy. The association of psoriasis in both RA and SLE groups was characterized by worse laboratory markers, diseases outcome, and response to therapy. In the RA + psoriasis group 4 patients (80%) had other coinciding diseases, such as hypertension, neurofibromatosis, Sjögren's syndrome, and systemic sclerosis, as compared to the RA group where 2 patients (40%) had hypertension and Sjögren's syndrome. There were no significant differences of the immunological serology markers between the 2 groups. The responses to disease-modifying antirheumatic drugs (DMARDs) therapy were significantly worse in the RA + psoriasis group, since none of the patients responded or had side effects of the DMARDs. All patients of the RA + psoriasis group were treated with biologicals and 2 patients (40%) needed to switch to another biological therapy, while in the RA group only 1 patient (20%) received biological therapy and all (100%) patients were in remission (defined as Das28 <2.1) (Tables 1 and 2). In the SLE + psoriasis group 7 patients had comorbidities (87.5%) as compared to the 6 patients (75%) in the SLE-only group. Similar to the RA groups there were no significant differences in immunological markers between the 2 groups. Otherwise, in the SLE + psoriasis group 5 patients (62.5%) had relapse, 2 patients (25%) had worsening outcome, and only 1 patient (12.5%) was in remission when compared to the SLE group, where all patients were in remission. In the SLE + psoriasis group all patients received more than 1 immunosuppressive agent and the systemic lupus international collaborating clinics (SLICC) index was elevated in 7 patients (87.5%) compared to the SLE group (37.5%). The average dose of corticosteroids (PED) was 17.5 mg in the SLE + psoriasis group and 11.4 mg in the SLE-only group (Tables 3 and 4).\n\n4. Discussion\nThe overlap between psoriasis and autoimmune diseases is unusual. Differential diagnostic problems may also occur. The prevalence of psoriasis in African Americans is 1.3% compared to the 2.5% in Caucasians [17]. In our database we found 25 patients (0.545%) with psoriasis from the 4344 autoimmune disorders. In the general population the prevalence of skin psoriasis is around 2-3%. The lower prevalence, found in our data base, can probably be attributed to concurrent existence of national tertiary dermatology centre taking care of psoriatic patients. Therefore, our centre followed those patients who suffer from psoriatic arthritis or other autoimmune disorders. We have confirmed that the overlapping psoriasis and autoimmune diseases result in the worsening of the autoimmune diseases, reflected by the increased corticosteroid usage, worse response to the therapy, and the appearance of other comorbidities. We have not observed a significantly higher tendency to develop more autoimmune diseases in patients with psoriatic arthritis. Particularly, in case of patients with RA and psoriasis, physicians should be aware of the possible development of psoriatic arthritis. Despite the unusual association there are several similarities in the innate and adaptive pathways and genetic and environmental—including the infections—background between psoriasis and autoimmune diseases.\n\nTh1, Th17, and IL-22-producing CD4 T cells in psoriasis and autoimmunity have recently been supposed. The concept of molecular mimicry is based on a structural similarity between a pathogen and a metabolite and self-structures. Epidemiological findings show a strong correlation between EBV infection and the risk of developing sclerosis multiplex, SLE, RA, and primer SS [18]. There are some gene variants evaluated to be involved and are common in the pathogenesis of the four diseases of cytokine pathways (e.g., IRF5, STAT4, and TNFSF4) leading to the development of autoimmunity [19]. Regarding the genetic association between psoriasis and autoimmunity, TNF-alpha-induced protein 3 (TNFAIP3) has been shown to be a major candidate. Multiple variants of TNFAIP3 could modulate development of autoimmunity in different diseases. The TNFAIP3 gene region has been implicated in the susceptibility to multiple autoimmune diseases in Europe. SNPs ~ 185 kb upstream from the TNFAIP3 gene have a strong association with risk of RA, type 1 diabetes (T1D), celiac disease (CeD), and Crohn's disease [20]. Two independent studies regard the association between TNFAIP3 and SLE in a European cohort [21, 22]. Wu et al. have confirmed in a well-powered, genetic case-control study that both psoriasis and autoimmune diseases have complex genetic basis; multiple genes contribute to disease risk [23]. Overlapping of some gene locations of different autoimmune diseases has been known and supports common pathogenic gene variants (PTPN 22, Csk, PAG, PSTPIP1, PDCD1, SLC9A3R1, CARD15, and SUMO4) transcript within these diseases [24]. TNF-alpha polymorphism or TNF-alpha can increase the development of psoriasis or psoriatic arthritis. TNF inhibitors are effective in the treatment of psoriasis as well as in RA; however they can induce antinuclear antibodies and even lupus [25].\n\nInterleukin-17 is a Th17 cytokine associated with inflammation, autoimmunity, and defence against some bacteria; it has been implicated in many chronic autoimmune diseases including psoriasis, Crohn's disease, autoimmune uveitis, SLE, ankylosing spondylitis, asthma, multiple sclerosis, and systemic sclerosis [26]. The pathophysiologic relevance of the IL-23-IL-17 axis in autoinflammatory diseases is highlighted by the clinical efficacy of antibodies targeting IL-23/IL-12 p40 and IL-17 in treating psoriasis, as well as the other systemic autoimmune diseases [27]. The level of IL-17 was significantly higher in serum of SLE patients than in normal controls, indicating that IL-17 may trigger the inflammatory process, although no correlation was found between serum IL-17 levels and disease manifestation or SLEDAI [28]. In general, the common IL-23-IL-17 axis may also initiate and maintain the coexistence of psoriasis and other systemic autoimmune diseases [27, 28].\n\nThe other prominent cytokine highlighting the common pathway is interferon- (IFN-) alpha, mainly produced by plasmacytoid dendritic cells (PDCs) [29]. IFN-alpha plays a pivotal role in the development of SLE, insulin-dependent diabetes mellitus (IDDM), or RA. In psoriatic lesions plasmacytoid dendritic cell infiltrations have been shown, indicating that IFN-alpha may contribute to the pathogenesis of these diseases [29–32].\n\nThe humoral and cellular immunity have been shown to act against endothelial antigens and moreover it has a greater risk of atherosclerosis in both diseases as RA and SLE. So, these processes highlighted the significance of autoimmunity in atherosclerotic processes. Both angiogenic and oxidative pathways have a common role in the pathophysiology of psoriasis and atherosclerosis. Psoriasis and autoimmune diseases have a strong relationship with lipid metabolism and oxidative stress. Heat shock protein (Hsp) and human Hsp are known as possible pathogenic links between infection and atherosclerosis, as well as infection and autoimmunity [33, 34]. However, the immune-mediated inflammatory disease (IMID) is a group of diseases without exact etiology, but involving common inflammatory pathways resulting in many diseases as psoriasis, psoriatic arthritis and atherosclerosis, also. Psoriasis and autoimmune diseases also associate with an increased risk of atherosclerosis. Activated inflammatory cells and proinflammatory cytokines contribute to the psoriatic lesions and the rupture of atherosclerotic plaque. Macrophages also interact with T cells and other cells via activation of the CD40-CD40 ligand pathway, which contributes to the atheromatous plaque rupture [34]. Anti-CD40 therapy has been shown to be efficacious in some autoimmune diseases, such as SLE, vasculitis, and pSS [35]. Several studies have shown the endothelial cell dysfunction, the deficiency of nitric oxide (NO)2, elevated endothelin 1 (ET-1), angiotensin II (Ang II), plasminogen activator inhibitor 1 (PAI-1), and cellular adhesion molecules. Furthermore, other common pathognomonic factors such as the Toll-like receptors (TLR2 and TLR4) play key roles in atherosclerosis. TLR2 and TLR4 bind to components of gram positive and gram negative bacteria which could be a pathognomonic factor in autoimmunity, as mentioned above [34].\n\nSerum leptin, resistin, and lipocalin are increased in psoriasis patients and have a potential important role for developing insulin resistance and cardiovascular disease in psoriasis. An adipose tissue secreted cytokine, called adiponectin, is able to improve insulin resistance. Its serum level is decreased in psoriatic patients. The decreased level of different adipokines and Th17 cytokine has also associated in patients with psoriasis and autoimmune diseases, as well. However, leptin, adiponectin, resistin, and visfatin play a significant role in physiopathology of several inflammatory diseases. Moreover, all are involved strongly in other relevant inflammatory conditions and autoimmune disorders [36].\n\nNutritional compounds and drugs also trigger autoimmune disease. There are some data about the association of the early exposure to dietary cow's milk proteins and a decreased risk of T1D; tienilic acid, dihydralazine, and halothane have been reported to induce autoimmune hepatitis. Stress and smoking are also associated susceptibilities to many autoimmune diseases [37].\n\nMoreover, there is also strong association between autoimmunity and psoriasis when analyzing new bone formations and bone erosion as cellular biomarkers such as osteoclast precursors; osteoprotegerin (OPG), matrix metalloproteinase 3, serum IL-6, and IL-2R alpha were found elevated. OPG is produced not only in bone but also in several other tissues, including the cardiovascular system, lungs, kidneys, immune tissues, and blood vessels. In vascular system, increased OPG levels may be related to endothelial lesion, intimal hyperplasia, smooth cell hypertrophy, or advanced plaque calcification [38].\n\n5. Summary\nWe believe that further prospective, cohort studies are required to determine real frequency of psoriasis in various autoimmune diseases as well as the incidence of autoimmune diseases within psoriatic patients. Positive and negative prognostic factors are still to be identified. The characteristics and outcome of autoimmune diseases and psoriasis also have to be followed.\n\nOur present findings suggest that psoriasis exists as a negative predictive factor for the clinical outcome of autoimmune diseases. Despite there being several similarities between the pathogenesis of psoriasis and autoimmune diseases it was surprising to find the low frequencies of coexistence.\n\nPatients with RA and psoriasis are more likely to receive biological therapy, while patients with SLE and psoriasis need significant higher doses of glucocorticoids. TNF-α inhibitors are effective in the treatment of psoriasis; however they can induce antinuclear antibodies and even lupus. Therapeutic considerations have to be done in overlapping cases. Biologicals with different ways of action, for example, targeting of IL-17 and IL-23, dendritic cell suppression, might reduce activity of both diseases. Röhn et al. and de Carvalho et al. explored the fact that neutralization of IL-17 by passive and active vaccination may be a novel therapeutic approach for the treatment of SLE and atherosclerosis [39, 40]. Targeting IFN-alpha, RANK-RANKL, and CD40-CD40L system could also be beneficial for the prevention and early therapeutic intervention in psoriasis and other related autoimmune diseases [30, 34, 35, 38].\n\nAcknowledgment\nAll of the charges will be paid by Swedish Orphan Biovitrum.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\n\nTable 1 Patient characteristics with rheumatoid arthritis associated with psoriasis. \n\nThe age of RA onset \tComorbidity \tImmunoserology \tActual clinical status \tDMARD therapy \tResponse to DMARD \tCorticosteroids (mg PED) \tBiological therapy \tResponse to biology therapy \tPsoriatic arthritis \t\n63 yrs \tHypertension \tANA, ACPA \tRemission \tSulfasalazine-leukopenia, oral methotrexate-gastrointestinal side effect, cyclosporine-with golimumab\tNonresponder \t—\tGolimumab \tRemission \tAxial \t\n\n\n\t\n46 yrs \t—\tRF, ACPA, ANA \tRemission \tOral methotrexate-ineffective, sulfasalazine-gastrointestinal side effect \tNonresponder \t—\tEtanercept \tRemission \tPeripheral \t\n\n\n\t\n59 yrs \tSystemic sclerosis \tRF, ACPA, ANA \tRemission \tChloroquine-gastrointestinal side effect sulfasalazine \tNonresponder \t—\tAdalimumab-ineffective, rituximab \tRemission \tPeripheral \t\n\n\n\t\n32 yrs \tHypertension \tRF, ACPA, ANA \tActive polyarthritis \tOral methotrexate-bone marrow toxicity azathioprine-ineffective cyclosporine-ineffective combination of chloroquine, sulfasalazine, oral methotrexate-GI side effect subcutaneous methotrexate \tIneffective \t>7.5 continuously \tAdalimumab-ineffective etanercept-ineffective golimumab-ineffective \tNonresponder \tPeripheral and axial \t\n\n\n\t\n40 yrs \tSjögren's syndrome, neurofibromatosis \tRF, ACPA, ANA, aCL IgM \tSevere glandular symptoms, active polyarthritis \tLeflunomide-ineffective, oral methotrexate-hepatotoxicity \tNonresponder \t—\tEtanercept \tJust started \tPeripheral \t\nRA: rheumatoid arthritis, ANA: anti-nuclear antibody, ACPA: anti-citrullinated peptide antibody, aCL IgM: anti-cardiolipin antibody immunoglobulin M, DMARD: disease-modifying antirheumatic drugs, and PED: prednisolone equivalent dose.\n\nTable 2 Patient characteristics with rheumatoid arthritis only.\n\nAt the age of RA onset \tComorbidity \tImmunoserology \tDMARD therapy \tResponse to DMARD \tCorticosteroids (mg PED)\tBiological therapy \tResponse to biology therapy \t\n63 yrs \tHypertension \tRF, ACPA \tSulfasalazine-ineffective, leflunomide-allergic side effect, oral methotrexate\tPartial response \t<7.5 \tTocilizumab \tRemission \t\n\n\n\t\n46 yrs \t—\tRF, ACPA, ANA \tCombination of oral methotrexate and chloroquine \tRemission \t10 \t—\t—\t\n\n\n\t\n59 yrs \tSjögren's syndrome \tRF, ACPA, ANA \tCombination of oral methotrexate and chloroquine \tRemission \t10 \t—\t—\t\n\n\n\t\n32 yrs \t—\tRF, ACPA, ANA \tCombination of subcutaneous methotrexate and chloroquine \tRemission \t—\t—\t—\t\n\n\n\t\n40 yrs \t—\tRF, ACPA \tSubcutaneous methotrexate \tRemission \t—\t—\t—\t\nRA: rheumatoid arthritis, ANA: anti-nuclear antibody, ACPA: anti-citrullinated peptide antibody, DMARD: disease-modifying antirheumatic drugs, and PED: prednisolone equivalent dose.\n\nTable 3 Patient characteristics with SLE associated with psoriasis.\n\nThe age of SLE onset\tComorbidity \tImmunoserology \tActual clinical status \tTherapy \tArthritis psoriatica \tCorticosteroids (mg PED) \tSLICC \t\n27 yrs \tLupus nephritis, autoimmune thyroiditis \tANA, aSSA, aSSB, aTPO \tRelapsing, remission by MMF \tCyclophosphamide, mycophenolate mofetil, methylprednisolone \tPeripheral \t25 \t1 \t\n\n\n\t\n54 yrs \tHypertension, gout, ischaemic heart disease, COPD, cataract \tANA, a-dsDNA \tRelapsing \tChloroquine, azathioprine, methylprednisolone, etanercept \tAxial \t12.5 \t4 \t\n\n\n\t\n45 yrs \t—\tANA, a-SM, a-SSA \tRemission \tOral methotrexate, leflunomide, chloroquine \t—\t—\t0 \t\n\n\n\t\n24 yrs \tRaynaud's syndrome, cutaneous vasculitis \tANA, a-dsDNA, a-SSA, aSSB, β2GPI IgG, hypocomplementaemia \tRelapsing \tMethylprednisolone, azathioprine, intravenous cyclophosphamide, IVIG, plasmapheresis, \t—\t30 \t1 \t\n\n\n\t\n33 yrs \tAutoimmune thyroiditis, nephrotic syndrome \tANA, a-TPO, lupus anticoagulant, aCL IgM \tRelapsing \tMethylprednisolone, chloroquine, oral methotrexate, \t—\t10 \t1 \t\n\n\n\t\n57 yrs \tSjögren's syndrome \tANA, a-SSA, a-SSB, a-dsDNA, hypocomplementaemia \tRelapsing \tOral methotrexate, methylprednisolone, sulfasalazine, intravenous cyclophosphamide \t—\t20 \t1 \t\n\n\n\t\n58 yrs\tSjögren's syndrome, urticaria vasculitis, ILD \tANA, a-dsDNA, a-chromatin, hypocomplementaemia \tWorsening of ILD, psoriasis, immunoserology \tOral methotrexate, sulfasalazine, intravenous cyclophosphamide \tAxial \t30 \t1 \t\n\n\n\t\n29 yrs \tSjögren's syndrome \tANA, a-dsDNA, a-SSA, a-SSB, anti-RNP, a-U1RNP, a-TG \tWorsening of psychosis, thrombocytopenia \tMethylprednisolone \t—\t12.5 \t1 \t\nSLE: systemic lupus erythematosus, COPD: chronic obstructive pulmonary disease, ILD: interstitial lung disease, ANA: anti-nuclear antibody, ACPA: anti-citrullinated peptide antibody, a-SSA: anti-Sjögren's syndrome A antibody, a-SSB: anti-Sjögren's syndrome B antibody, anti-RNP: anti-ribonucleoprotein antibody, a-dsDNA: anti-double stranded deoxyribonucleic acid antibody, β2GPI IgG: beta 2 glycoprotein I IgG, aCL IgM: anti-cardiolipin antibody immunoglobulin M, aU1RNP: anti-U1 ribonucleoprotein antibody, a-TG: anti-thyroglobulin antibody, a-TPO: anti-thyreoid peroxidase antibody, MMF: mycophenolate mofetil, PED: prednisolone equivalent dose, and SLICC: systemic lupus international collaborating clinics.\n\nTable 4 Patient characteristics with SLE only.\n\nThe age of SLE onset \tComorbidity \tImmunoserology \tActual clinical status \tTherapy \tCorticosteroids (mg PED) \tSLICC \t\n27 yrs \t—\tANA, a-SSA, a-SSB, a-U1RNP, hypocomplementaemia \tRemission \tAzathioprine, low-dose corticosteroid \t13.75 \t0 \t\n\n\n\t\n54 yrs \tGout, diabetes mellitus, COPD, ischemic heart disease \tANA, a-dsDNA, a-chromatin \tRemission \tLow-dose corticosteroid \t12.5 \t1 \t\n\n\n\t\n45 yrs \t—\tANA, a -Sm, a-SSA, a-U1RNP, aCL IgM\tRemission \t—\t20 \t2 \t\n\n\n\t\n24 yrs \tRaynaud's syndrome, Sjögren's syndrome, Hashimoto-thyroiditis, seronegative rheumatoid arthritis (erosive polyarthritis), idiopathic thrombocytopenic purpura \tANA, a-ENA, a-SSA, a-dsDNA, a-Sm, a-TPO \tRemission \t—\t10 \t0 \t\n\n\n\t\n33 yrs \tSjögren's syndrome \tANA, a-dsDNA, a-SSA, a-SSB, aCL IgM \tRemission \t—\t8.7 \t0 \t\n\n\n\t\n58 yrs \tSjögren's syndrome, \tANA, a-dsDNA, a-SSA, a-SSB, \tRemission \t—\t8.75 \t0 \t\ntype 2 diabetes mellitus \t\n\n\n\t\n57 yrs \tRheumatoid arthritis, sacroiliitis \tANA, a-ACPA, a-dsDNA, a-Sm, a-U1RNP \tRemission \t—\t7.5 \t0 \t\n\n\n\t\n29 yrs \tRheumatoid arthritis, asthma bronchial, aseptic femur-head necrosis, cataract, glaucoma \tANA, a-ACPA, a-dsDNA \tRemission \t—\t10 \t2 \t\nSLE: systemic lupus erythematosus, COPD: chronic obstructive pulmonary disease, ILD: interstitial lung disease, ANA: anti-nuclear antibody, a-SSA: anti-Sjögren's syndrome A antibody, a-SSB: anti-Sjögren's syndrome B antibody, a-chromatin: anti-chromatin antibody, anti-RNP: anti-ribonucleoprotein antibody, a-dsDNA: anti-double stranded deoxyribonucleic acid antibody, anti-Sm: anti-Smith antibody, aCL IgM: anti-cardiolipin antibody immunoglobulin M, a-U1RNP: anti-U1 ribonucleoprotein antibody, a-TPO: anti-thyreoid peroxidase antibody, MMF: mycophenolate mofetil, PED: prednisolone equivalent dose, and SLICC: systemic lupus international collaborating clinics.\n==== Refs\n1 Raychaudhuri S. K. Maverakis E. Raychaudhuri S. P. Diagnosis and classification of psoriasis Autoimmunity Reviews 2014 13 4-5 490 495 10.1016/j.autrev.2014.01.008 2-s2.0-84896319342 24434359 \n2 Wu J. J. Nguyen T. U. Poon K. Y. T. Herrinton L. J. The association of psoriasis with autoimmune diseases Journal of the American Academy of Dermatology 2012 67 5 924 930 10.1016/j.jaad.2012.04.039 2-s2.0-84872688172 22664308 \n3 Jones D. A. Yawalkar N. Suh K.-Y. Sadat S. Rich B. Kupper T. S. Identification of autoantigens in psoriatic plaques using expression cloning Journal of Investigative Dermatology 2004 123 1 93 100 10.1111/j.0022-202X.2004.22709.x 2-s2.0-3042633817 15191548 \n4 Fung E. Y. M. G. Smyth D. J. Howson J. M. M. Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus Genes & Immunity 2009 10 2 188 191 10.1038/gene.2008.99 2-s2.0-61849117976 19110536 \n5 Aletaha D. Neogi T. Silman A. J. 2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiativ Annals of the Rheumatic Diseases 2010 62 9 1580 1588 10.1136/ard.2010.138461 20699241 \n6 Shiboski S. C. Shiboski C. H. Criswell L. A. American College of rheumatology classification criteria for Sjögren's syndrome: a data-driven, expert consensus approach in the Sjögren's International Collaborative Clinical Alliance cohort Arthritis Care and Research 2012 64 4 475 487 10.1002/acr.21591 2-s2.0-84859739536 22563590 \n7 Petri M. Orbai A. M. Alarcón G. S. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus Arthritis & Rheumatology 2012 64 8 2677 2686 \n8 Wigley F. M. Raynaud’s phenomen Current Opinion in Rheumatology 1993 5 6 773 784 8117541 \n9 Basu N. Watts R. Bajema I. EULAR points to consider in the development of classification and diagnostic criteria in systemic vasculitis Annals of the Rheumatic Diseases 2010 69 10 1744 1750 10.1136/ard.2009.119032 2-s2.0-77955735444 20448283 \n10 van den Hoogen F. Khanna D. Fransen J. 2013 classification criteria for systemic sclerosis: an American college of rheumatology/European league against rheumatism collaborative initiative Annals of the Rheumatic Diseases 2013 72 11 1747 1755 10.1136/annrheumdis-2013-204424 2-s2.0-84885126599 24092682 \n11 Mosca M. Tani C. Vagnani S. The diagnosis and classification of undifferentiated connective tissue diseases Journal of Autoimmunity 2014 48-49 50 52 10.1016/j.jaut.2014.01.019 24518855 \n12 Gómez-Puerta J. A. Cervera R. Diagnosis and classification of the antiphospholipid syndrome Journal of Autoimmunity 2014 48-49 20 25 10.1016/j.jaut.2014.01.006 24461539 \n13 Milisenda J. C. Selva-O'Callaghan A. The diagnosis and classification of polymyositis Journal of Autoimmunity 2014 48-49 118 122 24461380 \n14 Tani C. Carli L. Vagnani S. The diagnosis and classification of mixed connective tissue disease Journal of Autoimmunity 2014 48-49 46 49 10.1016/j.jaut.2014.01.008 24461387 \n15 Gladman D. D. Antoni C. Mease P. Clegg D. O. Nash O. Psoriatic arthritis: epidemiology, clinical features, course, and outcome Annals of the Rheumatic Diseases 2005 64 2 ii14 ii17 10.1136/ard.2004.032482 2-s2.0-14244260176 15708927 \n16 Congi L. Roussou E. Clinical application of the CASPAR criteria for psoriatic arthritis compared to other existing criteria Clinical and Experimental Rheumatology 2010 28 3 304 310 2-s2.0-77956994481 20576225 \n17 Gelfand J. M. Stern R. S. Nijsten T. The prevalence of psoriasis in African Americans: results from a population-based study Journal of the American Academy of Dermatology 2005 52 1 23 26 10.1016/j.jaad.2004.07.045 2-s2.0-11144327646 15627076 \n18 Draborg A. H. Duus K. Houen G. Epstein-barr virus in systemic autoimmune diseases Clinical and Developmental Immunology 2013 2013 9 535738 10.1155/2013/535738 2-s2.0-84884230830 \n19 Lodolce J. P. Kolodziej L. E. Rhee L. African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity The Journal of Immunology 2010 184 12 7001 7009 2-s2.0-77953639241 10.4049/jimmunol.1000324 20483768 \n20 Lodolce J. P. Kolodziej L. E. Rhee L. African-derived genetic polymorphisms in TNFAIP3 mediate risk for autoimmunity Journal of Immunology 2010 184 12 7001 7009 10.4049/jimmunol.1000324 2-s2.0-77953639241 \n21 Ramos P. S. Criswell L. A. Moser K. L. A comprehensive analysis of shared loci between systemic lupus erythematosus (SLE) and sixteen autoimmune diseases reveals limited genetic overlap PLoS Genetics 2011 7 12 e1002406 10.1371/journal.pgen.1002406 2-s2.0-84855257058 \n22 Adrianto I. Wen F. Templeton A. Association of a functional variant downstream of TNFAIP3 with systemic lupus erythematosus Nature Genetics 2011 43 3 253 258 10.1038/ng.766 2-s2.0-79952192654 21336280 \n23 Wu J. J. Nguyen T. U. Poon K.-Y. T. Herrinton L. J. The association of psoriasis with autoimmune diseases Journal of the American Academy of Dermatology 2012 67 5 924 930 10.1016/j.jaad.2012.04.039 2-s2.0-84872688172 22664308 \n24 Bowcock A. M. The genetics of psoriasis and autoimmunity Annual Review of Genomics and Human Genetics 2005 6 93 122 10.1146/annurev.genom.6.080604.162324 2-s2.0-25844505509 \n25 Williams V. L. Cohen P. R. TNF alpha antagonist-induced lupus-like syndrome: report and review of the literature with implications for treatment with alternative TNF alpha antagonists International Journal of Dermatology 2011 50 5 619 625 10.1111/j.1365-4632.2011.04871.x 2-s2.0-79955003756 21506984 \n26 Bedoya S. K. Lam B. Lau K. Larkin J. III Th17 cells in immunity and autoimmunity Clinical and Developmental Immunology 2013 2013 16 986789 10.1155/2013/986789 \n27 Lowes M. A. Russell C. B. Martin D. A. Towne J. E. Krueger J. G. The IL-23/T17 pathogenic axis in psoriasis is amplified by keratinocyte responses Trends in Immunology 2013 34 4 174 181 10.1016/j.it.2012.11.005 2-s2.0-84875864504 23291100 \n28 Vincent F. B. Northcott M. Hoi A. Mackay F. Morand E. F. Clinical associations of serum interleukin-17 in systemic lupus erythematosus Arthritis Research and Therapy 2013 15 4, article R97 10.1186/ar4277 2-s2.0-84882529537 \n29 Cao W. Pivotal functions of plasmacytoid dendritic cells in systemic autoimmune pathogenesis Journal of Clinical & Cellular Immunology 2014 5 2 p. 212 \n30 Kassim S. H. Jordan J. Schreiter J. Adhikarakunnathu S. Baribaud F. San Mateo L. Systematic identification of novel SLE related autoantibodies responsible for type I IFN production in human plasmacytoid dendritic cells Cellular Immunology 2013 284 1-2 119 128 10.1016/j.cellimm.2013.07.017 2-s2.0-84883023691 23973875 \n31 Wright H. L. Thomas H. B. Moots R. J. Edwards S. W. Interferon gene expression signature in rheumatoid arthritis neutrophils correlates with a good response to TNFi therapy Rheumatology 2014 10.1093/rheumatology/keu299 \n32 Prens E. P. Kant M. van Dijk G. van der Wel L. I. Mourits S. van der Fits L. IFN-α enhances poly-IC responses in human keratinocytes by inducing expression of cytosolic innate RNA receptors: relevance for psoriasis Journal of Investigative Dermatology 2008 128 4 932 938 10.1038/sj.jid.5701087 2-s2.0-40649087191 17928888 \n33 Lu X. Kakkar V. The role of Heat Shock Protein (HSP) in atherosclerosis: pathophysiology and clinical opportunities Current Medicinal Chemistry 2010 17 10 957 973 10.2174/092986710790820688 2-s2.0-77950675317 20156167 \n34 Siegel D. Devaraj S. Mitra A. Raychaudhuri S. P. Raychaudhuri S. K. Jialal I. Inflammation, atherosclerosis, and psoriasis Clinical Reviews in Allergy & Immunology 2013 44 2 194 204 10.1007/s12016-012-8308-0 2-s2.0-84879498052 22359071 \n35 Xie J. H. Yamniuk A. P. Borowski V. Engineering of a novel anti-CD40L domain antibody for treatment of autoimmune diseases Journal of Immunology 2014 192 9 4083 4092 10.4049/jimmunol.1303239 2-s2.0-84899515806 \n36 Conde J. Scotece M. Gómez R. Adipokines: Biofactors from white adipose tissue. A complex hub among inflammation, metabolism, and immunity Biofactors 2011 37 6 413 420 10.1002/biof.185 2-s2.0-84155163931 22038756 \n37 Costenbader K. H. Karlson E. W. Cigarette smoking and autoimmune disease: what can we learn from epidemiology? Lupus 2006 15 11 737 745 10.1177/0961203306069344 2-s2.0-34447517875 17153844 \n38 McCarty M. F. DiNicolantonio J. J. The molecular biology and pathophysiology of vascular calcification Postgraduate Medicine 2014 126 2 54 64 10.3810/pgm.2014.03.2740 2-s2.0-84900559975 24685968 \n39 Röhn T. A. Jennings G. T. Hernandez M. Vaccination against IL-17 suppresses autoimmune arthritis and encephalomyelitis European Journal of Immunology 2006 36 11 2857 2867 10.1002/eji.200636658 2-s2.0-33751254750 17048275 \n40 de Carvalho J. F. Pereira R. M. R. Shoenfeld Y. Vaccination for atherosclerosis Clinical Reviews in Allergy & Immunology 2010 38 2-3 135 140 10.1007/s12016-009-8145-y 2-s2.0-77952489467 19554480\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0962-9351",
"issue": "2015()",
"journal": "Mediators of inflammation",
"keywords": null,
"medline_ta": "Mediators Inflamm",
"mesh_terms": "D001327:Autoimmune Diseases; D005938:Glucocorticoids; D006801:Humans; D011565:Psoriasis; D012216:Rheumatic Diseases",
"nlm_unique_id": "9209001",
"other_id": null,
"pages": "657907",
"pmc": null,
"pmid": "26339139",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "20699241;24062777;22038756;25125592;17153844;15191548;20156167;20448283;22563590;24461539;25077037;24454481;21336280;24518855;23968496;16124855;22664308;21506984;22174698;20576225;8117541;20483768;23291100;17928888;19554480;23973875;24092682;24670803;22553077;22359071;24461387;15708927;17048275;24685968;24434359;19110536;15627076;24461380",
"title": "Systemic Autoimmune, Rheumatic Diseases and Coinciding Psoriasis: Data from a Large Single-Centre Registry and Review of the Literature.",
"title_normalized": "systemic autoimmune rheumatic diseases and coinciding psoriasis data from a large single centre registry and review of the literature"
} | [
{
"companynumb": "HU-ORION CORPORATION ORION PHARMA-TREX2015-0573",
"fulfillexpeditecriteria": "1",
"occurcountry": "HU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drug... |
{
"abstract": "OBJECTIVE\n5-Azacitidine (AZA) is an agent widely used to treat myelodysplastic syndrome (MDS).\n\n\nMETHODS\nWe herein report an 83-year-old woman diagnosed with MDS who was treated with AZA. She tolerated the first cycle of AZA; however, severe adverse events involving haemorrhagic enteritis with multiple intestinal ulcers developed after the second and third cycles. Additionally, the interval between the administration of AZA and the development of haematochezia shortened with each cycle of AZA.\n\n\nCONCLUSIONS\nWe herein report as-yet-undescribed potential side effects, AZA-associated haemorrhagic enteritis that should be kept in mind.",
"affiliations": "Department of Hematology, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan.;Department of Gastroenterological Medicine, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan.;Department of Hematology, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan.;Department of Hematology, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan.;Department of Hematology, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan.;Department of Hematology, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan.;Department of Laboratory Medicine, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan.;Department of Gastroenterological Medicine, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan.;Department of Hematology, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan.;Department of Hematology, Tama-Hokubu Medical Center, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo, Japan.",
"authors": "Hagino|Takeshi|T|https://orcid.org/0000-0002-3164-9641;Shinomiya|Wataru|W|;Hidai|Hiroko|H|;Umeda|Miki|M|;Kurimoto|Miwa|M|;Saga|Reina|R|;Tsutsumi|Hisashi|H|;Shibata|Yoshiaki|Y|;Akiyama|Hideki|H|http://orcid.org/0000-0001-5788-8555;Motomura|Sayuri|S|",
"chemical_list": "D001374:Azacitidine",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.13146",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "45(4)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "azacitidine; colitis; haemorrhagic enteritis; myelodysplastic syndrome",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000369:Aged, 80 and over; D001374:Azacitidine; D003113:Colonoscopy; D004751:Enteritis; D005260:Female; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D009190:Myelodysplastic Syndromes",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "828-831",
"pmc": null,
"pmid": "32436280",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Azacitidine-associated haemorrhagic enteritis in a case of myelodysplastic syndrome: A case report.",
"title_normalized": "azacitidine associated haemorrhagic enteritis in a case of myelodysplastic syndrome a case report"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-20200508681",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LANSOPRAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Tremendous progress in the therapy of pediatric acute lymphoblastic leukemia (ALL) has been achieved through combination cytotoxic chemotherapy, leading to high cure rates, at the cost of significant life-threatening toxicity. The bispecific T-cell engager blinatumomab, recently approved for relapsed/refractory ALL, has a unique nonmyelotoxic toxicity profile. As blinatumomab causes B-cell depletion, the safety of its use during severe chemotherapy-induced toxicity is unclear. We report 11 pediatric patients with ALL, treated with blinatumomab following overwhelming chemotherapy-associated toxicity, with recovery of all patients and successful bridging to further antileukemia therapy. Blinatumomab can be considered for rare patients who cannot tolerate cytotoxic therapy.",
"affiliations": "The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, Israel.;Pediatric Hematology-Oncology Department, Ruth Rappaport Children's Hospital, Rambam Health Care Campus, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.;The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, Israel.;Department of Pediatric Hematology-Oncology, Soroka Medical Center, Ben Gurion University, Beer Sheva, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, Israel.;The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, Israel.;Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.;Department of Hematology, Shaare Zedek Medical Center, Jerusalem, Israel.;The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, Israel.;Department of Statistics, Hebrew University, Jerusalem, Israel.;Pediatric Hematology-Oncology, Hadassah Hebrew University Medical Center, Jerusalem, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Rina Zaizov Division of Pediatric Hematology-Oncology, Schneider Children's Medical Center, Petah Tikva, Israel.;Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"authors": "Elitzur|Sarah|S|0000-0002-3495-7578;Arad-Cohen|Nira|N|;Barzilai-Birenboim|Shlomit|S|;Ben-Harush|Miriam|M|;Bielorai|Bella|B|0000-0003-3066-6439;Elhasid|Ronit|R|0000-0002-5663-6919;Feuerstein|Tamar|T|;Gilad|Gil|G|;Gural|Alexander|A|;Kharit|Mira|M|;Litichever|Naomi|N|;Nirel|Ronit|R|;Weinreb|Sigal|S|;Wolach|Ofir|O|;Toren|Amos|A|;Izraeli|Shai|S|;Jacoby|Elad|E|0000-0003-1411-8942",
"chemical_list": "D018033:Antibodies, Bispecific; D000074322:Antineoplastic Agents, Immunological; C510808:blinatumomab",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27898",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "66(10)",
"journal": "Pediatric blood & cancer",
"keywords": "blinatumomab; childhood acute lymphoblastic leukemia; immunotherapy; treatment-related toxicity",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D018033:Antibodies, Bispecific; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007557:Israel; D008297:Male; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D012189:Retrospective Studies",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27898",
"pmc": null,
"pmid": "31264788",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric B-cell precursor acute lymphoblastic leukemia: Report from the Israeli Study Group of Childhood Leukemia.",
"title_normalized": "blinatumomab as a bridge to further therapy in cases of overwhelming toxicity in pediatric b cell precursor acute lymphoblastic leukemia report from the israeli study group of childhood leukemia"
} | [
{
"companynumb": "IL-AMGEN-ISRSP2019110351",
"fulfillexpeditecriteria": "2",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BLINATUMOMAB"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nWe present a case of choriocarcinoma in a viable pregnancy with the rare presentation of intractable lower back pain.\n\n\nMETHODS\nThe patient is a 34-year-old multiparous woman with her second pregnancy, and a history of scoliosis with spinal fixation. Her first pregnancy was uneventful, with a term vaginal delivery. She was hospitalized four times due to intractable back pain from 25 to 31 weeks, and terminated at 31 weeks. The placenta was unremarkable on gross examination. Postpartum, the patient developed obstructive ileus, requiring a rectosigmoid resection. She was diagnosed with metastatic choriocarcinoma to the liver, para-aortic lymph nodes, and mesentery. A week later, she developed micro-thrombosis of all limbs, massive ascites, pleural effusion. Patient refused chemotherapy and died on post-operative Day 15.\n\n\nCONCLUSIONS\nPresentation of choriocarcinoma in pregnancy varies widely. Clinicians should consider the differential diagnosis of choriocarcinoma when faced with abnormal unexplained symptoms during pregnancy.",
"affiliations": "Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Keelung, Taiwan. Electronic address: Luluhuang66@gmail.com.;Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Keelung, Taiwan. Electronic address: sing@cgmh.org.tw.;Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Keelung, Taiwan. Electronic address: ellenrobot@gmail.com.;Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Keelung, Taiwan; Department of Obstetrics and Gynecology, Chang Gung Memorial Hospital, Taipei, Taiwan; Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: thh20@cgmh.org.tw.",
"authors": "Huang|Lulu|L|;Huang|Shi-Yin|SY|;Lee|Ai-Lun|AL|;Hung|Tai-Ho|TH|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.1016/j.tjog.2021.09.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-4559",
"issue": "60(6)",
"journal": "Taiwanese journal of obstetrics & gynecology",
"keywords": "Choriocarcinoma; Clinical presentation; Lower back pain; Pregnancy",
"medline_ta": "Taiwan J Obstet Gynecol",
"mesh_terms": null,
"nlm_unique_id": "101213819",
"other_id": null,
"pages": "1098-1102",
"pmc": null,
"pmid": "34794745",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Choriocarcinoma in a viable pregnancy with the rare presentation of intractable lower back pain.",
"title_normalized": "choriocarcinoma in a viable pregnancy with the rare presentation of intractable lower back pain"
} | [
{
"companynumb": "TW-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-321435",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOCARBAMOL"
},
"d... |
{
"abstract": "This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high 'life threat' impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73years, range: 62-82; 37% >75years) at a median interval of 15·6 (range, 13-29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4-year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n=3), therapy discontinuations (no-response n=2; toxicity n=6), relapse (n=6) and death in CR (n=3). Incidence of cardiac grade 3-5 adverse events was 7/41 (17%; 95% confidence interval: 8-31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P=0·007) with patients scoring ≤7 having a longer TTF (66% vs. 29%; P=0·009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF.",
"affiliations": "Haematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute, Fondazione G. Pascale, IRCCS, Naples, Italy. g.corazzelli@istitutotumori.na.it",
"authors": "Corazzelli|Gaetano|G|;Frigeri|Ferdinando|F|;Arcamone|Manuela|M|;Lucania|Anna|A|;Rosariavilla|Maria|M|;Morelli|Emanuela|E|;Amore|Alfonso|A|;Capobianco|Gaetana|G|;Caronna|Antonietta|A|;Becchimanzi|Cristina|C|;Volzone|Francesco|F|;Marcacci|Gianpaolo|G|;Russo|Filippo|F|;De Filippi|Rosaria|R|;Mastrullo|Lucia|L|;Pinto|Antonio|A|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2141.2011.08786.x",
"fulltext": "\n==== Front\nBr J HaematolbjhBritish Journal of Haematology0007-10481365-2141Blackwell Publishing Ltd 10.1111/j.1365-2141.2011.08786.xHaematological MalignancyBiweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome-encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor-risk diffuse large B-cell lymphoma and moderate to high ‘life threat’ impact cardiopathy Corazzelli Gaetano 1Frigeri Ferdinando 1Arcamone Manuela 1Lucania Anna 2RosariaVilla Maria 2Morelli Emanuela 1Amore Alfonso 3Capobianco Gaetana 1Caronna Antonietta 4Becchimanzi Cristina 1Volzone Francesco 1Marcacci Gianpaolo 1Russo Filippo 1De Filippi Rosaria 15Mastrullo Lucia 2Pinto Antonio 11 Haematology-Oncology and Stem Cell Transplantation Unit, National Cancer InstituteFondazione ‘G. Pascale’, IRCCS2 HaematologyA.O. San Gennaro, ASL NA13 EGBP Surgery, Department of Abdominal Surgery D, National Cancer InstituteFondazione ‘G. Pascale’, IRCCS4 Cardiology, National Cancer Institute, Fondazione ‘G. Pascale’IRCCS5 Department of Cellular and Molecular Biology and Pathology, Faculty of Biotechnological Sciences, Federico II UniversityNaples, ItalyDr Gaetano Corazzelli, Haematology-Oncology and Stem Cell Transplantation Unit, Istituto Nazionale Tumori, Fondazione ‘G. Pascale’, IRCCS, via Mariano Semmola, 80131 Naples, Italy.E-mail: g.corazzelli@istitutotumori.na.itRe-use of this article is permitted in accordance with the Terms and Conditions set out at http://wileyonlinelibrary.com/onlineopenOnlineOpen_Terms\n\n9 2011 154 5 579 589 11 4 2011 31 5 2011 Copyright © 2011 Blackwell Publishing Ltd2011Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.This Phase II study assessed feasibility and efficacy of a biweekly R-COMP-14 regimen (rituximab, cyclophosphamide, non-pegylated liposome-encapsulated doxorubicin, vincristine and prednisone) in untreated elderly patients with poor-risk diffuse large B-cell lymphoma (DLBCL) and moderate to high ‘life threat’ impact NIA/NCI cardiac comorbidity. A total of 208 courses were delivered, with close cardiac monitoring, to 41 patients (median age: 73 years, range: 62–82; 37% >75 years) at a median interval of 15·6 (range, 13–29) days; 67% completed all six scheduled courses. Response rate was 73%, with 68% complete responses (CR); 4-year disease-free survival (DFS) and time to treatment failure (TTF) were 72% and 49%, respectively. Failures were due to early death (n = 3), therapy discontinuations (no-response n = 2; toxicity n = 6), relapse (n = 6) and death in CR (n = 3). Incidence of cardiac grade 3–5 adverse events was 7/41 (17%; 95% confidence interval: 8–31%). Time to progression and overall survival at 4-years were 77% and 67%, respectively. The Age-adjusted Charlson Comorbidity Index (aaCCI) correlated with failures (P = 0·007) with patients scoring ≤7 having a longer TTF (66% vs. 29%; P = 0·009). R-COMP-14 is feasible and ensures a substantial DFS to poor-risk DLBCL patients who would have been denied anthracycline-based treatment due to cardiac morbidity. The aaCCI predicted both treatment discontinuation rate and TTF.\n\nnon-pegylated liposomal doxorubicinelderlydiffuse large B-cell lymphomacardiotoxicityCharlson Comorbidity Index\n==== Body\nElderly patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) and a poor prognostic profile, according to the International Prognostic Index (IPI), were shown to benefit from shortening of the time interval between CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) chemotherapy cycles from 3 weeks (CHOP-21) to 2 weeks (CHOP-14) (Pfreundschuh et al, 2004, 2008). In these patients, biweekly CHOP plus rituximab (R) (R-CHOP-14) is regarded as a therapeutic standard for some cooperative groups and is a valuable option in clinical practice (Pfreundschuh et al, 2008; Rueda et al, 2008; Ziepert et al, 2010; Zwick et al, 2007).\n\nFurther exploration of dose-densified approaches to treat high-risk DLBCL in the elderly appears also justified due to: (i) the high initial relapse rate in elderly patients (60–80 years old) with poor IPI risk given R-CHOP-21 (Feugier et al, 2005) and their low chance of achieving a durable second remission (Corazzelli et al, 2009; Gisselbrecht et al, 2009), (ii) the comparable toxicity of R-CHOP-21 and R-CHOP-14 in terms of cardiac complications (Cunningham et al, 2009; Delarue et al, 2009; Pfreundschuh et al, 2004), (iii) the prospect of a less protracted, if not halved, therapy duration in elderly patients who display a limited physical and psychosocial compliance to prolonged treatments, and (iv) the recent recognition of the highly aggressive entity ‘Epstein-Barr virus (EBV)-positive DLBCL of the elderly’ (12% to 33% of DLBCL) with a median progression free survival of only about 1 year upon CHOP-21 +/− Rituximab (Park et al, 2007; Swerdlow et al, 2008).\n\nDelivery of densified R-CHOP in older patients with heart-related morbidities, may however, be challenging because of the acute, early and late cardiotoxicities of doxorubicin (Grann et al, 2006; Hershman et al, 2008). Prolongation of the QTc interval, arrhythmias, myopericarditis and increase of N-terminal (NT)-pro brain natriuretic peptide (proBNP), an early biomarker of ventricular dysfunction, were described during CHOP-like programmes, independently of the cumulative doxorubicin dosing (Elliott, 2006; Johnson, 2006). In general, the suggestion that fit patients with DLBCL, even if aged more than 80 years, should be evaluated for ‘adapted’ anthracycline-based regimens with curative intent (Bairey et al, 2006; Peyrade et al, 2010; Thieblemont et al, 2008) has to face the problem of cardiac risk factors and comorbidities. In this regard, the therapeutic approach remains pragmatic also due to the absence of international guidelines on cardioprotective agents and of uniform strategies for patients with cardiac risk factors (Hensley et al, 2009). A consensus regarding the optimal methods for cardiac monitoring during anthracycline chemotherapy is also lacking (Altena et al, 2009), so that current guiding principles are about the same as those used 20 years ago (Cheitlin et al, 2003; Klocke et al, 2003; Schwartz et al, 1987). Such issues are very relevant in the context of population-based practice, i.e. involving ‘non-study’ patients, where, differently from controlled trials, selection criteria and therapy optimization do not usually apply (Thieblemont & Coiffier, 2007).\n\nThe application of liposome-encapsulated formulations of doxorubicin has been suggested as a strategy to minimize cardiac side effects and favour a more selective drug uptake by lymphoma cells (Allen & Martin, 2004). Liposomal formulations display comparable efficacy with free anthracyclines, but are linked to more favourable bioavailability and biodistribution profiles (Batist et al, 2001; Levine et al, 2004; Tsavaris et al, 2002; Zaja et al, 2006). This enables the delivery of higher cumulative doses of liposomal anthracyclines with a lower risk of heart failure as compared to the parent compounds (Young et al, 2004). Whether the use of these liposome-encapsulated formulations might also represent a tool for the application of curative dose-intense regimens to older patients with highly chemosensitive tumours in the presence of cardiac risk factors, remains to be assessed.\n\nTo this end, we have conducted a pilot study to explore a dose-dense R-CHOP-like regimen (R-COMP-14) including non-pegylated liposome-encapsulated doxorubicin (NPLD) in elderly DLBCL patients falling into a poor-prognostic group by standard IPI and presenting moderate to high ‘life threat’ impact cardiopathy, as defined by the National Institute on Aging and the National Cancer Institute (NIA/NCI) criteria applied to non-Hodgkin lymphoma (NHL) (Janssen-Heijnen et al, 2005; Yancik et al, 1998). Patients were concurrently assessed through the age-adjusted Charlson Comorbidity Index (aaCCI) (Charlson et al, 1987; Hall et al, 2004; Thieblemont & Coiffier, 2007). We evaluated the feasibility of this biweekly R-COMP regimen, as indicated by the actual proportion of patients fully receiving the planned treatment, the incidence of cardiac adverse events (AE), and its therapeutic efficacy in terms of response and survival outcomes.\n\nPatients and methods\nPatients selection\nThis unsponsored study was approved by local ethic committees and conducted according to the Good Clinical Practice guidelines and the Declaration of Helsinki. All patients gave written informed consent to treatment and use of clinical data for research. Eligible patients were required to have newly diagnosed histologically confirmed DLBCL according to the World Health Organization (WHO) Lymphoma Classification (Jaffe et al, 2001), age > 60 years, intermediate-high and high standard IPI risk (The International Non-Hodgkin’s Lymphoma Prognostic Factors Project., 1993) and one or more condition(s) of moderate to high ‘life threat’ impact cardiac morbidity. This latter was defined according to the NIA/NCI index (Yancik et al, 1998) as applied to non-Hodgkin lymphoma patients (Janssen-Heijnen et al, 2005). In this regimen, an equal dose of NLPD was substituted for doxorubicin within the R-CHOP-14 platform. The following eligibility criteria were also required: negativity for human immunodeficiency virus and surface antigen of hepatitis B, Eastern Cooperative Group performance status (ECOG PS) 0–3, no previous chemotherapy or radiotherapy, creatinine clearance (CrCl) >30 ml/min, serum transaminases less than three times the normal value, bilirubin <34·2 μmol/l, absolute neutrophil count ≥1000 × 109/l, haemoglobin level ≥100 g/l, and platelet count ≥75 000 × 109/l, no history of congestive heart failure (CHF), left ventricular ejection fraction (LVEF) ≥45% at bi-dimensional echocardiography or, in selected cases (i.e. obese patient), multiple uptake gated acquisition (MUGA) scintigraphy. Myocardial infarction represented an exclusion criteria only if diagnosed within 12 months prior to R-COMP-14.\n\nComorbidity was assessed with the aaCCI (Charlson et al, 1987; Hall et al, 2004). Pre-treatment disease assessment included a contrast-enhanced total-body computed tomography scan, Fluorine-18 (18F)-Fluorodeoxyglucose Positron Emission Tomography (FDG-PET), bone marrow (BM) biopsy and lumbar puncture in case of testicular, breast, epidural or sinus involvement. Restaging was scheduled after three courses and a final evaluation was performed 4 weeks after the end of chemotherapy. No consolidation radiotherapy was scheduled.\n\nTreatment\nPatients were scheduled to receive six courses of R-COMP-14 (rituximab 375 mg/m2 on day 1, cyclophosphamide 750 mg/m2 on day 2, NLPD-Myocet® 50 mg/m2 on day 2, vincristine 1·4 mg/m2, up to a maximal dose of 2 mg on day 2, and prednisone 40 mg/m2 per day for 5 d) at a 2-week interval. Myocet® was purchased from Cephalon, Rome, Italy. Primary granulocyte colony-stimulating factor (G-CSF) support was employed from day 6 to day 10 of each course. The agent-specific relative dose intensity (RDI) for each drug was calculated as the ratio between the administered dose and the planned dose, described in mg/m2 per week. The regimen was administered on an inpatient basis for the first four courses and a 3–5 d prednisone pretreatment was given before the first cycle to patients with ECOG PS >1. All patients received rasburicase and appropriate hydration/alkalinization during the first course. Intrathecal prophylaxis with 50 mg of liposome-encapsulated cytarabine (Depocyte ®; Mundipharma, Cambridge, UK), on day 2 of cycles 1–4, was given in cases at risk for central nervous system (CNS) localization. No continuous use of acyclovir and cothrimoxazole was recommended but patients received ciprofloxacin and/or azythromycin prophylaxis, while fluconazole was employed as needed; febrile neutropenia was managed by hospitalization.\n\nThe prescription of QTc interval-prolonging drugs, such as some fluoroquinolones, macrolide antibiotics and itraconazole, was discouraged (Liu & Juurlink, 2004; Wolbrette, 2004), as well as use of tricyclic antidepressants, haloperidol and selective serotonin reuptake inhibitors (Liu & Juurlink, 2004; Wolbrette, 2004). Electrocardiography was repeated before each course together with bi-dimensional echocardiographic survey. No protocol-committed pre-emptive strategy was planned with agents recognized to have protective activity from doxorubicin-related cardiotoxicity, such as beta-blockers, angiotensin-converting-enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB); however patients continued to take their daily background cardiological medications, including beta-blockers and ACEI/ARB if previously prescribed.\n\nToxicity and dose modulation\nToxicity was evaluated using the NCI Common Terminology Criteria for Adverse Events (CTCAE) v3.0 toxicity scale (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf). Full blood cell counts, together with renal and hepatic function tests, were planned twice weekly after the first R-COMP-14 and weekly thereafter. The next chemotherapy cycle was scheduled at day 15, if neutrophil count >1000 × 109/l and platelet count >75 000 × 109/l. If the platelet count was <75 000 × 109/l the course was delayed for up to 2 weeks. In case of grade 4 thrombocytopenia, the doses of cyclophosphamide and doxorubicin were decreased by 25%. Dose reduction guidelines also included: (i) vincristine reduction, to a fixed dose of 1 mg, in case of grade 2 peripheral neuropathy or serum bilirubin 25·65–51·3 μmol/l or transaminases 2–3 times upper limit of normal (ULN) or alkaline phosphatase increased; decrease to 25% of dose if serum bilirubin 51·3–85·5 μmol/l; avoid use for grade 3–4 peripheral neuropathy, or serum bilirubin >85·5 μmol/l or aspartate transaminase >180 units, (ii) decrease cyclophosphamide to 75% of dose in case of CrCl <10 ml/min; and serum bilirubin 53–85·5 μmol/l or transaminases >3 times ULN; avoid use if serum bilirubin >85·5 μmol/l, and (iii) decrease of NPLD to 50% for bilirubin 34·2–51·3 μmol/l; to 25% for bilirubin 51·3–85·5 μmol/l. The doses of rituximab were not modified. Treatment was stopped in case of no response, lymphoma progression, patient refusal or, at the treating physicians judgment, in cases of intercurrent illness. Therapy was also withdrawn in case of the following CTCAE v3.0 grade 3 and 4 cardiac adverse events: (i) conduction abnormality/arrhythmia incompletely controlled medically (grade 3) or associated with CHF, hypotension, syncope or shock (grade 4), (ii) symptoms and testing consistent with ischaemia, unstable angina (grade 3) or acute myocardial infarction (grade 4), (iii) cardiac troponin serum levels consistent with unstable angina (grade 3) or myocardial infarction (grade 4), (iv) symptomatic left ventricular systolic dysfunction with CHF, or resting ejection fraction <40% responsive to intervention (grade 3) or poorly controlled (grade 4), (v) pericardial effusion with physiological (grade 3) or life-threatening consequences (grade 4), and (vi) symptomatic valvular disease controlled with medical therapy (grade 3), or life-threatening/disabling (grade 4).\n\nEndpoints\nThe primary safety endpoint was the incidence of cardiac events, defined as definite cardiac death, sudden death without documented non-cardiac aetiology and the occurrence of grade 3 and 4 cardiac adverse events according to CTCAE v3.0. The primary efficacy endpoints were complete response (CR) rate and time to treatment failure (TTF). Criteria for remission and survival outcomes were as published (Cheson et al, 2007). TTF was computed from the first day of treatment to either disease progression, relapse, or R-COMP-14 discontinuation due to patient refusal, grade 3 and 4 cardiac AE or the treating physicians decision on intercurrent illness. Death without progression within 4 weeks after the start of therapy was designated as early therapy-related death. Death without progression after completion of the whole treatment was also considered therapy-related if due to cardiac events. The age cut-off of 70 years and aaCCI were analysed for correlation with TTF.\n\nSecondary endpoints were time to progression (TTP), overall survival (OS) and disease-free survival (DFS) in complete responders. TTP was measured from the first day of treatment to the date of documented lymphoma progression or death as a result of lymphoma. OS was measured from the first day of treatment to the date of death as a result of any cause or last follow-up. DFS was calculated from the time of occurrence of CR until relapse or death as a result of lymphoma or treatment toxicity.\n\nStatistics\nIn order to avoid unacceptable toxicity, the Bryant and Day two-stage phase II trial design was chosen with αR = αT = 0·1 and β = 0·2. A cut-off point for the response rate (70%) and for severe cardiac events (20%) was established for the first 19 patients. On this basis, the completed stage-one trial of 19 patients proceeded to stage-two, up to 40 patients, if there were at least 11 responses and 13 ‘safe’ patients (Bryant & Day, 1995). Probabilities of early termination of the study in case of excessive toxicity were 72% in the presence of good response and 90% in case of poor response. Survival endpoints were analysed using the approach of Kaplan and Meier and estimations at 4 years were calculated with 95% confidence intervals (CI). Univariate analyses were performed using Fisher’s exact test and log rank test. Non-parametric linear regression was performed for correlation analysis. All P values were two-tailed. All efficacy and toxicity endpoints were updated at December 2010. Statistical analysis was performed with the Statistical Package for the Social Sciences (spss), version 14.0 (SPSS, Chicago, IL, USA).\n\nResults\nA total of 41 patients were prospectively accrued between January 2007 and July 2009; the two stages of the study design were both completed in the absence of excessive toxicity or unacceptably poor outcome and all patients were evaluable for toxicity and response. In stage-one of the study 19 patients were enrolled: the overall response rate (ORR) was 73·7% [13 CRs and one partial response (PR)], with severe cardiac events occurring in 11% of patients. Given that a response rate of at least 70% and a ≤20% incidence of severe cardiac events were required to proceed to stage-two, an additional 22 patients were enrolled. No statistically significant differences were detected between patients accrued in the two stages in terms of demographics, disease characteristics, comorbidity at presentation, and response to treatment (Table S1).\n\nBase-line characteristics\nThe clinical features of the entire patient population are summarized in Table I. The median age at the time of inclusion was 73 years and 15 patients (37%) were older than 75 years. Twenty-four patients had an IPI of 3, and in 17 the IPI was ≥4; 27 patients (71%) were in stage IV, 49% had B symptoms and 32% were assigned an ECOG PS > 1.\n\nTable I Patient characteristics\n\nCharacteristics\tn\t%\t\nPatients entered\t41\t100\t\nAge at treatment (years)\t\n Median (range)\t73 (62–82)\t\t\n 61–65\t6\t15\t\n 66–70\t9\t22\t\n 71–75\t11\t27\t\n 76–80\t10\t24\t\n >80\t5\t12\t\nMale gender\t23\t56\t\nClinical stage\t\n II\t4\t\t\n III\t10\t24\t\n IV\t27\t66\t\nB symptoms\t20\t49\t\nNo of extranodal sites ≥ 2\t14\t34\t\nBone marrow involvement\t9\t22\t\nLactate dehydrogenase > ULN\t33\t81\t\nECOG performance Status ≥ 2\t13\t32\t\nStandard IPI score\t\n 3\t24\t59\t\n 4–5\t17\t41\t\nBasal LVEF value (%)\t\n Median\t57\t\t\n Range\t45–67\t\t\nCardiovascular risk factors\t\n Chronic renal failure (GFR 30–50 ml/min per 1·73 m2)\t5\t12\t\n Hypertension, UAT\t12\t\t\n Diabetes mellitus, UAT\t8\t\t\n Hyperlipidemia, UAT\t14\t\t\nModerate impact heart-related conditions\t18\t44\t\n Prior myocardial infarction (>1 year)\t11\t27\t\n Valve disease\t7\t17\t\nHigh impact heart-related conditions\t23\t56\t\n Chronic, multivessel coronary disease, UAT\t19\t46\t\n Atrial fibrillation, UAT\t9\t22\t\n Conduction disturbances, UAT\t10\t24\t\n Hypertensive heart disease, UAT\t4\t10\t\nBeta-blockers and/or ACEI/ARB background treatment\t27\t65\t\nAge-adjusted Charlson Comorbidity Index\t\n Median\t8\t\t\n Range\t5–12\t\t\nULN, upper limit of normal range; ECOG, Eastern Cooperative Oncology Group; GFR, glomerular filtration rate; UAT, under active treatment; LVEF, left ventricular ejection fraction; IPI, international prognostic index; ACEI, angiotensin-converting-enzyme inhibitors; ARB, angiotensin receptor blockers.\n\nThe distribution of heart-related conditions with ‘life threat’ impact is also detailed in Table I. Moderate impact conditions, such as prior myocardial infarction and valve disease were present in 11 and seven cases respectively, while a large proportion of patients (56%) presented high-impact situations mainly consisting of ischaemic and arrhythmic cardiac diseases under active treatment (Table I). Cardiac risk factor hypertension, diabetes mellitus and dyslipidaemia were under medication in 34 cases, while moderate chronic renal failure (glomerular filtration rate 30–50 ml/min) affected 12% of patients. Two-thirds of patients had background treatment including ACEI/ARB and/or beta blockers. Median basal echocardiographic LVEF for the entire study population was 57% (range,45–67). Median aaCCI was 8 (range, 5–12).\n\nPrimary endpoints\nThe scheduled six courses of R-COMP-14 were completed by 27 patients (67%), including two patients who received two additional courses as CR consolidation for a destructive bone involvement (Table II). In these latter patients, aged 72 and 81 years, radiotherapy was excluded to allow osteosynthesis (right omerus, epiphyseal-metaphyseal area) in one case, and avoid post-actinic damage (left maxillary sinus, pterigoides laminae, left greater sphenoid wing and ethmoid septum) in the other. Three patients, aged 82, 69 and 78 years, all in CR at intermediate restaging, were considered to have completed their treatment after five courses (Table II): the first patient did not attend the scheduled sixth course for logistic reasons after relatives referred her to a distant community dwelling; the second skipped his sixth course so as not to delay radiofrequency ablation treatment of hepatocellular carcinoma; in the third patient, a psychiatric counsellor, upon the occurrence of a severe isolated memory loss of unknown cause, advised skipping the last course. These three complete responders were not considered as failures due to toxicity, treatment discontinuation or refusal.\n\nTable II Feasibility of R-COMP-14: status of patients and cause of termination of therapy after each cycle\n\n\tNo. of patients (%)\t\n\t\t\n\tCycle 1\tCycle 2\tCycle 3\tCycle 4\tCycle 5\tCycle 6\tCycle 7\tCycle 8\tTotal\t\nPatients receiving therapy\t41(100)\t39 (95)\t36 (88)\t31 (80)\t30 (73)\t27(67)\t2\t2\t\t\nEarly death\t2\t1\t\t\t\t\t\t\t3 (7)\t\nDiscontinuation for toxicity\t\t2\t3\t1\t\t\t\t\t6 (15)\t\n LVEF <40%\t\t\t2\t1\t\t\t\t\t3 (7)\t\n CTCAE Grade 3 arrhythmia\t\t1\t\t\t\t\t\t\t2 (5)\t\n CTCAE Grade 4 arrhythmia\t\t\t1\t\t\t\t\t\t\t\n Disseminated Zoster\t\t1\t\t\t\t\t\t\t1\t\nDiversion for no response\t\t\t\t2\t\t\t\t\t2\t\nTreatment completed\t\t\t\t\t3\t25\t\t2\t30 (73)\t\nLVEF, left ventricular ejection fraction; CTCAE, Common Terminology Criteria for Adverse Events version 3.0.\n\nOverall, a total of 208 courses were delivered, with a median time to recycle of 15·6 d (range, 13–29). Treatment delivery achieved an average RDI of 88·6% (cyclophosphamide 86%, NPLD 89%, vincristine 91%). Three patients received CNS prophylaxis with intrathecal liposomal cytarabine due to epidural (n=2) and paranasal sinus (n=1) localizations.\n\nDiscontinuation for toxicity occurred in a total of six patients (15%). This was due to widespread herpes zoster infection (n=1) and grade 3 cardiac events (n=5), namely decrease in LVEF (n=3) and grade 3 and grade 4 arrhythmia (n=2) (Table II). After stopping R-COMP-14, all these six patients did not receive any further chemotherapy but were given additional doses of rituximab, at biweekly intervals, up to a total of eight (n = 4) or ibritumomab-tiuxetan (n = 2). The cumulative incidence of failures due to early and late cardiac events was 17% (7/41; 95% CI 8% to 31%).\n\nThe ORR was 73% with 28 patients achieving CR (68%; 95% CI 54% to 82%). After a median period of observation for TTF of 27 months, 20 failures according to the protocol were observed: three early therapy-related deaths [at day +12 (undefined cause) and +13 (sepsis) of the first course, and at day +18 (sepsis) from the second cycle, respectively], eight treatment discontinuations [no response, i.e. less than PR/progressive disease (n = 2), toxicity (n = 6)], six relapses, three lymphoma-unrelated deaths in continuous CR, due to decompensated cirrhosis (n = 1) and late cardiac events (n = 2).\n\nThe 4-year TTF was 49% (95% CI 33% to 65%, median 19·2 months) without a significant advantage for patients younger than 70 years (63% vs. 40%; P = 0·12) (Table III, Figs 1A and 2A). In contrast, a statistically significant correlation with treatment failure was found for the aaCCI (r2=0·17, P = 0·007) (Fig 3). In particular, patients with an aaCCI score ≤7 (66%; 95% CI 46–86) displayed a longer TTF as compared to those with a score >7 (29%; 95% CI 8% to 49%)(P = 0·009) (Fig 2B). Early deaths and toxicity-related therapy discontinuations were also significantly more frequent among patients with aaCCI scores >7 (P = 0·02), while these events were not predicted by chronological age (Table III).\n\nTable III Response to therapy and events according to age and aaCCI\n\n\tTotal\tAge ≤ 70 years\tAge > 70 years\taaCCI ≤ 7\taaCCI > 7\t\n\t\t\t\t\t\t\n\t(n=41)\t(n=15)\t(n=26)\t(n=19<)\t(n=22)\t\n\t\t\t\t\t\t\n\tn\t%\t95% CI\tn\t%\tn\t%\tP*\tn\t%\tn\t%\tP*\t\nOverall response rate\t30\t73\t60–87\t13\t87\t17\t65\t0·16\t17\t89\t13\t59\t0·47\t\n CR\t28\t68\t54–82\t12\t80\t16\t61\t0·30\t15\t79\t13\t59\t0·62\t\n PR\t2\t\t\t1\t\t1\t\t\t2\t\t\t\t\t\nLess than PR\t2\t\t\t1\t\t1\t\t\t1\t\t1\t\t\t\nDiscontinuation\t6\t15\t4–25\t0\t\t6\t23}\t0·11\t1\t\t5\t23}\t0·02\t\nEarly therapy-related deaths\t3\t7\t1–15\t\t1\t2\t\t\t\t\t3\t\t\t\nRelapsed\t6\t21\t6–37\t\t\t\t\t\t\t\t\t\t\t\nDeaths for lymphoma\t6\t15\t4–25\t2\t\t4\t\t\t4\t\t2\t\t\t\nDeaths unrelated\t1\t\t\t1\t\t\t\t\t\t\t1\t\t\t\nLate therapy-related deaths\t2\t\t\t1\t\t1\t\t\t1\t\t1\t\t\t\nAlive\t29\t70\t57–85\t11\t73\t18\t69\t\t14\t73\t15\t68\t\t\n4-year survival\t\n TTF\t\t49\t33–65\t\t63\t\t40\t0·12\t\t66\t\t29\t0·009\t\n TTP\t\t77\t64–91\t\t84\t\t67\t0·32\t\t77\t\t70\t0·88\t\n OS\t\t67\t52–83\t\t70\t\t64\t0·75\t\t71\t\t65\t0·49\t\n DFS\t\t72\t55–90\t\t80\t\t66\t0·40\t\t77\t\t67\t0·63\t\naaCCI, age-adjusted Charlson comorbidity index; CR, complete response; PR, partial response; TTF, time to treatment failure; TTP, time to progression; OS, overall survival; DFS, disease-free survival.\n\n* All P values are two-sided.\n\nFig 1 Kaplan–Meier survival curves for the whole cohort (n = 41) (A) and complete responders (n = 28) (B).\n\nFig 2 Time to treatment failure according to age cut-off 70 years (A) and aaCCI (B).\n\nFig 3 Correlation of aaCCI with treatment failure. Regression line with 95% confidence band.\n\nMedian values of LVEF for the entire study population documented at 1 year after completion of treatment were superimposable to those present before treatment (Fig 4A), but differences in quartiles were evident. At midtreatment evaluation the LVEF had a 5% to 10% decrease in eight patients, while a >10% reduction was observed in five others. Among the latter group, three patients had their therapy stopped per protocol becuase the CTCAE limit for grade 3 toxicity, i.e. a LVEF <40%, was reached. Nevertheless, the remission status achieved by these three patients allowed a time to progression of 12+, 15+ and 16+ months, which was paralleled by a progressive recovery of their LVEF values. At 1 year from completion of treatment, 23 of 29 surviving patients did not show significant differences in LVEF as compared to pre-therapy values. A 10% to 15% reduction of LVEF was recorded in six cases, while two patients displayed a LVEF value below 40% (Table II and Fig 4B).\n\nFig 4 Variations in left ventricular ejection fraction (LVEF) throughout treatment up to 1-year after completion of treatment expressed in quartiles (A) and individual values (B). The bold line indicates the limit below which grade 3 and 4 toxicity for ‘left ventricular systolic dysfunction’ occur.\n\nHaematological toxicity was acceptable, with grade 3 and 4 thrombocytopenia occurring in nine patients (22%), grade 3 and 4 anaemia in six (15%) and grade 3 and 4 infections in eight (19%). Notably, at the time of final restaging, focal lung parenchymal uptake at FDG-PET was found in six patients (five of them were aged >75 years), which qualified as pulmonary infection (no Pneumocystis spp) and was treated effectively with antibacterial agents.\n\nSecondary endpoints\nAmong 28 complete responders, eight events were recorded, namely five relapses and three deaths in CR at months 13, 14 and 16, respectively; the first death was due to hepatic cirrhosis, the second to a sudden death, considered per protocol as a ‘cardiac event’ in the absence of any documented aetiology, the third to CHF. According to the adopted standardized criteria for DFS endpoint (Cheson et al, 2007), the first patient was censored at month 13, while the second and the third cases were both included as events, with a 4-year DFS of 72% (95% CI 55% to 90%) (Fig 1B).\n\nOverall, 12 patients (29%) died (Table III), yielding to an estimated 4-year OS of 67% (95% CI 52% to 83%). Causes of death included early toxic event (n = 3), lymphoma progression (n = 6) and lymphoma-unrelated cause (n = 3). The TTP rate was 77% (95% CI 69% to 91%) (Table III and Fig 1A). TTP survival analysis also included the six patients who had discontinued treatment due to toxicity. Among them, there were four CRs with a TTP of 12, 16, 20+ and 29+ months respectively, and two initial PRs whose TTP ended at months 8 and 14.\n\nDiscussion\nThis prospective study addressed two issues relevant to the management of DLBCL in the elderly. The first was to assess whether substitution of NPLD for conventional doxorubicin allowed the safe application of a dose-densified R-CHOP-like regimen to older patients with poor-risk disease (IPI ≥ 3) and moderate to high ‘life threat’ impact (NIA/NCI) cardiac comorbidity. The second was to evaluate the potential clinical benefit of R-COMP-14 in terms of CR, TTF and DFS rates in this subset of high-risk patients.\n\nAbout two-thirds of patients completed the entire six-course programme with a median average RDI approaching 90% for all of the drugs. These proportions are valuable because about one-third of patients were older than 75 years, i.e. above the upper age limit for enrollment into baseline studies (Feugier et al, 2005; Pfreundschuh et al, 2004). Response rate was aligned with results of non-cardiopathic patients with unfavourable IPI profiles (Pfreundschuh et al, 2008). The substantial DFS achieved supports the use of dose-dense treatment is worth ensuing also when age and cardiac comorbidity increase the complexity of lymphoma management and may affect survival (Aapro et al, 2010). The TTF, though hardened by a strict definition of failures, was also in keeping with recent literature (Feugier et al, 2005; Pfreundschuh et al, 2008). Early treatment discontinuation for toxicity occurred in only 15% of patients, all older than 70 years. All of these patients, despite receiving a reduced number of R-COMP-14 courses (median 3, range 2–4), achieved objective responses and contributed to the TTP curve. This indicates that delivery of even fewer cycles of doxorubicin-based chemotherapy remains an option to pursue in non-frail patients older than 70 years (Chrischilles et al, 2003). In this regard, application of fewer courses of densified R-COMP-14 might be of value.\n\nAlthough the importance of dose-intensity in aggressive NHL was confirmed in the rituximab era (Hirakawa et al, 2010), the superiority of R-CHOP-14 over R-CHOP-21 is highly debated, also due to interim results of ongoing randomized trials (Cunningham et al, 2009; Delarue et al, 2009). While these studies will eventually clarify the issue, R-CHOP-14 remains a possible option for elderly patients with a high IPI risk, given the significant relapse rate of R-CHOP-21 in this specific patient population (Feugier et al, 2005) and the inadequate results of salvage treatments (Corazzelli et al, 2009; Gisselbrecht et al, 2009). Concerns about the toxicity of biweekly R-CHOP, especially with regard to cardiac morbidity and infectious risk (Johnson, 2006; Tadmor et al, 2010), may restrain physicians from proposing this strategy to elderly individuals. Irrespective of dose-densification, older DLBCL patients with comorbidity, underlying heart disease, and/or poor PS are often precluded ‘a priori’ from a curative treatment. These conditions should not ‘per se’ contraindicate the application of R-CHOP (Johnson, 2006). This may reflect a cultural reluctance to treat individuals with a presumed defective resilience to treatment toxicity and the inadequacy of instruments to properly identify subclinical damage and prompt timely preventive measures and/or treatment interruptions (Aapro et al, 2010; Thieblemont & Coiffier, 2007). The present study was designed to overcome this conceptual framework by implementing a dose-dense anthracycline-containing regimen for patients with cardiac comorbidity through strict patient monitoring.\n\nThe cumulative incidence of failures due to grade 3–5 cardiac events was only 17% in our study. This proportion is apparently higher than that reported (5%) in a study of 72 elderly DLBCL patients treated with a 3-weekly R-COMP regimen (Luminari et al, 2010). However, strict enrollment criteria limited the overall burden of comorbidity in this latter study, as witnessed by the presence of clinically significant arrhythmic or ischaemic disease in only 14% of patients and the absence of cardiovascular risk factors in 47% of the cases (Luminari et al, 2010). A 5% to 15% incidence of grade 3–5 cardiovascular events was reported in two small series of elderly patients treated with an R-COMP-21 regimen (Rigacci et al, 2007; Visani et al, 2008). However, concomitant accrual of naïve and pretreated or frail patients, coupled to the heterogeneity and variable severity of cardiac comorbidity and cardiovascular risk factors in these two series, hampers a comparison with our study.\n\nIn five of our patients with normal pretreatment LVEF values, grade 3 cardiac events with LVEF reduction occurred between the 2nd and 4th course of R-COMP-14, despite the low cumulative dose of NPLD. Previous CHOP studies have described LVEF declines at a cumulative doxorubicin dose of only 200 mg/m2 (Limat et al, 2003; Nousiainen et al, 2002), highlighting diastolic dysfunction and heart failure with preserved left ventricular systolic function as early predictors of cardiotoxicity (Pudil et al, 2008). This suggests that LVEF should not be the only tool for the assessment of early cardiotoxicity in older NHL patients with preexisting cardiopathy but that additional cardiological evaluations and biomarkers studies are necessary (Albini et al, 2010; Altena et al, 2009). Serial measurements of proBNP levels were available in 44% of our patients (data not shown), but the presence of pre-treatment proBNP levels above the age-adjusted cut-off values, and their variations due to cardiological therapy, anaemia, infections and renal disease, affected the specificity and predictive value of this biomarker, as previously reported (Dodos et al, 2008).\n\nThe aaCCI, a prototypical and reliable comorbidity index, which includes lymphoma among the weighted medical conditions, was a robust predictor of treatment outcomes and survival in our cohort of cardiopathic DLBCL patients. Intriguingly, aaCCI scoring was a better predictor for early death and toxicity-related therapy discontinuation than age itself. This data supports the application of indexes, such as the aaCCI, in the specific situation of elderly NHL patients with heart disease. In this context, comorbidity assessment may account for breakthrough non-cardiac morbidities, including chronic renal failure, lung diseases, endocrine disorders (Khan et al, 1999), neutropenic sepsis (Ammann et al, 2001; ver Elst et al, 2000) or hypovolemic/hypotensive problems (Arlati et al, 2000), which can trigger secondary cardiac dysfunctions unrelated to cardiotoxicity from chemotherapy.\n\nPatients in our study could have benefited from a protective effect and/or improved cardiac compensatory mechanisms from their background cardiological therapy. As it is unclear whether preexisting heart disease increases susceptibility to anthracycline-induced damage or the impaired cardiac functional reserve increases vulnerability of older patients to additional myocardial injures (Hershman et al, 2008), a beneficial pharmacological action from beta-blockers and/or ACEI or ARB assumed by about two-thirds of our patients may be supposed. Notably, while a large amount of data on cardioprotective strategies was generated in childhood cancers and solid tumours (Cardinale et al, 2006; Lipshultz & Colan, 2004), information is scanty for DLBCL, a disease that typically affects elderly individuals and is exquisitely sensitive to anthracyclines. Therefore, future studies on treatment of old and very old patients with aggressive NHL should be designed to evaluate, together with less cardiotoxic anthracycline formulations, cardioprotective strategies and agents as well as noninvasive monitoring markers and methods to detect early signs of cardiotoxicity (Albini et al, 2010; Altena et al, 2009).\n\nWe documented the feasibility and efficacy of an R-COMP-14 regimen in poor-risk elderly DLBCL patients with significant cardiac comorbidity. Many of these high-risk patients, who eventually achieved complete and durable responses, would probably have been denied curative treatment based on the comorbidity burden and age. In the specific setting of cardiopathic patients with aggressive NHL, value of liposomal doxorubicin deserves comparison with the less cardiotoxic protracted infusions of doxorubicin or newer anthracycline congeners.\n\nSupported in part by the Ministry of Health (Ricerca Corrente and, Ricerca Finalizzata, FSN), Rome, Italy.\n\nAuthors' contribution\nAP, GC designed the study, analysed data, performed research and wrote the manuscript. FF designed the study, analysed data, performed research and reviewed the manuscript. MA, AL, MRL, EM, AA, GC, AC, CB, FV, GM, FR, RDF, LM performed the research, collected data and reviewed the manuscript.\n\nDisclosure\nAll of the authors have no financial or other conflicts of interest to declare.\n\nSupporting Information\nAdditional Supporting Information may be found in the online version of this article:\n\nTable S1. Patient characteristics and response according to Stage of accrual in the study.\n\n Please note: Wiley-Blackwell are not responsible for the content or functionality of any supporting materials supplied by the authors. Any queries (other than missing material) should be directed to the corresponding author for the article.\n==== Refs\nReferences\nAapro M Bernard-Marty C Brain EG Batist G Erdkamp F Krzemieniecki K Leonard R Lluch A Monfardini S Ryberg M Soubeyran P Wedding U Anthracycline cardiotoxicity in the elderly cancer patient: a SIOG expert position paper Annals of Oncology 2010 22 257 267 20956616 \nAlbini A Pennesi G Donatelli F Cammarota R De Flora S Noonan DM Cardiotoxicity of anticancer drugs: the need for cardio-oncology and cardio-oncological prevention Journal of the National Cancer Institute 2010 102 14 25 20007921 \nAllen TM Martin FJ Advantages of liposomal delivery systems for anthracyclines Seminars in Oncology 2004 31 5 15 15717735 \nAltena R Perik PJ van Veldhuisen DJ de Vries EG Gietema JA Cardiovascular toxicity caused by cancer treatment: strategies for early detection The Lancet Oncology 2009 10 391 399 19341970 \nAmmann P Fehr T Minder EI Gunter C Bertel O Elevation of troponin I in sepsis and septic shock Intensive Care Medicine 2001 27 965 969 11497154 \nArlati S Brenna S Prencipe L Marocchi A Casella GP Lanzani M Gandini C Myocardial necrosis in ICU patients with acute non-cardiac disease: a prospective study Intensive Care Medicine 2000 26 31 37 10663277 \nBairey O Benjamini O Blickstein D Elis A Ruchlemer R Non-Hodgkin’s lymphoma in patients 80 years of age or older Annals of Oncology 2006 17 928 934 16507563 \nBatist G Ramakrishnan G Rao CS Chandrasekharan A Gutheil J Guthrie T Shah P Khojasteh A Nair MK Hoelzer K Tkaczuk K Park YC Lee LW Reduced cardiotoxicity and preserved antitumor efficacy of liposome-encapsulated doxorubicin and cyclophosphamide compared with conventional doxorubicin and cyclophosphamide in a randomized, multicenter trial of metastatic breast cancer Journal of Clinical Oncology 2001 19 1444 1454 11230490 \nBryant J Day R Incorporating toxicity considerations into the design of two-stage phase II clinical trials Biometrics 1995 51 1372 1383 8589229 \nCardinale D Colombo A Sandri MT Lamantia G Colombo N Civelli M Martinelli G Veglia F Fiorentini C Cipolla CM Prevention of high-dose chemotherapy-induced cardiotoxicity in high-risk patients by angiotensin-converting enzyme inhibition Circulation 2006 114 2474 2481 17101852 \nCharlson ME Pompei P Ales KL MacKenzie CR A new method of classifying prognostic comorbidity in longitudinal studies: development and validation Journal of Chronic Diseases 1987 40 373 383 3558716 \nCheitlin MD Armstrong WF Aurigemma GP Beller GA Bierman FZ Davis JL Douglas PS Faxon DP Gillam LD Kimball TR Kussmaul WG Pearlman AS Philbrick JT Rakowski H Thys DM Antman EM Smith SC Jr Alpert JS Gregoratos G Anderson JL Hiratzka LF Hunt SA Fuster V Jacobs AK Gibbons RJ Russell RO ACC/AHA/ASE 2003 guideline update for the clinical application of echocardiography: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASE Committee to Update the 1997 Guidelines for the Clinical Application of Echocardiography) Circulation 2003 108 1146 1162 12952829 \nCheson 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 Hoppe RT Dreyling M Tobinai K Vose JM Connors JM Federico M Diehl V Revised response criteria for malignant lymphoma Journal of Clinical Oncology 2007 25 579 586 17242396 \nChrischilles EA Link BK Scott SD Delgado DJ Fridman M Factors associated with early termination of CHOP therapy and the impact on survival among patients with chemosensitive intermediate-grade non-Hodgkin’s lymphoma Cancer Control 2003 10 396 403 14581895 \nCorazzelli G Capobianco G Arcamone M Ballerini PF Iannitto E Russo F Frigeri F Becchimanzi C Marcacci G De Chiara A Pinto A Long-term results of gemcitabine plus oxaliplatin with and without rituximab as salvage treatment for transplant-ineligible patients with refractory/relapsing B-cell lymphoma Cancer Chemotherapy and Pharmacology 2009 64 907 916 19219604 \nCunningham D Smith P Mouncey P Qian W Pocock C Ardeshna KM Radford J McMillan A Linch D A phase III trial comparing R-CHOP 14 and R-CHOP 21 for the treatment of patients with newly diagnosed diffuse large B-cell non-Hodgkin’s lymphoma Journal of Clinical Oncology 2009 27 (Suppl; abstract 8506) \nDelarue R Tilly H Salles G Gisselbrecht C Mounier N Fournier M Molnar M Bonmati C Ghesquieres H Blanc M Germain D Girard L Haioun C Bosly A R-CHOP14 compared to R-CHOP21 in elderly patients with diffuse large B cell lymphoma: results of the interim analysis of the LNH03-6B GELA study Blood 2009 114 (abstract 406) \nDodos F Halbsguth T Erdmann E Hoppe UC Usefulness of myocardial performance index and biochemical markers for early detection of anthracycline-induced cardiotoxicity in adults Clinical Research in Cardiology 2008 97 318 326 18193371 \nElliott P Pathogenesis of cardiotoxicity induced by anthracyclines Seminars in Oncology 2006 33 S2 S7 16781283 \nver Elst KM Spapen HD Nguyen DN Garbar C Huyghens LP Gorus FK Cardiac troponins I and T are biological markers of left ventricular dysfunction in septic shock Clinical Chemistry 2000 46 650 657 10794747 \nFeugier P Van Hoof A Sebban C Solal-Celigny P Bouabdallah R Ferme C Christian B Lepage E Tilly H Morschhauser F Gaulard P Salles G Bosly A Gisselbrecht C Reyes F Coiffier B Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte Journal of Clinical Oncology 2005 23 4117 4126 15867204 \nGisselbrecht C Glass B Mounier N Gill D Linch D Trneny M Bosly A Shpilberg O Ketterer N Moskowitz C Schmitz N R-ICE versus R-DHAP in relapsed patients with CD20 diffuse large B-cell lymphoma followed by autologous stem cell transplantation [abstract] Journal of Clinical Oncology (ASCO Meeting Abstracts) 2009 27 8509 \nGrann VR Hershman D Jacobson JS Tsai WY Wang J McBride R Mitra N Grossbard ML Neugut AI Outcomes and diffusion of doxorubicin-based chemotherapy among elderly patients with aggressive non-Hodgkin lymphoma Cancer 2006 107 1530 1541 16933332 \nHall WH Ramachandran R Narayan S Jani AB Vijayakumar S An electronic application for rapidly calculating Charlson comorbidity score BMC Cancer 2004 4 94 15610554 \nHensley ML Hagerty KL Kewalramani T Green DM Meropol NJ Wasserman TH Cohen GI Emami B Gradishar WJ Mitchell RB Thigpen JT Trotti A 3rd von Hoff D Schuchter LM American Society of Clinical Oncology 2008 clinical practice guideline update: use of chemotherapy and radiation therapy protectants Journal of Clinical Oncology 2009 27 127 145 19018081 \nHershman DL McBride RB Eisenberger A Tsai WY Grann VR Jacobson JS Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin’s lymphoma Journal of Clinical Oncology 2008 26 3159 3165 18591554 \nHirakawa T Yamaguchi H Yokose N Gomi S Inokuchi K Dan K Importance of maintaining the relative dose intensity of CHOP-like regimens combined with rituximab in patients with diffuse large B-cell lymphoma Annals of Hematology 2010 89 897 904 20414658 \nJaffe ES Harris NL Stein H Vardiman JW Pathology and Genetics of Tumours of the Hematopoietic and Lymphoyd Tissues 2001 Lyon IARC Press \nJanssen-Heijnen ML van Spronsen DJ Lemmens VE Houterman S Verheij KD Coebergh JW A population-based study of severity of comorbidity among patients with non-Hodgkin’s lymphoma: prognostic impact independent of International Prognostic Index British Journal of Haematology 2005 129 597 606 15916681 \nJohnson SA Anthracycline-induced cardiotoxicity in adult hematologic malignancies Seminars in Oncology 2006 33 S22 S27 16781286 \nKhan IA Tun A Wattanasauwan N Win MT Hla TA Hussain A Vasavada BC Sacchi TJ Elevation of serum cardiac troponin I in noncardiac and cardiac diseases other than acute coronary syndromes American Journal of Emergency Medicine 1999 17 225 229 10337875 \nKlocke FJ Baird MG Lorell BH Bateman TM Messer JV Berman DS O’Gara PT Carabello BA Russell RO Jr Cerqueira MD St John Sutton MG DeMaria AN Udelson JE Kennedy JW Verani MS Williams KA Antman EM Smith SC Jr Alpert JS Gregoratos G Anderson JL Hiratzka LF Faxon DP Hunt SA Fuster V Jacobs AK Gibbons RJ Russell RO ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging--executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging) Circulation 2003 108 1404 1418 12975245 \nLevine AM Tulpule A Espina B Sherrod A Boswell WD Lieberman RD Nathwani BN Welles L Liposome-encapsulated doxorubicin in combination with standard agents (cyclophosphamide, vincristine, prednisone) in patients with newly diagnosed AIDS-related non-Hodgkin’s lymphoma: results of therapy and correlates of response Journal of Clinical Oncology 2004 22 2662 2670 15226333 \nLimat S Demesmay K Voillat L Bernard Y Deconinck E Brion A Sabbah A Woronoff-Lemsi MC Cahn JY Early cardiotoxicity of the CHOP regimen in aggressive non-Hodgkin’s lymphoma Annals of Oncology 2003 14 277 281 12562656 \nLipshultz SE Colan SD Cardiovascular trials in long-term survivors of childhood cancer Journal of Clinical Oncology 2004 22 769 773 14990630 \nLiu BA Juurlink DN Drugs and the QT interval - caveat doctor New England Journal of Medicine 2004 351 1053 1056 15356302 \nLuminari S Montanini A Caballero D Bologna S Notter M Dyer MJ Chiappella A Briones J Petrini M Barbato A Kayitalire L Federico M Nonpegylated liposomal doxorubicin (MyocetTM) combination (R-COMP) chemotherapy in elderly patients with diffuse large B-cell lymphoma (DLBCL): results from the phase II EUR018 trial Annals of Oncology 2010 21 1492 1499 20007997 \nNousiainen T Jantunen E Vanninen E Hartikainen J Early decline in left ventricular ejection fraction predicts doxorubicin cardiotoxicity in lymphoma patients British Journal of Cancer 2002 86 1697 1700 12087452 \nPark S Lee J Ko YH Han A Jun HJ Lee SC Hwang IG Park YH Ahn JS Jung CW Kim K Ahn YC Kang WK Park K Kim WS The impact of Epstein-Barr virus status on clinical outcome in diffuse large B-cell lymphoma Blood 2007 110 972 978 17400912 \nPeyrade F Jardin F Gisselbrecht C Thyss A Emile JF Castaigne S Coiffier B Haioun C Bologna S Fitoussi O Lepeu G Fruchart C Bordessoule D Blanc M Delarue R Janvier M Salles S Bosly A Tilly H Rituximab and Reduced Dose CHOP (R-mini-CHOP) for Patients Over 80 Years with Diffuse Large B-Cell Lymphoma (DLBCL) – Groupe d’Etude Des Lymphomes De l’Adulte (GELA) Study LNH03-7B Blood (ASH Annual Meeting Abstracts) 2010 116 (abstract 853) \nPfreundschuh M Trumper L Kloess M Schmits R Feller AC Rube C Rudolph C Reiser M Hossfeld DK Eimermacher H Hasenclever D Schmitz N Loeffler M Two-weekly or 3-weekly CHOP chemotherapy with or without etoposide for the treatment of elderly patients with aggressive lymphomas: results of the NHL-B2 trial of the DSHNHL Blood 2004 104 634 641 15016643 \nPfreundschuh M Schubert J Ziepert M Schmits R Mohren M Lengfelder E Reiser M Nickenig C Clemens M Peter N Bokemeyer C Eimermacher H Ho A Hoffmann M Mertelsmann R Trumper L Balleisen L Liersch R Metzner B Hartmann F Glass B Poeschel V Schmitz N Ruebe C Feller AC Loeffler M Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60) The Lancet Oncology 2008 9 105 116 18226581 \nPudil R Horacek JM Strasova A Jebavy L Vojacek J Monitoring of the very early changes of left ventricular diastolic function in patients with acute leukemia treated with anthracyclines Experimental Oncology 2008 30 160 162 18566583 \nRigacci L Mappa S Nassi L Alterini R Carrai V Bernardi F Bosi A Liposome-encapsulated doxorubicin in combination with cyclophosphamide, vincristine, prednisone and rituximab in patients with lymphoma and concurrent cardiac diseases or pre-treated with anthracyclines Hematological Oncology 2007 25 198 203 17654614 \nRueda A Sabin P Rifa J Llanos M Gomez-Codina J Lobo F Garcia R Herrero J Provencio M Jara C R-CHOP-14 in patients with diffuse large B-cell lymphoma younger than 70 years: a multicentre, prospective study Hematological Oncology 2008 26 27 32 17868190 \nSchwartz RG McKenzie WB Alexander J Sager P D’Souza A Manatunga A Schwartz PE Berger HJ Setaro J Surkin L Wackers FJT Zaret BL Congestive heart failure and left ventricular dysfunction complicating doxorubicin therapy. Seven-year experience using serial radionuclide angiocardiography American Journal of Medicine 1987 82 1109 1118 3605130 \nSwerdlow SH Campo E Harris NL Jaffe ES Pileri SA Stein H Thiele J Vardiman JW WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues 2008 4th edn Lyon IARC Press \nTadmor T McLaughlin P Polliack A A resurgence of Pneumocystis in aggressive lymphoma treated with R-CHOP-14: the price of a dose-dense regimen? Leukaemia & Lymphoma 2010 51 737 738 \nThe International Non-Hodgkin’s Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin’s lymphoma. The International Non-Hodgkin’s Lymphoma Prognostic Factors Project New England Journal of Medicine 1993 329 987 994 8141877 \nThieblemont C Coiffier B Lymphoma in older patients Journal of Clinical Oncology 2007 25 1916 1923 17488991 \nThieblemont C Grossoeuvre A Houot R Broussais-Guillaumont F Salles G Traulle C Espinouse D Coiffier B Non-Hodgkin’s lymphoma in very elderly patients over 80 years. A descriptive analysis of clinical presentation and outcome Annals of Oncology 2008 19 774 779 18065404 \nTsavaris N Kosmas C Vadiaka M Giannouli S Siakantaris MP Vassilakopoulos T Pangalis GA Pegylated liposomal doxorubicin in the CHOP regimen for older patients with aggressive (stages III/IV) non-Hodgkin’s lymphoma Anticancer Research 2002 22 1845 1848 12168880 \nVisani G Ferrara F Alesiani F Ronconi S Catarini M D’Adamo F Guiducci B Bernardi D Barulli S Piccaluga P Rocchi M Isidori A R-COMP 21 for frail elderly patients with aggressive B-cell non-Hodgkin lymphoma: a pilot study Leukaemia & Lymphoma 2008 49 1081 1086 \nWolbrette DL Drugs that cause Torsades de pointes and increase the risk of sudden cardiac death Current Cardiology Reports 2004 6 379 384 15306095 \nYancik R Wesley MN Ries LA Havlik RJ Long S Edwards BK Yates JW Comorbidity and age as predictors of risk for early mortality of male and female colon carcinoma patients: a population-based study Cancer 1998 82 2123 2134 9610691 \nYoung AM Dhillon T Bower M Cardiotoxicity after liposomal anthracyclines The Lancet Oncology 2004 5 654 15522651 \nZaja F Tomadini V Zaccaria A Lenoci M Battista M Molinari AL Fabbri A Battista R Cabras MG Gallamini A Fanin R CHOP-rituximab with pegylated liposomal doxorubicin for the treatment of elderly patients with diffuse large B-cell lymphoma Leukaemia & Lymphoma 2006 47 2174 2180 \nZiepert M Hasenclever D Kuhnt E Glass B Schmitz N Pfreundschuh M Loeffler M Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20+ B-cell lymphoma in the rituximab era Journal of Clinical Oncology 2010 28 2373 2380 20385988 \nZwick C Gleissner B Pfreundschuh M Aspects of chemotherapy schedules in young and elderly patients with aggressive lymphoma Clinical Lymphoma & Myeloma 2007 8 Suppl. 2 S43 S49 18284715\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0007-1048",
"issue": "154(5)",
"journal": "British journal of haematology",
"keywords": null,
"medline_ta": "Br J Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D015897:Comorbidity; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006331:Heart Diseases; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011241:Prednisone; D011379:Prognosis; D012306:Risk; D000069283:Rituximab; D016019:Survival Analysis; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "579-89",
"pmc": null,
"pmid": "21707585",
"pubdate": "2011-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18193371;15356302;17868190;11230490;12952829;11497154;20007921;18065404;17488991;16781283;20367567;12562656;12087452;15717735;15916681;16781286;20007997;3605130;19018081;12168880;17101852;15016643;19219604;10663277;15867204;20956616;12975245;17654614;18591554;14990630;3558716;18566583;17242396;15226333;17071492;18284715;8589229;19341970;16933332;16507563;10794747;15610554;10337875;18226581;17400912;9610691;15306095;18569635;8141877;20385988;20414658;14581895;15522651",
"title": "Biweekly rituximab, cyclophosphamide, vincristine, non-pegylated liposome-encapsulated doxorubicin and prednisone (R-COMP-14) in elderly patients with poor-risk diffuse large B-cell lymphoma and moderate to high 'life threat' impact cardiopathy.",
"title_normalized": "biweekly rituximab cyclophosphamide vincristine non pegylated liposome encapsulated doxorubicin and prednisone r comp 14 in elderly patients with poor risk diffuse large b cell lymphoma and moderate to high life threat impact cardiopathy"
} | [
{
"companynumb": "IT-PFIZER INC-2018530503",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "We present the rare case of a 47-year-old patient, suffering from cheilitis granulomatosa and lupus erythematosus discoid: this association is really exceptional because only once reported in English literature. In addition, the treatment of cheilitis granulomatosa is a challenge for the dermatologist: the gold standard, represented by steroids, is in fact designed as a short-time option. Our report confirms the good efficacy of methotrexate as a steroid-sparing agent.",
"affiliations": "Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, IT.;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, IT.;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, IT.;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, IT.;Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milano, IT.",
"authors": "Nazzaro|Gianluca|G|;Muratori|Simona|S|;Carrera|Carlo Giovanni|CG|;Coggi|Antonella|A|;Gianotti|Raffaele|R|",
"chemical_list": "D003879:Dermatologic Agents; D008727:Methotrexate",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nAn Bras DermatolAn Bras DermatolAnais Brasileiros de Dermatologia0365-05961806-4841Sociedade Brasileira de Dermatologia 10.1590/abd1806-4841.20153762Case ReportCheilitis granulomatosa associated with lupus erythematosus discoid and\ntreated with methotrexate: report of a case* Nazzaro Gianluca 1Muratori Simona 1Carrera Carlo Giovanni 1Coggi Antonella 1Gianotti Raffaele 11 Università degli Studi di Milano - Fondazione IRCCS Ca’\nGranda Ospedale Maggiore Policlinico - Milano, Itália.MAILING ADDRESS: Gianluca Nazzaro, Dipartimento di Fisiopatologia\nmedico-chirurgica e dei trapianti, Università degli Studi di Milano, Fondazione IRCCS\nCa’ Granda Ospedale Maggiore Policlinico, Via Pace, 9 - Milano. E-mail:\ngianluca.nazzaro@gmail.comConflicts of Interest: None.\n\nMay-Jun 2015 May-Jun 2015 90 3 Suppl 1 200 202 10 6 2014 15 7 2014 © 2015 by Anais Brasileiros de DermatologiaThis is an Open Access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial License which permits unrestricted\nnon-commercial use, distribution, and reproduction in any medium, provided the\noriginal work is properly cited.We present the rare case of a 47-year-old patient, suffering from cheilitis\ngranulomatosa and lupus erythematosus discoid: this association is really exceptional\nbecause only once reported in English literature. In addition, the treatment of\ncheilitis granulomatosa is a challenge for the dermatologist: the gold standard,\nrepresented by steroids, is in fact designed as a short-time option. Our report confi\nrms the good efficacy of methotrexate as a steroid-sparing agent.\n\nLupus erythematosus, discoidMelkersson-Rosenthal SyndromeMethotrexate\n==== Body\nINTRODUCTION\nMiescher cheilitis is a chronic condition of unknown aetiology, clinically characterized\nby recurrent or persistent swelling of one or both lips and histologically by non\nnecrotizing granulomas. Its therapy is usually a challenge for dermatologists: the first\nchoice is based on steroids, but, unfortunately, the result is temporary and additional\ntherapy is necessary.\n\nWe present a rare case of cheilitis granulomatosa associated with lupus erythematosus\ndiscoid, treated with methotrexate with complete resolution.\n\nCASE REPORT\nA 47-year-old white man attended our Department complaining about a persistent painless\nswelling of the upper lip, present for five years. The patient referred that at the\nonset this enlargement was episodic but recurrent. Family and personal history was\ncompletely negative.\n\nPhysical examination revealed a homogeneous swelling of the upper lip, without clinical\nsigns of erythema or edema of tongue and pharynx. Furthermore, in the same area, there\nwere some erythematous lesions, characterized also by closely adherent scales, that had\nappeared only one year before (Figure 1). Other\nsmaller erythematous lesions were present on the neck, while on the shoulders there were\nsome achromic and scarring lesions. Two skin biopsies for histopathological examination\nwere performed.\n\nFIGURE 1 Persistent swelling of the upper lip, associated with erythematous-desquamative\nlesions\n\nHistopathological examination of the swelling showed upper dermis vasodilation with\nperivascular infiltrate of lymphocytes, while in the reticular dermis non-necrotizing\ngranulomas constituted by epithelioid cells and Langhans' type cells were observed\n(Figure 2). In the other histology the\nepidermis was atrophic and characterized by hyperkeratosis and vacuolar degeneration of\nthe basal cells (Figure 3). The upper dermis\nshowed a perivascular and periadnexal infiltrate of lymphocytes, while a large amount of\nmucin was seen among collagen bundles.\n\nFIGURE 2 Non necrotizing granulomas in the reticular dermis [H-E 20x]\n\nFIGURE 3 Atrophic epidermis with hyperkeratosis and vacuolization of the basal layer. In\nthe dermis, perivascular infiltrate and deposit of mucin among collagen bundles\n[H-E 10x]\n\nLaboratory exams, including immunological markers, were totally negative or within\nnormal range.\n\nOur diagnosis was cheilitis granulomatosa, associated with lupus erythematosus\ndiscoid.\n\nWe treated the patient with hydroxychloroquine and methylprednisolone with prompt\nresolution of lupus, but during reduction of the steroid there was a new episode of\nswelling. Therefore, we added methotrexate 15 mg per week for six months, then reduced\nto 10 mg per week for two years. No relapses were reported by the patient during a\nthree-year follow-up.\n\nDISCUSSION\nMiescher cheilitis is a condition of unknown aetiology characterized by recurrent or\npersistent swelling of one or both lips. It was described by Guido Miescher in 1945,\nafter Melkersson and Rosenthal recognized the syndrome that nowadays holds their name in\n1933.1 This syndrome, in fact,\nis composed of three symptoms: cheilitis granulomatosa, paralysis of facial nerve and\nfissured tongue. Miescher, several years later, noticed that in many cases cheilitis was\nnot followed by the other two conditions and therefore considered it as a unique\nmanifestation. Nevertheless, it should be stressed that the simultaneous presence of two\nor three elements of the syndrome is very uncommon and therefore Miescher cheilitis may\nbe considered sometimes as a temporaneous diagnosis. 2\n\nCheilitis granulomatosa is a rare inflammatory granulomatosus disease, characterized by\nnon caseating granulomas, vasodilation and perivascular lymphocytic infiltrate. In the\nhistological differential diagnosis, Crohn disease, sarcoidosis and infectious\nmycobacterial conditions must be included. Furthermore, some authors consider cheilitis\ngranulomatosa as the extraintestinal form of Crohn disease, preceding or following the\ndiagnosis of intestinal disease of several years and suggesting to rule out inflammatory\nbowel disease in case the patient complains of gastrointestinal symptoms. 3,4\n\nThe first manifestation of cheilitis granulomatosa is a painless swelling involving one\nor both lips: this episode may resolve in a few hours and a relapse may occur in the\nfollowing days. The episodes may increase in duration until they become persistent.\nSometimes, the swelling is accompanied by headache, mild fever and other non specific\nsymptoms.\n\nTo confirm the diagnosis, a biopsy for histopathological examination is necessary. In\nearly stages, only perivascular infiltrate and edema of the upper dermis are found,\nwhile in chronic stages, non necrotizing granulomas composed of epithelioid cells are\npresent in the reticular dermis.\n\nAs the causative mechanisms are unclear, probably a polyetiological interplay of\nenvironmental exposures and genetic predisposition, the therapy is actually a challenge\nto dermatologists: in English literature, there are nowadays only a few case reports or\nsmall case series, with no comparative trials. The golden standard is usually based on\nsteroids: intralesional triamcinolone has been suggested by many authors as the first\nchoice therapy, followed by topical clobetasol and systemic steroids. 5 Nevertheless the result is temporary and\nthis kind of therapy must be stopped after a while for the well known side effects;\ntherefore, additional therapy is necessary. Other options are clofazimine, antibiotics\nsuch as tetracycline and metronidazole, immunomodulators, such as infliximab,\nthalidomide, dapsone and methotrexate. 6\n\nOur case is really exceptional because of the association, very rare in English\nliterature, of cheilitis granulomatosa and lupus erythematosus discoid: to our\nknowledge, it has been reported only once. 7,8 This association could\nhelp to clarify the pathogenesis of cheilitis granulomatosa as an immunological disease\nbut further studies are required.\n\nThe second reason for interest is the therapy we chose. Initially we treated our patient\nwith systemic steroid, as suggested by most reports, but at the dose reduction a relapse\nwas recorded. A new systemic therapy was administered that could also be used with lupus\nerythematosus discoid: hydroxychloroquine and methotrexate, with a ready benefit. Our\ncase, therefore, represents another evidence of the effectiveness of methotrexate as a\nsteroid-sparing drug in cheilitis granulomatosa. 9,10\n\nFinancial Support: None.\n\nHow to cite this article: Nazzaro G, Muratori S, Carrera CG, Coggi A,\nGianotti R. Cheilitis granulomatosa associated with lupus erythematosus discoid and\ntreated with methotrexate: report of a case. An Bras Dermatol. 2015;90(3 Suppl\n1):S197-9.\n\n* Work performed at the Dipartimento di Fisiopatologia medico-chirurgica e dei\ntrapianti, Università degli Studi di Milano - Fondazione IRCCS Ca’ Granda Ospedale\nMaggiore Policlinico - Milano, Itália.\n==== Refs\nReferences\n1 Miescher G Über essentielle granulmatöse Makrocheilie (Cheilitis\ngranulomatosa) Dermatologica 1945 91 57 85 \n2 van der Waal RI.Schulten EA.van de Scheur MR.Wauters IM.Starink TM.van der\nWaal I Cheilitis granulomatosa J Eur Acad Dermatol Venereol 2001 15 519 523 11843210 \n3 Dupuy A Cosnes J Revuz J Delchier JC Gendre JP Cosnes A Oral Crohn disease Arch Dermatol 1999 135 439 442 10206051 \n4 Kano Y Shiohara T Yagita A Nagashima M Association between cheilitis ganulomatosa and Crohn's\ndisease J Am Acad Dermatol 1993 28 801 801 8496438 \n5 Bacci C Valente ML Successful treatment of cheilitis granulomatosa with intralesional\ninjection of Triamcinolone J Eur Acad Dermatol Venereol 2010 24 363 364 19845820 \n6 Banks T Gada S A comprehensive review of current treatments for granulomatous\ncheilitis Br J Dermatol 2012 166 934 937 22187977 \n7 Elias MK Mateen FJ Weiler CR The Melkersson-Rosenthal syndrome: a retrospective study of biopsied\ncases J Neurol 2013 260 138 143 22836908 \n8 Binckley GW Melkersson-rosenthal syndrome with associated features of chronic\ndiscoid lupus erythematosus and sarcoidosis Arch Dermatol 1964 90 111 111 14149709 \n9 van der Waal RI Schulten EA van der Meij EH Scheur MR Starink TM van der Waal I Cheilitis granulomatosa: overview of 13 patients with long-term\nfollow-up--results of management Int J Dermatol 2002 41 225 229 12066767 \n10 Tonkovic-Capin V Galbraith SS Rogers 3rd RS Binion DG Yancey KB Cutaneous Crohn's disease mimicking Melkersson-Rosenthal syndrome:\ntreatment with methotrexate J Eur Acad Dermatol Venereol 2006 20 449 452 16643147\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0365-0596",
"issue": "90(3 Suppl 1)",
"journal": "Anais brasileiros de dermatologia",
"keywords": null,
"medline_ta": "An Bras Dermatol",
"mesh_terms": "D001706:Biopsy; D003879:Dermatologic Agents; D020405:Dermis; D006801:Humans; D008046:Lip; D008179:Lupus Erythematosus, Discoid; D008297:Male; D008556:Melkersson-Rosenthal Syndrome; D008727:Methotrexate; D008875:Middle Aged; D016896:Treatment Outcome",
"nlm_unique_id": "0067662",
"other_id": null,
"pages": "200-2",
"pmc": null,
"pmid": "26312716",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11843210;12066767;8496438;10206051;14149709;16643147;19845820;22187977;22836908",
"title": "Cheilitis granulomatosa associated with lupus erythematosus discoid and treated with methotrexate: report of a case.",
"title_normalized": "cheilitis granulomatosa associated with lupus erythematosus discoid and treated with methotrexate report of a case"
} | [
{
"companynumb": "IT-ANTARES PHARMA, INC.-2015-LIT-ME-0109",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"druga... |
{
"abstract": "We present the fatal outcome in a 31-year-old woman of Latin-American origin diagnosed with dermatomyositis. There were three months between death and the onset of symptoms. The initial presentation was normal dermatological symptoms to which were shortly added clinical signs of effects on the lungs, as was shown radiologically and through pulmonary function tests which were subsequently identified histologically as Hamman-Rich syndrome. The patient was treated with high doses of corticosteroids, intravenous (IV) immunoglobulin, cyclophosphamide and cyclosporin. We carried out a review of the literature on pulmonary compromise in dermatomyositis, clinical and anatomopathological forms and treatment alternatives.",
"affiliations": null,
"authors": "Macía-Villa|C C|CC|;Guillén-Astete|C A|CA|;Larena-Grijalba|C|C|;Zea-Mendonza|A|A|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-464X",
"issue": "39(3)",
"journal": "Acta reumatologica portuguesa",
"keywords": null,
"medline_ta": "Acta Reumatol Port",
"mesh_terms": "D000328:Adult; D003882:Dermatomyositis; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D011658:Pulmonary Fibrosis",
"nlm_unique_id": "0431702",
"other_id": null,
"pages": "270-3",
"pmc": null,
"pmid": "25326409",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Fatal outcome in a case of dermatomyositis and Hamman-Rich syndrome.",
"title_normalized": "fatal outcome in a case of dermatomyositis and hamman rich syndrome"
} | [
{
"companynumb": "PHHY2016ES149150",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": null,
"druga... |
{
"abstract": "A 70-year-old Japanese man with mantle cell lymphoma underwent extensive chemotherapy and radiation because of the relapse of mantle cell lymphoma. He developed mediastinal emphysema and a pneumothorax 14 days after treatment with 560 mg of ibrutinib. The mediastinal emphysema and the right pneumothorax disappeared after the ibrutinib treatment was tapered off. The patient developed interstitial pneumonia without any infection and new lesions of mantle cell lymphoma in the lungs after restarting treatment with 560 mg of ibrutinib. In this case, the patient developed pneumonia after retreatment with ibrutinib, suggesting the small lung fibrosis that penetrated the mediastinum might have caused the emphysema and pneumothorax.",
"affiliations": "Department of Hematology, Hakodate Municipal Hospital, 1-10-1, Minato-cho, Hakodate, 041-8680, Japan. yutsutsu@shore.ocn.ne.jp.;Department of Hematology, Hakodate Municipal Hospital, 1-10-1, Minato-cho, Hakodate, 041-8680, Japan.;Department of Hematology, Hakodate Municipal Hospital, 1-10-1, Minato-cho, Hakodate, 041-8680, Japan.;Department of Hematology, Hakodate Municipal Hospital, 1-10-1, Minato-cho, Hakodate, 041-8680, Japan.;Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.",
"authors": "Tsutsumi|Yutaka|Y|;Sekine|Takahiro|T|;Ito|Shinichi|S|;Matsuoka|Satomi|S|;Teshima|Takanori|T|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1007/s40800-019-0098-3",
"fulltext": "\n==== Front\nDrug Saf Case RepDrug Saf Case RepDrug Safety - Case Reports2199-11622198-977XSpringer International Publishing Cham 307900809810.1007/s40800-019-0098-3Case ReportIbrutinib Caused Mediastinal Emphysema and Pneumothorax in the Treatment of a Patient with Mantle Cell Lymphoma Tsutsumi Yutaka +81-138-43-2000yutsutsu@shore.ocn.ne.jp 1Sekine Takahiro 1Ito Shinichi 1Matsuoka Satomi 1Teshima Takanori 21 0000 0004 0640 759Xgrid.413530.0Department of Hematology, Hakodate Municipal Hospital, 1-10-1, Minato-cho, Hakodate, 041-8680 Japan 2 0000 0001 2173 7691grid.39158.36Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 21 2 2019 21 2 2019 12 2019 6 1 3© The Author(s) 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial 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 70-year-old Japanese man with mantle cell lymphoma underwent extensive chemotherapy and radiation because of the relapse of mantle cell lymphoma. He developed mediastinal emphysema and a pneumothorax 14 days after treatment with 560 mg of ibrutinib. The mediastinal emphysema and the right pneumothorax disappeared after the ibrutinib treatment was tapered off. The patient developed interstitial pneumonia without any infection and new lesions of mantle cell lymphoma in the lungs after restarting treatment with 560 mg of ibrutinib. In this case, the patient developed pneumonia after retreatment with ibrutinib, suggesting the small lung fibrosis that penetrated the mediastinum might have caused the emphysema and pneumothorax.\n\nissue-copyright-statement© The Author(s) 2019\n==== Body\nKey Points\n\nThe development of mediastinal emphysema and pneumothorax as a result of ibrutinib treatment has not been reported before.\t\nThe patient recovered from mediastinal emphysema and a right pneumothorax after tapering off the dosage of ibrutinib.\t\nThe complication of emphysema and pneumothorax was consistently observed in a patient receiving ibrutinib who had previously undergone extensive chemotherapy and radiation treatment.\t\n\n\n\nIntroduction\nIbrutinib is an irreversible small-molecule inhibitor of Bruton’s tyrosine kinase with efficacy in B-cell malignancies, including small lymphocytic lymphoma, chronic lymphocytic lymphoma, marginal zone lymphoma, and mantle cell lymphoma (MCL) [1, 2]. Here, we report the case of a patient with MCL who developed mediastinal emphysema and a pneumothorax after treatment with ibrutinib.\n\nCase Presentation\nThe patient was a 70-year-old man who developed MCL in March 2006. The patient was administered two courses of R-CHOP [rituximab 375 mg/m2 on day 1, cyclophosphamide 750 mg/m2 on day 2, doxorubicin 50 mg/m2 on day 2, vincristine 1.5 mg/m2 on day 2 (maximum 2 mg/day), and prednisolone 60 mg/day from days 2 to 6], but he developed drug-induced pneumonia. He was treated with prednisolone for the drug-induced pneumonia and recovered. He was then treated with four courses of ESHAP (cisplatin 25 mg/m2 on days 1–4, etoposide 40 mg/m2 on days 1–4, cytarabine 2000 mg/m2 on day 5, and methylate prednisolone 500 mg/day on days 1–5) and went into complete remission in November 2006.\n\nIn August 2012, the patient had a recurrence in the stomach. Radiation therapy (36 Gy/24 fr) was performed on the patient’s stomach for the MCL. The patient was administered 375 mg/m2 of rituximab every 2–3 months. However, the patient developed new lesions of MCL in the scapula in September 2013, and we administered radiation therapy (40 Gy/20 fr) again. After the second complete remission, the patient was administered rituximab on a weekly to bi-weekly basis, which was gradually extended to 2–3 months.\n\nIn September 2014, we observed a laryngeal tumor. The tumor grew gradually, thus rituximab treatment was administered weekly again in November 2015. By April 2016, the laryngeal tumor was still present, thus the patient was administered eight courses of rituximab and bendamustine (rituximab 375 mg/m2 on day 1, bendamustine 90 mg/m2 on day 2). The patient went into a third complete remission in January 2017, but developed swelling of the mesenteric lymph nodes.\n\nOn 7 September, 2017, the MCL recurred again. The patient was then administered two courses of rituximab and bendamustine (rituximab 375 mg/m2 on day 1 and bendamusutine 90 mg/m2 on days 2–3). The patient also developed gastric cancer complications on 9 September. The patient underwent a distal gastrectomy on 27 October; thus, the treatment of his MCL was interrupted. The MCL progressed and the mesenteric lymph nodes fused to form a bulky abdominal tumor in January 2018. Histopathological diagnosis from a biopsy of the abdominal tumor on 12 January indicated MCL. We administered 560 mg of ibrutinib on 15 January, 2018. Although we observed that the tumor became smaller, the patient reported chest pains on 29 January, 2018. Computed tomography (CT) showed a recurrence of interstitial pneumonia (IP), mediastinal emphysema, and a right pneumothorax (Fig. 1a). Although the abdominal tumor became smaller (though had not disappeared), it was highly likely that mediastinal emphysema and a pneumothorax had occurred with ibrutinib treatment. Therefore, there was a possibility that continuing the treatment with ibrutinib could lead to the recurrence or development of new lesions of mediastinal emphysema and pneumothorax. At the same time, there was also the possibility of aggravation of MCL upon sudden discontinuation of ibrutinib treatment.Fig. 1 a Emphysema and pneumothorax observed 14 days after the administration of ibrutinib. b Emphysema and pneumothorax disappeared after reducing the dosage of ibrutinib. c Interstitial pneumonia developed after restarting the ibrutinib treatment\n\n\n\n\nAccordingly, we could not continue the treatment with 560 mg of ibrutinib, thus we gradually tapered the dosage off from 19 March. The mediastinal emphysema and right pneumothorax disappeared by 23 April (Fig. 1b). After the ibrutinib dosage was tapered off, CT images taken on 20 June showed that the abdominal tumor had regrown. The CT images did not show any new lymphoma lesions in the lungs. The patient developed IP on 17 July (Fig. 1c) without any infection (such as a fungus or Pneumocystis jirovecii) and new MCL lesions in the lungs after being treated with 560 mg of ibrutinib (restarted from 26 June). The patient died on 23 July because of the progression of MCL.\n\nThe mediastinal emphysema and right pneumothorax were new adverse reactions (occurrence of IP is not a new report), and had a score of least 7 on the Naranjo Adverse Drug Reaction Probability Scale [3]. The reactions occurred after ibrutinib administration and improved following the reduction or discontinuation of ibrutinib, they were not caused by MCL or stomach cancer, and did not become more severe even after continuing the administration of other drugs, indicating they are adverse events from ibrutinib treatment.\n\nDiscussion\nIbrutinib is sometimes effective with autoimmune diseases [4, 5], inflammation of check-point immunotherapy [6], and graft-vs.-host disease [7, 8]. These reports suggest that ibrutinib modulates B- and T-cell functions and controls immune reactions. However, in vivo, ibrutinib was sometimes reported to lead to the development of IP. Almost all of these patients recovered after the administration of corticosteroids rather than ibrutinib [9–11].\n\nIn this case, certain mechanisms were considered as the cause of the mediastinal emphysema and pneumothorax that developed after the patient was treated with ibrutinib. The first was the small lymphoma lesions on the marginal region of the patient’s lung. After ibrutinib was administered, the small lymphoma lesions disappeared and the lung tissue did not recover. However, lung lymphoma lesions were not observed in the CT images taken on 17 July, after the uncontrollable progression of the disease. Second, small IP developed after the first administration of ibrutinib, and IP penetrated the mediastinum to develop mediastinal emphysema and a pneumothorax. In fact, after the ibrutinib treatment was restarted, IP development was observed in the CT images taken on 23 July. These suggested that the small lung fibrosis that penetrated the mediastinum might have caused the emphysema and pneumothorax in this case.\n\nThe reasons why IP occurred when we administered ibrutinib are still unclear. Gu et al. reported that ibrutinib treatment leads to the progression of IP in bleomycin-induced pulmonary fibrosis [9]. They showed that ibrutinib treatment increased the apoptosis of epithelial cells and enhanced inflammation and inflammatory cell infiltration in the lungs.\n\nIbrutinib also increased transforming growth factor-beta expression and myofibroblast generation. In this case, cytokine (transforming growth factor-beta) changes were not measured and bronchoalveolar lavage fluid testing was not performed. We believe this is the first case report of mediastinal emphysema and pneumothorax as a result of ibrutinib treatment. After eliminating various possibilities, we concluded that they are caused by the penetration of small IP.\n\nConclusion\nThe details of the mechanism of the emphysema and pneumothorax were unclear. However, the complication of emphysema and pneumothorax was consistently observed in an ibrutinib-treated patient who had previously received extensive chemotherapy and radiation treatment.\n\n\nAcknowledgements\nThe authors are grateful for the assistance provided by the staff at the Hematology Unit, Hakodate Municipal Hospital.\n\nAuthor Contributions\nYT, TS, and SI collected the clinical information about the case. YT drafted the manuscript, and SM and TT critically reviewed and revised the manuscript. All authors read and approved the final version submitted for publication.\n\nCompliance with Ethical Standards\nFunding\nNo sources of funding were received for the preparation of this case report.\n\nConflict of Interest\nYutaka Tsutsumi, Takahiro Sekine, Shinichi Ito, Satomi Matsuoka and Takanori Teshima have no conflicts of interest that are directly relevant to the content of this case report.\n\nEthics Approval\nThis study was approved by the local Ethics Committee of the Hakodate Municipal Hospital Institutional Review Board.\n\nConsent to Participate\nWritten informed consent was obtained from the patient described in the report. A copy of the consent may be requested from the corresponding author.\n==== Refs\nReferences\n1. Byrd JC Brown JR O’Brien S Barrientos JC Kay NE Reddy NM Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia New Engl J Med. 2014 371 3 213 223 10.1056/NEJMoa1400376 24881631 \n2. Wang Michael L. Blum Kristie A. Martin Peter Goy Andre Auer Rebecca Kahl Brad S. Jurczak Wojciech Advani Ranjana H. Romaguera Jorge E. Williams Michael E. Barrientos Jacqueline C. Chmielowska Ewa Radford John Stilgenbauer Stephan Dreyling Martin Jedrzejczak Wieslaw Wiktor Johnson Peter Spurgeon Stephen E. Zhang Liang Baher Linda Cheng Mei Lee Dana Beaupre Darrin M. Rule Simon Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results Blood 2015 126 6 739 745 10.1182/blood-2015-03-635326 26059948 \n3. Gallagher RM Kirkham JJ Mason JR Bird KA Williamson PR Nunn AJ Development and inter-rater reliability of the Liverpool adverse drug reaction causality assessment tool PLoS One. 2011 6 12 e28096 10.1371/journal.pone.0028096 22194808 \n4. Chang BY Huang MM Francesco M Chen J Sokolove J Magadala P Robinson WH The Bruton tyrosine kinase inhibitor PCI-32765 ameliorates autoimmune arthritis by inhibition of multiple effector cells Arthritis Res Ther. 2011 13 4 R115 10.1186/ar3400 21752263 \n5. Honigberg LA Smith AM Sirisawad M Verner E Loury D Chang B The Bruton tyrosine kinase inhibitor PCI-32765 blocks B cell activation and is efficacious in models of autoimmune disease and B-cell malignancy Proc Natl Acad Sci USA 2010 107 29 13075 13080 10.1073/pnas.1004594107 20615965 \n6. Sagiv-Barfi I Kohrt HE Czerwinski DK Ng PP Chang BY Levy R Therapeutic antitumor immunity by checkpoint blockade is enhanced by ibrutinib, an inhibitor of both BTK and ITK Proc Natl Acad Sci USA 2015 112 9 E966 E972 10.1073/pnas.1500712112 25730880 \n7. Schutt SD Fu J Nguyen H Bastian D Heinrichs J Wu Y Inhibition of BTK and ITK with ibrutinib is effective in the prevention of chronic graft versus-host disease in mice PLoS One 2015 10 9 e0137641 10.1371/journal.pone.0137641 26348529 \n8. Dubovsky JA Flynn R Du J Harrington BK Zhong Y Kaffenberger B Ibrutinib treatment ameliorates murine chronic graft versus host disease J Clin Invest. 2014 124 11 4867 4876 10.1172/JCI75328 25271622 \n9. Gu Y Huang B Yang Y Qi M Lu G Xia D Ibrutinib exacerbates bleomycin-induced pulmonary fibrosis via promoting inflammation Inflammation. 2018 41 3 904 913 10.1007/s10753-018-0745-3 29532266 \n10. Jungmann S Ludwig WD Schonfeld N Blum TG Großwendt C Boch C A patient with non-Hodgkin lymphoma and nonspecific interstitial pneumonia during ibrutinib therapy Case Rep Oncol Med. 2017 2017 5640186 29259834 \n11. Mato AR Islam P Daniel C Strelec L Kaye AH Brooks S Ibrutinib-induced pneumonitis in patients with chronic lymphocytic leukemia Blood. 2016 127 8 1064 1067 10.1182/blood-2015-12-686873 26702066\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2199-1162",
"issue": "6(1)",
"journal": "Drug safety - case reports",
"keywords": null,
"medline_ta": "Drug Saf Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101674544",
"other_id": null,
"pages": "3",
"pmc": null,
"pmid": "30790080",
"pubdate": "2019-02-21",
"publication_types": "D016428:Journal Article",
"references": "20615965;21752263;22194808;24881631;25271622;25730880;26059948;26348529;26702066;29259834;29532266",
"title": "Ibrutinib Caused Mediastinal Emphysema and Pneumothorax in the Treatment of a Patient with Mantle Cell Lymphoma.",
"title_normalized": "ibrutinib caused mediastinal emphysema and pneumothorax in the treatment of a patient with mantle cell lymphoma"
} | [
{
"companynumb": "JP-JNJFOC-20181024379",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BENDAMUSTINE HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Neuroblastoma (NB) is the most frequent extracranial solid tumor in children. More than 50% of patients present with widespread (stage M) or refractory disease. In these patients, event-free and overall survival was improved by the addition of the anti-disialoganglioside antibody dinutuximab beta (DB) following multimodal conventional therapy. However, the prognosis of patients with refractory/relapsed NB remains poor. In the past decade, immunotherapy approaches with checkpoint inhibitors were approved for patients with certain malignant diseases such as melanoma or Hodgkin lymphoma. In preclinical models, DB resulted in an upregulation of the programmed cell death protein 1 (PD-1) checkpoint in NB cell lines and a combined treatment of DB with a murine anti-PD-1 checkpoint inhibitor showed a synergistic effect in a NB mouse model.\n\n\n\nTwo patients were admitted with refractory metastatic NB. In the 4-year-old girl, NB was diagnosed in 2013. She completed her first-line therapy with a first remission in 2015, but suffered a relapse in 2017. Treatment with chemotherapy and DB resulted in progressive disease after transient improvement. In the 17-year-old young man, NB was first diagnosed in April 2010. After two local relapses in 2011 and 2014, a metastatic relapse and a large abdominal tumor bulk were found in 2018. Despite transient improvement with multimodal therapy, progressive metastatic disease was observed in May 2019. Both patients had a satisfactory quality of life. Therefore, treatment with DB and nivolumab was performed-in the girl from October 2018 until August 2019, in the young man since June 2019. Tolerance to treatment was excellent. The girl continues to be in complete remission 6 months after therapy was stopped. In the young man, the soft tissue lesions disappeared completely, the skeletal lesions regressed substantially after 9 months of his still ongoing treatment.\n\n\n\nThe combination of DB with the checkpoint inhibitor nivolumab led to complete and a very good partial remission in two patients with relapsed/refractory NB. Prospective trials are warranted to clarify the role of this novel approach in a larger number of patients.",
"affiliations": "Department of Pediatric Hematology and Oncology, Greifswald University Medicine, Greifswald, Germany karoline.ehlert@med.uni-greifswald.de.;Department of Pediatric Hematology and Oncology, Greifswald University Medicine, Greifswald, Germany.;Department of Nuclear Medicine, Greifswald University Medicine, Greifswald, Germany.;Institute for Diagnostic Radiology, Greifswald University Medicine, Greifswald, Germany.;Department of Pediatric Hematology and Oncology, Greifswald University Medicine, Greifswald, Germany.;Department of Pediatric Hematology and Oncology, Greifswald University Medicine, Greifswald, Germany.;Department of Pediatric Hematology and Oncology, Greifswald University Medicine, Greifswald, Germany.",
"authors": "Ehlert|Karoline|K|;Hansjuergens|Ina|I|;Zinke|Andreas|A|;Otto|Sylke|S|;Siebert|Nikolai|N|;Henze|Guenter|G|;Lode|Holger|H|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000077594:Nivolumab; C112746:dinutuximab",
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2020-000540",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426 BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\n32414861\njitc-2020-000540\n10.1136/jitc-2020-000540\nCase Report\n1506\nNivolumab and dinutuximab beta in two patients with refractory\nneuroblastoma\nEhlert Karoline 1 Hansjuergens Ina 1 Zinke Andreas 2 Otto Sylke 3 Siebert Nikolai 1 Henze Guenter 14 Lode Holger 1 1 Department of Pediatric\nHematology and Oncology, Greifswald University\nMedicine, Greifswald,\nGermany\n2 Department of Nuclear\nMedicine, Greifswald University Medicine,\nGreifswald, Germany\n3 Institute for Diagnostic\nRadiology, Greifswald University Medicine,\nGreifswald, Germany\n4 Department of Pediatric\nOncology and Hematology, Charité University Medicine\nBerlin, Campus Virchow Klinikum, Berlin, Germany\nCorrespondence to Dr Karoline Ehlert;\nkaroline.ehlert@med.uni-greifswald.de\n2020 \n15 5 2020 \n8 1 e00054013 4 2020 © Author(s) (or their employer(s)) 2020. Re-use permitted under\nCC BY-NC. No commercial re-use. See rights and permissions. Published by\nBMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative\nCommons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to\ndistribute, remix, adapt, build upon this work non-commercially, and license their\nderivative works on different terms, provided the original work is properly cited,\nappropriate credit is given, any changes made indicated, and the use is non-commercial.\nSee http://creativecommons.org/licenses/by-nc/4.0/.Background\nNeuroblastoma (NB) is the most frequent extracranial solid tumor in children. More than\n50% of patients present with widespread (stage M) or refractory disease. In these\npatients, event-free and overall survival was improved by the addition of the\nanti-disialoganglioside antibody dinutuximab beta (DB) following multimodal conventional\ntherapy. However, the prognosis of patients with refractory/relapsed NB remains poor. In\nthe past decade, immunotherapy approaches with checkpoint inhibitors were approved for\npatients with certain malignant diseases such as melanoma or Hodgkin lymphoma. In\npreclinical models, DB resulted in an upregulation of the programmed cell death protein\n1 (PD-1) checkpoint in NB cell lines and a combined treatment of DB with a murine\nanti-PD-1 checkpoint inhibitor showed a synergistic effect in a NB mouse model.\n\nCase presentations\nTwo patients were admitted with refractory metastatic NB. In the 4-year-old girl, NB\nwas diagnosed in 2013. She completed her first-line therapy with a first remission in\n2015, but suffered a relapse in 2017. Treatment with chemotherapy and DB resulted in\nprogressive disease after transient improvement. In the 17-year-old young man, NB was\nfirst diagnosed in April 2010. After two local relapses in 2011 and 2014, a metastatic\nrelapse and a large abdominal tumor bulk were found in 2018. Despite transient\nimprovement with multimodal therapy, progressive metastatic disease was observed in May\n2019. Both patients had a satisfactory quality of life. Therefore, treatment with DB and\nnivolumab was performed—in the girl from October 2018 until August 2019, in the\nyoung man since June 2019. Tolerance to treatment was excellent. The girl continues to\nbe in complete remission 6 months after therapy was stopped. In the young man, the soft\ntissue lesions disappeared completely, the skeletal lesions regressed substantially\nafter 9 months of his still ongoing treatment.\n\nConclusions\nThe combination of DB with the checkpoint inhibitor nivolumab led to complete and a\nvery good partial remission in two patients with relapsed/refractory NB. Prospective\ntrials are warranted to clarify the role of this novel approach in a larger number of\npatients.\n\nantibodies, neoplasmimmunotherapyneuroblastomapediatricsspecial-featureunlocked\n==== Body\nBackground\nNeuroblastoma (NB) is the most frequent, solid malignancy in childhood outside the central\nnervous system. More than 90% of children with NB are diagnosed until the age of\n6 years. The presence of MYCN amplification and/or metastatic\ndisease (stage M) are considered high-risk features in patients with NB. In this group,\n5-year event-free survival is still below 50% despite multimodal therapy including\nchemotherapy, surgery, radiotherapy, high-dose chemotherapy with autologous stem cell rescue\nand maintenance therapy.1 Therefore, identifying new\ntreatment strategies for these patients is of major importance.\n\nDisialoganglioside (GD2) is a glycolipid of the cell membrane. It is found on\nall NB cells with limited expression on normal tissue,2 and is an established target for immunotherapy in patients with NB.\n\nIn the ANBL 0032 study of the Children’s Oncology Group, administration of the\nhuman/mouse chimeric anti-GD2 antibody ch14.18 produced in SP2/0 cells\n(dinutuximab) in combination with granulocyte macrophage colony-stimulating factor (GM-CSF)\nand interleukin 2 (IL-2) resulted in an improved survival of patients with high-risk\nNB.3 Similarly, two trials of the International\nSociety of Paediatric Oncology European Neuroblastoma (SIOPEN) group showed a benefit for\npatients with high-risk NB treated with dinutuximab beta (DB). DB is different from\ndinutuximab as this variant was produced in Chinese hamster ovary cells. This introduced\nvariations in the glycosylation pattern followed by enhanced antibody effector\nfunctions.4 Improved survival was found in\nfirst-line maintenance treatment (HR-NBL-SIOPEN/1 study5) as well as in patients with relapsed and refractory NB.6\n\nDB was approved by the European Medicines Agency in 2017 for the treatment of patients with\nrelapsed or refractory NB. The primary mechanism of action of DB is the induction of an\nantibody-dependent cell-mediated cytotoxicity, mediated mainly by natural killer (NK)\ncells.7 The contribution of macrophages, monocytes\nand neutrophils to the clinical effect of DB is not clear to date. The cytotoxic response of\neffector cells is activated by immunoglobulin receptors (FCGR) on the cell surface on\nrecognition of DB bound to NB cells.8 FCGR3A is\nexpressed on the surface of NK cells and FCGR2A is expressed on macrophages, monocytes and\nneutrophils. Frequent clinical adverse effects of DB include the induction of neuropathic\npain and capillary leak syndrome.6\n\nWhereas passive immune therapy with DB has evolved as a treatment option for pediatric\npatients with high-risk NB, active immune therapy approaches such as checkpoint inhibitors\nhave been developed and approved for adult patients with cancer.9 The first checkpoint inhibitor ipilimumab targeting the CTLA-4 molecule\nwas approved for patients with melanoma in 2011.10\nProgrammed cell death protein 1 (PD-1) is another checkpoint mainly expressed on activated T\ncells and NK cells.11 PD-1 inhibits immune responses\nafter binding to its programmed death ligands, PD-L1 and PD-L2. PD-L1 is expressed on\nhematopoietic and epithelial cells, PD-L2 on macrophages and dendritic cells. An\nupregulation of both ligands can be observed in malignant diseases, PD-L1 predominantly in\nsolid tumors, PD-L2 in B cell lymphoma.9 In NB, PD-L1\nexpression is low. However, a constitutive and inducible PD-L1 expression was shown in\nseveral cell lines.12 13\n\nNivolumab is a monoclonal antibody that inhibits the PD-1/PD-L1 checkpoint by specifically\nbinding to PD-1 and is approved for the treatment of patients with malignant diseases\nincluding melanoma, non-small cell lung cancer and Hodgkin lymphoma.\n\nIn a preclinical NB model it was demonstrated that low PD-L1 expression was upregulated by\nthe treatment with DB, and a combined treatment with a murine anti-PD-1 antibody and DB\ninduced a synergistic anti-NB immune response in a syngeneic mouse model.14 Therefore, this combination might be a reasonable\napproach for patients with NB. As both DB and nivolumab lead to immune system activation,\nautoimmune phenomena are possible adverse effects particularly to be considered with this\napproach. Here, we report the results of combined treatment with nivolumab and DB in two\npatients with relapsed/refractory NB.\n\nCase presentations\nPatient 1\nIn August 2013, a 4-year-old girl was diagnosed with MYCN-amplified,\nmetastatic retroperitoneal NB stage M according to the International Neuroblastoma Staging\nSystem (INSS). As the patient’s NB was 123I-metaiodobenzylguanidine\n(mIBG)-negative, 18F-fluoro-2-deoxyglucose positron emission\ntomography/computed tomography (18F-FDG PET/CT) was used for tumor assessments.\nThe girl received multimodal high-intensity first-line and relapse treatment (table 1). She was admitted to the University\nChildren’s Hospital Greifswald in December 2017 with active disease. From December\n2017 until September 2018, she was first treated with a combination of DB and chemotherapy\nelements from the NB protocol NB2004. As the girl developed prolonged periods of\ngranulocytopenia and recurrent urinary tract infections, we decided to continue her\ntreatment with DB and irinotecan/temozolomide. After an initial response she developed\nprogressive disease in September 2018 as demonstrated by MRI and PET/CT (figure 1A). The expression of GD2 was\nconfirmed in September 2018 after obtaining tumor tissue to explore further therapeutic\noptions.\n\nFigure 1 PET/CT in patient 1. The black and white arrows indicate the most prominent soft\ntissue metastases in the pelvic and inguinal region. (A) September 2018, prior to\ntherapy with DB and nivolumab. (B) January 2019, pseudoprogression with a more intense\nPET signal. (C) May 2019. (D) October 2019. (E) March 2020. In C, D and E there is no\nevidence of the former soft tissue metastases. PET/CT, positron emission\ntomography/computed tomography.\n\nTable 1 Key details of the patients’ diagnosis and treatment\n\nDate\tDisease stage\tTreatment\t\n\n4-Year old girl\n\t\t\nAugust 2013 to 2015\n(home\ncountry)\t\nDiagnosis of retroperitoneal NB, stage 4 (INSS), MYCN\namplified\n\nFirst CR\n\n\n\t\nChemotherapy according to HR-NBL1/SIOPEN (rapid COJEC, TVD)\n\nHD chemotherapy with busulfan/melphalan and ASCT\n\nTwo tumor resections in May 2014 and July 2014\n\nLocal radiotherapy to the lumbar region\n\nImmunotherapy with dinutuximab beta and IL-2\n\n\n\t\nJanuary 2017 to November 2017\n(home\ncountry)\t\nFirst relapse, localized advanced\n\nPR\n\n\n\t\nTumor resection\n\nChemotherapy according to the RIST trial, partly with bevacizumab\n\nSecond HD chemotherapy with thiotepa/cyclophosphamide and ASCT\n\nSecond radiotherapy\n\n\n\t\nDecember 2017 to September 2018\t\nPR\n\nPR followed by PD\n\n\n\t\nImmunotherapy with dinutuximab beta in combination with chemotherapy\ncourses from trial NB2004 (N5, N6)\n\nImmunotherapy with dinutuximab beta in combination with\nirinotecan/temozolomide\n\n\n\t\nOctober 2018 to August 2019\t\nPD\n\nSecond CR in May 2019\n\n\n\tImmunotherapy with dinutuximab beta and\nnivolumab\t\nAugust 2019 to March 2020\t\nPersistent second complete remission (CR)\n\n\n\tNone\t\n\n17-Year-old young man\n\t\nApril 2010 to July 2010\t\nDiagnosis of left adrenal NB, stage 2 (INSS), MYCN\nnon-amplified\n\nFirst CR\n\n\n\t\nTumor surgery\n\nChemotherapy according to trial NB2004 (2x N5, 2x N6, composition see\nabove)\n\n\n\t\nJuly 2011 to July 2012\t\nFirst relapse, local\n\nPD in July 2012\n\n\n\t\nChemotherapy according to the RIST trial (composition see above)\n\nTumor resection, one course of postsurgical cyclophosphamide\n\nImmunotherapy with dinutuximab beta and IL-2\n\n\n\t\nJuly 2012–October 2012\t\nPD\n\nSecond CR\n\n\n\t\nChemotherapy according to trial NB2004 (2x N8)\n\nTumor resection\n\n\n\t\nFebruary 2014–July 2014\t\nSecond relapse, local\n\nThird complete remission\n\n\n\t\nTumor resection\n\nRadiotherapy\n\nSystemic therapy declined\n\n\n\t\nJune 2018 to May 2019\t\nThird relapse, metastatic\n\nPR followed by PD\n\n\n\t\nChemotherapy according to trial NB2004 (N5/N6 courses)\n\nTumor resection (nephrectomy and adrenalectomy left)\n\nLocal radiotherapy\n\nmIBG-therapy\n\n\n\t\nJune 2019 to ongoing\t\nPD\n\nPR\n\n\n\t\nImmunotherapy with DB and nivolumab\n\n\n\t\nASCT, autologous stem cell transplantation; CR, complete remission; DB, dinutuximab\nbeta; HD, high dose; IL-2, interleukin 2; INSS, International Neuroblastoma Staging\nSystem; mIBG, metaiodobenzylguanidine; N5, cisplatin, etoposide, vindesine; N6,\nvincristine, dacarbacine, ifosfamide, doxorubicin; N8, topotecan, cyclophosphamide,\netoposide; NB, neuroblastoma; NB2004, neuroblastoma 2004 protocol (Germany); PD,\nprogressive disease; PR, partial remission; Rapid COJEC, carboplatin, etoposide,\ncisplatin, cyclophosphamide; RIST, sirolimus, irinotecan, dasatinib, temozolomide;\nTVD, topotecan, vincristine, doxorubicin.\n\nConsidering the reduced tolerance to her relapse treatment, but her still good quality of\nlife, we decided to apply a combined immunotherapy using nivolumab and DB. From October\n2018 until August 2019, the girl received 19 doses of nivolumab (3 mg/kg body\nweight (BW) every 2 weeks) and 8 courses of DB (100 mg/m² body surface area\nin 10 days, every 6 weeks). In January 2019, progressive disease was suspected in routine\nMRI and PET/CT scans (figure 1B). Nevertheless, we\ndecided to continue treatment, as the general condition of the girl was excellent.\nInterestingly, PET/CT scans in May 2019 (figure 1C),\nAugust 2019, November 2019 (figure 1D) and March 2020\n(figure 1E) showed a complete resolution of the\ndisease with no residual tumors in the retroperitoneal and inguinal region. This was\nconfirmed by MRI scans. We decided to stop immunotherapy 3 months after the patient\nachieved the second complete remission. Autoimmune phenomena were not observed during or\nafter immunotherapy. The girl did not receive any blood products from October 2018 until\nMarch 2020. Apart from a single urinary tract infection in December 2018, tolerance to\ntreatment was excellent. She is disease-free, at home with her parents, visits school and\nis fully active.\n\nPatient 2\nThe 17-year-old young man was diagnosed in April 2010 with MYCN\nnon-amplified NB, INSS stage L, originating from the left adrenal gland. After two local\nrelapses, his disease progressed to stage M in June 2018 with multiple bone metastases and\na large abdominal mass at the site of the primary tumor. The first-line and relapse\ntreatments followed a high-intensity multimodal approach (table 1). Treatment from June 2018 until May 2019 included chemotherapy\naccording to the high-risk group in neuroblastoma 2004 protocol (Germany), resection of\nthe large abdominal mass with left-sided nephrectomy and local radiotherapy. We intended\nto proceed to mIBG therapy followed by high-dose chemotherapy and autologous stem cell\nrescue. However, the therapeutic mIBG scan from May 2019 revealed a considerable increase\nof bone metastases. As high-dose chemotherapy is not an option in progressive disease,\nthis concept of treatment was abandoned. Detailed analysis of the tumor tissue after\nresection in January 2019 had confirmed the expression of GD2 and PD-L1.\n\nDespite progressive disease, the patient still had a good quality of life without\ncontinuous pain or relevant disabilities. Based on the experience with patient 1 and the\nexploitation of all conventional therapeutic options, we applied DB and nivolumab. From\nJune 2019 until February 2020, the patient received 19 doses of nivolumab (3 mg/kg\nBW, every 2 weeks) and 7 courses of DB (100 mg/m² in 10 days, every 6\nweeks). In February 2020, we found a substantial regression of skeletal lesions in mIBG\nscans (figure 2A, B). He is still receiving\ntreatment. The young man had one febrile episode caused by an infection of the central\nvenous line. We did not observe any autoimmune phenomena. He did not receive any blood\nproducts from June 2019 until February 2020. His quality of life is excellent. He married\nin August 2019, is fully active and plans to resume his academic career.\n\nFigure 2 mIBG in patient 2. The black arrows indicate the most prominent skeletal and soft\ntissue metastases in the pelvic bone, in the skull and in the para-aortal region\n(level of the 12th thoracic vertebral body). (A) May 2019, prior to therapy with DB\nand nivolumab. (B) March 2020, substantial regression of the skeletal metastases and\nresolution of the soft tissue metastases. DB, dinutuximab beta; mIGB,\nmetaiodobenzylguanidine.\n\nIn both patients, tumor markers as catecholamine metabolites in the urine and\nneuron-specific enolase were checked several times during treatment. However, we did not\nfind any consistent association with the results of the imaging studies.\n\nDiscussion\nFirst-line treatment for patients with high-risk NB involves a multimodal approach\ncombining chemotherapy, surgery, high-dose chemotherapy with autologous stem cell rescue\nwith or without mIBG therapy and external beam radiotherapy. In addition, maintenance\ntherapy with DB is standard of care in high-risk NB.15\n\nPatients with refractory disease or multiple relapses of NB have a dismal prognosis when\nstandard treatment approaches have failed.16 Immune\ntherapy with DB either alone or in combination with a haploidentical stem cell transplant\nprocedure is an option currently explored for individual patients.17\n\nIn the past decade, checkpoint inhibitors have gained particular interest in various\nmalignant diseases of adult patients including melanoma, non-small cell lung cancer and\nHodgkin lymphoma.18–20 Since 2011,\nseven checkpoint inhibitors have been approved including nivolumab. Based on the observation\nthat DB leads to an upregulation of the PD-1/PD-L1 checkpoint14 in a preclinical model with a synergistic therapeutic effect when combined with\nan anti-PD-1 antibody, we applied this combination in two heavily pretreated patients with\nrelapsed/refractory NB. The outcome was very promising as both patients showed an excellent\nresponse to this treatment. In patient 1, progressive disease was suspected at staging\nexaminations after 3 months of therapy. It is well known, that checkpoint inhibitors\nmay result in pseudoprogression after the first few weeks of treatment due to\nimmunotherapy-induced inflammatory reaction.21\nConsidering pseudoprogression and the excellent general condition of the patient, we decided\nto continue her treatment as planned. Four months later, all PET-positive lesions had\ndisappeared. The complete response was confirmed by MRI scans. The CR was stable as further\nPET/CTs at the end of therapy and in the patient’s 3-month and 6-month follow-up\nrevealed no evidence of disease. In patient 2, the response to treatment was documented by\nMRI and mIBG scans. Regression of tumor tissue was clearly seen in the patient’s soft\ntissue lesions and in the bone metastases. As both patients had previous, unsuccessful\ntherapies with DB alone or in combination with IL-2 or chemotherapy, we consider the\naddition of immune therapy with nivolumab as the decisive element for the favorable outcome\ndocumented in our two patients.\n\nConclusions\nWe report the first results of a combined treatment with nivolumab and DB in two patients\nwith relapsed/refractory NB. The response to treatment was excellent. The first patient is\nnow 6 months after end of therapy in ongoing complete remission. The second patient\nhas reached a partial remission and is still receiving treatment. Treatment-related\ntoxicities were mild and well manageable; in particular, we did not observe any autoimmune\nphenomena. Both patients have an excellent quality of life and are fully active. These\nresults suggest that combined immune therapy with nivolumab and DB may be a promising\nstrategy to be explored in a prospective clinical trial.\n\nThe authors thank Frank Amtsberg for his technical support.\n\nContributors: KE wrote the original manuscript draft. GH, HL and IH reviewed the draft. AZ and SO\ncontributed and reviewed the imaging studies. HL, GH and NS were closely involved in the\nconception of this individual treatment approach. All authors read and approved the\nmanuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency\nin the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nEthics approval: Written informed consent was obtained in both patients.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Pinto NR , Applebaum MA ,\nVolchenboum SL , et al .\nAdvances in risk classification and treatment strategies for\nneuroblastoma\n. J Clin Oncol \n2015 ;33 :3008 –17\n.\n10.1200/JCO.2014.59.4648 26304901 \n2 Svennerholm L ,\nBoström K , Fredman P , et al .\nGangliosides and allied glycosphingolipids in human peripheral nerve and\nspinal cord\n. Biochim Biophys Acta \n1994 ;1214 :115 –23\n.\n10.1016/0005-2760(94)90034-5 7918590 \n3 Yu AL , Gilman AL , Ozkaynak MF , et al .\nAnti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for\nneuroblastoma\n. N Engl J Med \n2010 ;363 :1324 –34\n.\n10.1056/NEJMoa0911123 20879881 \n4 Zeng Y , Fest S , Kunert R , et al .\nAnti-neuroblastoma effect of ch14.18 antibody produced in CHO cells is\nmediated by NK-cells in mice\n. Mol Immunol \n2005 ;42 :1311 –9\n.\n10.1016/j.molimm.2004.12.018 15950727 \n5 Ladenstein R ,\nPötschger U ,\nValteau-Couanet D , et al .\nInvestigation of the role of Dinutuximab Beta-Based immunotherapy in the\nSIOPEN high-risk neuroblastoma 1 trial (HR-NBL1)\n.\nCancers \n2020 ;12 . 10.3390/cancers12020309 . [Epub ahead of print: 28 Jan 2020].\n6 Mueller I , Ehlert K , Endres S , et al .\nTolerability, response and outcome of high-risk neuroblastoma patients\ntreated with long-term infusion of anti-GD2 antibody\nch14.18/CHO\n. MAbs \n2018 ;10 :55 –61\n.\n10.1080/19420862.2017.1402997 29120699 \n7 Siebert N , Jensen C ,\nTroschke-Meurer S , et al .\nNeuroblastoma patients with high-affinity FCGR2A, -3A and stimulatory KIR\n2DS2 treated by long-term infusion of anti-GD2 antibody\nch14.18/CHO show higher ADCC levels and improved event-free survival\n.\nOncoimmunology \n2016 ;5 :e1235108. 10.1080/2162402X.2016.1235108 27999754 \n8 Cheung N-KV , Sowers R , Vickers AJ , et al .\nFCGR2A polymorphism is correlated with clinical outcome after\nimmunotherapy of neuroblastoma with anti-GD2 antibody and granulocyte macrophage\ncolony-stimulating factor\n. J Clin Oncol \n2006 ;24 :2885 –90\n.\n10.1200/JCO.2005.04.6011 16682723 \n9 Topalian SL , Drake CG , Pardoll DM \nImmune\ncheckpoint blockade: a common denominator approach to cancer therapy\n.\nCancer Cell \n2015 ;27 :450 –61\n.\n10.1016/j.ccell.2015.03.001 25858804 \n10 Cameron F , Whiteside G , Perry C \nIpilimumab:\nfirst global approval\n. Drugs \n2011 ;71 :1093 –104\n.\n10.2165/11594010-000000000-00000 21668044 \n11 van Dam LS , de Zwart VM ,\nMeyer-Wentrup FAG \nThe role\nof programmed cell death-1 (PD-1) and its ligands in pediatric cancer\n.\nPediatr Blood Cancer \n2015 ;62 :190 –7\n.\n10.1002/pbc.25284 25327979 \n12 Boes M ,\nMeyer-Wentrup F \nTLR3\ntriggering regulates PD-L1 (CD274) expression in human neuroblastoma\ncells\n. Cancer Lett \n2015 ;361 :49 –56\n.\n10.1016/j.canlet.2015.02.027 25697485 \n13 Dondero A , Pastorino F , Della\nChiesa M , et al .\nPD-L1 expression in metastatic neuroblastoma as an additional mechanism\nfor limiting immune surveillance\n. Oncoimmunology \n2015 ;5 :e1064578. 10.1080/2162402X.2015.1064578 26942080 \n14 Siebert N , Zumpe M ,\nJüttner M , et al .\nPD-1 blockade augments anti-neuroblastoma immune response induced by\nanti-GD2 antibody ch14.18/CHO\n.\nOncoimmunology \n2017 ;6 :e1343775. 10.1080/2162402X.2017.1343775 29123953 \n15 Simon T , Hero B , Schulte JH , et al .\n2017 GPOH guidelines for diagnosis and treatment of patients with\nneuroblastic tumors\n. Klin Padiatr \n2017 ;229 :147 –67\n.\n10.1055/s-0043-103086 28561228 \n16 Yi ES , Son MH , Hyun JK , et al .\nPredictors of survival in patients with high-risk neuroblastoma who\nfailed tandem high-dose chemotherapy and autologous stem cell\ntransplantation\n. Pediatr Blood Cancer \n2020 ;67 :e28066. 10.1002/pbc.28066 31736249 \n17 Illhardt T , Toporski J ,\nFeuchtinger T , et al .\nHaploidentical stem cell transplantation for Refractory/Relapsed\nneuroblastoma\n. Biol Blood Marrow Transplant \n2018 ;24 :1005 –12\n.\n10.1016/j.bbmt.2017.12.805 29307718 \n18 Herrscher H , Robert C \nImmune\ncheckpoint inhibitors in melanoma in the metastatic, neoadjuvant, and adjuvant\nsetting\n. Curr Opin Oncol \n2020 ;32 :106 –13\n.\n10.1097/CCO.0000000000000610 31876547 \n19 Khan M , Lin J , Liao G , et al .\nComparative analysis of immune checkpoint inhibitors and chemotherapy in\nthe treatment of advanced non-small cell lung cancer: a meta-analysis of randomized\ncontrolled trials\n. Medicine \n2018 ;97 :e11936. 10.1097/MD.0000000000011936 30113497 \n20 Merryman RW , Armand P , Wright KT , et al .\nCheckpoint blockade in Hodgkin and non-Hodgkin lymphoma\n.\nBlood Adv \n2017 ;1 :2643 –54\n.\n10.1182/bloodadvances.2017012534 29296917 \n21 Kiriu T , Yamamoto M , Nagano T , et al .\nPseudo-progression and the neutrophil-to-lymphocyte ratio in non-small\ncell lung cancer treated with immune checkpoint inhibitors: a case-control\nstudy\n. Onco Targets Ther \n2019 ;12 :10559 –68\n.\n10.2147/OTT.S228138 31819535\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2051-1426",
"issue": "8(1)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "antibodies, neoplasm; immunotherapy; neuroblastoma; pediatrics",
"medline_ta": "J Immunother Cancer",
"mesh_terms": "D000293:Adolescent; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D002675:Child, Preschool; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local; D009447:Neuroblastoma; D000077594:Nivolumab; D011379:Prognosis; D016879:Salvage Therapy",
"nlm_unique_id": "101620585",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32414861",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25858804;29123953;31819535;16682723;32013055;20879881;31736249;15950727;27999754;29120699;30113497;29296917;25327979;7918590;25697485;26304901;29307718;31876547;21668044;28561228;26942080",
"title": "Nivolumab and dinutuximab beta in two patients with refractory neuroblastoma.",
"title_normalized": "nivolumab and dinutuximab beta in two patients with refractory neuroblastoma"
} | [
{
"companynumb": "DE-ACCORD-221696",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
"drug... |
{
"abstract": "The clinical course and treatment in the first 2.5 years of life of a term-born girl with a severe onset of respiratory symptoms in the neonatal period caused by a p.Cys121Phe/C121F mutation in the gene of surfactant protein C (SFTPC) is described. During the first 9 months of life, she was mechanically ventilated. With methylprednisolone pulse therapy and oral prednisolone, she could eventually gradually be weaned from mechanical ventilation. At the age of 2.5 years, she is in a good clinical condition without any respiratory support and has a normal nutritional status and neurodevelopment. This clinical course with neonatal onset of respiratory insufficiency is remarkable since most patients with SFTPC mutations present with milder respiratory symptoms in the first years of life.",
"affiliations": "Department of Pediatrics, VieCuri Medical Centre, Venlo, The Netherlands.",
"authors": "van Hoorn|Jeroen|J|;Brouwers|Arno|A|;Griese|Matthias|M|;Kramer|Boris|B|",
"chemical_list": "D037721:Pulmonary Surfactant-Associated Protein C",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008168:Lung; D037721:Pulmonary Surfactant-Associated Protein C; D012121:Respiration, Artificial; D012127:Respiratory Distress Syndrome, Newborn; D014057:Tomography, X-Ray Computed; D015300:Ventilator Weaning",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24648475",
"pubdate": "2014-03-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20003372;21034611;20403820;23719253;15709974;16355106;19443464;20118944;17575475;11207353;15647591;21849033",
"title": "Successful weaning from mechanical ventilation in a patient with surfactant protein C deficiency presenting with severe neonatal respiratory distress.",
"title_normalized": "successful weaning from mechanical ventilation in a patient with surfactant protein c deficiency presenting with severe neonatal respiratory distress"
} | [
{
"companynumb": "NL-ENDO PHARMACEUTICALS INC-PNIS20140004",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugaddition... |
{
"abstract": "BACKGROUND\nAntibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) have been consistently found in a range of demyelinating disorders. In this context, MOG-IgG-associated optic neuritis (ON) has been suggested as a new subset of optic neuropathy. However, clinical manifestations and distinctive characteristics have only rarely been described.\n\n\nMETHODS\nA retrospective case series of three patients with MOG-IgG-associated ON. Clinical morphological features using imaging techniques are presented.\n\n\nRESULTS\nThree patients (8-year-old boy, 28-year-old female, 48-year-old male) were included. An 8-year-old boy suffered from a bilateral ON with severe visual loss. The best-corrected visual acuity (BCVA) was 0.05 in the right eye and finger counting in the left eye. The patient had a previous episode of acute disseminated encephalomyelitis (ADEM) with a right abducens nerve palsy. Visual acuity recovered after repeated cycles of intravenous methylprednisolone pulse therapy and 10 cycles of plasma exchange. During the last follow-up, BCVA was 0.9 in the right eye and 0.8 in the left eye. A 28-year-old female presented with a bilateral ON. Her BCVA was 0.5 in the right eye and 0.8 in the left eye. She fully recovered with pulse methylprednisolone therapy (1000 mg/d) with tapering after the second cycle and had a BCVA of 1.0 during the last follow-up visit. A 48-year-old male suffered from a relapsing bilateral ON. At first presentation, BCVA was 0.1 in the right eye and finger counting in the left eye. BCVA fully recovered after each pulse therapy with intravenous methylprednisolone (two cycles). Since the first relapse, the patient has been receiving long-term immunosuppression with rituximab. Despite rituximab and low-dose oral prednisone, the patient had another relapse with a left ON. After a third cycle with intravenous methylprednisolone, he partially recovered. BCVA at last follow-up was 1.0 in the right and 0.8 in the left eye.\n\n\nCONCLUSIONS\nMOG-IgG antibodies have been identified in different acquired demyelinating syndromes. The patients reported had an ADEM followed by bilateral ON, an isolated bilateral ON, and a relapsing bilateral ON. Individual treatment strategies led to substantial visual recovery in all patients. We recommend inclusion of MOG-IgG antibodies in the diagnostic workup at least after the first recurrence of ON since they can serve as a diagnostic and potential prognostic tool and might lead to specific therapeutic recommendations.",
"affiliations": "Department of Ophthalmology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.;Department of Ophthalmology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.;Neurologie, KSSG, Sankt Gallen, Switzerland.;Neuropädiatrie, Ostschweizer Kinderspital, St. Gallen, Switzerland.;Department of Ophthalmology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.",
"authors": "Heckmann|Jan|J|;Todorova|Margarita|M|;Müller|Stefanie|S|;Broser|Philip Julian|PJ|;Sturm|Veit|V|",
"chemical_list": "D001323:Autoantibodies; D063308:Myelin-Oligodendrocyte Glycoprotein",
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1068-2506",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-2165",
"issue": "237(4)",
"journal": "Klinische Monatsblatter fur Augenheilkunde",
"keywords": null,
"medline_ta": "Klin Monbl Augenheilkd",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D063308:Myelin-Oligodendrocyte Glycoprotein; D009900:Optic Nerve; D009902:Optic Neuritis; D012189:Retrospective Studies",
"nlm_unique_id": "0014133",
"other_id": null,
"pages": "458-463",
"pmc": null,
"pmid": "32092775",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "First Clinical Experience with Anti-myelin Oligodendrocyte Glycoprotein Antibody-Positive Optic Neuritis.",
"title_normalized": "first clinical experience with anti myelin oligodendrocyte glycoprotein antibody positive optic neuritis"
} | [
{
"companynumb": "CH-GYP-000003",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugadmin... |
{
"abstract": "BACKGROUND\nParoxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease, arising from the mutation of clonal hematopoietic stem cells, with an estimated incidence of 1 to 5 cases per million individuals. In pregnant women, adequate information regarding the prevalence of PNH is lacking, and its management has been a challenge because of the significant complications in this group. The condition is diagnosed based on clinical findings and laboratory tests. Eculizumab, the drug of choice for the treatment of PNH, reduces hemolysis and stabilizes hemoglobin levels, thereby decreasing the need for blood transfusions and improving the overall quality of life.\n\n\nMETHODS\nA 38-year-old woman was diagnosed with PNH in 2007 and eculizumab therapy was initiated at the end of 2014. She became pregnant in September 2015 and presented various decompensations from forced reductions in therapy due to the nonavailability of eculizumab. The pregnancy was interrupted in week 35, but the well-being of the newborn was not compromised. The patient, however, had to remain hospitalized for resolution of acute kidney insufficiency, anemia, and intense hemolysis, which were reverted by means of intravenous hydration, transfusion of 10 packed red blood cell units, and eculizumab therapy.\n\n\nCONCLUSIONS\nThe rarity of the disease and the lack of protocols for its management during pregnancy hampered the treatment of the patient. However, the symptoms were progressively treated as they appeared, based on laboratory tests since it was necessary to circumvent and handle the lack of eculizumab which was not readily available in Brazil's Public Health System.",
"affiliations": "Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória (EMESCAM) Scientific Writing Office, EMESCAM Department of Hematology, EMESCAM Department of Pediatrics, EMESCAM, Vitória, ES Post-Graduate Program Stricto Sensu, Faculdade de Medicina do ABC, Santo André, SP, Brazil.",
"authors": "Bastos|Juliana Marques Coelho|JMC|;Pinheiro|Patrícia Leal|PL|;Rocha|Lissa Canedo|LC|;Bicalho|Elisa Cao|EC|;Cazeli|Alessandra Barbosa|AB|;Marcondes|Síbia Soraya|SS|;Pinasco|Gustavo Carreiro|GC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000012155",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health MD-D-18-0228410.1097/MD.0000000000012155121554800Research ArticleClinical Case ReportTherapeutic challenges in pregnant women with paroxysmal nocturnal hemoglobinuria A case reportBastos Juliana Marques Coelho MDab∗Pinheiro Patrícia Leal MDabRocha Lissa Canedo MDaBicalho Elisa Cao MDaCazeli Alessandra Barbosa MDcMarcondes Síbia Soraya MDcPinasco Gustavo Carreiro MD, MSbdeNA. a Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória (EMESCAM)b Scientific Writing Office, EMESCAMc Department of Hematology, EMESCAMd Department of Pediatrics, EMESCAM, Vitória, ESe Post-Graduate Program Stricto Sensu, Faculdade de Medicina do ABC, Santo André, SP, Brazil.∗ Correspondence: Juliana Marques Coelho Bastos, Faculdade de Medicina, Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória, Vitória, ES, Brazil (e-mail: julianamcbastos@hotmail.com).9 2018 07 9 2018 97 36 e1215520 4 2018 8 8 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nIntroduction:\nParoxysmal nocturnal hemoglobinuria (PNH) is a rare acquired disease, arising from the mutation of clonal hematopoietic stem cells, with an estimated incidence of 1 to 5 cases per million individuals. In pregnant women, adequate information regarding the prevalence of PNH is lacking, and its management has been a challenge because of the significant complications in this group. The condition is diagnosed based on clinical findings and laboratory tests. Eculizumab, the drug of choice for the treatment of PNH, reduces hemolysis and stabilizes hemoglobin levels, thereby decreasing the need for blood transfusions and improving the overall quality of life.\n\nCase presentation:\nA 38-year-old woman was diagnosed with PNH in 2007 and eculizumab therapy was initiated at the end of 2014. She became pregnant in September 2015 and presented various decompensations from forced reductions in therapy due to the nonavailability of eculizumab. The pregnancy was interrupted in week 35, but the well-being of the newborn was not compromised. The patient, however, had to remain hospitalized for resolution of acute kidney insufficiency, anemia, and intense hemolysis, which were reverted by means of intravenous hydration, transfusion of 10 packed red blood cell units, and eculizumab therapy.\n\nConclusion:\nThe rarity of the disease and the lack of protocols for its management during pregnancy hampered the treatment of the patient. However, the symptoms were progressively treated as they appeared, based on laboratory tests since it was necessary to circumvent and handle the lack of eculizumab which was not readily available in Brazil's Public Health System.\n\nKeywords\ncase reporteculizumabhigh-risk pregnancyparoxysmal nocturnal hemoglobinuriaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nParoxysmal nocturnal hemoglobinuria (PNH), a rare and acquired hemolytic anemia, is caused by an alteration of hematopoietic stem cells resulting from a somatic mutation in the PIGA gene.[1,6] This gene is involved in the synthesis of glycosylphosphatidylinositol (GPI), an anchor for various membrane proteins, such as the CD55 (complement decay-accelerating factor) and CD59 (membrane inhibitor of reactive lysis), which are regulators of the complement system.[1–4,6,7] GPI deficiency in PNH results in multiple proteins not being expressed on the cell surface, making the cells exceptionally susceptible to the lytic effects of the complement system.[1,2]\n\nDue to the rarity of the disease and difficulty in its diagnosis, the exact incidence of PNH is not fully known.[1] At an estimated 1 to 5 cases per million individuals, it is believed to be common among the Orientals, principally the South Asians.[1,8] PNH can occur at any age, but a higher incidence has been observed in the third decade of life, with a comparable distribution between the 2 sexes.[4,9] The diagnosis of PNH is made through clinical findings, immunophenotyping by flow cytometry and analysis of the PIGA gene.[10,11]\n\nSymptoms of PNH usually include fatigue, dyspnea, abdominal pain, pulmonary hypertension, thrombotic events, and chronic kidney disease (CKD).[4,6] Thrombocytopenia, leucopenia, and bone marrow failure are common and contribute to disease-related mortality and morbidity.[13] In addition, intravascular hemolysis is seen in affected individuals, as the erythrocytes are more susceptible to attack by the complement system.[14] Studies have shown that compared to the general population, patients with PNH have a 62 times higher risk of thrombotic events and 6 times higher risk of CKD.[4]\n\nSurgery, trauma, and pregnancy are suggested risk factors for breakthrough hemolysis.[15] Although not always modifying the prognosis, pregnancy complicates the management of PNH, putting both the mother and fetus at a significantly higher risk.[5,10,16,17] There is very little information on the prevalence of PNH in pregnant women, and part of the difficulty in its diagnosis is due to other pregnancy-related clinical situations, such as the HELLP syndrome, pre-eclampsia, and thrombocytopenia that mimic PNH, leading to misdiagnosis.[12] The complications include potentially fatal thrombotic events, infections, hemorrhaging, anemia, increased risk of abortions, infant death, and prematurity.[13] The maternal and perinatal mortality rates can reach 20% and 10%, respectively.[16]\n\nDespite the high rates of morbidity, there are no well-defined protocols to manage PNH. Eculizumab has been reported to be effective for the treatment of PNH,[2,10,11] and clinical trials have shown that it reduces hemolysis and stabilizes the levels of hemoglobin (Hb), thereby, reducing the need for blood transfusions and improving the overall quality of life.[4,10,14,18]\n\nHere we present the case of a 38-year-old woman with PNH who became pregnant and was treated with eculizumab. Given that there are only a few reports on PNH in pregnant women and there is a clear lack of guidelines for its management in this group of patients, we believe that this case report will be a significant contribution to the field and will lead to new studies on PNH during pregnancy.\n\n2 Case report\nA 38-year-old white woman patient was diagnosed with PNH in 2007 when she presented with persistent fatigue, epigastralgia, nausea, and hemolytic anemia. She had no history of previous thromboembolism. The diagnosis was based on clinical findings, laboratory testing, and immunophenotyping by flow cytometry, which revealed low levels of both CD55 and CD59 expression on erythrocytes and granulocytes. Since there was no specific treatment available at that time, she was treated with a corticoid, 80 mg/d.\n\nThe patient was re-admitted to the hematology clinic at the end of 2014, complaining of fatigue, epigastralgia, and choluria. This time she was started on eculizumab, a humanized monoclonal antibody that prevents erythrocytic lysis and thereby, stabilizes the levels of Hb. Two weeks prior to starting the eculizumab treatment, she was vaccinated against meningitis caused by the bacteria, Neisseria meningitidis, as recommended by the European Medicines Agency. The patient's blood work at the beginning of the treatment revealed the following: Hb: 12 g/dL, lactate dehydrogenase (LDH): 1111 U/L, and reticulocyte count: 117,800/mm3 (Fig. 1). The loading dose offered was 600 mg/wk for 4 weeks, followed by a maintenance treatment of 900 mg every 14 days. The patient presented no adverse effects to the medication and showed improvement in her symptoms. Since eculizumab was not registered with ANVISA (National Health Surveillance Agency), it was not easily available in Brazil's Public Health System and had to be obtained from supporting institutions.\n\nFigure 1 Changes in reticulocyte counts, levels of hemoglobin, and lactic dehydrogenase.\n\nThe patient became pregnant in September 2015 and, in November of that same year, presented with clinical decompensation due to hemolysis, with the following laboratory data: Hb: 9.6 g/dL, reticulocyte count: 317,420/mm3, and LDH: 354 U/L (Fig. 1). We increased the dose of eculizumab from 900 to 1200 mg. She was also given ferrous sulfate and folic acid due to the pregnancy. The diagnosis of PNH associated with pregnancy justified the initiation of prophylaxis with enoxaparin at a dose of 60 mg, twice a day, to counter the high risk of thrombosis. There was an improvement in the symptoms after increasing the dose of eculizumab, though the ferrous sulfate was not well tolerated, resulting in nausea and choluria during the initial days of use.\n\nDuring the course of the pregnancy, the patient presented with other decompensations including anemia and epigastralgia, due to the forced reductions in the dose of eculizumab, which became unavailable. In the 35th gestational week, she presented with intense hemolysis with Hb: 3.8 g/dL, LDH: 1370 U/L, urea: 96 mg/dL, and creatinine: 5.1 mg/dL (Fig. 1), indicative of severe anemia and acute kidney insufficiency (AKI), which necessitated an early delivery.\n\nAnticoagulation was achieved during pregnancy with enoxaparin (60 mg) every 12 hours. Closer to the delivery date, due to the weight gain, it was increased to 80 mg, which was then maintained at the initial dose of 60 mg for 45 days postpartum.\n\nThe newborn was healthy, with signs of good vitality (Apgar score 9/9) and was of normal weight (2140 g) for the gestational age. The patient, however, remained hospitalized for resolution of AKI and intense hemolytic anemia, which were reverted by means of intravenous hydration, transfusion of 10 U of packed red blood cells, and 1200 mg eculizumab given every 7 days. She was discharged after 10 days, with the following values: LDH: 472.6 U/L, Hb: 8.1 g/dL, creatinine: 2.7 mg/dL, and urea: 25 mg/dL (Fig. 1).\n\nThe patient's clinical improvement was gradual. Her condition was stable at the first consultation at the ambulatory clinic, with the following values: LDH: 370 U/L, reticulocyte count: 203,180/mm3, Hb: 10 g/dL, urea: 37 mg/dL, and creatinine: 1.83 mg/dL.\n\nThis study was approved by the Ethics Committee of Escola Superior de Ciências da Santa Casa de Misericórdia de Vitória (Protocol 59622216.0.0000.5065). The patient has given informed consent authorizing the use and disclosure of her protected health information.\n\n3 Discussion\nEculizumab is the only therapy approved by the US Food and Drug Administration for PNH, and is, therefore, the drug of choice.[3,5,19] It is a humanized monoclonal antibody directed against the complement C5 protein terminal, which results in the inhibition of erythrocytic cellular lysis.[2,4,6,10,15] It reduces intravascular hemolysis and stabilizes the levels of Hb, thereby decreasing the necessity for blood transfusions and improving the overall quality of life in patients with PNH.[3,5,6,16]\n\nIncrease in the dosage and frequency of eculizumab given as needed during pregnancy has been reported in the literature.[2,3,6,10,13] In the present case, the dose was increased from 900 to 1200 mg, every 2 weeks. Despite not having been established, more benefits than harm have been cited with reference to the use of these intervals, between 12 and 16 days. The final decision was left to the discretionary judgment of the physician in charge.[15] Danilov et al[13] have reported successfully treating PNH during pregnancy by giving 600 mg of eculizumab intravenously, once a week for 4 weeks, followed by 900 mg once a week.\n\nIn this case, we opted for 1200 mg every 2 weeks, because of the unavailability of the drug. The patient responded well to this regimen, remaining asymptomatic while receiving the medication. However, the forced interruptions in the treatment again due to a lack of medication led to decompensations. Since the therapeutic objective remained the improvement of symptoms and stabilization in the levels of Hb (keeping the minimal levels around 10 mg/dL), as proposed by Melo et al,[16] transfusions of packed red blood cells and adjuvant were required.\n\nThe effects of eculizumab on the fetus, including its permeability across the placenta and excretion in breast milk, are not well known.[5,6,10] Therapeutic doses of eculizumab in pregnant women have been shown not to affect the complement system of the newborn.[5] However, 1 study has detected eculizumab in samples of cord blood, leading to the conclusion that it passes through the placenta, but the levels are not high enough to activate the complement system.[5,6,10] Similarly, the drug is not excreted in measurable quantities in breast milk, thus making breastfeeding safe.[5,6,10] Therefore, despite the still obscure strategies, the use of eculizumab in pregnancy produces satisfactory results, based on the findings reported in recent studies.[6,16] In this case, the patient had started the treatment before pregnancy, and there was no impact on the newborn. Since there is no consensus regarding the best time to start the drug, its use must be individualized, weighing the risks and benefits for each patient.\n\nSpecial attention needs to be paid to pregnancy-associated thrombosis in patients with PNH. Though more than 45% of the pregnancies in women with PNH result in abortion or spontaneous interruption, maternal mortality due to fatal thrombotic events, has been reported in only about 6% of the cases.[6,13] Other studies have shown that 29% to 44% of patients with PNH suffered at least 1 thromboembolic event during the course of their disease.[20] Therefore, routine utilization of a low molecular load of heparin should be initiated as soon as pregnancy is confirmed, though there is no consensus on how long to use it postpartum. While some studies suggest 3 months,[13] others suggest 1 to 2 months,[6,16] and there are still others that do not determine the duration.[10] In this study, a low molecular load of heparin was used for one-and-a-half months, and there were no thrombotic events.\n\nIn patients with PNH, delivery by cesarean section is the preferred choice in order to prevent maternal or fetal complications. The acceleration of fetal lung maturity is considered and is not contraindicated by PNH.[21] In this case, the decision of cesarean delivery was obstetric and was justified by the serious clinical symptoms including hemolysis and AKI. We utilized corticoids for the acceleration of lung maturity. Studies have reported a high rate of premature births in patients with PNH,[6] with up to 29% of the cases requiring preterm deliveries due to, among other reasons, preeclampsia, and fall in platelet counts.[10] Melo et al[16] have suggested that prematurity is the principal cause of perinatal fetal death, defining it as an iatrogenic cause. In this study, the due date was based on the clinical chart of the patient, after evaluating the risk of thrombosis. The well-being of the fetus was monitored by Doppler ultrasonography. Though there were no signs of fetal distress, the patient presented a high risk of thrombosis, AKI, and increased severity in symptoms, which led to the early interruption of gestation via cesarean section.[16]\n\nBased on the possible complications, the general consensus is that pregnant patients with PNH should be treated in tertiary hospitals, with multidisciplinary teams, including an obstetrician, hematologist, intensive care unit specialist, and anesthesiologist.[21]\n\n4 Conclusion\nEculizumab, which is the drug of choice to treat PNH, is expensive and is not widely available in Brazil's Public Health System. During the treatment, the clinical decompensations were sensitive to small dosage alterations, making it difficult to manage and control the disease effectively. Since the medication modifies the course of the disease, making it essential for better prognosis, and decrease in complications for this group of patients, regular and uninterrupted access to eculizumab is necessary. Further studies are required to standardize the treatment protocols, thus ensuring better outcomes in patients with PNH.\n\nAcknowledgement\nWe thank the Centro Acadêmico Aloísio Sobreira Lima – CAAL for the support offered.\n\nAuthor contributions\nConceptualization: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Sibia Soraya Marcondes, Alessandra Barbosa Cazelli, Gustavo Carreiro Pinasco.\n\nData curation: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Sibia Soraya Marcondes, Alessandra Barbosa Cazelli, Gustavo Carreiro Pinasco.\n\nFormal analysis: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Lissa Canedo Rocha, Elisa Cao Bicalho, Sibia Soraya Marcondes, Alessandra Barbosa Cazelli, Gustavo Carreiro Pinasco.\n\nInvestigation: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Lissa Canedo Rocha, Elisa Cao Bicalho, Sibia Soraya Marcondes.\n\nMethodology: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Lissa Canedo Rocha, Elisa Cao Bicalho, Sibia Soraya Marcondes, Alessandra Barbosa Cazelli, Gustavo Carreiro Pinasco.\n\nProject administration: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Sibia Soraya Marcondes, Gustavo Carreiro Pinasco.\n\nSupervision: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Lissa Canedo Rocha, Sibia Soraya Marcondes, Alessandra Barbosa Cazelli, Gustavo Carreiro Pinasco.\n\nValidation: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Lissa Canedo Rocha, Elisa Cao Bicalho, Sibia Soraya Marcondes, Alessandra Barbosa Cazelli, Gustavo Carreiro Pinasco.\n\nVisualization: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Lissa Canedo Rocha, Elisa Cao Bicalho, Sibia Soraya Marcondes, Alessandra Barbosa Cazelli, Gustavo Carreiro Pinasco.\n\nWriting – original draft: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Lissa Canedo Rocha, Elisa Cao Bicalho.\n\nWriting – review & editing: Juliana Marques Coelho Bastos, Patrícia Leal Pinheiro, Lissa Canedo Rocha, Elisa Cao Bicalho, Sibia Soraya Marcondes, Alessandra Barbosa Cazelli, Gustavo Carreiro Pinasco.\n\nAbbreviations: AKI = acute kidney insufficiency, CKD = chronic kidney disease, GPI = glycosylphosphatidylinositol, Hb = hemoglobin, LDH = lactate dehydrogenase, PNH = paroxysmal nocturnal hemoglobinuria.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Arruda MM Rodrigues CA Yamamoto M \nParoxysmal nocturnal hemoglobinuria: from physiopathology to treatment . Rev Assoc Med Bras \n2010 ;56 :214–21 .20498998 \n[2] Dezern AE Dorr D Brodsky RA \nPredictors of hemoglobin response to eculizumab therapy in paroxysmal nocturnal hemoglobinuria . Eur J Haematol \n2013 ;90 :16–24 .23046169 \n[3] DeZern AE Brodsky RA \nParoxysmal nocturnal hemoglobinuria: a complement-mediated hemolytic anemia . Hematol Oncol Clin North Am \n2015 ;29 :479–94 .26043387 \n[4] Hillmen P Muus P Röth A \nLong-term safety and efficacy of sustained eculizumab treatment in patients with paroxysmal nocturnal haemoglobinuria . Br J Haematol \n2013 ;162 :62–73 .23617322 \n[5] Hallstensen RF Bergseth G Foss S \nEculizumab treatment during pregnancy does not affect the complement system activity of the newborn . Immunobiology \n2015 ;220 :452–9 .25468724 \n[6] Al-Ani F Chin-Yee I Lazo-Langner A \nEculizumab in the management of paroxysmal nocturnal hemoglobinuria: patient selection and special considerations . Ther Clin Risk Manag \n2016 ;12 :1161–70 .27536121 \n[7] Gargiulo L Papaioannou M Sica M \nGlycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria . Blood \n2013 ;121 :2753–62 .23372165 \n[8] Hussain S Qureshi A Kazi J \nKidney involvement in paroxysmal nocturnal hemoglobinuria . Nephron Clin Pract \n2013 ;123 :28–35 .23752125 \n[9] Arrizabalaga B Colado E Gaya A \nConsenso Español para el diagnóstico y tratamiento de la hemoglobinuria paroxística nocturna . MedClin \n2016 ;146 :278–85 .\n[10] Kelly RJ Höchsmann B Szer J \nEculizumab in pregnant patients with paroxysmal nocturnal hemoglobinuria . N Engl J Med \n2015 ;373 :1032–9 .26352814 \n[11] Jang J Seok Kim J Yoon S-S \nPredictive factors of mortality in population of patients with paroxysmal nocturnal hemoglobinuria (PNH): results from a Korean PNH registry . J Korean Med Sci \n2016 ;31 :214–21 .26839475 \n[12] Vekemans MC Lambert C Ferrant A \nManagement of pregnancy in paroxysmal nocturnal hemoglobinúria on long-term eculizumab . Blood Coagul Fibrinolysis \n2015 ;26 :464–6 .25688464 \n[13] Danilov AV Smith H Craigo S \nParoxysmal nocturnal hemoglobinuria (PNH) and pregnancy in the era of eculizumab . Leuk Res \n2009 ;33 :2008–9 .\n[14] Kelly R Arnold L Richards S \nThe management of pregnancy in paroxysmal nocturnal haemoglobinuria on long term eculizumab . Br J Haematol \n2010 ;149 :446–50 .20151973 \n[15] Nakayama H Usuki K Echizen H \nEculizumab dosing intervals longer than 17 days may be associated with greater risk of breakthrough hemolysis in patients with paroxysmal nocturnal hemoglobinuria . Biol Pharm Bull \n2016 ;39 :285–8 .26830487 \n[16] Melo A Gorgal RC Amaral J \nClinical management of paroxysmal nocturnal haemoglobinuria in pregnancy: three case reports . Blood Transfus \n2011 ;9 :99–103 .21084002 \n[17] Parker C Omine M Richards S \nDiagnosis and management of paroxysmal nocturnal hemoglobinuria . Blood \n2005 ;106 :3699–709 .16051736 \n[18] Brodsky AR \nHow I treat paroxysmal nocturnal hemoglobinuria . Blood \n2009 ;113 :6522–7 .19372253 \n[19] Risitano AM \nParoxysmal nocturnal hemoglobinuria in the era of complement inhibition . Am J Hematol \n2016 ;91 :359–60 .26852134 \n[20] Hillmen P Muus P Dührsen U \nEffect of the complement inhibitor eculizumab on thromboembolism in patients with paroxysmal nocturnal hemoglobinuria . Blood \n2007 ;110 :4123–8 .17702897 \n[21] Nomura ML Surita FGC Parpinelli MA \nParoxysmal nocturnal hemoglobinuria in pregnancy . Rev Bras Ginecol Obstet \n2004 ;26 :579–82 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "97(36)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D019468:Disease Management; D005260:Female; D006457:Hemoglobinuria, Paroxysmal; D006801:Humans; D011247:Pregnancy; D011250:Pregnancy Complications, Hematologic",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e12155",
"pmc": null,
"pmid": "30200112",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Therapeutic challenges in pregnant women with paroxysmal nocturnal hemoglobinuria: A case report.",
"title_normalized": "therapeutic challenges in pregnant women with paroxysmal nocturnal hemoglobinuria a case report"
} | [
{
"companynumb": "BR-ALEXION PHARMACEUTICALS INC.-A201812482",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditio... |
{
"abstract": "Many centers continue to routinely perform transesophageal echocardiograms before atrial fibrillation (AF) ablation procedures in patients treated with direct oral anticoagulants (DOACs). One study suggested that the procedures could be done without transesophageal echocardiogram but used intracardiac echocardiography imaging of the appendage from the right ventricular outflow. This study aimed to assess the safety of ablation for AF without transesophageal echocardiogram screening or intracardiac echocardiography imaging of the appendage in DOAC compliant patients.\n\n\n\nAll patients undergoing AF ablation at the Cleveland Clinic (2011-2018) were enrolled in a prospectively maintained data registry. All consecutive patients presenting with AF or atrial flutter on DOAC were included. Periprocedural thromboembolic complications were assessed.\n\n\n\nA total of 900 patients were included. Their median CHA2DS2-VASc score was 2 (interquartile range 1-3). All were on DOACs (333 rivaroxaban, 285 dabigatran, 281 apixaban, and 1 edoxaban). Thromboembolic complications occurred in 4 patients (0.3%): 2 ischemic strokes, 1 transient ischemic attack without residual deficit, and 1 splenic infarct; all with no further complications. Bleeding complications occurred in 5 patients (0.4%): 2 pericardial effusions (1 intraoperative, 1 after 30 days, both drained), 3 groin hematomas (1 of them due to needing heparin for venous thrombosis, none required interventions). No patients required emergent surgeries.\n\n\n\nIn DOAC compliant patients who present for ablation in AF/atrial flutter, the procedures could be performed without transesophageal echocardiogram screening or intracardiac echocardiography imaging of the appendage; with low risk of complications.",
"affiliations": "Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.;Center for Atrial Fibrillation, Section of Cardiac Pacing and Electrophysiology, Heart and Vascular Institute, Cleveland Clinic, OH.",
"authors": "Diab|Mohamed|M|;Wazni|Oussama M|OM|;Saliba|Walid I|WI|;Tarakji|Khaldoun G|KG|;Ballout|Jad A|JA|;Hutt|Erika|E|;Rickard|John|J|;Baranowski|Bryan|B|;Tchou|Patrick|P|;Bhargava|Mandeep|M|;Chung|Mina|M|;Varma|Niraj|N|;Martin|David O|DO|;Dresing|Thomas|T|;Callahan|Thomas|T|;Cantillon|Daniel|D|;Kanj|Mohamed|M|;Hussein|Ayman A|AA|",
"chemical_list": "D065427:Factor Xa Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCEP.119.008301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-3084",
"issue": "13(9)",
"journal": "Circulation. Arrhythmia and electrophysiology",
"keywords": "atrial fibrillation; atrial flutter; echocardiography; stroke",
"medline_ta": "Circ Arrhythm Electrophysiol",
"mesh_terms": "D000368:Aged; D020517:Atrial Appendage; D001281:Atrial Fibrillation; D001282:Atrial Flutter; D017115:Catheter Ablation; D016208:Databases, Factual; D017548:Echocardiography, Transesophageal; D065427:Factor Xa Inhibitors; D005240:Feasibility Studies; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D009820:Ohio; D011446:Prospective Studies; D011667:Pulmonary Veins; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D020521:Stroke; D013923:Thromboembolism; D016896:Treatment Outcome; D019564:Unnecessary Procedures",
"nlm_unique_id": "101474365",
"other_id": null,
"pages": "e008301",
"pmc": null,
"pmid": "32706992",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Ablation of Atrial Fibrillation Without Left Atrial Appendage Imaging in Patients Treated With Direct Oral Anticoagulants.",
"title_normalized": "ablation of atrial fibrillation without left atrial appendage imaging in patients treated with direct oral anticoagulants"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-039104",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "EDOXABAN TOSYLATE"
},
... |
{
"abstract": "A 46-year old man presented with lower right quadrant abdominal pain caused by abdominal trauma. Abscess drainage was performed after the diagnosis of retroperitoneal abscess in the ileocecal portion of the colon. Type 2 advanced cancer was found in the cecum and ascending colon. Surgery was performed after improvement of inflammation. Considering the difficulty of curative resection for retroperitoneal invasion, we first performed ileo-transverse colon anastomosis. After surgery, the patient received FOLFOX with panitumumab(Pmab)as neoadjuvant chemotherapy. After 6 courses of this regimen, contrast enhanced computed tomography revealed shrinkage of the tumor. We performed a second surgery but the tumor was unresectable because of retroperitoneal invasion. After 47 courses of chemotherapy(5-FU plus LV with Pmab), the tumor was stable and we observed no distant metastasis. A third surgery was performed, and we were able to perform ileocecal resection including the retroperitoneum. The pathological diagnosis was pT4b(SI), pN1, ly2, V2, pPM0, pDM0, R0, pStage III a. On histological examination, the efficacy of chemotherapy was evaluated as Grade 1a. The patient received adjuvant chemotherapy with capecitabine and remains healthy without any evidence of recurrence more than 10 months after surgery.",
"affiliations": "Dept. of Surgery, Fuchu Hospital.",
"authors": "Aomatsu|Naoki|N|;Uchima|Yasutake|Y|;Nobori|Chihoko|C|;Kurihara|Shigeaki|S|;Yamakoshi|Yoshihito|Y|;Wang|En|E|;Nagashima|Daisuke|D|;Hirakawa|Toshiki|T|;Iwauchi|Takehiko|T|;Morimoto|Junya|J|;Tei|Seika|S|;Nakazawa|Kazunori|K|;Takeuchi|Kazuhiro|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(12)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000005:Abdomen; D000007:Abdominal Injuries; D000971:Antineoplastic Combined Chemotherapy Protocols; D044682:Colon, Ascending; D003110:Colonic Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D013997:Time Factors",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1766-1768",
"pmc": null,
"pmid": "29394769",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Curatively Resected Ascending Colon Cancer after Long-Term Chemotherapy Found in Abdominal Trauma.",
"title_normalized": "a case of curatively resected ascending colon cancer after long term chemotherapy found in abdominal trauma"
} | [
{
"companynumb": "JP-PFIZER INC-2018012442",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "Enoxaparin is a commonly used hospital medication and in rare instances may result in development of erythema multiforme. Management of these patients can be challenging. Physicians must maintain a high index of suspicion and consider the indication for enoxaparin therapy prior to withdrawal of the medication.",
"affiliations": "University of Chicago Pritzker School of Medicine Chicago Illinois.;Division of Dermatology NorthShore University HealthSystem Skokie Illinois.;Division of Dermatology NorthShore University HealthSystem Skokie Illinois.",
"authors": "Schadler|Eric D|ED|0000-0002-4197-9011;Joyce|Joel C|JC|;Haugen|Reshma N|RN|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.1752",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1752CCR31752Case ReportCase ReportsPostpartum eruption of enoxaparin‐induced erythema multiforme SCHADLER et al.Schadler Eric D. http://orcid.org/0000-0002-4197-9011eric.schadler@uchospitals.edu \n1\nJoyce Joel C. \n2\nHaugen Reshma N. \n2\n\n1 \nUniversity of Chicago Pritzker School of Medicine\nChicago\nIllinois\n\n2 \nDivision of Dermatology\nNorthShore University HealthSystem\nSkokie\nIllinois\n* Correspondence: Eric D. Schadler, University of Chicago Pritzker School of Medicine, 9933 Woods Drive Suite 100, Skokie, IL 60077 (eric.schadler@uchospitals.edu).23 8 2018 10 2018 6 10 10.1002/ccr3.2018.6.issue-101966 1969 18 4 2018 11 7 2018 13 7 2018 © 2018 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.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.Key Clinical Message\nEnoxaparin is a commonly used hospital medication and in rare instances may result in development of erythema multiforme. Management of these patients can be challenging. Physicians must maintain a high index of suspicion and consider the indication for enoxaparin therapy prior to withdrawal of the medication.\n\ndrug eruptiondrug reactionenoxaparinerythema multiformelow molecular weight heparin source-schema-version-number2.0component-idccr31752cover-dateOctober 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.5.0.1 mode:remove_FC converted:15.10.2018\n\n\nSchadler \nED \n, \nJoyce \nJC \n, \nHaugen \nRN \n. Postpartum eruption of enoxaparin‐induced erythema multiforme . Clin Case Rep . 2018 ;6 :1966 –1969 . 10.1002/ccr3.1752\n==== Body\n1 INTRODUCTION\nErythema multiforme (EM) is a cutaneous condition that manifests with variable phenotypes, the hallmark lesion being targetoid in nature. While commonly attributed to infections, EM can also be secondary to drugs and malignancy; however, the causative etiology often remains unknown. Enoxaparin is a frequently used anticoagulant, often administered following surgery or during pregnancy to prevent deep vein thrombosis. Herein, we describe a rare cutaneous drug reaction to enoxaparin resulting in erythema multiforme.\n\n2 CASE REPORT\nA 27‐year‐old postpartum woman presented to the emergency room with pruritic pink macules and papules distributed on the bilateral legs, forearms, shoulders, and abdomen (Figure 1). Two weeks prior to presentation she was diagnosed with a hospital‐acquired pulmonary embolus following preterm delivery of her twin pregnancy. She was immediately started on enoxaparin (50 mg) administered daily following identification of the embolus. After approximately 10 days of therapy she first noticed the pruritic lesions beginning.\n\nFigure 1 Pink macules and papules on the legs were present at the initial presentation\n\nShe denied any new food, medication, or other exposures with the exception of enoxaparin (50 mg daily). Review of systems was negative for fevers, chills, sick contacts, sores on the mucus membranes, abdominal pain, or other systemic complaints. No viral sampling was performed given the lack of systemic symptoms. Laboratory work‐up for heparin/platelet factor‐4 antibodies was negative and complete blood count was unremarkable (WBC = 3.9 × 103/μL; RBC = 3.74 × 106/μL; Hemoglobin = 11.2 g/dL; platelet count = 246 × 103/μL). She was diagnosed with a nonspecific inflammatory papular dermatitis and started on triamcinolone ointment with planned outpatient follow‐up.\n\nThree days after evaluation in the emergency department she presented to the outpatient dermatology clinic for progression of her rash and significant pruritus. A review of systems was unchanged. Physical examination revealed dozens of 2‐8‐mm blanching pink papules with surrounding faint halos distributed on the arms, legs, abdomen, and back (Figure 2A). Due to the change in morphology, biopsies of an active abdominal lesion for H&E stain and immunofluorescence were performed to rule out pregnancy‐related dermatoses including late onset pruritic urticarial papules and plaques of pregnancy (PUPPP) and pemphigoid gestationis. In the meantime, she was continued on triamcinolone.\n\nFigure 2 A, The rash evolved into numerous papules with surrounding erythema. B, H&E stain at 20× magnification was consistent with a drug eruption\n\nShe returned to the clinic 1 week following biopsy for follow‐up. During this time period her condition had considerably worsened necessitating an urgent care visit where she was started on 20 mg of prednisone per day, with minimal improvement after 4 days of treatment. On physical examination, the development of numerous targetoid pink plaques with dusky centers and erosions, distributed on the arms, legs, back, abdomen, and chest, was seen (Figure 3). No mucosal involvement or systemic symptoms were present except extreme pruritus. Histologic findings revealed perivascular lymphocytic inflammation, necrotic keratinocytes, and increased dermal mucin consistent with a drug eruption (Figure 2B). Interestingly, an eosinophilic infiltrate was not identified as would be expected in a drug‐related process. Direct immunofluorescence was negative. Based on the temporal relation of lesions to initiation of enoxaparin, a diagnosis of enoxaparin‐induced erythema multiforme was made. She was started on prednisone 60 mg daily and initiated warfarin therapy for anticoagulation. Enoxaparin was continued as bridging therapy until achieving therapeutic anticoagulation with warfarin, and subsequently discontinued.\n\nFigure 3 Examination revealed characteristic targetoid lesions\n\nUpon discontinuation of enoxaparin there was rapid improvement within a week with cessation of new lesion development and desquamation of old lesions (Figure 4).\n\nFigure 4 Following discontinuation of enoxaparin, lesions began to desquamate and no new lesions were identified\n\n3 DISCUSSION\nAdverse cutaneous drug reactions (ACDR) occur in approximately 1%‐3% of hospitalized patients.1 Enoxaparin, a low‐molecular weight heparin (LMWH), is a commonly used medication in the inpatient setting. It functions by binding antithrombin III, thereby accelerating the inactivation of factor Xa within the coagulation cascade. The most common cutaneous reaction to enoxaparin is delayed‐type hypersensitivity reaction at the injection site. A less common but recognized risk is heparin‐induced thrombocytopenia resulting from antibodies against heparin/platelet factor‐4. Rarely, reports of bullous hemorrhagic dermatosis and drug reaction with eosinophilia and systemic symptoms syndrome are described.2, 3 To our knowledge no cases of enoxaparin‐induced erythema multiforme have been described.\n\nErythema multiforme is an acute mucocutaneous condition that classically presents with targetoid lesions. It is most commonly secondary to a recent viral infection (>90%); however, other causes include drugs, autoimmunity, malignancy, and immunizations.4 Currently, the pathogenesis is not fully understood, and most studies that discuss this use cases of Herpes simplex virus (HSV)‐induced EM. Interestingly, HSV‐induced EM involves interferon‐γ as a principle cytokine whereas drug‐induced EM is associated with tumor necrosis factor alpha (TNF‐α) implying a different disease pathway.4 Although biopsy is not required for diagnosis of EM, it may be useful in atypical cases to rule out other causes. This case of drug‐induced EM was unique for two distinct reasons. First, management of her condition created a clinical conundrum. Standard management of drug‐induced EM includes immediate removal of the offending agent. This patient had multiple risk factors for thrombosis and development of pulmonary emboli, thus prohibiting immediate withdrawal of enoxaparin. In the setting of her recent hospital‐acquired pulmonary embolus, the decision to initiate warfarin therapy and bridge with enoxaparin until achieving a therapeutic international normalized ratio (INR) was made. This decision was dictated by the maternal‐fetal‐medicine team responsible for management of her anticoagulation; it is unclear if the use of a different LMWH was discussed. Alternative options to use a heparin bridge and immediately discontinue enoxaparin were discussed, but would necessitate hospital admission making this cost ineffective and placing the patient at additional hospital associated risks. Until enoxaparin could be withdrawn, high‐dose prednisone provided temporary symptomatic relief.\n\nSecond, this case was diagnostically challenging due to our patient's postpartum presentation. New‐onset dermatoses in the postpartum period may include a variety of pregnancy‐related conditions, including pruritic urticarial papules and plaques of pregnancy (PUPPP), papular dermatitis of pregnancy, and pemphigoid gestationis. Although the rash in this case was extending further into the postpartum period than expected, PUPPP was considered given the bland appearance and the extreme pruritus associated with her initial presentation. Once the clinical morphology changed our differential diagnosis shifted and biopsy was performed. Until this point, clinical suspicion for EM or drug‐related process was low.\n\n4 CONCLUSION\nThis case illustrates a rare drug reaction to enoxaparin. Diagnosis of EM demands a high index of suspicion as it may resemble multiple conditions. Consideration of drug‐related dermatoses can decrease time to diagnosis and allow for rapid withdrawal of an offending agent.\n\nCONFLICTS OF INTEREST\nNone to disclose.\n\nAUTHOR CONTRIBUTIONS\nES: Drafted the initial manuscript and assisted with revision process. Collected photographs and data to be used in manuscript. JJ: Performed major revisions of manuscript for important intellectual content. Assisted with gathering photographs. RH: Conception of the case report. Performed major revisions of manuscript for important intellectual content.\n==== Refs\nREFERENCES\n1 \n\nSvensson \nCK \n, \nCowen \nEW \n, \nGaspari \nAA \n. Cutaneous drug reactions . Pharmacol Rev . 2001 ;53 (3 ):357 ‐379 .11546834 \n2 \n\nShim \nJ‐S \n, \nChung \nSJ \n, \nKim \nB‐K \n, et al. Bullous hemorrhagic dermatosis due to enoxaparin use in a bullous pemphigoid patient . Asia Pac Allergy . 2017 ;7 (2 ):97 ‐101 .28487841 \n3 \n\nRonceray \nS \n, \nDinulescu \nM \n, \nLe Gall \nF \n, et al. Enoxaparin‐induced DRESS syndrome . Case Rep Dermatol . 2012 ;4 (3 ):233 ‐237 .23185158 \n4 \n\nSokumbi \nO \n, \nWetter \nDA \n. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist . Int J Dermatol . 2012 ;51 (8 ):889 ‐902 .22788803\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "6(10)",
"journal": "Clinical case reports",
"keywords": "drug eruption; drug reaction; enoxaparin; erythema multiforme; low molecular weight heparin",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1966-1969",
"pmc": null,
"pmid": "30349708",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports",
"references": "11546834;22788803;23185158;28487841",
"title": "Postpartum eruption of enoxaparin-induced erythema multiforme.",
"title_normalized": "postpartum eruption of enoxaparin induced erythema multiforme"
} | [
{
"companynumb": "US-SA-2018SA252307",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ENOXAPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nMore than 85% of pediatric cancer cases and 95% of deaths occur in resource-poor countries that use less than 5% of the world's health resources. In the developed world, approximately 81% of children with cancer can be cured. Models applicable in the most resource-poor settings are needed to address global inequities in pediatric cancer treatment.\n\n\nMETHODS\nBetween 2006 and 2011, a cohort of children received cancer therapy using a new approach in rural Rwanda. Children were managed by a team of a Rwandan generalist doctor, Rwandan nurse case manager, Rwanda-based US-trained pediatrician, and US-based pediatric oncologist. Biopsies and staging studies were obtained in-country. Pathologic diagnoses were made at US or European laboratories. Rwanda-based clinicians and the pediatric oncologist jointly generated treatment plans by telephone and email.\n\n\nRESULTS\nTreatment was provided to 24 patients. Diagnoses included lymphomas (n = 10), sarcomas (n = 9), leukemias (n = 2), and other malignancies (n = 3). Standard chemotherapy regimens included CHOP, ABVD, VA, COP/COMP, and actino-VAC. Thirteen patients were in remission at the completion of data collection. Two succumbed to treatment complications and nine had progressive disease. There were no patients who abandoned treatment. The mean overall survival was 31 months and mean disease-free survival was 18 months.\n\n\nCONCLUSIONS\nThese data suggest that chemotherapy can be administered with curative intent to a subset of cancer patients in this setting. This approach provides a platform for pediatric cancer care models, relying on local physicians collaborating with remote specialist consultants to deliver subspecialty care in resource-poor settings.",
"affiliations": "Partners In Health, Boston, Massachusetts.;Ministry of Health, Kigali, Rwanda.;Partners In Health, Boston, Massachusetts.;Inshuti Mu Buzima, Kigali, Rwanda.;Ministry of Health, Kigali, Rwanda.;Brigham and Women's Hospital, Boston, Massachusetts.;Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.;Boston Children's Hospital, Boston, Massachusetts.;Partners In Health, Boston, Massachusetts.",
"authors": "Stulac|Sara|S|;Mark Munyaneza|Richard B|RB|;Chai|Jeanne|J|;Bigirimana|Jean Bosco|JB|;Nyishime|Merab|M|;Tapela|Neo|N|;Chaffee|Sara|S|;Lehmann|Leslie|L|;Shulman|Lawrence N|LN|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25903",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "63(5)",
"journal": "Pediatric blood & cancer",
"keywords": "Africa; partnership; pediatric oncology; resource-poor",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008954:Models, Biological; D009367:Neoplasm Staging; D009369:Neoplasms; D012424:Rural Population; D012432:Rwanda; D015996:Survival Rate",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "813-7",
"pmc": null,
"pmid": "26785111",
"pubdate": "2016-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Initiating Childhood Cancer Treatment in Rural Rwanda: A Partnership-Based Approach.",
"title_normalized": "initiating childhood cancer treatment in rural rwanda a partnership based approach"
} | [
{
"companynumb": "US-JNJFOC-20160614942",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": ... |
{
"abstract": "Pneumonia is one of the leading causes of death in older people, with high mortality rates (> 80%). One of the bacterial pathogens causing pneumonia is Staphylococcus aureus. The unique adaptive ability of S. aureus to a broad range of antibiotics has led to the emergence of methicillin-resistant S. aureus (MRSA) strain. MRSA pneumonia remains a relatively uncommon infection in older people, but it is associated with a very high mortality rate. We report two cases of MRSA pneumonia that highlight the severe clinical presentation and virulence of MRSA infections in geriatric population. MRSA pneumonia can present with mostly an uncontrollable clinical evolution and an infaust prognosis. Therefore, clinicians should be aware of MRSA pneumonia in patients with comorbidities, recent hospitalization with antibiotic treatment, previous MRSA infections and also in patients residing in nursing homes/revalidation centers. Low prevalence of MRSA combined with a lack of highly distinctive clinical features makes accurate targeting of empirical treatment with antibiotics very difficult. Currently, monotherapy with linezolid or vancomycin remain the first choice, in adult patients with proven MRSA infection. Despite the higher age related mortality rates, there are no specific treatment guidelines for older patients.",
"affiliations": "Department of Internal Medicine, University Hospital Ghent , Ghent , Belgium.;Department of Internal Medicine, University Hospital Ghent , Ghent , Belgium.;Department of Internal Medicine, University Hospital Ghent , Ghent , Belgium.;Department of Clinical Chemistry, Microbiology and Immunology, University Hospital Ghent , Ghent , Belgium.;Department of Internal Medicine, University Hospital Ghent , Ghent , Belgium.",
"authors": "Kiselinova|M|M|;Velghe|A|A|https://orcid.org/0000-0002-0421-2719;Piers|R|R|;Verhasselt|B|B|https://orcid.org/0000-0002-4645-1144;Van Den Noortgate|N|N|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "England",
"delete": false,
"doi": "10.1080/17843286.2018.1547854",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1784-3286",
"issue": "74(6)",
"journal": "Acta clinica Belgica",
"keywords": "Methicillin-resistant S. Aureus MRSA; community-acquired pneumonia; health care-associated pneumonia; older people",
"medline_ta": "Acta Clin Belg",
"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D000071997:Blood Culture; D003428:Cross Infection; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D020380:Needs Assessment; D009735:Nursing Homes; D018579:Patient Selection; D011023:Pneumonia, Staphylococcal; D011379:Prognosis; D012307:Risk Factors; D061665:Time-to-Treatment; D014640:Vancomycin",
"nlm_unique_id": "0370306",
"other_id": null,
"pages": "456-459",
"pmc": null,
"pmid": "30444192",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Methicillin-resistant staphylococcus aureus pneumonia in older people: a diagnostic and therapeutic challenge.",
"title_normalized": "methicillin resistant staphylococcus aureus pneumonia in older people a diagnostic and therapeutic challenge"
} | [
{
"companynumb": "BE-PFIZER INC-2018026096",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": "3",
... |
{
"abstract": "Inotuzumab ozogamicin (InO) is an anti-CD22 monoclonal antibody-drug (calicheamicin) conjugate that has shown superior efficacy compared to conventional chemotherapy in relapsed/refractory (RR) B-cell acute lymphocytic leukemia (ALL) patients. We sought to find the safety and efficacy of InO in a real-world setting.\n\n\n\nA multicenter cohort analysis on 84 RR ALL patients who received InO outside of clinical trials was conducted to evaluate response and toxicity.\n\n\n\nThe median (range) age of patients at InO initiation was 50 (20-87) years. Forty patients (48%) had ≥ 3 therapies and 23 patients (27%) underwent allogeneic hematopoietic stem-cell transplantation (allo-HCT) before InO. The median (range) number of cycles of InO provided was 2 (1-6), and cumulative dose was 3.3 (1.8-9.3) mg/m2. Overall response rate (complete remission/complete remission with incomplete count recovery) was 63%; 44% had complete remission with minimal residual disease negativity. Twenty-three patients (27%) with response received allo-HCT. The median duration of response was 11.5 months and when censored at allo-HCT was not reached (51% in remission at 2 years). The median overall survival after InO was 11.6 months and when censored at time of allo-HCT was 13.6 months. The most common grade 3 or higher adverse events observed were transaminitis (16%), hyperbilirubinemia (5%), bleeding (4%), veno-occlusive disease (2%), and hyperglycemia (2%). In multivariate analysis, allo-HCT after InO did not retain favorable significance for duration of response (hazard ratio = 1.27; 95% confidence interval, 0.89-1.61; P = .2) or overall survival (hazard ratio = 1.10; 95% confidence interval, 0.37-3.25; P = .85).\n\n\n\nInO was well tolerated and had significant efficacy in RR B-cell ALL patients.",
"affiliations": "Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Department of Hematology and Oncology, Stanford University Cancer Center, Stanford, CA.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA.;Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.;Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, CA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.;Division of Hematology, Mayo Clinic, Rochester, MN.;Division of Hematology, Mayo Clinic, Rochester, MN.;Department of Hematology and Oncology, Stanford University Cancer Center, Stanford, CA.;Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL.;Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL.;Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT.;Department of Internal Medicine, Section of Hematology, Yale School of Medicine, New Haven, CT.;Karmanos Cancer Institute, Detroit, MI.;Karmanos Cancer Institute, Detroit, MI.;Carbone Cancer Center, University of Wisconsin, Madison, WI.;Robert H. Lurie Comprehensive Cancer Center, Northwestern Hospital, Chicago, IL.;Robert H. Lurie Comprehensive Cancer Center, Northwestern Hospital, Chicago, IL.;Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH.;Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI. Electronic address: eatallah@mcw.edu.",
"authors": "Badar|Talha|T|;Szabo|Aniko|A|;Wadleigh|Martha|M|;Liedtke|Michaela|M|;Arslan|Shukaib|S|;Siebenaller|Caitlin|C|;Aldoss|Ibrahim|I|;Schultz|Elizabeth|E|;Hefazi|Mehrdad|M|;Litzow|Mark R|MR|;Kuo|Eric|E|;Wang|Amy|A|;Curran|Emily|E|;Shallis|Rory M|RM|;Podoltsev|Nikolai|N|;Balasubramanian|Suresh|S|;Yang|Jay|J|;Mattison|Ryan|R|;Burkart|Madelyn|M|;Dinner|Shira|S|;Advani|Anjali|A|;Atallah|Ehab|E|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000080045:Inotuzumab Ozogamicin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2020.03.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "20(8)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Allogeneic HCT; B-cell ALL; Ph-positive ALL; RR ALL; VOD",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D000080045:Inotuzumab Ozogamicin; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "556-560.e2",
"pmc": null,
"pmid": "32291234",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Real-World Outcomes of Adult B-Cell Acute Lymphocytic Leukemia Patients Treated With Inotuzumab Ozogamicin.",
"title_normalized": "real world outcomes of adult b cell acute lymphocytic leukemia patients treated with inotuzumab ozogamicin"
} | [
{
"companynumb": "US-PFIZER INC-2020010254",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INOTUZUMAB OZOGAMICIN"
},
"drugadditional": "3... |
{
"abstract": "Primary biliary cholangitis (PBC) is an autoimmune disease that affects the small bile ducts. The only treatments currently approved in our country are ursodeoxycholic acid (UDCA) and obeticholic acid. Different indices evaluate the response after one year of treatment. The aim of our study was to evaluate the different predictive scores and prognostic factors of response to UDCA.\n\n\n\nRetrospective single-centre study in which clinical and analytical data of patients diagnosed with PBC were collected from January 1987 to December 2015. The response after one year of treatment was evaluated using the different response scores and their concordance degree using the Kappa index. The area under the receiver operating characteristic curve (AUROC) was calculated to determine the predictive capacity of the scores. Likewise, the prognostic factors of response to treatment were analysed.\n\n\n\nWe included 153 patients. The bivariate analysis showed a statistically significant relationship between the initial high levels of alkaline phosphatase and cholesterol and the poor response to treatment. The best AUROC was in Paris-I score (0.81). The concordance between the different scores was low. The GLOBE score was valid to evaluate the prognosis.\n\n\n\nBasal alkaline phosphatase and cholesterol were predictors of poor outcome. The best predictive qualitative score in our cohort patients was Paris-I. There was a poor concordance between the different predictive scores. GLOBE score is valid to evaluate prognosis.",
"affiliations": "Unidad de Hepatología, Servicio de Aparato Digestivo, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, España.;Unidad de Hepatología, Servicio de Aparato Digestivo, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, España.;Unidad de Hepatología, Servicio de Aparato Digestivo, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España.;Unidad de Hepatología, Servicio de Aparato Digestivo, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España.;Unidad de Hepatología, Servicio de Aparato Digestivo, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España.;Servei d'Estadística Aplicada, Universitat Autònoma de Barcelona, Barcelona, España.;Unidad de Hepatología, Servicio de Aparato Digestivo, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, España; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Instituto de Salud Carlos III, Madrid, España. Electronic address: mvergara@tauli.cat.;Unidad de Hepatología, Servicio de Aparato Digestivo, Parc Taulí Hospital Universitari, Institut d'Investigació i Innovació Parc Taulí I3PT, Universitat Autònoma de Barcelona, Sabadell, Barcelona, España.",
"authors": "Brunet|Eduard|E|;Hernández|Leticia|L|;Miquel|Mireia|M|;Sánchez-Delgado|Jordi|J|;Dalmau|Blai|B|;Valero|Oliver|O|;Vergara|Mercedes|M|;Casas|Meritxell|M|",
"chemical_list": "D014580:Ursodeoxycholic Acid; D002784:Cholesterol; D000469:Alkaline Phosphatase",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.medcli.2018.08.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7753",
"issue": "152(10)",
"journal": "Medicina clinica",
"keywords": "Colangitis biliar primaria; Factores pronósticos; Historia natural; Natural history; Predictive scores; Primary biliary cholangitis; Prognostic factors; Ursodeoxycholic acid; Ácido ursodeoxicólico; Índices predictivos",
"medline_ta": "Med Clin (Barc)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000469:Alkaline Phosphatase; D019540:Area Under Curve; D015992:Body Mass Index; D002784:Cholesterol; D015897:Comorbidity; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008099:Liver; D008103:Liver Cirrhosis; D008105:Liver Cirrhosis, Biliary; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012372:ROC Curve; D012189:Retrospective Studies; D012720:Severity of Illness Index; D016896:Treatment Outcome; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "0376377",
"other_id": null,
"pages": "377-383",
"pmc": null,
"pmid": "30297252",
"pubdate": "2019-05-17",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Analysis of predictive response scores to treatment with ursodeoxycholic acid in patients with primary biliary cholangitis.",
"title_normalized": "analysis of predictive response scores to treatment with ursodeoxycholic acid in patients with primary biliary cholangitis"
} | [
{
"companynumb": "ES-ALLERGAN-1849973US",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "URSODIOL"
},
"drugadditional": "3",
"dr... |
{
"abstract": "A 47-year-old white male with a 5-year history of type 2 diabetes mellitus presented to clinic with uncontrolled hyperglycemia, weight loss, and body aches that impeded his ability to work and sleep. He had initially controlled his diabetes successfully with weight loss and exercise. However, in the previous 6 months he had noticed unintentional weight loss. He was evaluated at another clinic where he was prescribed sitagliptin/metformin (Janumet) for his uncontrolled hyperglycemia. After 6 weeks his blood glucose had not significantly improved, and an endocrinologist prescribed insulin glargine (Lantus) and insulin aspart (NovoLog). About 3 days later he developed migratory joint pains and myalgias. After some weeks his insulin regimen was changed to insulin detemir (Levemir), and his myalgia symptoms briefly improved but then worsened. He experienced tingling of his feet that caused increasing difficulty sleeping. His review of systems was remarkable for fatigue, weight loss, polydipsia, polyphagia, polyuria, myalgias and arthralgias, numbness and tingling of both feet, and difficulty sleeping.",
"affiliations": null,
"authors": "Sankoorikal|Vivek-Thomas J|VT|;Ricks|Janet|J|",
"chemical_list": "D007328:Insulin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0026-6396",
"issue": "57(7)",
"journal": "Journal of the Mississippi State Medical Association",
"keywords": null,
"medline_ta": "J Miss State Med Assoc",
"mesh_terms": "D018771:Arthralgia; D003924:Diabetes Mellitus, Type 2; D004342:Drug Hypersensitivity; D006801:Humans; D006943:Hyperglycemia; D007328:Insulin; D008297:Male; D008875:Middle Aged; D063806:Myalgia; D015431:Weight Loss",
"nlm_unique_id": "7505622",
"other_id": null,
"pages": "213-5",
"pmc": null,
"pmid": "28485557",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "When the Treatment Becomes the Problem.",
"title_normalized": "when the treatment becomes the problem"
} | [
{
"companynumb": "US-SA-2017SA109787",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INSULIN GLARGINE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo examine the molecular mechanisms by which bicalutamide may cause heart failure in an elderly patient.\n\n\nMETHODS\nRetrospective analysis of bicalutamide as a cause of heart failure in Mr FD, an 82 years old with prostate cancer.\n\n\nRESULTS\nFollowing months of therapy, Mr FD was diagnosed with heart failure. Bicalutamide has been ceased, but 21 months later, Mr FD was still on heart failure medications, and passed away months later probably due to complications of prostate cancer. The Naranjo ADR probability scale gave this case a score of seven.\n\n\nCONCLUSIONS\nThe Naranjo scale strongly suggests that bicalutamide was the cause of heart failure. Apoptosis seems to be one of the mechanisms mediating heart failure, with the involvement of many molecular actors, such as ET-1, Bcl-2 and cyclin-A. The author believes this to be the first analysis describing bicalutamide as a probable cause of heart failure.",
"affiliations": "a HARP Medication Management , St Vincent's Hospital , Fitzroy , Australia.",
"authors": "Guirguis|Kyrillos|K|",
"chemical_list": "D000726:Androgen Antagonists; D000813:Anilides; D009570:Nitriles; D014105:Tosyl Compounds; C053541:bicalutamide",
"country": "England",
"delete": false,
"doi": "10.1517/14740338.2015.1131819",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1474-0338",
"issue": "15(3)",
"journal": "Expert opinion on drug safety",
"keywords": "Adverse drug reaction; Bicalutamide; apoptosis; elderly; heart failure; prostate cancer",
"medline_ta": "Expert Opin Drug Saf",
"mesh_terms": "D000369:Aged, 80 and over; D000726:Androgen Antagonists; D000813:Anilides; D017209:Apoptosis; D006333:Heart Failure; D006801:Humans; D008297:Male; D009570:Nitriles; D011471:Prostatic Neoplasms; D014105:Tosyl Compounds",
"nlm_unique_id": "101163027",
"other_id": null,
"pages": "297-302",
"pmc": null,
"pmid": "26745594",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bicalutamide causes heart failure in an elderly patient with prostate cancer.",
"title_normalized": "bicalutamide causes heart failure in an elderly patient with prostate cancer"
} | [
{
"companynumb": "AU-MYLANLABS-2016M1013209",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BICALUTAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Since November 2008, an 80-year-old man had been administered hydroxyurea and aspirin for the treatment of essential thrombocythemia (ET). In January 2012, his white blood cell count was markedly elevated, and he was treated with busulfan and cytarabine. In October 2012, he was hospitalized because of fever and general malaise, and a central venous port was placed in the right anterior chest owing to difficulty obtaining peripheral vascular access. Approximately 2 weeks after port placement, a subcutaneous mass was observed near the port. The patient died in November 2012 owing to exacerbation of the original disease. Autopsy revealed transformation to acute myeloid leukemia( AML; M2 subtype) and myeloid sarcoma (MS) in lymph nodes and the right anterior chest. The incidence of transformation of ET to AML is low, and MS as a comorbidity is rare. However, the risk of MS complications should be considered in patients with hematological malignancies due to recent increases in the use of central venous ports in such cases.",
"affiliations": "Dept. of Gastroenterology and Hematology/Clinical Oncology, Steel Memorial Muroran Hospital.",
"authors": "Kuroda|Hiroyuki|H|;Jomen|Wataru|W|;Yoshida|Masahiro|M|;Usami|Makoto|M|;Shimoyama|Saori|S|;Yamada|Michiko|M|;Abe|Tomoyuki|T|;Sakurai|Tamaki|T|;Fujii|Shigeyuki|S|;Maeda|Masahiro|M|;Fujita|Miri|M|;Nagashima|Kazuo|K|;Uemura|Satoko|S|;Kanari|Yusuke|Y|;Kato|Junji|J|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(2)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000369:Aged, 80 and over; D001344:Autopsy; D002471:Cell Transformation, Neoplastic; D017809:Fatal Outcome; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D023981:Sarcoma, Myeloid; D013920:Thrombocythemia, Essential",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "215-9",
"pmc": null,
"pmid": "25743142",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Subcutaneous myeloid sarcoma in a patient with essential thrombocythemia that transformed into acute myeloid leukemia.",
"title_normalized": "subcutaneous myeloid sarcoma in a patient with essential thrombocythemia that transformed into acute myeloid leukemia"
} | [
{
"companynumb": "JP-ASPEN PHARMA TRADING LIMITED US-AG-2015-002019",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drug... |
{
"abstract": "Denosumab, an inhibitor of receptor activator of nuclear factor κ-B ligand, is an approved treatment of giant cell tumor of bone (GCTB) in adults and \"skeletally mature\" adolescents. Safety concerns include oversuppression of bone remodelling, with risk of osteonecrosis of the jaw (ONJ) and atypical femur fractures during treatment in adults and rebound hypercalcemia after treatment cessation in children. To date, ONJ has never been reported in children or adolescents.\n\n\n\nTo describe serious adverse effects during and following high-dose denosumab therapy in GCTB patients.\n\n\n\nTwo adolescents (14 and 15 years) and a young adult (40 years) received fixed-dose denosumab for GCTB for 1.3 to 4 years (cumulative dose, 47 to 98 mg/kg), which was stopped because of development of ONJ in one adolescent and bilateral femoral cortical stress reactions in the young adult. All three patients developed rebound hypercalcemia with acute kidney injury 5.5 to 7 months after denosumab cessation.\n\n\n\nThe ONJ necessitated surgical debridement. Rebound hypercalcemia (serum calcium, 3.1 to 4.3 mmol/L) was unresponsive to hyperhydration alone, requiring repeated doses of calcitonin or intravenous bisphosphonate treatment. Hypercalcemia recurred in two patients within 4 weeks, with normal serum calcium profiles thereafter. All patients were naive to chemotherapy, radiotherapy, bisphosphonates, and corticosteroids and were metastases free, confirming the causative role of denosumab in these complications.\n\n\n\nThese suppression-release effects of high-dose denosumab on bone remodeling raise questions about safety of fixed dosing and treatment duration. In young people, weight-adjusted dosing and safety monitoring during and after antiresorptive therapy is required.",
"affiliations": "Department of Endocrinology and Diabetes, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, West Midlands B4 6NH, United Kingdom.;Department of Orthopaedics, Philippine General Hospital, 1000 Manila, Philippines.;Department of Medical Oncology, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield HX3 0PW, United Kingdom.;Department of Orthopaedic Oncology, The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham B31 2AP, United Kingdom.;Department of Medical Oncology, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield HX3 0PW, United Kingdom.;Department of Maxillofacial Surgery, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield HD3 3EA, United Kingdom.;Department of Maxillofacial Surgery, Calderdale and Huddersfield NHS Foundation Trust, Huddersfield HD3 3EA, United Kingdom.;Department of Orthopaedic Oncology, The Royal Orthopaedic Hospital NHS Foundation Trust, Birmingham B31 2AP, United Kingdom.;Department of Endocrinology and Diabetes, Birmingham Women's and Children's Hospital NHS Foundation Trust, Birmingham, West Midlands B4 6NH, United Kingdom.",
"authors": "Uday|Suma|S|;Gaston|Czar Louie|CL|;Rogers|Luke|L|;Parry|Michael|M|;Joffe|Johnathan|J|;Pearson|John|J|;Sutton|David|D|;Grimer|Robert|R|;Högler|Wolfgang|W|",
"chemical_list": "D000069448:Denosumab",
"country": "United States",
"delete": false,
"doi": "10.1210/jc.2017-02025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-972X",
"issue": "103(2)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": null,
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D001859:Bone Neoplasms; D000069448:Denosumab; D005260:Female; D018212:Giant Cell Tumor of Bone; D006801:Humans; D006934:Hypercalcemia; D008297:Male",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "596-603",
"pmc": null,
"pmid": "29211870",
"pubdate": "2018-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Osteonecrosis of the Jaw and Rebound Hypercalcemia in Young People Treated With Denosumab for Giant Cell Tumor of Bone.",
"title_normalized": "osteonecrosis of the jaw and rebound hypercalcemia in young people treated with denosumab for giant cell tumor of bone"
} | [
{
"companynumb": "GB-BAUSCH-BL-2018-005934",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN"
},
"drugadditional": "3",
... |
{
"abstract": "Deficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, such as vasculitis, inflammation, and hematologic manifestations. Some associations of clinical features can mimic autoimmune lymphoproliferative syndrome (ALPS). We report a case of a female patient who fulfilled the 2009 National Institute of Health revised criteria for ALPS and received a delayed diagnosis of DADA2. During her childhood, she suffered from autoimmune hemolytic anemia, immune thrombocytopenia, and chronic lymphoproliferation, which partially responded to multiple lines of treatments and were followed, at 25 years of age, by pulmonary embolism, septic shock, and bone marrow failure with myelodysplastic evolution. The patient died from the progression of pulmonary disease and multiorgan failure. Two previously unreported variants of gene ADA2/CECR1 were found through next-generation sequencing analysis, and a pathogenic role was demonstrated through a functional study. A single somatic STAT3 mutation was also found. Clinical phenotypes encompassing immune dysregulation and marrow failure should be evaluated at the early stage of diagnostic work-up with an extended molecular evaluation. A correct genetic diagnosis may lead to a precision medicine approach consisting of the use of targeted treatments or early hematopoietic stem cell transplantation.",
"affiliations": "Hematology Unit, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Unitá Operativa Semplice Dipartimentale (UOSD) Genetics and Genomics of Rare Diseases, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Clinica Pediatrica e Reumatologia e Centro Malattie Autoinfiammatorie e Immunodeficienze, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Clinica Pediatrica e Reumatologia e Centro Malattie Autoinfiammatorie e Immunodeficienze, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Hematology Unit, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Hematology Unit, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Clinica Pediatrica e Reumatologia e Centro Malattie Autoinfiammatorie e Immunodeficienze, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Hematology Unit, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Covid Hospital, Unità Operativa di Malattie Infettive, Dipartimento di Scienze Pediatriche, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Covid Hospital, Unità Operativa di Malattie Infettive, Dipartimento di Scienze Pediatriche, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Hematopoietic Stem Cell Transplantation Unit, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Unitá Operativa Semplice Dipartimentale (UOSD) Genetics and Genomics of Rare Diseases, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Hematology Unit, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Hematology Unit, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Clinica Pediatrica e Reumatologia e Centro Malattie Autoinfiammatorie e Immunodeficienze, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.;Hematology Unit, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy.",
"authors": "Dell'Orso|Gianluca|G|;Grossi|Alice|A|;Penco|Federica|F|;Caorsi|Roberta|R|;Palmisani|Elena|E|;Terranova|Paola|P|;Schena|Francesca|F|;Lupia|Michela|M|;Ricci|Erica|E|;Montalto|Shana|S|;Pierri|Filomena|F|;Ceccherini|Isabella|I|;Fioredda|Francesca|F|;Dufour|Carlo|C|;Gattorno|Marco|M|;Miano|Maurizio|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2021.754029",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.754029\nImmunology\nCase Report\nCase Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure\nDell’Orso Gianluca 1\n\nGrossi Alice 2\n\nPenco Federica 3\nCaorsi Roberta 3\n\nPalmisani Elena 1\nTerranova Paola 1\nSchena Francesca 3\n\nLupia Michela 1\nRicci Erica 4\n\nMontalto Shana 4\n\nPierri Filomena 5\nCeccherini Isabella 2\n\nFioredda Francesca 1\n\nDufour Carlo 1\nGattorno Marco 3\n\nMiano Maurizio 1 *\n\n1 Hematology Unit, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy\n2 Unitá Operativa Semplice Dipartimentale (UOSD) Genetics and Genomics of Rare Diseases, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy\n3 Clinica Pediatrica e Reumatologia e Centro Malattie Autoinfiammatorie e Immunodeficienze, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy\n4 Covid Hospital, Unità Operativa di Malattie Infettive, Dipartimento di Scienze Pediatriche, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy\n5 Hematopoietic Stem Cell Transplantation Unit, Istituto di Ricerca e Cura a Carattere Scintifico (IRCCS) Istituto Giannina Gaslini, Genoa, Italy\nEdited by: Markus G. Seidel, Medical University of Graz, Austria\n\nReviewed by: V. Koneti Rao, National Institutes of Health (NIH), United States; Catharina Schuetz, University Hospital Carl Gustav Carus, Germany\n\n*Correspondence: Maurizio Miano, mauriziomiano@gaslini.org\nThis article was submitted to Primary Immunodeficiencies, a section of the journal Frontiers in Immunology\n\n14 10 2021\n2021\n12 75402905 8 2021\n23 9 2021\nCopyright © 2021 Dell’Orso, Grossi, Penco, Caorsi, Palmisani, Terranova, Schena, Lupia, Ricci, Montalto, Pierri, Ceccherini, Fioredda, Dufour, Gattorno and Miano\n2021\nDell’Orso, Grossi, Penco, Caorsi, Palmisani, Terranova, Schena, Lupia, Ricci, Montalto, Pierri, Ceccherini, Fioredda, Dufour, Gattorno and Miano\nhttps://creativecommons.org/licenses/by/4.0/ This 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.\nDeficiency of adenosine deaminase 2 (DADA2) is an autosomal recessive disease associated with a highly variable clinical presentation, such as vasculitis, inflammation, and hematologic manifestations. Some associations of clinical features can mimic autoimmune lymphoproliferative syndrome (ALPS). We report a case of a female patient who fulfilled the 2009 National Institute of Health revised criteria for ALPS and received a delayed diagnosis of DADA2. During her childhood, she suffered from autoimmune hemolytic anemia, immune thrombocytopenia, and chronic lymphoproliferation, which partially responded to multiple lines of treatments and were followed, at 25 years of age, by pulmonary embolism, septic shock, and bone marrow failure with myelodysplastic evolution. The patient died from the progression of pulmonary disease and multiorgan failure. Two previously unreported variants of gene ADA2/CECR1 were found through next-generation sequencing analysis, and a pathogenic role was demonstrated through a functional study. A single somatic STAT3 mutation was also found. Clinical phenotypes encompassing immune dysregulation and marrow failure should be evaluated at the early stage of diagnostic work-up with an extended molecular evaluation. A correct genetic diagnosis may lead to a precision medicine approach consisting of the use of targeted treatments or early hematopoietic stem cell transplantation.\n\nbone marrow failure (BMF)\nprimary immune regulatory disorders (PIRDS)\nautoimmune lymphoproliferative syndrome (ALPS)\nnext-generation sequencing (NGS)\nDADA2\ninborn errors of immunity (IEI)\n==== Body\npmcIntroduction\n\nDeficiency of adenosine deaminase type 2 (DADA2) is an autosomal recessive disease caused by loss-of-function mutations of the ADA2/CECR1 gene, which encodes adenosine deaminase type 2 (ADA2) (1). ADA2 is partially homologous to adenosine deaminase type 1 (ADA1) (1), which is involved in a key step of purine metabolism by breaking down adenosine (Ado) and 2′-deoxyadenosine (dAdo) to deoxyinosine (2, 3). However, ADA2 has a distinct 59-kDa structure and a lower affinity to Ado and dAdo, accounting for a limited role in purine metabolism and additional non-redundant functions. In fact, one type of adenosine deaminase cannot compensate for the absence of the other enzyme, as ADA1 deficiency results in severe combined immunodeficiency (1). Unlike ADA1, ADA2 forms homodimers with a molecular weight of ~110 kDa (3), and it is produced by activated monocytes, macrophages, and dendritic cells during inflammatory response, as in patients with an autoimmune disease or infections (1, 4–7). For proper translocation to extracellular space, ADA2 needs to be N-glycosylated (8). Upon release, ADA2 binds to the surface of various immune cells, possibly through the PRB domain (9), to induce the T-cell-dependent differentiation of monocytes into macrophages and a growth factor activity, which is partially unknown. ADA2 deficiency is associated with monocyte polarization to M1 macrophages, which are known to induce inflammation and tissue damage and increase the release of proinflammatory cytokines (1, 9, 10).\n\nThe clinical onset of DADA2 was reported before 1 and 10 years of age in 24 and 77% of patients, respectively, with a mortality rate of 8% before the age of 30 years. The clinical features of 161 patients have been retrospectively reported by Meyts et al. in 2018 (1), showing a highly variable and misleading clinical presentation due to vasculitis/vasculopathy of small- and medium-sized arteries. Skin manifestations were reported in >75% of patients, while neurological involvement with ischemic or hemorrhagic stroke was present in 50%, with potential underestimation when presenting as transient ischemic attacks (1). Consistent with a systemic inflammatory process, most patients experience recurrent fever, myalgia, arthralgia, serositis, and elevated inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein (3). Less commonly, gastrointestinal and renal involvement, arthritis, and myositis were reported (11, 12). In addition to the mentioned inflammatory features, significant hematologic and immunologic involvement has been described recently. Hypogammaglobulinemia and a common variable immune deficiency (CVID) phenotype have been described in 25% of patients, with or without concurrent findings of vasculopathy (1, 3). Clonal lymphoproliferation (13), generalized lymphoadenopathy (>10%), and splenomegaly (up to 30%) were also reported. Other later reports described further hematological manifestations, including pure red cell aplasia (PRCA), and cytopenia affecting one or more cell lineages (12, 14). The specific association of symptoms might resemble autoimmune lymphoproliferative syndrome (ALPS), as described in a report by Alsultan (15). The severity of the marrow failure of the patient may lead to the indication of hemopoietic stem cell transplantation (HSCT), which represents the only curative option for congenital diseases (16). HSCT has been used in patients with a severe phenotype (10, 17–19) that did not respond to medical treatments such as tumor necrosis factor (TNF) inhibitors, which represent the best option in controlling fever episodes and vasculopathy and in preventing stroke (1, 20, 21).\n\nWe describe a case of a young woman with a long history of ALPS during childhood followed by rapid evolution to bone marrow failure, which resulted from carrying a novel pathogenic genotype of the ADA2/CECR1 gene.\n\nCase Presentation\n\nThe clinical history of the patient is summarized in Figure 1 . Apart from chickenpox and measles that occurred despite specific vaccination, no significant clinical issues were reported during early childhood. Another center followed up with her since the age of 5 years after an episode of trilinear cytopenia associated with splenomegaly. The marrow examination demonstrated good cellularity. No detailed information on therapeutic approaches was available at that time. Her family reported that she was treated with high-dose steroid therapy, transfusions, anti-thymocyte globulin, and cyclosporine A, with a complete recovery on platelet count and a partial response on other cell lines.\n\nFigure 1 Clinical history previous to referral at our Center.\n\nThree years later, an episode of acute autoimmune hemolytic anemia (AIHA) was successfully treated with splenectomy. At the age of 16, she developed several new episodes of AIHA associated with chronic lymphoproliferation and high values of T cell receptor αβ+ CD4- CD8- double-negative T cells (DNT). Defective Fas-mediated T-cell apoptosis was demonstrated in two different laboratories in order to obtain diagnostic confirmation. She received a diagnosis of ALPS, according to the 2009 National Institute of Health (NIH) revised criteria (22). Along with steroid treatment, she received other lines of therapy, such as cyclophosphamide, rituximab, micophenolate mofetil, azathioprine, vincristine, and, lastly, tacrolimus. All these therapeutic options, performed over about 10 years, only resulted in a partial response of steroid-dependent AIHA. In fact, attempts to withdraw steroids were followed by an increased transfusion need. At that stage, the bone marrow examination was still normal.\n\nAt the age of 25, during follow-up at the other center, she received a chest X-ray, which revealed a potential lung nodule that required further evaluations. A computed tomography scan and lung scintigraphy showed features of pulmonary embolism, leading to a diagnosis of pulmonary hypertension without any previous symptom or thrombotic event. Thrombophilia screening demonstrated protein S deficiency; therefore, apixaban prophylaxis was started. Meanwhile, she developed septic shock from Streptococcus gallolyticus, requiring intensive care. One year later, she was referred to our center for a second opinion because of worsening anemia despite the steroid and tacrolimus treatment.\n\nTable 1 shows the significant results of a blood examination performed on admission to our center. Hyporegenerative anemia and mild neutropenia were found. An immunological re-evaluation confirmed that her case fulfilled the 2009 NIH ALPS criteria, but with a significant reduction in immunoglobulin levels, and her plasma-soluble FAS ligand levels were normal. The trephyne biopsy showed severe erythroid hypoplasia, associated with normal myeloid/lymphoid cellularity and megakaryocytes. The marrow progenitor assay demonstrated reduced numbers of burst forming unit-erythroid and colony-forming unit for granulocytes and macrophages. The addition of the plasma of the patient to heterologous marrow cell precursors inhibited cellular growth and differentiation, possibly suggesting a humoral inhibitory effect on the marrow progenitor cells. Based on the clinical and laboratory findings and on the unsatisfactory control of the clinical symptoms, tacrolimus was substituted by sirolimus, while the steroids were slowly tapered off. Due to the absence of data on immunoglobulin levels before rituximab administration, it was not possible to determine whether hypogammaglobulinemia was either treatment- or disease-related, although the previously failed attempt to immunize against measles and chickenpox raised the suspicion of a previous CVID phenotype. Therefore, a program of regular subcutaneous immunoglobulin administration was started in order to reduce any risk of secondary infections related to the immunosuppressive treatment. Iron chelation treatment was also started due to elevated ferritin levels secondary to previous intensive transfusion support. Since sirolimus did not produce any response, erythropoietin was additionally administered weekly. At that stage, the patient was continuously offered HSCT, but it was strongly refused.\n\nTable 1 Significant laboratory tests at admission in our center.\n\n\tResults\tReference range\t\nHemoglobin\t9.2 g/dl\t11.5–16.5\t\nLactic dehydrogenase\t983 U/L\t84–480\t\nHaptoglobin\t<2 mg/dl\t15–160\t\nTotal lymphocyte count\t7,150/mmc\t3,600–9,800\t\nLymphocyte subsets\t\nCD3+TCRαβ+CD4−CD8− DNT cells\t5.1% (365/mmc)\t<1.5% of total lymphocytes\t\nB cells CD 19+\t2.6% (186/mmc)\t6–19%\t\nB cells CD27+ (CD19+ tot)\t15.9% (1,137/mmc)\t>15%\t\nCD3CD25+/CD3HLADR+ ratio\t0%\t>1\t\nCD3+TCR αβ+ CD4−CD8− B220+ cells a\t82.7% (5,913/mmc)\t<60%\t\nAutoimmune lymphoproliferative syndrome (ALPS) biomarkers\t\nPlasma sFASL levels\t0.5 pg/ml\t0\n>200 in ALPS\t\nElevated plasma interleukin-10 levels\t<1 pg/ml\t<1 pg/ml\n>20 in ALPS\t\nElevated serum or plasma vitamin B12 levels\t374 ng/L\t191–663\n>1,500 in ALPS\t\nElevated plasma interleukin-18 levels\t5,750 pg/ml\t36–258\n>500 in ALPS\t\nImmunoglobulin G\t254 mg/dl\t700–1600\t\nImmunoglobulin A\t13 mg/dl\t70–400\t\nImmunoglobulin M\t299 mg/dl\t40–230\t\na Increased B220+ T lymphocytes are significantly associated with ALPS with good specificity (23–25).\n\nAt 5 months after being referred to our center, the patient developed severe neutropenia and fever, requiring hospitalization. The trephine biopsy demonstrated severely reduced granulocytopoiesis and erythropoiesis and dysmegakaryocytopoiesis. The patient quickly developed an overwhelming hyperinflammatory syndrome and, due to the progressive worsening of her respiratory function, she was admitted to the intensive care unit. Unfortunately, despite extracorporeal membrane oxygenation, the patient died from progressive multiorgan failure and right ventricular cardiac thrombosis.\n\nDiagnostic Assessment\n\nDuring the follow-up at our center, a next-generation sequencing (NGS) panel that included genes related to both congenital marrow failure and immune dysregulation syndromes (26, 27) was applied to our proband (II-1 in Figure 2 ). Unfortunately, the results were released only a few days before the death of the patient and showed two germline mutations of the ADA2/CECR1 gene (OMIM#607575; transcript NM_001282225.2): (i) c.563T>C, leading to p.Leu188Pro, reported also by Michniacki in 2018 in association with DADA2 (28), and (ii) c.559A>C, leading to p.Thr187Pro, previously unreported. Based on the American College of Medical Genetics and Genomics criteria (29), both variants are classified as having a “likely pathogenic” effect and, consistent with the autosomal recessive inheritance of DADA2 (OMIM#615688), they turned out to be inherited by her father and mother, respectively ( Figure 2 ). These observations confirmed the causal role of the ADA2/CECR1 genotype of our patient on her condition. Both mutations were also found in the sister of the patient (II-2 in Figure 2 ), who displayed a clinical history of polyarticular arthritis of the small joints of the hands, along with Raynaud’s phenomenon, hip and knee arthralgia, mild leukopenia, and mild thrombocytopenia. After the result of the genetic test, a targeted immunological screening revealed hypogammaglobulinemia and increased values of DNT cells (2.5%) in the mother of the patient (I-2 in Figure 2 ).\n\nFigure 2 Family tree.\n\nSince none of the ADA2/CECR1 variants found in our patient were reported in any database of pathogenic mutations at the moment of her genetic diagnosis, a functional analysis on peripheral monocytes was performed to test their effect on ADA2 activity. These cells were isolated by adherence, after peripheral blood mononuclear cell Ficoll–Paque separation, and were then cultured in phosphate-buffered saline with exogenous adenosine (Sigma Aldrich) with or without ADA1 inhibitor erythro-9-(2-hydroxy-3-nonyl) adenine (Sigma Aldrich) for 4 h at 37°C with 5% of CO2. The supernatants were collected, and the activity enzyme was indirectly evaluated in high-performance liquid chromatography through the measurement of the adenosine-derived products (inosine and hypoxanthine) as a surrogate marker of enzyme activity (20). As shown in Figure 3 , no adenosine metabolites were detectable in our patient (Pt 1), thus suggesting a complete loss of enzymatic activity. Consistently, both the patient and her sister presented compound heterozygosity for the same variants, and we could demonstrate a complete absence of inosine, the most important adenosine-derived product.\n\nFigure 3 Functional assay of ADA2 activity.\n\nFinally, a heterozygous pathogenic somatic mutation on STAT3 (p.Lys658Arg) was also identified in our patient. The same mutation was found neither in her parents nor in her sister, and its somatic origin was confirmed by its absence in the skin fibroblasts of the patient.\n\nDiscussion\n\nThe clinical history of the patient was characterized by symptoms and laboratory findings fulfilling the 2009 NIH ALPS diagnostic criteria (22), followed, in early adulthood, by the onset of more specific features of DADA2, such as vasculopathy, marrow failure, and hyperinflammatory symptoms (1).\n\nADA2/CECR1 missense, frameshift mutations, splicing defects, or deletions have been described as pathogenic and were distributed in all different structural domains (3, 11, 30, 31). In a recent work, Lee et al. performed a literature review and a genotype comparison of vasculitis and hematologic phenotypes in DADA2. In the manuscript, the ADA2/CECR1 mutations were clustered in groups according to their predicted residual enzymatic activity. The prevalence of PRCA or marrow failure features was greater in groups according to their lower predicted enzymatic activity (<3% residual enzymatic activity), in particular, with insertion–deletion mutations (indels), early-termination mutations, and missense mutations, including Leu188Pro, which we found in our patient (32). However, the pathogenic mechanism of the residual enzymatic activity toward vasculitis or marrow failure remains to be determined.\n\nThe two novel ADA2/CECR1 mutations found in our case could explain both the ALPS and DADA2 phenotypes.\n\nUnusual phenotypes with features overlapping both rheumatological and hematological disorders have been already reported not only in DADA2 patients but also in other autoinflammatory/autoimmune disorders (23), which can show the expansion of DNT cells and other ALPS markers, making the diagnosis particularly challenging. Similarly, a significant proportion of ALPS patients may also present with a consistent inflammatory phenotype (23).\n\nIn the first phases of the disease, the patient fulfilled the NIH 2009 ALPS criteria (22). However, some typical ALPS biomarkers, such as sFAS, IL-10, and vitamin B12, resulted to be normal. The immunoglobulin levels in this patient were not a reliable diagnostic criterion due to a previous rituximab treatment (33). In addition, although anemia was initially secondary to peripheral autoimmune hemolysis with normal marrow cellularity, in the following years, it became hyporegenerative with erythroid hypoplasia and tested negative in both direct and indirect antiglobulin tests, a feature atypical of ALPS. Over the past 10–15 years, improvements in genomic technologies have led to the description of a number of monogenic disorders mimicking ALPS. These rare conditions, defined as CVID or ALPS-like phenotypes, clinically resemble ALPS and, therefore, are often misdiagnosed, highlighting the urgent need to revise the NIH ALPS diagnostic criteria based on increased knowledge of the pathogenic mechanisms and biomarkers of such disorders (23–25, 34, 35). Therefore, an earlier genetic diagnosis should be performed in all patients with immune dysregulation to define a more precise therapeutic strategy and to make a proper assessment in case of stem cell transplantation. The most important signal for correctly diagnosing and treating this patient was the progressive evolution of the clinical phenotype over time, with prevalent inflammatory features, vasculitis, and bone marrow failure with PRCA, although such signs and symptoms of DADA2 and the disease itself were still mostly unknown at that time.\n\nIn our patient, marrow involvement, initially characterized by PRCA, evolved into severe trilinear marrow failure, in keeping with the concept that DADA2 phenotypes likely represent a continuum rather than different categories (32).\n\nA colony-forming unit assay clearly showed not only the reduced growth of marrow progenitor cells but also an inhibitory effect on the plasma of the patient with heterologous marrow progenitors, suggesting a potential contribution of humoral immunity possibly related to immune dysregulation. Indeed the pathogenesis of marrow failure in ADA2 deficiency remains largely not understood. An ADA2 knocked-down zebrafish model displays neutropenia, thus supporting an intrinsic role of ADA2 in normal hematopoiesis (12). On the other hand, human ADA2 was shown to have an in vitro growth factor activity (7) whose absence may have contributed to the development of marrow failure.\n\nIn addition, the coexistence of strongly diminished ADA2 activity with an oligosymptomatic phenotype in the sister can be explained by well-known intrafamilial phenotypic variability despite the same underlying homozygous mutations (11,19,30,36–40). However, even if individuals with biallelic ADA2/CECR1 pathogenic variants were reported to have remained asymptomatic until adulthood or to have never developed clinical manifestations of DADA2 (41), the sister of our patient is currently following up with another adult rheumatology center.\n\nA gain-of-function, likely pathogenic somatic heterozygous STAT3 somatic mutation, was also shown by the NGS panel in the marrow cell of our patient. This variant had not been previously reported. The STAT3 gene (42) encodes a transcription factor activated in response to cytokine signaling, and germline gain-of-function STAT3 mutations were reported after whole-exome sequencing and whole-genome sequencing studies as new potential genetic drivers of ALPS-like phenotypes (43, 44). On the other hand, somatic heterozygous STAT3 gain-of-function mutations are also reported in literature in association with myelodysplastic syndrome (45–47). We found this mutation only in cells derived from the hematopoietic lineage, while skin fibroblasts resulted as wild type for STAT3. Unfortunately, it is not possible to define the contribution of the STAT3 mutation in our patient due to the unavailability of marrow samples and genetic tests at the onset of her symptoms. We can only speculate that such mosaicism might have been either a sign of a myelodysplastic evolution or present since diagnosis, contributing to the onset of the ALPS phenotype, similar to somatic mutations in the FAS gene (48, 49).\n\nThe overlap between marrow failure and immune dysregulation has recently been documented by our group in a large study cohort of patients (27). This reinforces the idea that young patients with marrow failure should undergo early immunological screening and be offered genetic tests by either extended next-generation sequencing panels (50), which include genes leading to primary immune deficiencies, or unbiased whole-exome sequencing, when available. In fact, improvements in diagnostic accuracy may lead to an early targeted therapy. In our patient, an earlier diagnosis of DADA2 could have led to a more prompt and tailored treatment with anti-TNF alpha, potentially improving the inflammatory phenotype and controlling the progression of the disease (1, 21, 32). The previous indication to splenectomy could have been further evaluated, balancing rewards and risks as infectious risk, if a genetic diagnosis was available at that moment. She experienced an episode of sepsis and a hyperinflammation evolving in fatal multiorgan failure with cardiac thrombosis: the association of splenectomy and several immunosuppressive treatments could have represented the risk factors for such complications. HSCT, even in the absence of a genetic diagnosis, could have prevented the fatal progression of other co-morbidities, but the patient strongly refused it. This procedure may be considered earlier for patients with severe hematologic presentation (10, 17–19, 32).\n\nIn conclusion, this case report suggests that clinical phenotypes encompassing immune dysregulation and marrow failure should be evaluated at the early stage of diagnostic work-up with an extended molecular evaluation that includes genes that cause both groups of disorders. Proper genetic diagnosis may lead to precision medicine approach and targeted treatments.\n\nData Availability Statement\n\nThe datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: (https://www.ncbi.nlm.nih.gov/clinvar/) VCV000973671.1, VCV000973614.1, and VCV000421491.2.\n\nAuthor Contributions\n\nGD and MM conceived the presented idea. GD, RC, EP, ER, SM, FiP, MG, CD, and MM reviewed the clinical information presented. MG, CD, and MM oversaw the writing, data collection, and editing process. IC, MG, FF, CD, and MM provided critical review of the manuscript. PT and ML performed immunological assays. AG and IC performed genetic diagnosis. FeP, RC, and FS performed functional assay on a research basis. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest\n\nPublisher’s Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nAcknowledgments\n\nWe acknowledge ERG S.p.A., Rimorchiatori Riuniti (Genoa), Cambiaso Risso Marine (Genoa), Saar Depositi Oleari Portuali (Genoa), ONLUS Nicola Ferrari. and Ministero della Salute -Ricerca corrente 2021 for supporting the activity of Hematology Unit of IRCCS Istituto Giannina Gaslini.\n==== Refs\nReferences\n\n1 Meyts I Aksentijevich I . Deficiency of Adenosine Deaminase 2 (DADA2): Updates on the Phenotype, Genetics, Pathogenesis, and Treatment. J Clin Immunol (2018) 38 (5 ):569–78. doi: 10.1007/s10875-018-0525-8\n2 Simmonds HA Webster DR Perrett D Reiter S Levinsky RJ . Formation and Degradation of Deoxyadenosine Nucleotides in Inherited Adenosine Deaminase Deficiency. Biosci Rep (1982) 2 (5 ):303–14. doi: 10.1007/BF01115116\n3 Lee PY . Vasculopathy, Immunodeficiency, and Bone Marrow Failure: The Intriguing Syndrome Caused by Deficiency of Adenosine Deaminase 2. Front Pediatr (2018) 6 :282. doi: 10.3389/fped.2018.00282 30406060\n4 Iwaki-Egawa S Namiki C Watanabe Y . Adenosine Deaminase 2 From Chicken Liver: Purification, Characterization, and N-Terminal Amino Acid Sequence. Comp Biochem Physiol B Biochem Mol Biol (2004) 137 (2 ):247–54. doi: 10.1016/j.cbpc.2003.11.010\n5 Zavialov AV Engström A . Human ADA2 Belongs to a New Family of Growth Factors With Adenosine Deaminase Activity. Biochem J (2005) 391 (Pt 1 ):51–7. doi: 10.1042/BJ20050683\n6 Iwaki-Egawa S Yamamoto T Watanabe Y . Human Plasma Adenosine Deaminase 2 is Secreted by Activated Monocytes. Biol Chem (2006) 387 (3 ):319–21. doi: 10.1515/BC.2006.042\n7 Zavialov AV Gracia E Glaichenhaus N Franco R Zavialov AV Lauvau G . Human Adenosine Deaminase 2 Induces Differentiation of Monocytes Into Macrophages and Stimulates Proliferation of T Helper Cells and Macrophages. J Leukoc Biol (2010) 88 (2 ):279–90. doi: 10.1189/jlb.1109764\n8 Lee PY Huang Y Zhou Q Schnappauf O Hershfield MS Li Y . Disrupted N-Linked Glycosylation as a Disease Mechanism in Deficiency of ADA2. J Allergy Clin Immunol (2018) 142 (4 ):1363–5. doi: 10.1016/j.jaci.2018.05.038\n9 Kaljas Y Liu C Skaldin M Wu C Zhou Q Lu Y . Human Adenosine Deaminases ADA1 and ADA2 Bind to Different Subsets of Immune Cells. Cell Mol Life Sci (2017) 74 (3 ):555–70. doi: 10.1007/s00018-016-2357-0\n10 Van Eyck L Hershfield MS Pombal D Kelly SJ Ganson NJ Moens L . Hematopoietic Stem Cell Transplantation Rescues the Immunologic Phenotype and Prevents Vasculopathy in Patients With Adenosine Deaminase 2 Deficiency. J Allergy Clin Immunol (2015) 135 (1 ):283–7.e5. doi: 10.1016/j.jaci.2014.10.010 25457153\n11 Navon Elkan P Pierce SB Segel R Walsh T Barash J Padeh S . Mutant Adenosine Deaminase 2 in a Polyarteritis Nodosa Vasculopathy. N Engl J Med (2014) 370 (10 ):921–31. doi: 10.1056/NEJMoa1307362\n12 Zhou Q Yang D Ombrello AK Zavialov AV Toro C Zavialov AV . Early-Onset Stroke and Vasculopathy Associated With Mutations in ADA2. N Engl J Med (2014) 370 (10 ):911–20. doi: 10.1056/NEJMoa1307361\n13 Trotta L Martelius T Siitonen T Hautala T Hämäläinen S Juntti H . ADA2 Deficiency: Clonal Lymphoproliferation in a Subset of Patients. J Allergy Clin Immunol (2018) 141 (4 ):1534–7. doi: 10.1016/j.jaci.2018.01.012\n14 Van Eyck L Liston A Wouters C . Mutant ADA2 in Vasculopathies. N Engl J Med (2014) 371 (5 ):480. doi: 10.1056/NEJMc1405506\n15 Alsultan A Basher E Alqanatish J Mohammed R Alfadhel M . Deficiency of ADA2 Mimicking Autoimmune Lymphoproliferative Syndrome in the Absence of Livedo Reticularis and Vasculitis. Pediatr Blood Cancer (2018) 65 (4 ). doi: 10.1002/pbc.26912\n16 Miano M Porta F Locatelli F Miniero R La Nasa G Di Bartolomeo P . Unrelated Donor Marrow Transplantation for Inborn Errors. Bone Marrow Transplant (1998) 21 Suppl 2 :S37–41. doi: 10.1038/sj.bmt.1705173\n17 van Montfrans J Zavialov A Zhou Q . Mutant ADA2 in Vasculopathies. N Engl J Med (2014) 371 (5 ):478. doi: 10.1056/NEJMc1405506\n18 Hsu AP West RR Calvo KR Cuellar-Rodriguez J Parta M Kelly SJ . Adenosine Deaminase Type 2 Deficiency Masquerading as GATA2 Deficiency: Successful Hematopoietic Stem Cell Transplantation. J Allergy Clin Immunol (2016) 138 (2 ):628–30. doi: 10.1016/j.jaci.2016.03.016\n19 Hashem H Kumar AR Müller I Babor F Bredius R Dalal J . Hematopoietic Stem Cell Transplantation Rescues the Hematological, Immunological, and Vascular Phenotype in DADA2. Blood (2017) 130 (24 ):2682–8. doi: 10.1182/blood-2017-07-798660\n20 Caorsi R Penco F Grossi A Insalaco A Omenetti A Alessio M . ADA2 Deficiency (DADA2) as an Unrecognised Cause of Early Onset Polyarteritis Nodosa and Stroke: A Multicentre National Study. Ann Rheum Dis (2017) 76 (10 ):1648–56. doi: 10.1136/annrheumdis-2016-210802\n21 Caorsi R Omenetti A Picco P Buoncompagni A Minoia F Federici S . Long-Term Efficacy of Etanercept in ADA2 Deficiency. Pediatr Rheumatol (2014) 12 (S1 ):P72. doi: 10.1186/1546-0096-12-S1-P72\n22 Oliveira JB Bleesing JJ Dianzani U Fleisher TA Jaffe ES Lenardo MJ . Revised Diagnostic Criteria and Classification for the Autoimmune Lymphoproliferative Syndrome (ALPS): Report From the 2009 NIH International Workshop. Blood (2010) 116 (14 ):e35–40. doi: 10.1182/blood-2010-04-280347\n23 Mendonça LO Matucci-Cerinic C Terranova P Casabona F Bovis F Caorsi R . The Challenge of Early Diagnosis of Autoimmune Lymphoproliferative Syndrome in Children With Suspected Autoinflammatory/Autoimmune Disorders. Rheumatology (2021) keab361. doi: 10.1093/rheumatology/keab361/6257227 33909886\n24 Renno T Attinger A Rimoldi D Hahne M Tschopp J MacDonald HR . Expression of B220 on Activated T Cell Blasts Precedes Apoptosis. Eur J Immunol (1998) 28 (2 ):540–7. doi: 10.1002/(SICI)1521-4141(199802)28:02<540::AID-IMMU540>3.0.CO;2-Y\n25 Bleesing JJH Brown MR Dale JK Straus SE Lenardo MJ Puck JM . TcR-α/β+ CD4–CD8– T Cells in Humans With the Autoimmune Lymphoproliferative Syndrome Express a Novel CD45 Isoform That Is Analogous to Murine B220 and Represents a Marker of Altered O-Glycan Biosynthesis. Clin Immunol (2001) 100 (3 ):314–24. doi: 10.1006/clim.2001.5069\n26 Miano M Cappelli E Pezzulla A Venè R Grossi A Terranova P . FAS-Mediated Apoptosis Impairment in Patients With ALPS/ALPS-Like Phenotype Carrying Variants on CASP10 Gene. Br J Haematol (2019) 187 (4 ):502–8. doi: 10.1111/bjh.16098\n27 Miano M Grossi A Dell’Orso G Lanciotti M Fioredda F Palmisani E . Genetic Screening of Children With Marrow Failure. The Role of Primary Immunodeficiencies. Am J Hematol (2021) 96 (9 ):1077–86. doi: 10.1002/ajh.26242\n28 Michniacki TF Hannibal M Ross CW Frame DG DuVall AS Khoriaty R . Hematologic Manifestations of Deficiency of Adenosine Deaminase 2 (DADA2) and Response to Tumor Necrosis Factor Inhibition in DADA2-Associated Bone Marrow Failure. J Clin Immunol (2018) 38 (2 ):166–73. doi: 10.1007/s10875-018-0480-4\n29 Richards S Aziz N Bale S Bick D Das S Gastier-Foster J . Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med (2015) 17 (5 ):405–24. doi: 10.1038/gim.2015.30\n30 Van Montfrans JM Hartman EAR Braun KPJ Hennekam EAM Hak EA Nederkoorn PJ . Phenotypic Variability in Patients With ADA2 Deficiency Due to Identical Homozygous R169Q Mutations. Rheumatol (Oxford) (2016) 55 (5 ):902–10. doi: 10.1093/rheumatology/kev439\n31 Batu ED Karadag O Taskiran EZ Kalyoncu U Aksentijevich I Alikasifoglu M . A Case Series of Adenosine Deaminase 2-Deficient Patients Emphasizing Treatment and Genotype-Phenotype Correlations. J Rheumatol (2015) 42 (8 ):1532–4. doi: 10.3899/jrheum.150024\n32 Lee PY Kellner ES Huang Y Furutani E Huang Z Bainter W . Genotype and Functional Correlates of Disease Phenotype in Deficiency of Adenosine Deaminase 2 (DADA2). J Allergy Clin Immunol (2020) 145 (6 ):1664–72.e10. doi: 10.1016/j.jaci.2019.12.908 31945408\n33 Ottaviano G Marinoni M Graziani S Sibson K Barzaghi F Bertolini P . Rituximab Unveils Hypogammaglobulinemia and Immunodeficiency in Children With Autoimmune Cytopenia. J Allergy Clin Immunol Pract (2020) 8 (1 ):273–82. doi: 10.1016/j.jaip.2019.07.032\n34 Völkl S Rensing-Ehl A Allgäuer A Schreiner E Lorenz MR Rohr J . Hyperactive mTOR Pathway Promotes Lymphoproliferation and Abnormal Differentiation in Autoimmune Lymphoproliferative Syndrome. Blood (2016) 128 (2 ):227–38. doi: 10.1182/blood-2015-11-685024\n35 Maccari ME Fuchs S Kury P Andrieux G Völkl S Bengsch B . A Distinct CD38+CD45RA+ Population of CD4+, CD8+, and Double-Negative T Cells is Controlled by FAS. J Exp Med (2021) 218 (2 ):e20192191. doi: 10.1084/jem.20192191 33170215\n36 Maggiore R Grossi A Fioredda F Palmisani E Terranova P Cappelli E . Unusual Late-Onset Enteropathy in a Patient With Lipopolysaccharide-Responsive Beige-Like Anchor Protein Deficiency. J Pediatr Hematol Oncol (2020) 42 (8 ):e768–71. doi: 10.1097/MPH.0000000000001708\n37 Gaefke CL Metts J Imanirad D Nieves D Terranova P Dell’Orso G . Case Report: A Novel Pathogenic Missense Mutation in FAS: A Multi-Generational Case Series of Autoimmune Lymphoproliferative Syndrome. Front Pediatr (2021) 9 :624116. doi: 10.3389/fped.2021.624116 33816397\n38 Mazzoni M Dell’Orso G Grossi A Ceccherini I Viola S Terranova P . Underlying CTLA4 Deficiency in a Patient With Juvenile Idiopathic Arthritis and Autoimmune Lymphoproliferative Syndrome Features Successfully Treated With Abatacept-A Case Report. J Pediatr Hematol Oncol (2021). doi: 10.1097/MPH.0000000000002120\n39 Palmisani E Miano M Micalizzi C Calvillo M Pierri F Terranova P . Clinical Features and Therapeutic Challenges of Cytopenias Belonging to Alps and Alps-Related (ARS) Phenotype. Br J Haematol (2019) 184 (5 ):861–4. doi: 10.1111/bjh.15178\n40 Farmer JR Foldvari Z Ujhazi B De Ravin SS Chen K Bleesing JJH . Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients With RAG Deficiency. J Allergy Clin Immunol Pract (2019) 7 (6 ).\n41 Aksentijevich I Sampaio Moura N Barron K . Adenosine Deaminase 2 Deficiency (2019). Available at: https://www.omim.org/entry/607575.\n42 STAT3 OMIM. Available at: https://www.omim.org/entry/102582?search=stat3&highlight=stat3.\n43 Holland SM DeLeo FR Elloumi HZ Hsu AP Uzel G Brodsky N . STAT3 Mutations in the Hyper-IgE Syndrome. N Engl J Med (2007) 357 (16 ):1608–19. doi: 10.1056/NEJMoa073687\n44 Bride K Teachey D . Autoimmune Lymphoproliferative Syndrome: More Than a FAScinating Disease. F1000Research (2017) 6 :1928. doi: 10.12688/f1000research.11545.1 29123652\n45 Koskela HLM Eldfors S Ellonen P van Adrichem AJ Kuusanmäki H Andersson EI . Somatic STAT3 Mutations in Large Granular Lymphocytic Leukemia. N Engl J Med (2012) 366 (20 ):1905–13. doi: 10.1056/NEJMoa1114885\n46 Casanova J-L Holland SM Notarangelo LD . Inborn Errors of Human JAKs and STATs. Immunity (2012) 36 (4 ):515–28. doi: 10.1016/j.immuni.2012.03.016\n47 Jerez A Clemente MJ Makishima H Rajala H Gómez-Seguí I Olson T . STAT3 Mutations Indicate the Presence of Subclinical T-Cell Clones in a Subset of Aplastic Anemia and Myelodysplastic Syndrome Patients. Blood (2013) 122 (14 ):2453–9. doi: 10.1182/blood-2013-04-494930\n48 Holzelova E Vonarbourg C Stolzenberg M-C Arkwright PD Selz F Prieur A-M . Autoimmune Lymphoproliferative Syndrome With Somatic Fas Mutations. N Engl J Med (2004) 351 (14 ):1409–18. doi: 10.1056/NEJMoa040036\n49 Rieux-Laucat F Magérus-Chatinet A Neven B . The Autoimmune Lymphoproliferative Syndrome With Defective FAS or FAS-Ligand Functions. J Clin Immunol (2018) 38 (5 ):558–68. doi: 10.1007/s10875-018-0523-x\n50 Grossi A Miano M Lanciotti M Fioredda F Guardo D Palmisani E . Targeted NGS Yields Plentiful Ultra-Rare Variants in Inborn Errors of Immunity Patients. Genes (Basel) (2021) 12 (9 ):1299. doi: 10.3390/genes12091299 34573280\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-3224",
"issue": "12()",
"journal": "Frontiers in immunology",
"keywords": "DADA2; autoimmune lymphoproliferative syndrome (ALPS); bone marrow failure (BMF); inborn errors of immunity (IEI); next-generation sequencing (NGS); primary immune regulatory disorders (PIRDS)",
"medline_ta": "Front Immunol",
"mesh_terms": null,
"nlm_unique_id": "101560960",
"other_id": null,
"pages": "754029",
"pmc": null,
"pmid": "34721429",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "23926297;9521064;14990221;29411230;11513545;27663683;31876783;30877075;30406060;31945408;6980023;15459302;29391253;26867732;26233953;29951947;33909886;29123652;24552285;29271561;27130863;22591296;28974505;22520845;20453107;33170215;25457153;33625086;31377437;31309545;25075848;27099149;33816397;9630323;25741868;16542154;29936104;17881745;34000087;15926889;28522451;34573280;20538792;29527658;29911256;25075845;24552284",
"title": "Case Report: Deficiency of Adenosine Deaminase 2 Presenting With Overlapping Features of Autoimmune Lymphoproliferative Syndrome and Bone Marrow Failure.",
"title_normalized": "case report deficiency of adenosine deaminase 2 presenting with overlapping features of autoimmune lymphoproliferative syndrome and bone marrow failure"
} | [
{
"companynumb": "IT-VELOXIS PHARMACEUTICALS-2021VELIT-000893",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditio... |
{
"abstract": "We aimed to investigate whether proteinuria in the first trimester of pregnancy in Familial Mediterranean fever (FMF) patients has an impact on pregnancy outcome and perinatal and neonatal outcome of pregnancies. A total of 66 pregnant with FMF were compared with healthy controls at the same gestational weeks. Patients with FMF had a higher antenatal hospitalisation rate (34.8% vs. 6.1%, respectively, p < .01) and higher rate of 2 or more miscarriages. FMF patients with or without obstetric complications also had a similar amount of 24-h urine proteinuria in the first trimester. Patients on colchicine therapy during pregnancy had more frequent attacks in pregnancy (59.3% vs. 18.2%, respectively, p: .012). The rates of preeclampsia, preterm delivery, foetal anomalies, small for gestation age neonates and primary caesarean rate were similar between groups. In conclusion; FMF had no significant impact on pregnancy. Neither attacks in pregnancy nor basal proteinuria were associated with adverse outcomes.Impact statementWhat is already known on this subject? Familial Mediterranean fever (FMF) is an autosomal recessive disease characterised by inflammation of the serosal, synovial and cutaneous tissues with recurrent attacks. One of the most serious complications of FMF is amyloidosis that can cause end-stage renal disease. Outcomes of FMF on pregnancy have been analysed by only few studies. Amyloidosis based on the initial renal function may adversely affect pregnancies. It has been reported that FMF patients with renal amyloidosis may suffer pregnancy complications to a greater extent.What do the results of this study add? There have been few studies on the correlation between FMF, proteinuria and pregnancy outcomes. In our study we found that FMF had no significant impact on pregnancy. Neither attacks in pregnancy nor basal proteinuria were associated with adverse outcomes.What are the implications of these findings for clinical practice and/or further research? Our study suggested that FMF had no relationship between pregnancy outcomes. However, our study population is relatively small. It will contribute to comprehensive studies involving a larger population. Future studies should be performed to investigate the effects of basal proteinuria in pregnancy with FMF.",
"affiliations": "Hematology and Stem Cell Transplantation Clinic, Ankara Oncology Education and Research Hospital, Ankara, Turkey.;Department of Perinatology, Hatay State Hospital, Hatay, Turkey.;Center of Genetic Diagnosis, Duzen Laboratory Group, Ankara, Turkey.;Department of Perinatology, Mersin State Hospital, Hatay, Turkey.;Department of Maternal-Fetal Medicine Unit, University of Health Sciences, Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey.;Department of Perinatology, Mersin State Hospital, Hatay, Turkey.;Department of Obstetrics and Gynecology, Acıbadem University, Vocational School of Health Sciences, Istanbul, Turkey.;Department of Maternal-Fetal Medicine Unit, University of Health Sciences, Zekai Tahir Burak Women's Health Education and Research Hospital, Ankara, Turkey.",
"authors": "Iskender|D|D|;Kara|O|O|;Ozturk Kaymak|A|A|;Daglar|H K|HK|;Kirbas|A|A|;Iskender|C T|CT|;Kaymak|O|O|;Celen|S|S|",
"chemical_list": "D003078:Colchicine",
"country": "England",
"delete": false,
"doi": "10.1080/01443615.2019.1700944",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0144-3615",
"issue": "40(8)",
"journal": "Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology",
"keywords": "Composite obstetric morbidity; familial Mediterranean fever; pregnancy; proteinuria",
"medline_ta": "J Obstet Gynaecol",
"mesh_terms": "D000328:Adult; D000686:Amyloidosis; D016022:Case-Control Studies; D002585:Cesarean Section; D003078:Colchicine; D000013:Congenital Abnormalities; D010505:Familial Mediterranean Fever; D005260:Female; D006760:Hospitalization; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007674:Kidney Diseases; D011225:Pre-Eclampsia; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First; D047928:Premature Birth; D011507:Proteinuria",
"nlm_unique_id": "8309140",
"other_id": null,
"pages": "1102-1105",
"pmc": null,
"pmid": "32270724",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Association between basal proteinuria levels and pregnancy outcomes in familial Mediterranean fever.",
"title_normalized": "association between basal proteinuria levels and pregnancy outcomes in familial mediterranean fever"
} | [
{
"companynumb": "TR-ALKEM LABORATORIES LIMITED-TR-ALKEM-2020-01469",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"druga... |
{
"abstract": "Atopobium vaginae is an anaerobic Gram-positive bacterium recognized as a causative agent of bacterial vaginosis and associated with preterm delivery. Invasive infection and bacteremia have been rarely reported. We describe the case of a woman expecting her firstborn child who presented with a A. vaginae bacteremia during labor. Identification was performed using 16S rRNA gene sequencing. Both maternal and fetal outcomes were favorable due to the maternal treatment with amoxicillin-clavulanic acid. We identified three other cases in the literature with different fetal outcome. The genetic diversity of A. vaginae should be further explored in order to reveal potential strains with differential pathogenic potential.",
"affiliations": "Department of Infectious Diseases, Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium. Electronic address: Nicolas_dauby@stpierre-bru.be.;Department of Microbiology, Laboratoire Hospitalier Universitaire de Bruxelles - Universitair Laboratorium Brussel (LHUB-ULB), Brussels, Belgium; Faculté de Médecine et Pharmacie, Université de Mons (UMONS), Mons, Belgium.;Department of Microbiology, Laboratoire Hospitalier Universitaire de Bruxelles - Universitair Laboratorium Brussel (LHUB-ULB), Brussels, Belgium.;Department of Obstetrics & Gynecology, Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium.;Department of Microbiology, Laboratoire Hospitalier Universitaire de Bruxelles - Universitair Laboratorium Brussel (LHUB-ULB), Brussels, Belgium.;Department of Microbiology, Laboratoire Hospitalier Universitaire de Bruxelles - Universitair Laboratorium Brussel (LHUB-ULB), Brussels, Belgium.;Department of Microbiology, Laboratoire Hospitalier Universitaire de Bruxelles - Universitair Laboratorium Brussel (LHUB-ULB), Brussels, Belgium.;Department of Microbiology, Laboratoire Hospitalier Universitaire de Bruxelles - Universitair Laboratorium Brussel (LHUB-ULB), Brussels, Belgium.;Department of Infectious Diseases, Centre Hospitalier Universitaire Saint-Pierre, Université Libre de Bruxelles (ULB), Brussels, Belgium.",
"authors": "Dauby|Nicolas|N|;Martiny|Delphine|D|;Busson|Laurent|L|;Cogan|Alexandra|A|;Meghraoui|Alaeddine|A|;Argudín|Maria Angeles|MA|;Nonhoff|Claire|C|;Hallin|Marie|M|;Konopnicki|Déborah|D|",
"chemical_list": "D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D004275:DNA, Ribosomal; D012336:RNA, Ribosomal, 16S; D065093:beta-Lactamase Inhibitors; D019980:Amoxicillin-Potassium Clavulanate Combination",
"country": "England",
"delete": false,
"doi": "10.1016/j.anaerobe.2018.09.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-9964",
"issue": "59()",
"journal": "Anaerobe",
"keywords": "16S rRNA gene; Atopobium vaginae; Bacteremia; MALDI TOF-MS; Pregnancy",
"medline_ta": "Anaerobe",
"mesh_terms": "D039903:Actinobacteria; D000328:Adult; D019980:Amoxicillin-Potassium Clavulanate Combination; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D004269:DNA, Bacterial; D004275:DNA, Ribosomal; D005260:Female; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D012336:RNA, Ribosomal, 16S; D017422:Sequence Analysis, DNA; D016896:Treatment Outcome; D065093:beta-Lactamase Inhibitors",
"nlm_unique_id": "9505216",
"other_id": null,
"pages": "212-214",
"pmc": null,
"pmid": "30291902",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": null,
"title": "Atopobium vaginae intrapartum bacteremia: A case report with a literature review.",
"title_normalized": "atopobium vaginae intrapartum bacteremia a case report with a literature review"
} | [
{
"companynumb": "NL-ALKEM LABORATORIES LIMITED-BE-ALKEM-2018-09592",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFUROXIME AXETIL"
},
... |
{
"abstract": "Human metapneumovirus (hMPV) is an enveloped virus that causes serious respiratory tract infection among immunocompromised populations especially haematopoietic stem cell transplant (HSCT) recipients. Here, we describe 3 cases of hMPV infection which led to mortality among post HSCT adults. 66 post HSCT adults enrolled between January 2017 and March 2019 at Dr. B. R. Ambedkar Institute Rotary Cancer Hospital, AIIMS, New Delhi, were followed up for a period varying from 16 days to 18 months for any episode of respiratory illness until March 2019. Real time reverse transcriptase polymerase chain reaction (rRT-PCR) was used to detect the virus from appropriate specimens when symptoms of acute respiratory infection appeared. Samples from 88 out of a total of 172 episodes of suspected acute respiratory infection could be tested by rRT-PCR. Of these, 9 episodes were positive for hMPV. Three patients with hMPV associated lower respiratory tract infection (LRTI) expired within 30 days of HSCT. The possible risk factors associated with mortality included LRTI, infection during early post-transplant period (first week following HSCT), absolute lymphocyte count less than 200/µl, absolute neutrophil count less than 500/µl, use of steroid within 30 days prior to infection and need for mechanical ventilation.",
"affiliations": "Amity Institute of Virology and Immunology, Amity University, Sector 125, Noida, Uttar Pradesh 201313 India.;Department of Internal Medicine, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029 India.;Amity Institute of Virology and Immunology, Amity University, Sector 125, Noida, Uttar Pradesh 201313 India.;Department of Life Sciences, School of Basic Sciences & Research, Sharda University, Knowledge Park-III, Greater, Noida, Uttar Pradesh 201310 India.;Department of Internal Medicine, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029 India.;Virology Laboratory, Department of Microbiology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029 India.;Virology Laboratory, Department of Microbiology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029 India.;Department of Medical Oncology, AIIMS (Dr BRA Institute Rotary Cancer Hospital), New Delhi, 110029 India.;Virology Laboratory, Department of Microbiology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110029 India.",
"authors": "Jethani|Jyoti|J|;Samad|Sameer|S|;Kumar|Prashant|P|;Angel|Bennet|B|;Wig|Naveet|N|;Choudhary|Aashish|A|;Brijwal|Megha|M|;Kumar|Lalit|L|;Dar|Lalit|L|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1007/s13337-021-00670-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2347-3584",
"issue": null,
"journal": "Virusdisease",
"keywords": "Early post‐transplant; Hematopoietic stem cell transplant (HSCT); Human metapneumovirus (hMPV); Multiple myeloma; Respiratory viral infection",
"medline_ta": "Virusdisease",
"mesh_terms": null,
"nlm_unique_id": "101624144",
"other_id": null,
"pages": "1-6",
"pmc": null,
"pmid": "33718531",
"pubdate": "2021-03-08",
"publication_types": "D016428:Journal Article",
"references": "23680472;16107960;17689145;27260872;24295817;22802096;16873237;16520475",
"title": "Human metapneumovirus infection in haematopoietic stem cell transplant recipients: a case series.",
"title_normalized": "human metapneumovirus infection in haematopoietic stem cell transplant recipients a case series"
} | [
{
"companynumb": "IN-PFIZER INC-202100941565",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "To highlight the rare yet devastating complication of CMV retinitis in a minimally immunosuppressed patient eight yr after liver transplantation for biliary atresia. A 22-yr-old female status-post deceased donor liver transplant at age 13 secondary to biliary atresia receiving single agent immunosuppression presented with acute, unilateral, profound decrease in visual acuity. The patient was diagnosed to have acute onset unilateral CMV retinitis. Retinal examination uncovered classical appearance of retinal whitening and retinal hemorrhages with extensive macular involvement. CMV retinitis can occur as a late complication following liver transplantation. Additionally, CMV retinal disease can occur in the absence of laboratory evidence of CMV infection and independent of additional clinical features suggesting CMV disease. Currently, there is no standard of care regarding screening for CMV retinitis, and thus, further research is needed to define the need for potential changes in current clinical practices and post-transplant screening protocols.",
"affiliations": "Pediatric Liver Care Center, Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.",
"authors": "Squires|James E|JE|;Sisk|Robert A|RA|;Balistreri|William F|WF|;Kohli|Rohit|R|",
"chemical_list": "D007166:Immunosuppressive Agents; D015774:Ganciclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/j.1399-3046.2012.01752.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "17(1)",
"journal": "Pediatric transplantation",
"keywords": null,
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D001656:Biliary Atresia; D003587:Cytomegalovirus; D017726:Cytomegalovirus Retinitis; D005260:Female; D015774:Ganciclovir; D006801:Humans; D007166:Immunosuppressive Agents; D017093:Liver Failure; D016031:Liver Transplantation; D013997:Time Factors; D014785:Vision, Ocular; D055815:Young Adult",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "E16-9",
"pmc": null,
"pmid": "22738313",
"pubdate": "2013-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "18086275;15364214;7603215;11272601;21199215;22139888;15023154;17511815;8904861;20353469;20224515;9437324;11914998;12904846",
"title": "Isolated unilateral cytomegalovirus retinitis: a rare long-term complication after pediatric liver transplantation.",
"title_normalized": "isolated unilateral cytomegalovirus retinitis a rare long term complication after pediatric liver transplantation"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/15/0046115",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "Haemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of pathological immune activation characterised by extreme inflammation. We present a case of a young Filipino man consulting for non-specific symptoms of fever, body malaise and weight loss. Prominent physical examination findings included gross pallor, cachexia and hepatosplenomegaly. Laboratory results revealed pancytopaenia, while bone marrow examination revealed haemophagocytosis. Further workup for HLH showed hypertriglyceridaemia, hypofibrinogenaemia and hyperferritinaemia (fulfilling 6 of 8 diagnostic criteria). Exhaustive serological and haematological examinations showed chronic hepatitis B virus infection and past evidence of Epstein-Barr virus infection as possible triggers. The patient was started on antiviral therapy, high-dose steroids and chemotherapy. He initially improved, but eventually succumbed to severe fungal sepsis and pulmonary haemorrhage. An autopsy confirmed the diagnosis of HLH.",
"affiliations": "Department of Medicine, University of the Philippines-Philippine General Hospital, Manila, Philippines.;Department of Medicine, University of the Philippines-Philippine General Hospital, Manila, Philippines.",
"authors": "Yu|Marc Gregory|MG|;Chua|Jamie|J|",
"chemical_list": "D000970:Antineoplastic Agents; D000998:Antiviral Agents; D013256:Steroids",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000970:Antineoplastic Agents; D000998:Antiviral Agents; D017809:Fatal Outcome; D019694:Hepatitis B, Chronic; D006801:Humans; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D010679:Philippines; D013256:Steroids; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27284096",
"pubdate": "2016-06-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23233578;16937360;6354720;24505517;14558048;12467966;16307542;10674906;2058392;17675268;10583959;10367794;22160031;12239144",
"title": "Virus-associated haemophagocytic lymphohistiocytosis in a young Filipino man.",
"title_normalized": "virus associated haemophagocytic lymphohistiocytosis in a young filipino man"
} | [
{
"companynumb": "PH-009507513-1608PHL000349",
"fulfillexpeditecriteria": "1",
"occurcountry": "PH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "Recurrent/refractory hematologic malignancies have a poor prognosis, and there is a need for novel treatment regimens that can be tolerated by this heavily pretreated patient group. Clofarabine has antileukemic activity with an acceptable toxicity profile. In a phase I clinical trial (NCT00824135), we substituted clofarabine for fludarabine in a well-established reduced-intensity conditioning regimen for a T cell-depleted, mismatched-related (haploidentical) donor transplant backbone and explored the maximum tolerated dose of clofarabine in this combination in 15 patients undergoing hematopoietic cell transplantation for recurrent/refractory or secondary leukemia. Clofarabine was well tolerated at a dose of 50 mg/m/d for 5 days in this regimen, with minimal treatment-related mortality in a heavily pretreated group of high-risk patients. All patients exhibited quick hematopoietic recovery, with median times to neutrophil and platelet engraftment being 11 and 16 days, respectively. Transient elevation of transaminases was the most common toxicity-observed in 13 patients (86.7%), with 6 (40%) grade III or above. Three patients (20%) developed hepatic veno-occlusive disease. Eleven patients (73.3%) died, with the most common cause of death being disease relapse (in 9 patients [60%]), followed by treatment-related mortality (in 2 patients [13.3%]). Four (26.6%) of the patients are long-term survivors.",
"affiliations": "Departments of Oncology.;Biostatistics.;Biostatistics.;Departments of Oncology.;Departments of Oncology.;Pharmaceutical Sciences.;Pathology.;Department of Pediatrics, University of Tennessee Health Science Center, Memphis, TN.",
"authors": "Sharma|Akshay|A|;Kang|Guolian|G|;Sunkara|Anusha|A|;Inaba|Hiroto|H|;Jeha|Sima|S|;Cross|Shane J|SJ|;Geiger|Terrence|T|;Triplett|Brandon|B|",
"chemical_list": "D000077866:Clofarabine",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001222",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "40(8)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D064591:Allografts; D002648:Child; D002675:Child, Preschool; D000077866:Clofarabine; D018572:Disease-Free Survival; D005260:Female; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D012307:Risk Factors; D015996:Survival Rate; D019172:Transplantation Conditioning",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e479-e485",
"pmc": null,
"pmid": "29750747",
"pubdate": "2018-11",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24771494;20008227;11869952;12791647;23082952;24942362;26367221;11504749;9052912;25460355;22367344;24440659;1600415;2790129;17889352;14551141;25854284;15599932;24076323;22887831;17222760;10691873;23085831;23838349;21716139;3321587;11298592;21252987;11071652;8674058;1707752;27184623;17016426;22079470;10800061;26752456;19887774",
"title": "Haploidentical Donor Transplantation Using a Novel Clofarabine-containing Conditioning Regimen for Very High-risk Hematologic Malignant Neoplasms.",
"title_normalized": "haploidentical donor transplantation using a novel clofarabine containing conditioning regimen for very high risk hematologic malignant neoplasms"
} | [
{
"companynumb": "US-MYLANLABS-2018M1088747",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOFARABINE"
},
"drugadditional": null,
... |
{
"abstract": "Although rare, secondary clonal hematologic neoplasia may occur after successful therapy for acute promyelocytic leukemia (APL). These secondary clonal events may be considered therapy-related, but may also be due to an underlying background of clonal hematopoiesis from which both malignancies may develop. In this manuscript, we describe two patients with secondary clones after APL therapy characterized in one patient by deletion of chromosome 11q23 and, in the other, by monosomy of chromosome 7, and also provide a review of all secondary clonal disorders described after APL therapy. We suggest that since most reports identify karyotypic abnormalities not typically associated with chemotherapy, there may be another mechanism underlying secondary clonal development after complete response to initial APL therapy.",
"affiliations": "Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, LA, California, USA.;Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, LA, California, USA.;Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, LA, California, USA.",
"authors": "Gaut|Daria|D|;Sasine|Joshua|J|;Schiller|Gary|G|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.lrr.2018.04.005",
"fulltext": "\n==== Front\nLeuk Res RepLeuk Res RepLeukemia Research Reports2213-0489Elsevier S2213-0489(18)30009-810.1016/j.lrr.2018.04.005ArticleSecondary clonal hematologic neoplasia following successful therapy for acute promyelocytic leukemia (APL): A report of two cases and review of the literature Gaut Daria dgaut@mednet.ucla.eduaSasine Joshua jsasine@mednet.ucla.edubSchiller Gary gschiller@mednet.ucla.edub⁎a Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, LA, California, USAb Division of Hematology/Oncology, Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, LA, California, USA⁎ Corresponding author. gschiller@mednet.ucla.edu16 4 2018 2018 16 4 2018 9 65 71 16 1 2018 16 3 2018 7 4 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Although rare, secondary clonal hematologic neoplasia may occur after successful therapy for acute promyelocytic leukemia (APL). These secondary clonal events may be considered therapy-related, but may also be due to an underlying background of clonal hematopoiesis from which both malignancies may develop. In this manuscript, we describe two patients with secondary clones after APL therapy characterized in one patient by deletion of chromosome 11q23 and, in the other, by monosomy of chromosome 7, and also provide a review of all secondary clonal disorders described after APL therapy. We suggest that since most reports identify karyotypic abnormalities not typically associated with chemotherapy, there may be another mechanism underlying secondary clonal development after complete response to initial APL therapy.\n\nKeywords\nAcute myelocytic leukemia (AML)Secondary cloneMyelodysplastic syndrome (MDS)Therapy-related acute myelocytic leukemia (t-AML)Therapy-related myelodysplastic syndrome (t-MDS)Abbreviations\nAML, acute myelocytic leukemiaAPL, acute promyelocytic leukemiaATO, arsenic trioxideATRA, all-trans retinoic acidATG, antithymyocyte globulinCR, complete remissionFISH, fluorescence in situ hybridization6-MP, 6-mercaptopurineMDS, myelodysplastic syndromePML-RARalpha, promyelocytic leukemia/Retinoic acid receptor alphat-AML, therapy-related acute myelocytic leukemiat- MDS, therapy-related myelodysplastic syndrome\n==== Body\n1 Introduction\nAcute promyelocytic leukemia (APL) is a biologic and clinically well-defined subtype of acute myeloid leukemia typically characterized by the balanced translocation of chromosomes 15 and 17 resulting in fusion of the promyelocytic (PML) and retinoic acid receptor alpha (RARalpha) genes. The disease is also characterized by an unique response to the differentiating agent all-trans retinoic acid (ATRA). Combination therapy of ATRA with either chemotherapy or arsenic trioxide (ATO) has made APL a highly curable leukemia [1], [2], [3]. Nevertheless, relapses occurring after a complete remission (CR) of APL do occur and usually derive from their original APL [4]. Secondary myelodysplastic syndrome (MDS) or acute myelocytic leukemia (AML) developing in APL patients in complete remission (CR) is rare but has been documented. Here we describe two patients who initially were diagnosed with acute promyelocytic leukemia (APL) and later relapsed with a distinct neoplastic hematopoietic clone that was not, on simple cytogenetic findings, ancestrally related to the original APL.\n\n2 Case reports\nThe first patient was a 76-year-old woman with a past medical history of hypertension, diabetes, hypothyroidism, berylliosis requiring corticosteroids, and renal insufficiency who originally presented in February of 2009 with dizziness and orthostatic hypotension. Laboratory studies revealed pancytopenia with blasts on the peripheral blood smear. Bone marrow biopsy showed acute promyelocytic leukemia and t(15:17) was detected with fluorescence in situ hybridization (FISH). Her disease was characterized as intermediate-risk with a white blood cell count of 1.5 × 103/uL and a platelet count of 34 × 103/uL [5]. She received induction chemotherapy with all-trans retinoic acid (ATRA) 45 mg/m2/day and idarubicin 12 mg/m2 × 4 doses, achieving complete remission, followed by consolidation chemotherapy consisting of intermittent ATRA and idarubicin 5 mg/m2 × 4 doses. Following recovery of blood counts, idarubicin was discontinued due to cardiomyopathy (ejection fraction 39%) and consolidation continued with arensic trioxide (ATO) 45 mg daily for 5 days per week for an abbreviated course of 3 weeks. Maintenance therapy with methotrexate 15 mg weekly and ATRA 50 mg twice daily continued for 18 months. Two years following completion of maintenance therapy, she developed thrombocytopenia with bone marrow biopsy negative for recurrent leukemia. Seven years following her initial remission, she developed anemia as well. Bone marrow biopsy at this time revealed 20–25% myeloid blasts and cytogenetic testing identified deletion of chromosome 11q23 in 7 out of 20 metaphase cells examined, but FISH was negative for the t(15;17) translocation. Next-generation DNA sequencing was performed on the Illumina Miseq to identify somatic variants in 54 of the most commonly mutated genes in myeloid malignancies, and mutations in Additional Sex combs-like Transcriptional Regulator 1 (ASXL1), PHD finger protein 6 (PHF6), and TET methylcytosine dioxygenase 2 (TET2) were also detected. Reinduction with cytarabine 200 mg/m2 × 7 days and idarubicin 12 mg/m2 × 3 days was attempted without remission. Karyotype then revealed deletion of the long arm of chromosome 7 (del 7q22) in 19 or 20 metaphase cells analyzed. Decitabine therapy produced a modest response, and she died after further attempts at reinduction.\n\nThe second patient was a 65-year-old man who originally presented in December of 2014 with fevers, fatigue, thrombocytopenia, anemia, and leukocytosis. Peripheral blood smear revealed blasts with Auer rods, and bone marrow biopsy demonstrated acute promyelocytic leukemia with t(15;17) present. His disease was characterized as high-risk given a white blood cell count of 56.1 × 103/uL [5]. The patient initially received ATRA 45 mg/m2/day and ATO 0.15 mg/kg daily but developed symptomatic QT prolongation and proceeded to treatment with idarubicin. His course was complicated by prolonged neutropenia with Pseudomonas bacteremia and Aspergillus pneumonia requiring filgrastim and granulocyte transfusions. Bone marrow biopsy following induction was negative for blast cells with normal molecular pathology and negative FISH testing for the t(15;17) translocation. He received three cycles of consolidation consisting of ATRA with idarubicin, mitoxantrone, and cytarabine followed by maintenance therapy with methotrexate 15 mg weekly, 6-mercaptopurine (6-MP) 50 mg daily, and intermittent ATRA 50 mg bid. One year into maintenance, the patient developed pancytopenia, and methotrexate and 6-MP were stopped. A short time later, he developed intermittent right facial paresthesia. MRI brain was concerning for hypointensity over the cerebellum, reflective of subarachnoid bleeding, and hyperintensity in some regions. Lumbar puncture revealed 78% promyelocytes with cytogenetics from cerebrospinal fluid positive for t(15;17). Bone marrow biopsy showed no evidence of blasts, but the karyotype disclosed a new set of anomalies with monosomy of chromosome 7 and an extra marker chromosome in 18 of 20 cells observed (+mar(18)). There were no marrow cells with t(15;17) by FISH or routine karyotype. Hematologic malignancy sequencing panel noted two mutations in the SET binding protein 1 (SETBP1) with allele frequency 36% and 12%. The patient was treated with intrathecal methotrexate 12 mg and intrathecal cytarabine 100 mg followed by whole brain radiation, 2 Gy x 9 fractions. Repeat bone marrow biopsy one month later revealed no excess blasts by flow cytometry, but the karyotype showed persistent monosomy 7 and an extra marker chromosome in all 20 cells observed (+mar(20)). The patient received systemic chemotherapy consisting of cytarabine 100 mg/m2 × 7 days and daunorubicin 60 mg/m2 followed by allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning of busulfan, fludarabine, and antithymocyte globulin (ATG). Post-bone marrow transplant bone marrow biopsy showed no evidence of disease and full donor chimerism. Repeat MRI brain/orbits showed resolution of previously seen enhancement. The patient is doing well 10 months post-bone marrow transplant.\n\n3 Discussion\nWe describe two patients who developed distinct AML clones without t(15;17) following treatment for APL. Such secondary clonal hematologic neoplasia occurring after successful therapy for APL is rare but has been documented, and these cases are illustrated in Table 1\n[6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34]. Frequencies ranging from 1–9.8% [18], [20], [29], [33] have been reported with a median latency period of 35.6 months (range 1–158 months) after remission of APL. Two separate hypotheses can describe this observation of the secondary clonal hematologic neoplasia: (1) these diseases may be an outgrowth of an existing undetectable subclone or (2) they may be two independent clones evolved from separate hematopoietic stem cells, likely a result of toxicity from chemotherapy.Table 1 Literature review of secondary MDS/AML following treatment for APL.\n\nTable 1Reference\tInitial karyotype\tYear of Diagnosis\tAPL risk stratification\tTherapy for APL\tTime of relapse after CR (months)\tRelapse Disease: MDS or AML\tRelapse karyotype\tSurvival after emergence of second clone\t\n\t\t\t\tATRA\tTopoisomerase II Inhibitors\tAlkylating Agents\tAllogeneic SCT\t\t\t\t\t\n6\t46XY, t(15;17)(q21;q11)[19] /46,XY,inv(6)(p24q13), t(15;17)(q21;q11)[39]\tUnknown\tIntermediate\tX\tX (idarubicin, mitoxantrone)\t\t\t4\tMDS→AML\t44,X,-Y,−7 [41]\tExpired 1 year later\t\n6\tt(15;17)(q22;q11) in 94% of studied cells\tUnknown\tIntermediate\tX\tX (idarubicin, mitoxantrone)\t\t\t20\tMDS\t46,XX,del(5)(q13q33)\tAlive, unknown amount of time later\t\n7\t46,XX,t(15;17)(q22;q21)\t1997\tIntermediate or low\tX\tX (idarubicin, etoposide)\t\t\t26\tMDS→AML (M6)\t46,XX,−5,add(6)(p23-25), + 8,add(17)(p13) [10]\tExpired 7 months later\t\n8\t46,XY,t(15;17)(q22;11) [20]\t1987\tLow\t\tX (daunorubicin, etoposide)\t\t\t33\tMDS→AML (M1)\t46 XY,t(7;21)(q31;q22) [13]\tExpired 75 months later\t\n9\t46,XY,t(15;17)\t1987\tLow\t\tX (daunorubicin, aclarubicin, mitoxantrone, etoposide)\t\t\t43\tAML\t46,XY,t(3;21)(q26;q22), der(4)t(4;?)(q27;?),der(7) t(4;7)(q27;q22), der(16)t(16;?)(p11.2;?) [20]\tExpired 5 months later\t\n10\t46,XY,t(15;17)\t1992\tLow\tX\tX (idarubicin)\t\t\t32\tMDS\t46,XX,−7, + marker[10]/ 45, XX,−7[7]/ 46,XX[3]\tAlive 1 year later\t\n11\t46,XY,t(15;17)(q22;q12)\tUnknown\tUnknown\t\tX (idarubicin, doxorubicin, etoposide)\tX (cyclophosphamide)\t\t26\tBiphenotypic leukemia\t45,XY,−7[7]\tPalliative care 15 months later\t\n12\t46,XX,t(15;17)(q22;q21)\t1984–1991\tIntermediate or low\t\tX (idarubicin, etoposide)\t\tX\t49\tAML (M4)\t46,XX,t(10;11)(p14;q21)\tExpired 2 months later\t\n13\t46,XY,t(15;17)\tUnknown\tUnknown\t\tX (idarubicin, mitoxantrone)\t\tX\t36\tAML\t45,XY,−7\tExpired at unclear date\t\n14\t46,XX,t(15;17)(q22;q21)\tUnknown\tIntermediate or low\t\tX (daunorubicin)\tX (cyclophosphamide)\t\t24\tMDS (RAEB)→AML (M2)\t45,XX,dic(5;17)(q11;p11)/ 43, idem,−7,−20\tExpired 6 months later\t\n15\t46,XY,t(15;17)(q22;q21)\tUnknown\tUnknown\t\tX (etoposide)\tX (cyclophosphamide)\t\t43\tAML (M2)\t46,XY,t(10;11)(q23;p15)\tAlive 26 months later\t\n16\t47,XX, + 8,t(15;17)(q22;q21)\t1993\tHigh\tX\tX (daunorubicin)\t\t\t29\tMDS (RAEB)\t45,XX,−5,−7, + 11 [6]/ 47,XX, + 8,t(15;17)(q22;q21) [14]\tExpired 5 months later\t\n16\t46,XX,−3(q24;q26), −5(q23;q32), t(7;11)(p11; p12), t(15;17)(q22;q21)\t1996\tHigh\tX\tX (daunorubicin)\t\t\t23\tMDS (RAEB)→ M0 AML after 6 months\t45, XX,−7\tExpired 11.5 months later\t\n17\t46,XX,t(15;17)\t1992\tHigh\t\tX (daunorubicin, mitoxantrone, etoposide)\t\t\t∼84\tMDS RAEB\t43–45XX, del(5)(q15)[8],−7[7], + 9(q34)[3],−18[4],−21[5], + mar[3], + r[2], + dmin[3][cp8]\tExpired 3 months later\t\n18\t46,XX,t(15;17)\t1989–1993\tLow\t\tX (idarubicin)\t\t\t48\tMDS detected concomitantly with AML (M4)\t46,XX,t(10;11)(p14;q21)\tExpired of GVHD (day + 50)\t\n18\t46,XX,t(15;17)\t1989–1993\tLow\tX\tX (idarubicin)\t\t\t43\tMDS→AML\t45,XX,−7\tAlive 18 months later\t\n18\t46,XY,t(15;17)\t1989–1993\tLow\tX\tX (idarubicin)\t\t\t46\tMDS\tN/A (lack of evaluable metaphase)\tExpired 1 month later\t\n18\t46,XY,t(15;17)\t1989–1993\tHigh\t\tX (idarubicin)\t\t\t48 (33 from second CR)\tMDS→AML\t46,XY,del(5q-)\tExpired 5 months later\t\n18\t46,XX,t(15;17)\t1989–1993\tHigh\tX\tX (idarubicin)\t\tX\t24 (2 from second CR)\tMDS\t46,XX\tAlive 12 months later\t\n19\t46,XX,t(15;17)\t2000\tIntermediate\tX\tX (idarubicin, etoposide)\t\t\t52\tMDS\t46,XX,del(2q-),del7(q31)\t\t\n\tExpired 9 months later\t\t\t\t\t\t\t\t\t\t\t\n20\t46,XX,t(15;17)(q22;q21)\t1991–1998\tIntermediate or Low\tX\tX (daunorubicin)\t\t\t13 after original APL diagnosis, additional APL relapse 7 months after MDS diagnosis\tMDS (RA)\t46, XX, del(5)(q22q34),(t15;21)(p11; q21),−17, + mar\tExpired 25.4 months later\t\n20\t46,XY,t(15;17)(q22;q21)\t1991–1998\tIntermediate or Low\tX\tX (daunorubicin, mitoxantrone and idarubicin at relapse)\tX (cyclophosphamide at relapse)\tX (for relapse)\t46 (6 from second CR)\tMDS (RAEB)→ M0 AML after 1 month\t43,XY,del(5)(q12q35),add(11) (q23), dup(12)(q12q22), −17,−18,−22\tExpired 0.8 months later\t\n20\t46,XY,del(9)(q21q31), t(15;17)(q22;q21)\t1991–1998\tIntermediate or Low\tX\tX (daunorubicin)\t\t\t111\tMDS (RA)\t45,XY,−5,der(7)t(7;20) (q11;p? or q?), der(10)t(7;10;20) (q3?;q2?;p? or q?),−13,der(17)t(10;17) (q2?;p11),−20, del(20)(q11), + mar1, + mar3/ 47, idem,del(X)(q26), der(1) (1;?)(p36;?), + 8, + mar2\tAlive 24 months later\t\n20\tFailure\t1991–1998\tIntermediate or Low\tX\tX (daunorubicin)\t\t\t74\tMDS(RA)→ M0 AML after 18 months\t45,XY,−8,t(8;11)(q32;q21)\tExpired 7.5 months later\t\n20\t46,XY,t(15; 17)(q22;q21)\t1991–1998\tIntermediate or Low\tX\tX (daunorubicin)\t\t\t47\tMDS (RAEB-t)\t45,XY,t(3;17)(p11;q11), del(5)(q13q33), del(6)(p22),−17\tAlive 4 months later\t\n21\t46,XX,t(15;17)\t1996\tIntermediate\tX\tX (idarubicin, daunorubicin)\t\t\t40\tMDS (RAEB)→ M2 AML after 6 months\t45,XX,del(4)(q31),−5, add(5) (q35),−7,der(17), t(17;?)(p11;?),−18, + mar1, + mar2[cp21]/ 46,XX [4]\tExpired 9 months later\t\n22\t46,XX,t(15;17)\t1999\tUnknown\tX\tX (idarubicin)\t\t\t18\tM4 AML\t46,XX,t(9;11)(p12;q23) [24]\tExpired a few days after diagnosis\t\n23\t46,XY (PML/RARA + )\t1995\tIntermediate or low\tX\tX (mitoxantrone, etoposide, daunorubicin)\t\t\t20\tMDS (RAEB)→AML (M2) after 10 months\t47,XY, + 8[2]/ 46,XY [18]\tAlive, unknown amount time\t\n24\t46,XX,i(17)(q10)[20] (PML - RARA + )\t2001\tLow\tX\tX (idarubicin)\t\t\t10\tM5 AML\t46,XX, t(8;16)(p11.2;p13.3),inv(11) (p15q22∼q23)[11]/ 47,idem, + i(8)(q10)[9]\tAlive 1 year later\t\n25\t46, XY, t(15;17)(q22;q21)\t1991\tHigh\tX\tX (daunorubicin)\t\t\t6\tM3 AML (rare Auer rods)\t46,XY,t(3;6)(q26;q15)\tAlive 15 months later\t\n26\t46,XY,t(15;17)\tUnknown\tLow\tX\tX (daunorubicin)\t\t\t∼36\tM2 AML\t45,XY,−7,t(3;21)(q26;q22)\tExpired 2 years later\t\n27\t46,XX,t(15;17)\t1994\tHigh\tX\tX (idarubicin, etoposide)\t\t\t∼1\tNA\t46,XX,t(11;19)(q13;q13.3) in 12% of cells\tAlive 18 months s/p autotransplantation\t\n28\t46,XY,t(15;17)(q22;q21) [24]\t1996\tUnknown\tX\tX (idarubicin)\t\t\t∼8\tNA\t46,XY,del(11)(q21)[2]/ 46,XY[50]\tExpired at unknown date\t\n28\t46,XY,t(15;17)(q22;q21) [18]/ 46,XY[1]\t1997\tUnknown\tX\tX (idarubicin, mitoxantrone, etoposide)\t\t\t∼1\tNA\t46,XY,del(11)(q14q23) [1], 46,XY [39]\tAlive, 1126 days later\t\n29\t46,XY,t(15;17)\t1997–2009\tHigh\tX\t\t\t\t46\tNA\t46,XY,del(20)(q11)[4]/ 46,XY[38]\tAlive 89 days later\t\n29\t46,XX,t(15;17)\t1997–2009\tIntermediate\tX\tX (idarubicin)\t\t\t23\tNA\t46,XX,del(20)(q11)[2]/ 46,XX[36]\tAlive 44 days later\t\n29\t46,XY,t(15;17)\t1997–2009\tUnknown\tX\tX (amsacrine)\t\t\t8\tNA\t46,XY,del(11)(q21)[2]/ 46,XY[50]\tExpired 10 months later\t\n29\t46,XY,t(15;17)\t1997–2009\tIntermediate\tX\tX (idarubicin, mitoxantrone)\t\t\t1\tNA\t46,XY,del(11)(q14q23)[1]/ 46,XY[39]\tAlive 36 months later\t\n29\t46,XY,t(15;17)\t1997–2009\tIntermediate\tX\tX (idarubicin)\t\t\t38\tNA\t47,XY, + 15[2]/ 46,XY[38]\tAlive 18 months later\t\n29\t46,XY,t(15;17)\t1997–2009\tLow\tX\tX (idarubicin)\t\t\t53\tNA\t46,XY,t(3;12)(q11.2;q13)[3]/ 46,XY[40]\tAlive 20 months later\t\n29\t46,XX,t(15;17)\t1997–2009\tLow\tX\tX (idarubicin)\t\t\t23\tNA\t46,XX,dup(1)(q21q32)[4]/ 46,XX[51]\tAlive 24 months later\t\n29\t46,XY,t(15;17)\t1997–2009\tIntermediate\tX\tX (idarubicin)\t\t\t22\tAML\t46,XY,del(5)(q?22),add(7) (q?32)[3]/ 46,XY[35]\tExpired 23 months later\t\n29\t46,XY,t(15;17)\t1997–2009\tIntermediate\tX\tX (idarubicin)\t\t\t22\tMDS\t46,XY,del(5)(q13q31)[4]/ 46,XY[46]\tAlive 38 months later\t\n29\t46,XX,t(15;17)\t1997–2009\tHigh\tX\tX (idarubicin)\t\t\t30\tNA\t46,XX,del(7)(q22q36)[3]/, 46,XX[68]\tAlive 22 months later\t\n29\t46,XX,t(15;17)\t1997–2009\tLow\tX\tX (idarubicin)\t\t\t47\tMDS\t45,XX,−7[9]/ 45, idem,?idic(X)(q11)[6]/ 46,XX[26]\tAlive 37 months later\t\n29\t46,XY,t(15;17)\t1997–2009\tIntermediate\tX\tX (idarubicin)\t\t\t30\tMDS→AML\t45,XY,−5,add(17)(p12)[4]/ 44,sl,−7[2]/45,sdl1, + mar1[2]/ 46,XY[36]\tExpired 22 months later\t\n30\t46,XX,t(15;17)\tUnknown\tIntermediate or low\tX\tX (daunorubicin)\t\t\t36\tAML M2\tNormal\tExpired within 1 year\t\n31\t46,XX,t(15;17)(q22;q21) [10]/ 46,XX [14]\tUnknown\tIntermediate\tX\tX (idarubicin, mitoxantrone)\t\t\t20\tMDS\t46,X,del(X)(q22q28),t(2;11) (q37;q23),del(7) (q22q36)[9]\tExpired 10 months later\t\n32\t46,XX,t(15;17)\t1988\tIntermediate or low\t\tX (daunorubicin)\t\t\t158\tMDS\t47,XY, + 1,i(1)(q10)\tAlive 37 months later\t\n33\t46,XX,t(15;17)\t1994\tUnknown\tX\tX (idarubicin)\t\t\t∼24\tMDS\t45,XX,−5,add(17)(p11.2)\tExpired within 1 year\t\n34\t46,XY,t(15;17)(q22;q21)\t2001\tUnknown\tX\tX (idarubicin)\t\t\t∼36\tNA\t46,XY,del(20)(q11q13)\tAlive, unknown time later\t\n\n\nThe well-described entities of therapy-related myelodysplasia (t-MDS) and acute myeloid leukemia (t-AML) are known to occur following therapy with either alkylating agents or topoisomerase II inhibitors [35], [36]. They are characterized by distinct cytogenetic abnormalities: loss of chromosome 5 or 7 with alkylating agents [37], [38] and 11q23 and 21q22 aberrations with topoisomerase II inhibitors [39], [40]. The most common primary therapies for APL include anthracyclines, which are believed to work through topoisomerase II enzyme inhibition, in addition to 6-MP, methotrexate, and ATRA. It has been hypothesized that methotrexate, 6-MP, or ATRA might modify anthracycline leukemogenesis and contribute to the development of a secondary leukemia [7], [10], [16], [21]. Alkylating agents, however, are not commonly used therapies for APL. Indeed, out of the cases reported of secondary clones following APL therapy, only 4 received an alkylating agent (cyclophosphamide). However, the karyotypes of the secondary clones, including those not treated with alkylating agents, most commonly had characteristics typically associated with prior therapy with an alkylating agent: 16 patients had deletion of all or part of chromosome 7 [6], [10], [11], [13], [14], [16], [17], [18], [19], [21], [26], [29], [31] and 15 patients had deletion of all or part of chromosome 5 [6], [7], [16], [17], [18], [20], [21], [29], [33]. Despite the fact that all patients were treated with topoisomerase II inhibitors (anthracyclines), only 4 patients, or 6 including our patients, presented with karyotypes typical of prior therapy with a topoisomerase II inhibitor [17], [28], [29]. Almost half of the patients (23) did not have karyotypic abnormalities at all associated with t-MDS/t-AML. This result suggests either that anthracycline therapy may induce such alkylating agent-type karotypic aberrations in APL patients [32] or that the secondary clones were not in fact therapy-induced. Another possibility to consider is induction of a selective advantage to pre-existing hematopoietic stem cell subclones carrying certain mutations, such as TP53 or SETD2, that allowed them to expand preferentially after treatment [41], [42].\n\nSuch secondary clones detected after APL therapy may have been derived from an ancestral pre-leukemia stem cell that developed into APL and thereafter contributed to the second disorder. Clonal evolution has been well-defined in AML [43], [44] and has also been described in APL [45], [46]. A similar theory has been proposed for secondary unrelated clones in CML patients that developed deletions of chromosome 5 and 7 after CML treatment with interferon alpha or imatinib mesylate in the absence of chemotherapy [47], [48]. The fact that many patients presented with secondary myelodysplasia may yield support for this theory of clonal evolution. Of the 50 cases of secondary clonal neoplasia following APL treatment reported in the literature, more than half (28) developed myelodysplasia. Furthermore, selected cases of initial diagnosis of APL with concurrent myelodysplastic changes have been reported [8], though it is uncommon.\n\nGoing against the theory of clonal evolution and more in support of chemotherapy-induced secondary MDS/AML is the fact that no cases of secondary AML have been reported after arsenic/ATRA therapy for APL without exposure to chemotherapy. However, given that this therapeutic regimen has only recently become standard practice [49], there may not yet have been sufficient time to observe such secondary malignancies. Indeed, the majority of the patients in Table 1 were treated prior to this new therapy.\n\n4 Conclusion\nIn conclusion, secondary clonal hematologic neoplasia following APL treatment is increasingly being reported. We have described an additional two patients with such a phenomenon. Further research is needed to determine the causality of such secondary clones in terms of relation to chemotherapy versus a common leukemic progenitor and to assess its clinical implications.\n\n5 Clinical practice points\n• Secondary clonal hematologic neoplasia occurring after successful therapy for APL is rare but has been documented.\n\n• We describe an additional two patients with secondary clones after APL therapy characterized in one patient by deletion of chromosome 11q23 and, in the other, by monosomy of chromosome 7.\n\n• A thorough review of the literature suggests that most of these secondary neoplasms contain karyotypic abnormalities not typically associated with chemotherapy, arguing against a therapy-induced mechanism.\n\n• It is possible that such secondary clones instead represent clonal evolution from an ancestral preleukemic stem cell capable of differentiating into both APL and MDS/AML.\n\n\n\nConflict of interest\nThe authors whose names are listed immediately below certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.\n\nAppendix Supplementary materials\nImage, application 1 \n\nAcknowledgment\nNone.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nSupplementary material associated with this article can be found, in the online version, at doi:10.1016/j.lrr.2018.04.005.\n==== Refs\nReferences\n1 Mandelli F. Diverio D. Avvisati G. Molecular remission in PML/RAR alpha-positive acute promyelocytic leukemia by combined all-trans retinoic acid and idarubicin (AIDA) therapy. Gruppo Italiano–Malattie Ematologiche Maligne dell'Adulto and Associazione Italiana di Ematologia ed Oncologia Pediatrica Cooperative Groups Blood 90 3 1997 1014 1021 9242531 \n2 Sanz M.A. Martín G. Rayón C. A modified AIDA protocol with anthracycline-based consolidation results in high antileukemic efficacy and reduced toxicity in newly diagnosed PML/RARalpha-positive acute promyelocytic leukemia. PETHEMA group Blood 94 9 1999 3015 3021 10556184 \n3 Lo Coco F. Avvisati G. Vignetti M. Retinoic acid and arsenic trioxide for acute promyelocytic leukemia N. Engl. J. Med. 369 2 2013 111 121 23841729 \n4 Avvisati G. Lo Coco F. Mandelli F. Acute promyelocytic leukemia: Clinical and morphologic features and prognostic factors Semin. Hematol. 38 1 2001 4 12 \n5 Sanz M.A. Lo Coco F. Martín G. Definition of relapse risk and role of nonanthracycline drugs for consolidation in patients with acute promyelocytic leukemia: a joint study of the PETHEMA and GIMEMA cooperative groups Blood 96 4 2000 1247 1253 10942364 \n6 Panizo C. Patiño A. Lecumberri R. Secondary myelodysplastic syndrome after treatment for promyelocytic leukemia: clinical and genetic features of two cases Cancer Genet. Cytogenet. 143 2 2003 178 181 12781455 \n7 Pecci A. Invernizzi R. A therapy-related myelodysplastic syndrome with unusual features in a patient treated for acute promyelocytic leukemia Haematologica 86 1 2001 102 103 11146580 \n8 Jubashi T. Nagai K. Miyazaki Y. A unique case of t(15;17) acute promyelocytic leukaemia (M3) developing into acute myeloblastic leukaemia (M1) with t(7;21) at relapse Br. J. Haematol. 83 4 1993 665 668 8518183 \n9 Miyazaki H. Ino T. Sobue R. Translocation (3;21)(q26;q22) in treatment-related acute leukemia secondary to acute promyelocytic leukemia Cancer Genet. Cytogenet. 74 2 1994 84 86 8019966 \n10 Bseiso A.W. Kantarjian H. Estey E. Myelodysplastic syndrome following successful therapy of acute promyelocytic leukemia Leukemia 11 1 1997 168 169 9001434 \n11 Felice M.S. Rossi J. Gallego M. Acute trilineage leukemia with monosomy of chromosome 7 following an acute promyelocytic leukemia Leuk. Lymphoma. 34 3-4 1999 409 413 10439380 \n12 Todisco E. Testi A.M. Avvisati G. Therapy-related acute myelomonocytic leukemia following successful treatment for acute promyelocytic leukemia Leukemia 9 9 1995 1583 1585 7658728 \n13 Meloni G. Diverio D. Vignetti M. Autologous bone marrow transplantation for acute promyelocytic leukemia in second remission: prognostic relevance of pretransplant minimal residual disease assessment by reverse-transcription polymerase chain reaction of the PML/RAR alpha fusion gene Blood 90 3 1997 1321 1325 9242568 \n14 Hatzis T. Standen G.R. Howell R.T. Savill C. Wagstaff M. Scott G.L. Acute promyelocytic leukaemia (M3): relapse with acute myeloblastic leukaemia (M2) and dic(5;17) (q11;p11) Am. J. Hematol. 48 1 1995 40 44 7832190 \n15 Sawada H. Morimoto H. Wake A. Yamasaki Y. Izumi Y. Therapy-related acute myeloid leukemia with t(10;11)(q23;p15) following successful chemotherapy for acute promyelocytic leukemia with t(15;17)(q22;q21) Int. J. Hematol. 69 4 1999 270 271 10407587 \n16 Zompi S. Legrand O. Bouscary D. Therapy-related acute myeloid leukaemia after successful therapy for acute promyelocytic leukaemia with t(15;17): a report of two cases and a review of the literature Br. J. Haematol. 110 3 2000 610 613 10997972 \n17 Au W.Y. Lam C.C. Ma E.S. Man C. Wan T. Kwong Y.L. Therapy-related myelodysplastic syndrome after eradication of acute promyelocytic leukemia: cytogenetic and molecular features Hum. Pathol. 32 1 2001 126 129 11172306 \n18 Latagliata R. Petti M.C. Fenu S. Therapy-related myelodysplastic syndrome–acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem Blood 99 3 2002 822 824 11806982 \n19 Gündüz E. Akay O.M. Durak B. Gülbaş Z. Therapy-related myelodysplastic syndrome following acute promyelocytic leukemia and biphenotypic acute leukemia following stem cell transplantation in the same patient Turk. J. Haematol. 24 2 2007 85 87 27263623 \n20 Lobe I. Rigal-Huguet F. Vekhoff A. Myelodysplastic syndrome after acute promyelocytic leukemia: the European APL group experience Leukemia 17 8 2003 1600 1604 12886249 \n21 Athanasiadou A. Saloum R. Zorbas I. Therapy-related myelodysplastic syndrome with monosomy 5 and 7 following successful therapy for acute promyelocytic leukemia with anthracyclines Leuk. Lymphoma. 43 12 2002 2409 2411 12613533 \n22 Annunziata M. Palmieri S. Pocali B. Therapy-related acute myeloid leukemia with t(9;11)(p12;q23) in a patient treated for acute promyelocytic leukemia Hematol. J. 4 4 2003 289 291 12872155 \n23 Stavroyianni N. Yataganas X. Abazis D. Pangalos C. Meletis J. Acute promyelocytic leukemia relapsing into FAB-M2 acute myeloid leukemia with trisomy 8 Cancer Genet. Cytogenet. 117 1 2000 82 83 10700873 \n24 Lee G.Y. Christina S. Tien S.L. Acute promyelocytic leukemia with PML-RARA fusion on i(17q) and therapy-related acute myeloid leukemia Cancer Genet. Cytogenet. 159 2 2005 129 136 15899384 \n25 Desangles F. Vilain E. Arborio M. De Revel T. Flandrin G. t(15;17) hypergranular acute promyelocytic leukemia (M3) developing into a t(3;6) M3 without t(15;17) at relapse Leuk. Lymphoma. 19 1–2 1995 185 188 8574167 \n26 Betancourt-García R.D. Castro J. Fernández A.C. López-Enríquez A. Fradera J. Pacheco E. Acquired acute myelogenous leukemia after therapy for acute promyelocytic leukemia with t(15;17): a case report and review of the literature P R Health Sci. J. 28 2 2009 146 150 19530558 \n27 Temperani P. Luppi M. Giacobbi F. Occurrence of a novel t(11;19)(q13;q13.3) in complete remission of acute promyelocytic leukemia Cancer Genet. Cytogenet. 101 1 1998 35 38 9460497 \n28 Campbell L.J. Rayeroux K.C. Arkell K. Catalano J.V. Cole-Sinclair M.F. Appearance of del(11q) in two patients with acute promyelocytic leukaemia treated with all-trans retinoic acid and combination chemotherapy Br. J. Haematol. 118 1 2002 243 245 12100154 \n29 Batzios C. Hayes L.A. He S.Z. Secondary clonal cytogenetic abnormalities following successful treatment of acute promyelocytic leukemia Am. J. Hematol. 84 11 2009 715 719 19806661 \n30 Sahoo R.K. Kumar L. Kumar R. Sharma A. Acute promyelocytic leukemia relapsing into acute myeloid leukemia-M2 with normal cytogenetics Indian J. Med. Paediatr. Oncol. 34 4 2013 327 329 24604968 \n31 Snijder S. Mellink C.H.M. van der Lelie H. Translocation (2;11)(q37;q23) in therapy-related myelodysplastic syndrome after treatment for acute promyelocytic leukemia Cancer Genet. Cytogenet. 180 2 2008 149 152 18206542 \n32 Pawarode A. Finlay E. Sait S.N. Barcos M. Baer M.R. Isochromosome 1q in a myelodysplastic syndrome after treatment for acute promyelocytic leukemia Cancer Genet. Cytogenet. 167 2 2006 155 160 16737916 \n33 Garcia-Manero G. Kantarjian H.M. Kornblau S. Estey E. Therapy-related myelodysplastic syndrome or acute myelogenous leukemia in patients with acute promyelocytic leukemia (APL) Leukemia 16 9 2002 1888 \n34 Mallo M. Salido M. Espinet B. Could ATRA/Idarubicin treatment of acute promyelocytic leukemia induce the appearance of new clonal cytogenetic abnormalities in patients in complete remission Leuk. Res. 31 9 2007 1315 1317 17092559 \n35 Rund D. Ben-Yehuda D. Therapy-related leukemia and myelodysplasia: evolving concepts of pathogenesis and treatment Hematology 9 3 2004 179 187 15204099 \n36 Godley L.A. Larson R.A. Therapy-related myeloid leukemia Semin. Oncol. 35 4 2008 418 429 18692692 \n37 Smith S.M. Le Beau M.M. Huo D. Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series Blood 102 1 2003 43 52 12623843 \n38 Rund D. Krichevsky S. Bar-Cohen S. Therapy-related leukemia: clinical characteristics and analysis of new molecular risk factors in 96 adult patients Leukemia 19 11 2005 1919 1928 16167058 \n39 Andersen M.K. Christiansen D.H. Kirchhoff M. Pedersen-Bjergaard J. Duplication or amplification of chromosome band 11q23, including the unrearranged MLL gene, is a recurrent abnormality in therapy-related MDS and AML, and is closely related to mutation of the TP53 gene and to previous therapy with alkylating agents Genes Chromosomes Cancer 31 1 2001 33 41 11284033 \n40 Pedersen-Bjergaard J. Timshel S. Andersen M.K. Andersen A.S. Philip P. Cytogenetically unrelated clones in therapy-related myelodysplasia and acute myeloid leukemia: experience from the Copenhagen series updated to 180 consecutive cases Genes Chromosomes Cancer 23 4 1998 337 349 9824207 \n41 Wong T.N. Ramsingh G. Young A.L. Role of TP53 mutations in the origin and evolution of therapy-related acute myeloid leukaemia Nature 518 7540 2014 552 555 25487151 \n42 Mar B.G. Chu S.H. Kahn J.D. SETD2 alterations impair DNA damage recognition and lead to resistance to chemotherapy in leukemia Blood 130 24 2017 2631 2641 29018079 \n43 Ding L. Ley T.J. Larson D.E. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing Nature 481 7382 2012 506 510 22237025 \n44 Jan M. Snyder T.M. Corces-Zimmerman M.R. Clonal evolution of preleukemic hematopoietic stem cells precedes human acute myeloid leukemia Sci. Transl. Med. 4 149 2012 149ra118 \n45 Zhang X. Zhang Q. Dahlström J. Genomic analysis of the clonal origin and evolution of acute promyelocytic leukemia in a unique patient with a very late (17 years) relapse Leukemia 28 8 2014 1751 1754 24651096 \n46 Dimov N.D. Medeiros L.J. Ravandi F. Bueso-Ramos C.E. Acute promyelocytic leukemia at time of relapse commonly demonstrates cytogenetic evidence of clonal evolution and variability in blast immunophenotypic features Am. J. Clin. Pathol. 133 3 2010 484 490 20154288 \n47 Fayad L. Kantarjian H. O'Brien S. Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases Leukemia 11 5 1997 767 771 9180306 \n48 Andersen M.K. Pedersen-Bjergaard J. Kjeldsen L. Dufva I.H. Brøndum-Nielsen K. Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8 Leukemia 16 7 2002 1390 1393 12094265 \n49 Cicconi L. Lo-Coco F. Current management of newly diagnosed acute promyelocytic leukemia Ann. Oncol. 27 8 2016 1474 1481 27084953\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0489",
"issue": "9()",
"journal": "Leukemia research reports",
"keywords": "6-MP, 6-mercaptopurine; AML, acute myelocytic leukemia; APL, acute promyelocytic leukemia; ATG, antithymyocyte globulin; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; Acute myelocytic leukemia (AML); CR, complete remission; FISH, fluorescence in situ hybridization; MDS, myelodysplastic syndrome; Myelodysplastic syndrome (MDS); PML-RARalpha, promyelocytic leukemia/Retinoic acid receptor alpha; Secondary clone; Therapy-related acute myelocytic leukemia (t-AML); Therapy-related myelodysplastic syndrome (t-MDS); t- MDS, therapy-related myelodysplastic syndrome; t-AML, therapy-related acute myelocytic leukemia",
"medline_ta": "Leuk Res Rep",
"mesh_terms": null,
"nlm_unique_id": "101608906",
"other_id": null,
"pages": "65-71",
"pmc": null,
"pmid": "29892552",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "11284033;9824207;9242568;17092559;18206542;11172535;10700873;29018079;8574167;16737916;10556184;9180306;12886249;11172306;12094265;24651096;8518183;19530558;12613533;10407587;20154288;22237025;22932223;12872155;16167058;10439380;19806661;24604968;27084953;12623843;9242531;25487151;7832190;8019966;7658728;10942364;12200720;15204099;18692692;11146580;15899384;12781455;10997972;27263623;12100154;9460497;23841729;11806982;9001434",
"title": "Secondary clonal hematologic neoplasia following successful therapy for acute promyelocytic leukemia (APL): A report of two cases and review of the literature.",
"title_normalized": "secondary clonal hematologic neoplasia following successful therapy for acute promyelocytic leukemia apl a report of two cases and review of the literature"
} | [
{
"companynumb": "US-ACCORD-069946",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MERCAPTOPURINE"
},
"drugadditional": "1",
"d... |
{
"abstract": "Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab.\n\n\n\nWe identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 10 9 /L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration.\n\n\n\nTwenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses.\n\n\n\nShort treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing condition.",
"affiliations": "Department of Nephrology, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain.;Department of Nephrology, University Hospital Reina Sofía, Córdoba, Spain.;Department of Nephrology, University Hospital A Coruña, A Coruña, Spain.;Department of Pediatric Nephrology, University Hospital La Fe, Valencia, Spain.;Department of Nephrology, University Hospital Dr Peset, Valencia, Spain.;Department of Nephrology, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain.;Department of Nephrology, University Hospital Puerta de Hierro, Madrid, Spain.;Department of Nephrology, University Hospital Fundación Jiménez Díaz, Madrid, Spain.;Department of Hematology, University Hospital La Fe, Valencia, Spain.;Department of Nephrology, University Hospital Clinic, Barcelona, Spain.;Department of Nephrology, University Hospital Nuestra Señora de La Candelaria, Santa Cruz de Tenerife, Spain.;Department of Nephrology, University Hospital A Coruña, A Coruña, Spain.;Department of Pediatric Nephrology, University Hospital La Fe, Valencia, Spain.;Department of Nephrology, University Hospital Dr Peset, Valencia, Spain.;Department of Nephrology, University Hospital Nuestra Señora de La Candelaria, Santa Cruz de Tenerife, Spain.;Department of Nephrology, University Hospital Clinic, Barcelona, Spain.;Department of Nephrology, University Hospital de Ciudad Real, Ciudad Real, Spain.;Department of Nephrology, University Hospital de Jaén, Jaén, Spain.;Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid and Centro de Investigación Biomédica en Red en Enfermedades Raras, Madrid, Spain.;Department of Nephrology, University Hospital Reina Sofía, Córdoba, Spain.;Department of Nephrology, University Hospital Puerta de Hierro, Madrid, Spain.;Department of Nephrology, University Hospital Fundación Jiménez Díaz, Madrid, Spain.;Department of Nephrology, University Hospital Fundación Jiménez Díaz, Madrid, Spain.;Department of Nephrology, University Hospital Reina Sofía, Córdoba, Spain.;Department of Nephrology, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain.;Department of Nephrology, University Hospital A Coruña, A Coruña, Spain.;Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid and Centro de Investigación Biomédica en Red en Enfermedades Raras, Madrid, Spain.;Department of Nephrology, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain.",
"authors": "Cavero|Teresa|T|;Rabasco|Cristina|C|;López|Antía|A|;Román|Elena|E|;Ávila|Ana|A|;Sevillano|Ángel|Á|;Huerta|Ana|A|;Rojas-Rivera|Jorge|J|;Fuentes|Carolina|C|;Blasco|Miquel|M|;Jarque|Ana|A|;García|Alba|A|;Mendizabal|Santiago|S|;Gavela|Eva|E|;Macía|Manuel|M|;Quintana|Luis F|LF|;María Romera|Ana|A|;Borrego|Josefa|J|;Arjona|Emi|E|;Espinosa|Mario|M|;Portolés|José|J|;Gracia-Iguacel|Carolina|C|;González-Parra|Emilio|E|;Aljama|Pedro|P|;Morales|Enrique|E|;Cao|Mercedes|M|;Rodríguez de Córdoba|Santiago|S|;Praga|Manuel|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D051056:Complement Inactivating Agents; D007166:Immunosuppressive Agents; C481642:eculizumab; D003404:Creatinine",
"country": "England",
"delete": false,
"doi": "10.1093/ndt/gfw453",
"fulltext": "\n==== Front\nNephrol Dial TransplantNephrol. Dial. TransplantndtNephrology Dialysis Transplantation0931-05091460-2385Oxford University Press 2833966010.1093/ndt/gfw453gfw453Original ArticlesCLINICAL SCIENCEAcute Kidney InjuryEculizumab in secondary atypical haemolytic uraemic syndrome Cavero Teresa 1Rabasco Cristina 2López Antía 3Román Elena 4Ávila Ana 5Sevillano Ángel 1Huerta Ana 6Rojas-Rivera Jorge 7Fuentes Carolina 8Blasco Miquel 9Jarque Ana 10García Alba 3Mendizabal Santiago 4Gavela Eva 5Macía Manuel 10Quintana Luis F. 9María Romera Ana 11Borrego Josefa 12Arjona Emi 13Espinosa Mario 2Portolés José 6Gracia-Iguacel Carolina 7González-Parra Emilio 7Aljama Pedro 2Morales Enrique 1Cao Mercedes 3Rodríguez de Córdoba Santiago 13Praga Manuel 1141 Department of Nephrology, Instituto de Investigación Hospital 12 de Octubre (imas12), Madrid, Spain2 Department of Nephrology, University Hospital Reina Sofía, Córdoba, Spain3 Department of Nephrology, University Hospital A Coruña, A Coruña, Spain4 Department of Pediatric Nephrology, University Hospital La Fe, Valencia, Spain5 Department of Nephrology, University Hospital Dr Peset, Valencia, Spain6 Department of Nephrology, University Hospital Puerta de Hierro, Madrid, Spain7 Department of Nephrology, University Hospital Fundación Jiménez Díaz, Madrid, Spain8 Department of Hematology, University Hospital La Fe, Valencia, Spain9 Department of Nephrology, University Hospital Clinic, Barcelona, Spain10 Department of Nephrology, University Hospital Nuestra Señora de La Candelaria, Santa Cruz de Tenerife, Spain11 Department of Nephrology, University Hospital de Ciudad Real, Ciudad Real, Spain12 Department of Nephrology, University Hospital de Jaén, Jaén, Spain13 Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Madrid and Centro de Investigación Biomédica en Red en Enfermedades Raras, Madrid, Spain14 Department of Medicine, Complutense University, Madrid, SpainCorrespondence and offprint requests to: Manuel Praga; E-mail: mpragat@senefro.org3 2017 20 2 2017 20 2 2017 32 3 466 474 17 9 2016 28 11 2016 © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA.2017This 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 non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\n\nBackground. Complement dysregulation occurs in thrombotic microangiopathies (TMAs) other than primary atypical haemolytic uraemic syndrome (aHUS). A few of these patients have been reported previously to be successfully treated with eculizumab.\n\n\nMethods. We identified 29 patients with so-called secondary aHUS who had received eculizumab at 11 Spanish nephrology centres. Primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 109/L) and haemoglobin, disappearance of all the markers of microangiopathic haemolytic anaemia (MAHA), and improvement of renal function, with a ≥25% reduction of serum creatinine from the onset of eculizumab administration.\n\n\nResults. Twenty-nine patients with secondary aHUS (15 drug-induced, 8 associated with systemic diseases, 2 with postpartum, 2 with cancer-related, 1 associated with acute humoral rejection and 1 with intestinal lymphangiectasia) were included in this study. The reason to initiate eculizumab treatment was worsening of renal function and persistence of TMA despite treatment of the TMA cause and plasmapheresis. All patients showed severe MAHA and renal function impairment (14 requiring dialysis) prior to eculizumab treatment and 11 presented severe extrarenal manifestations. A rapid resolution of the TMA was observed in 20 patients (68%), 15 of them showing a ≥50% serum creatinine reduction at the last follow-up. Comprehensive genetic and molecular studies in 22 patients identified complement pathogenic variants in only 2 patients. With these two exceptions, eculizumab was discontinued, after a median of 8 weeks of treatment, without the occurrence of aHUS relapses.\n\n\nConclusion. Short treatment with eculizumab can result in a rapid improvement of patients with secondary aHUS in whom TMA has persisted and renal function worsened despite treatment of the TMA-inducing condition.\n\natypical haemolytic uraemic syndromecomplement activationeculizumabthrombotic microangiopathiesInstituto de Salud Carlos III: REDinRENRD 016/009Fondo de Investigaciones Sanitarias13/02502 and ICI14/00350Ministerio de Economia y CompetitividadSAF2015-66287RAutonomous Region of MadridS2010/BMD-2316Seventh Framework Programme European Union Project EURenOmics305608\n==== Body\nINTRODUCTION\nThrombotic microangiopathies (TMAs) is a group of devastating diseases with very different aetiologies that share common characteristic features at presentation: microangiopathic haemolytic anaemia (MAHA) [typified by anaemia, elevated lactate dehydrogenase (LDH), decreased serum haptoglobin and the presence of schistocytes in peripheral blood smear], thrombocytopenia and organ damage, mainly the kidneys and the nervous system. The pathogenesis of TMA is based on a diffuse and severe vascular endothelial injury inducing characteristic histological lesions in affected organs: platelet thrombus occluding vessels, swelling and detachment of endothelial cells, and thickening of arterioles and capillaries [1–5].\n\nThe most widely accepted classification establishes four categories of TMA: Shiga toxin-producing Escherichia coli haemolytic uraemic syndrome (STEC-HUS), thrombotic thrombocytopenic purpura (TTP), atypical haemolytic uraemic syndrome (aHUS) and secondary TMA [1–5]. This last group includes a long list of clinical entities in which the occurrence of TMA has been repeatedly reported: drug treatments [6, 7], systemic diseases [8–10], pregnancy/postpartum [11, 12], cancer [7, 13], haematopoietic stem cell and organ transplantation [14, 15], systemic infections [16, 17], glomerular diseases [18, 19], malignant hypertension [20] and some very rare conditions such as intestinal lymphangiectasia [21] or methylmalonicaciduria [22]. The pathogenesis of STEC-HUS, TTP and aHUS has been largely clarified in recent years [1–5], but the pathogenic pathways through which endothelial damage is induced in secondary TMA are not completely elucidated. It is generally accepted that in a significant number of patients within the group of secondary TMA there is a complement-related damage to the endothelium.\n\nEculizumab is a humanized monoclonal antibody that binds to complement C5 and prevents the formation of C5b-9, the membrane attack complex of the terminal complement pathway [23]. The efficacy and safety of eculizumab in aHUS has been demonstrated by observational studies and prospective multicentre trials [23, 24].\n\nComplement is a tightly controlled part of our innate immunity, fundamental among other things for the elimination of pathogens and cellular debris generated by normal tissue homeostasis. aHUS caused by pathogenic variants in the genes coding for complement components and regulators, or by autoantibodies against these proteins [1–5, 25, 26], is referred here as primary aHUS, as suggested in the KDIGO Controversies Conference on aHUS and C3G [27]. The genetic and acquired factors associated with primary aHUS cause complement dysregulation resulting in damage to the endothelial cells in the microvasculature of the kidneys and other organs. While complement dysregulation is central to the pathogenesis of primary aHUS, cumulative evidence suggests that complement hyperactivation and dysregulation also occurs in other forms of TMA apart from primary aHUS, including some patients with STEC-HUS and TTP, and may be particularly relevant in an important number of secondary TMA cases (reviewed in [28]). We will refer to these cases of TMA as secondary aHUS. Further supporting the involvement of complement dysregulation in other forms of TMA apart from primary aHUS, individual case reports and small series of patients have been published in recent years showing a beneficial effect of eculizumab in cases of TMA associated with haematopoietic stem cell transplantation [29, 30], antiphospholipid syndrome [31, 32], systemic diseases [33, 34], pregnancy/postpartum [35] and drug treatments [36–38]. However, the small number of reported cases and the well-known tendency to preferentially publish those cases responding positively to new therapies prevents the generalization of such positive results.\n\nTo assess the potential benefit of eculizumab in this, so-called, secondary aHUS, we designed a collaborative retrospective study to identify these cases and revise those who had received eculizumab, independently of the aetiological factor causing the TMA and the final outcome of the eculizumab treatment.\n\nMATERIALS AND METHODS\nStudy population and treatment\nPatients with secondary aHUS treated with eculizumab were identified in 11 Spanish hospitals. Inclusion criteria were: (i) evidence of TMA, defined by the presence of low platelet count (<150 × 109/L), MAHA (low haemoglobin, LDH level above the upper limit of the normal range, decreased serum haptoglobin and presence of schistocytes in peripheral blood examination), negative Coombs test, normal activity of ADAMTS-13, negative Shiga toxin and impaired renal function fulfilling the criteria of acute kidney injury (AKI) [39]; (ii) diagnosis of secondary TMA, based on the presence of a precipitating cause listed among the recognized aetiologies of secondary TMA [5]; (iii) persistence of TMA and worsening of renal function despite the treatment of the TMA-precipitating trigger or disease; and (iv) treatment with eculizumab after previous treatments had failed. Exclusion criteria included previous episodes of TMA and, in renal transplant patients, the diagnosis of aHUS or C3 glomerulopathies in native kidneys. Patients fulfilling these inclusion and exclusion criteria were included in the study, independently of the TMA cause and patient’s outcome after eculizumab treatment.\n\nEculizumab was administered in all the patients intravenously at a dose of 900 mg/week for 4 weeks, and then 1200 mg every 2 weeks. Plasmapheresis was discontinued in all the patients once they started eculizumab. All the patients received anti-meningococcal vaccination, according to label instructions, and received antibiotic prophylaxis. The duration of eculizumab therapy was decided by the treating physician, based on the patient’s response and individual characteristics. Baseline data were considered to be the data coinciding with the detection of TMA. Follow-up was defined as the interval between the onset of eculizumab and the last visit or death.\n\nData collection\nData were compiled from the medical records of the participating centres using a uniform protocol and included age, gender, blood pressure and cause of TMA. Analytical variables included haemoglobin, platelet count, haptoglobin, LDH, presence of schistocytes in peripheral blood smear, Coombs test, ADAMTS-13 determination, Shiga toxin detection, serum creatinine (SCr), estimated glomerular filtration rate (eGFR), which was calculated using the four-variable Modification of Diet in Renal Disease equation, serum albumin and urinalysis. Results of the genetic analysis, performed in 22 patients were registered following a common protocol.\n\nTreatments received before eculizumab, number of plasmapheresis sessions and the time interval between TMA onset and the initiation of eculizumab treatment were recorded, as well as the duration of eculizumab therapy and the cumulative dose administered to every patient. Complications occurring during plasmapheresis and eculizumab treatment, side effects, the occurrence of end-stage renal disease and deaths were also recorded.\n\nRenal biopsies were performed in 18 patients and were reviewed for this study at every participating centre. Histological signs of TMA included glomerular and arteriolar thrombus, thickening of arteriolar walls, swelling and detachment of endothelial cells, widening of subendothelial space in glomerular capillaries and glomerular retraction.\n\nOutcomes\nThe primary outcome was TMA resolution, defined by a normalization of platelet count (>150 × 109/L), normalization of haemoglobin, disappearance of all the markers of MAHA and recovery of renal function, with a ≥25% reduction in SCr in two consecutive measurements for ≥4 weeks from the onset of eculizumab administration. Secondary outcomes were the normalization of platelet count and haemoglobin with the disappearance of MAHA markers, the number of patients requiring dialysis, a ≥25% and a ≥50% reduction from the onset of eculizumab in SCr and the number of patients with an eGFR ≥60 mL/min/1.73 m2 at latest follow-up.\n\nStatistical analysis\nContinuous variables were expressed as median and interquartile (25th and 75th percentile) range. Categorical variables were expressed as frequencies and percentages. Categorical variables were compared with the Fisher’s exact probability test and the medians were compared using the Mann–Whitney U test. To compare more than two categorical variables, the chi-square (χ2) test was used. Statistical analyses were performed with STATA software for Windows, version 12.0 (Statacorp LP, College Station, TX, USA) with two-sided hypothesis testing and a P < 0.05 as the criteria for statistical significance.\n\nOther methods\nComplement genetic and molecular studies are described in detail in Supplementary Methods.\n\nRESULTS\nClinical characteristics\nTwenty-nine patients were included in the study. Their main clinical characteristics at the onset of eculizumab treatment are summarized in Tables 1–4. MAHA and AKI were evident in all patients. Normal ADAMTS-13 activity was assessed in all patients, with a median value of 68% (60–78%). Stool analysis for Shiga toxin detection and Coombs test, performed in 14 and 24 patients, respectively, were negative. Fourteen patients (48%) were undergoing dialysis at the onset of eculizumab due to the severity of renal failure and/or volume expansion. Severe extrarenal manifestations were observed in 11 patients (38%): five patients presented with seizures, three had decreased level of consciousness, four headache and blurred vision, and one had dilated cardiomyopathy.\nTable 1 Characteristics at the initiation of eculizumab treatment\n\n\tPatients (n = 29)\t\nAge (years)a\t51.8 (36.2–59.6)\t\nGender, no. (%), male\t16 (55.2)\t\nCause of aHUS, no. (%)\t\t\nDrug-induced\t15 (51.7)\t\n Tacrolimus\t14 (93.3)\t\n Everolimus\t4 (26.7)\t\n Sirolimus\t1 (6.7)\t\nSystemic disease\t8 (27.6)\t\n SLE\t3 (37.5)\t\n Scleroderma\t2 (25)\t\n Vasculitis (EGPA)\t2 (25)\t\n Antiphospholipid syndrome\t1 (12.5)\t\nOther causes\t6 (20.7)\t\n Pregnancy/postpartum\t2 (33.3)\t\n Cancer related\t2 (33.3)\t\n Acute humoral rejection renal transplant\t1 (16.7)\t\n Primary intestinal lymphangiectasia\t1 (16.7)\t\nTime from aHUS diagnosis to eculizumab treatment (days)\t13 (7–26)\t\nExtrarenal manifestation, no. (%)\t11 (37.9)\t\nDialysis before eculizumab, no. (%)\t14 (48.3)\t\nLaboratory findings\t\t\n SCr (mg/dL)a\t4 (3.4–5.6)\t\n eGFR (mL/min/1.73 m2)a\t13 (7.7–19.0)\t\nLDH (mg/dL)a\t960 (570–1950)\t\n Haptoglobin (mg/dL)a\t5 (0–12)\t\nHaemoglobin (g/dL)a\t8.8 (8.1–9.9)\t\nPlatelet count (×1000/µL)a\t73 (51–113)\t\n Schystocites, no. (%)\t28 (96.6)\t\nFollow-up (months)a\t5.2 (4.2–14.1)\t\neGFR, estimated glomerular filtration rate; EGPA, eosinophilic granulomatosis with polyangiitis; SCr, serum creatinine; aHUS, atypical haemolytic uraemic syndrome; LDH, lactate dehydrogenase.\n\na Median (25th–75th percentile).\n\nTable 2 Drug-induced aHUS\n\nPatient\tAge (years), gender\tOffending drug\tTreatment before eculizumab\tPE no. of sessions\tEculizumab (duration, no. of doses)\tTime from aHUS to eculizumab (days)\tHighest SCr (mg/dL) HD (Yes/No)\tLatest SCr (mg/dL)\tFollow-up (months)\t\n1\t43, female\tTacrolimusa\tDW + PE\t3\t2 weeks, 2\t4\t3.8 No\t1.1\t16.2\t\n2\t63 female\tTacrolimusa\tDW + PE\t10\t18 weeks, 11\t53\t3.1 Yes\t2.0\t5.9\t\n3\t34, male\tTacrolimusa\tPE\t3\t24 weeks, 14\t10\t9.8 Yes\t2.6\t6.7\t\n4\t18, female\tTacrolimusa\tDW + PE\t2\t3 weeks, 3\t14\t2.1 No\t2\t9.6\t\n5\t52, female\tTacrolimusa\tDW\t–\t8 weeks, 6\t26\t2.9 No\t1.2\t8.3\t\n6\t43, male\tTacrolimusa\tDW + PE\t6\t30 weeks, 17\t35\t3.8 Yes\t1.1\t16.2\t\n7\t36, female\tEverolimusa\tDW + PE\t6\t6 weeks, 5\t9\t4.2 No\t2.1\t17.5\t\n8\t60, male\tTacrolimusb\tDW\t–\t4 weeks, 4\t53\t3.4 Yes\t2.5\t3.4\t\n9\t67, male\tTacrolimus, everolimusb\tDW + PE\t6\t6 weeks, 5\t10\t1.8 No\t2.0\t1.7\t\n10\t59, male\tTacrolimus, everolimusb\tDW + PE\t5\t10 weeks, 7\t7\t3.5 No\t2.0\t4.8\t\n11\t65, male\tTacrolimus, everolimusb\tDW + PE\t6\t2 weeks, 2\t9\t3.3 No\t2.4\t4.5\t\n12\t51, male\tTacrolimusc\tDW + PE\t2\t4 weeks, 4\t10\t2.4 No\t0.6\t2.9\t\n13\t54, female\tTacrolimus, sirolimusc\tDW + PE\t7\t3 weeks, 3\t7\t4.2 Yes\t1.2\t1.5\t\n14\t55, male\tTacrolimusd\tDW + PE\t12\t18 weeks, 11\t27\t3.0 No\t2.4\t14.1\t\n15\t42, female\tTacrolimuse\tDW + PE\t3\t3 weeks, 3\t13\t1.4 No\t0.5\t17.0\t\nDW, drug withdrawn; HD, haemodialysis (Yes/No); PE, plasma exchange; SCr, serum creatinine; aHUS, atypical haemolytic uraemic syndrome.\n\na Kidney transplant.\n\nb Lung transplant.\n\nc Haematopoietic stem cell transplantation.\n\nd Liver transplant.\n\ne Heart transplant.\n\nTable 3 aHUS associated with systemic disease\n\nPatient\tAge (years), gender\tSystemic disease\tTreatment before eculizumab\tPE no. of sessions\tEculizumab (duration, no. of doses)\tTime from aHUS to eculizumab (days)\tHighest SCr (mg/dL) HD (Yes/No)\tLatest SCr (mg/dL)\tFollow-up (months)\t\n16\t51, female\tSLEa\tCS + Cyc + Rtx + PE\t10\t4 weeks, 4\t31\t4.2 Yes\tDialysis\t0.9\t\n17\t16, female\tSLEa\tCS + MMF\t–\t10 weeks, 7\t1\t7.1 Yes\tDialysis\t4.2\t\n18\t52, female\tSLE\tCS + Cyc + PE\t27\t2 weeks, 2\t38\t6.4 Yes\t4.2\t4.0\t\n19\t63, male\tScleroderma\tCS + Cyc + PE\t10\t6 weeks, 5\t55\t4.9 No\tDialysis\t12.9\t\n20\t56, male\tScleroderma\tCS + Mtx + PE\t10\t8 weeks, 6\t25\t3.7 No\t3.4\t4.3\t\n21\t52, male\tEGPA\tCS + Cyc\t–\t16 weeks, 10\t5\t3.5 No\t2.3\t4.3\t\n22\t49, male\tEGPA\tCS + Cyc + PE\t2\t130 weeks, ongoing\t15\t6.5 Yes\tDialysis\t29.5\t\n23\t38, male\tPrimary APS\t–\t–\t14 weeks, 9\t1\t9.5 Yes\t3.4\t4.4\t\naaHUS, atypical haemolytic uraemic syndrome; APS, Antiphospholip syndrome; CS, corticosteroids; Cyc, cyclophosphamide; EGPA, eosinophilic granulomatosis with polyangiitis; HD, Hemodialysis (Yes/No); Mtx, methotrexate; MMF, mycophenolate mofetil; ND, not done; PE, plasma exchange; Rtx, rituximab; SCr, serum creatinine; SLE, systemic lupus erythematosus.\n\nTable 4 Other causes of secondary aHUS\n\nPatient\tAge (years), gender\tTMA cause\tTreatment before eculizumab\tPE no. of sessions\tEculizumab (duration, no. of doses)\tTime from aHUS to eculizumab (days)\tHighest SCr (mg/dL) HD (Yes/No)\tLatest SCr (mg/dL)\tFollow-up (months)\t\n24\t27, female\tPostpartum\tPE\t15\t46 weeks, 25\t24\t4.1 No\t1.5\t13\t\n25\t35, female\tPostpartum\tPE\t8\t16 weeks, 10\t17\t5.9 Yes\t1.2\t4.2\t\n26\t61, male\tCancer-related aHUSa\tBilateral orchiectomy + PE\t2\t10 weeks, 7\t3\t11.1 Yes\t0.9\t5.2\t\n27\t73, male\tCancer-related aHUSa\tAntiandrogentherapy + PE\t4\t81 weeks, 43\t4\t8.7 Yes\t1.0\t22.6\t\n28\t35, male\tAcute humoral rejection\tCS + IVIg + Rtx + PE\t5\t3 weeks, 3\t7\t4.9 No\t1.6\t10.7\t\n29\t13, female\tPrimary intestinal lymphangiectasia\tPE\t4\t64 weeks, ongoing\t21\t5.4 Yes\t0.3\t16.4\t\nCS, corticosteroids; HD, haemodialysis; IVIg, intravenous immunoglobulin; PE, plasma exchange; Rtx, rituximab; SCr, serum creatinine; aHUS, atypical haemolytic uraemic syndrome.\n\na Cancer-related aHUS:metastatic prostate cancer.\n\n\n\nCauses of aHUS and treatment before eculizumab\nAs shown in Table 1, aHUS was induced by drugs in 15 patients, by systemic diseases in 8, by postpartum in 2, by cancer in 2, by acute humoral rejection in 1 and by primary intestinal lymphangiectasia in 1. All drug-induced aHUS corresponded to transplanted patients who had received a kidney graft (seven patients), lung (four patients), haematopoietic stem cells (two patients), liver (one patient) or heart (one patient) (Table 2). In seven patients with a kidney graft (#1 to #7), median interval between transplantation and aHUS detection was 14 days (7–20). Induction treatment consisted of corticosteroids, tacrolimus and mycophenolate mofetil in all of them. Four patients (#1, #2, #3 and #6) also received antithymocyte globulin.\n\nThe offending drug was tacrolimus (combined with everolimus in patients #9, #10 and #11 and with sirolimus in patient #13, Table 2) in all but one patient (Table 2), in whom aHUS was attributed to everolimus (patient #7). Offending drugs were discontinued in all the patients but one (patient #3), without TMA improvement (Table 2). In this patient (hyperimmunized recipient of a second transplant), tacrolimus was maintained due to the high risk of rejection.\n\nEculizumab was initiated after only two to three sessions of plasmapheresis in patients #1, #3, #4 and #12 with drug-induced aHUS (Table 2) due to the progressive deterioration in these cases of renal function and the persistence of severe extrarenal manifestations (seizures, blurred vision, decreased level of consciousness), as well as the appearance of plasmapheresis-related complications, transfusion-related reaction and bleeding in patients #4 and #12.\n\nSystemic disease-related aHUS occurred in eight patients: systemic lupus erythematosus (SLE) in three, systemic scleroderma in two, eosinophilic granulomatosis with polyangiitis (EGPA) in two and primary antiphospholipid syndrome in one (Table 3). All the patients with systemic diseases developed aHUS in their native kidneys, with the exception of the patient with primary antiphospholipid syndrome, who presented aHUS 7 days after renal transplantation. In four out of eight patients (50%), aHUS was the first manifestation of the disease (patients #16, #17, #19 and #20). Patients with systemic diseases received different types of immunosuppressive treatments before eculizumab (Table 3).\n\nSix patients presented a miscellany of secondary TMA causes: aHUS appearing after delivery in two patients, cancer-related aHUS in two (metastatic prostate cancer in both), aHUS associated with acute humoral rejection in a kidney transplant patient and with primary intestinal lymphangiectasia in another patient (Table 4). Antiandrogenic therapy, immunosuppressive anti-rejection treatments and antibiotics have been prescribed for prostate cancer, humoral rejection and intestinal lymphangiectasia, respectively.\n\nPlasmapheresis was performed before the onset of eculizumab in 24 patients (83%), 13 with drug-induced aHUS, 5 with systemic diseases, 2 with postpartum aHUS, 2 with cancer-related aHUS, 1 with acute humoral rejection and 1 with primary intestinal lymphangiectasia (Tables 2–4). Complications related to the performance of plasmapheresis were transfusion-related reactions (five), deep vein thrombosis (two), bleeding (one) and hypotension (one).\n\nRenal biopsies\nRenal biopsies were performed in 18 patients (62%). Characteristic lesions of TMA were found in all of them. A renal biopsy was performed in six out of seven kidney transplant patients with drug-induced aHUS (patients #2, #3, #4, #5, #6 and #7). No lesions of antibody-mediated rejection (AMR) were found and C4d staining was negative in all of them. C3 glomerulopathy was diagnosed in patient #11, on the basis of strong, isolated deposits of C3 in immunofluorescence studies. A membranoproliferative glomerulonephritis likely associated with hepatitis C virus infection was found in patient #14 (Table 2). Among patients with aHUS associated with systemic diseases, a class IV-S (C) lupus nephritis with advanced glomerular and interstitial sclerosing lesions was found in two patients with SLE (patients #16 and #17, Table 3) and a class IV-G (A) lupus nephritis in the remaining SLE patient (patient #18, Table 3). Patients with EGPA showed histological signs of vasculitis (fibrinoid necrosis in glomerular capillaries and arterioles with eosinophilic granulomas and interstitial infiltration by eosinophils) in addition to TMA. Renal biopsy in patient #24, with postpartum aHUS, showed characteristic lesions of TMA with no tubular necrosis. Renal biopsy in the patient with acute humoral rejection-induced aHUS showed histological signs of acute humoral rejection (tubulitis, arteritis, C4d-positive staining) in addition to TMA.\n\nEculizumab treatment\nEculizumab was started 13 (7–26) days after the onset of aHUS. In two patients (#22 and #29, Tables 2–4), investigators decided to maintain eculizumab after TMA resolution due to the identification of complement pathogenic variants in CFH and CFHR1 (see ‘Complement genetic studies’ section). In 27 remaining patients, eculizumab was discontinued after 8 (3–18) weeks. The average number of eculizumab doses in these 27 patients was 6 (3–11).\n\nOutcomes\nA rapid improvement in haematological and renal abnormalities after the onset of eculizumab was observed in 20 patients (69%) (Table 5 and Figure 1). The rate of response varied according to the aetiology of aHUS: 12/15 (80%) among drug-induced aHUS, 6/6 (100%) in postpartum, cancer-related, acute humoral rejection and intestinal lymphangiectasia, and 2/8 (25%) in aHUS associated with systemic diseases (Table 6). Among the latter, only one patient with EGPA and the patient with primary antiphospholipid syndrome showed TMA resolution after eculizumab treatment (Tables 2–4). The interval between eculizumab initiation and TMA resolution averaged 12 (7–17) days. All extrarenal manifestations showed a rapid and dramatic improvement.\nFIGURE 1 Changes in (A) serum creatinine, (B) haemoglobin and (C) platelet count.\n\nTable 5 Changes from baseline in haematological parameters and renal function\n\n\tBaseline\tEculizumab onset\t4 weeks\t12 weeks\tLast follow-up\t\nPlatelet count (×1000/µL)a\t65 (45–109)\t73 (51–113)\t166 (142–219)\t202 (157–254)\t182 (163–237)\t\nHaemoglobin (g/dL)a\t8.7 (7.8–10.4)\t8.8 (8.1–9.9)\t10.5 (10–11.1)\t11 (10.2–12.3)\t11.8 (10.2–12.4)\t\nHaptoglobin (mg/dL)a\t5 (0–5)\t5 (0–12)\t69 (32–115)\t118 (88–141)\t116 (86–135)\t\nSerum creatinine (mg/dL)a\t3.5 (2.7–5.2)\t4.0 (3.4–5.6)\t2.3 (1.1–3.9)\t2.1 (1.1–3.5)\t2.0 (1.1–2.6)\t\neGFR (mL/min/1.73 m2)a\t18 (8.9–26)\t13 (7.7–19)\t27 (17–54)\t32 (26–71)\t34 (28–63)\t\neGFR, glomerular filtrate rate.\n\na Median (25th–75th percentile).\n\nTable 6 Outcomes\n\n\tBaseline\tEculizumab onset\t4 weeks\t12 weeks\tLast follow-up\t\nTMA response, no. (%)\t\t\t\t\t\t\nTotal\t0 (0)\t0 (0)\t11 (37.9)\t19 (65.5)\t20 (68.9)\t\nRelated to drugs\t0 (0)\t0 (0)\t6 (40)\t12 (80)\t12 (80)\t\nRelated to systemic disease\t0 (0)\t0 (0)\t1 (12.5)\t1 (12.5)\t2 (25)\t\nRelated to other causes\t0 (0)\t0 (0)\t4 (66.7)\t6 (100)\t6 (100)\t\nPatients undergoing dialysis, no. (%)\t4 (13.8)\t14 (48.3)\t4 (13.8)\t4 (13.8)\t4 (13.8)\t\nPatients with ≥50% decrease from baseline SCr, no. (%)\t0 (0)\t0 (0)\t10 (34.5)\t14 (48.3)\t15 (51.7)\t\nPatients with eGFR ≥60 mL/min/1.73 m2\t0 (0)\t0 (0)\t6 (20.7)\t10 (34.5)\t10 (34.5)\t\nTMA, thrombotic microangiopathy; eGFR, glomerular filtrate rate; SCr, serum creatinine.\n\n\n\nResolution of haematological abnormalities with no improvement in renal function was observed in six patients (patients #4, #9, #17, #18, #20 and #22). In three cases (patients #8, #16 and #19), both haematological abnormalities and renal function impairment persisted despite eculizumab treatment (Tables 2–4).\n\nAt the last follow-up, the number of patients requiring dialysis had decreased to 4 (13%), a ≥25% decrease in SCr was observed in 20 patients (69%), a ≥50% decrease in 15 (52%) and 10 patients (35%) had achieved an eGFR ≥60 mL/min/1.73 m2.\n\nNo differences in baseline characteristics were observed between responder and non-responder patients, but there was a significantly higher number of patients with aHUS associated with systemic diseases among non-responders. Interestingly, the duration of eculizumab treatment was significantly longer in responder patients and there was a non-significant trend towards a longer interval between aHUS diagnosis and onset of eculizumab in non-responder patients (Table 7).\nTable 7 Differences between responder and non-responder patients\n\n\tResponders (n = 20)\tNon-responders (n = 9)\tP\t\nAge (years)a\t47.4 (35.9–57.5)\t51.9 (49.9–60.1)\t0.57\t\nGender, no. (%), male\t11 (55.0)\t5 (55.6)\t1\t\nBaseline SCr (mg/dL)a\t3.4 (2.8–4.5)\t3.4 (1.8–6.2)\t0.75\t\nSCr at the onset of Eculizumab (mg/dL)a,b\t3.8 (3.2–5.4)\t4.5 (3.4–6.7)\t0.82\t\nDialysis, no. (%)b\t9 (45)\t5 (55.6)\t0.70\t\nHaemoglobin (g/dL)a,b\t9.0 (8.1–10)\t8.3 (7.7–104)\t0.65\t\nPlatelet count (×1000/µL)a,b\t78 (51–138)\t61 (29–80)\t0.25\t\nCause of aHUS, no. (%)\t\t\t0.004\t\nSystemic disease\t2 (25)\t6 (75)\t\t\nDrug induced\t12 (80)\t3 (20)\t\t\nOther causes\t6 (100)\t0 (0)\t\t\nPlasma exchange, no. (%)\t17 (85)\t7 (77.8)\t0.50\t\nTime between aHUS and eculizumab (days)a\t9.5 (6–22.5)\t25 (14–38)\t0.059\t\nEculizumab duration (weeks)a\t11.6 (4–24.7)\t4.4 (3–8.4)\t0.003\t\nSCr, serum creatinine; aHUS, atypical haemolytic uraemic syndrome.\n\na Median (25th–75th percentile).\n\nb At the onset of eculizumab.\n\n\n\nComplement genetic studies\nComprehensive complement studies were performed in 22/29 patients (Supplementary Table). These include western blot analyses and quantification of components, search for anti-Factor H (FH) autoantibodies and genetic screenings to identify pathogenic variants and copy number variations. Only two patients carry pathogenic variants. Patient #22, affected by EGPA, carries two pathogenic changes in CFHR1 (L290S and A296V) resulting in a mutant FHR-1 protein that competes with FH regulation on endothelial surfaces, and patient #29, affected by intestinal lymphangiectasia, who presents a pathogenic variant in CFH (C597*) that results in a partial FH deficiency. Patients #11 and #12 carry anti-FH autoantibodies, but presented normal C3 levels and do not have the CFHR3–CFHR1 deletion, suggesting that these anti-FH autoantibodies may not be functionally relevant in the context of aHUS. Finally, some patients carry genetic variants in complement genes with unknown functional significance that were considered non-pathogenic.\n\nSafety\nEculizumab was well tolerated. Serious infections occurred in two transplanted patients during eculizumab administration (prostatic abscess in one, herpes zoster infection in the other) but they were likely related to immunosuppressive treatment and resolved with appropriate treatments.\n\nDISCUSSION\nOur study shows that eculizumab is an effective treatment for severe cases of secondary aHUS. In 20/29 eculizumab-treated patients (69%), there was a normalization of haemoglobin and platelet count together with a renal function improvement of at least a ≥25% reduction in SCr from the onset of eculizumab treatment. Renal function recovery was remarkable, allowing the discontinuation of dialysis in 10/14 patients. A decrease ≥50% in SCr was observed in 15 patients, and 10 patients (35%) showed an eGFR ≥60 mL/min/1.73 m2 at the last follow-up. Eculizumab has been reported to be beneficial in individual cases or small series of secondary TMA [29–38], haematopoietic stem cell transplantation-induced aHUS being the entity in which the effects of eculizumab treatment have been more extensively documented [29, 30]. Our study is the first to confirm these positive effects in a relatively large series of secondary aHUS patients.\n\nTMA responses after eculizumab treatment were particularly remarkable in patients with drug-induced aHUS (80% of TMA resolution) and in a miscellaneous group of secondary aHUS that included postpartum, cancer, acute humoral rejection and intestinal lymphangiectasia (100%). Although many patients with drug-induced aHUS show a rapid resolution after withdrawal of the offending drug, TMA can persist in others, requiring additional therapeutic measures because of life-threatening organ involvement or progressive renal impairment [7, 40]. Plasmapheresis, immunosuppression and, in a few patients, eculizumab [36–38] have been tried in these resistant cases. Our results confirm that eculizumab is very effective to rapidly resolve TMA and improve renal function in this type of resistant drug-induced secondary aHUS.\n\nTacrolimus was the most common offending drug among our patients with drug-induced aHUS. Although tacrolimus discontinuation likely collaborated in TMA resolution, the rapid and dramatic improvement associated with eculizumab administration suggests a direct effect of complement blockade in TMA response in these patients. On the other hand, AMR in renal transplant patients can present features of TMA in renal biopsies and some reports have suggested a beneficial effect of eculizumab in AMR [41]. However, no lesions of AMR were observed in the renal biopsies of our kidney transplant patients with drug-induced aHUS and C4d staining was negative in all of them.\n\nOn the contrary, our results show limited benefit of eculizumab administration in patients with systemic diseases (25% of TMA responses). Only one patient with primary antiphospholipid syndrome and another with ANCA vasculitis responded to eculizumab, whereas patients with SLE (three), scleroderma (two) and ANCA vasculitis (one) did not. These data do not agree with the eculizumab benefits reported in anecdotic cases of scleroderma-like syndrome and lupus nephritis complicated with aHUS [33, 34], but it should be stressed that our patients with SLE, scleroderma and ANCA vasculitis presented severe lesions in their renal biopsies at the initiation of eculizumab treatment.\n\nPatients included in the study were treated according with the condition triggering TMA (discontinuation of the offending drug in drug-induced cases, immunosuppressive therapy in systemic diseases and humoral rejection, antitumoral treatment in cancer-related cases), and plasmapheresis was performed in 24 patients (83%) before initiation of eculizumab treatment. Despite these measures, renal function continued to deteriorate in all the patients and, at the time of eculizumab initiation, 14 patients (48%) were requiring dialysis. Persistent severe anaemia and thrombocytopenia was present in all patients (Table 1). Eculizumab rapidly resulted in the responder patients (20/29) in an improvement of renal function and the disappearance of all haematological abnormalities (Table 5 and Figure 1). Among the non-responders, the haematological abnormalities disappeared with eculizumab in 6/9 patients, although none of them showed a substantial renal function recovery. Extrarenal manifestations showed a rapid resolution after eculizumab initiation. Particularly dramatic was the rapid disappearance of life-threatening neurological complications (seizures, coma) in patients #12, #13, #15, #19, #20 and #22.\n\nComplement is activated in several types of TMA other than primary aHUS [28]. In STEC-HUS, Shiga toxin upregulates the membrane adhesion molecule P-selectin, which binds C3b and activates the complement alternative pathway (AP) [42, 43]. Low C3 and increased sC5b-9 have been reported in most severe cases of STEC-HUS [44, 45]. In TTP, levels of complement activation markers correlated with disease activity and deposition of C3 and C5b-9 have been demonstrated in endothelial cells [46, 47]. Interestingly, some patients with STEC-HUS and TTP not responding to plasmapheresis have been successfully treated with eculizumab [48, 49]. Regarding drug-induced aHUS, it has been shown that endothelial cells exposed to calcineurin inhibitors release microparticles that activate the AP [50]. Inflammatory conditions, platelet-derived microparticles and blood coagulation proteins induce complement activation, which in turn increments endothelial damage and microvascular thrombosis [51, 52].\n\nProspective studies with eculizumab in primary aHUS have shown a significant inverse correlation between the delay in the onset of the treatment and the degree of renal function recovery [24]. As shown in Table 7, an almost significant trend towards a longer delay in eculizumab therapy and a significantly shorter duration of treatment were observed among our non-responder patients. Further studies are needed to confirm whether an earlier treatment with eculizumab or a longer administration are associated with more positive responses and a greater recovery of renal function in patients with these secondary forms of aHUS.\n\nComprehensive complement molecular and genetic studies were performed in 22 patients, but pathogenic variants were found only in two patients (Supplementary Table). With the exception of these two patients (#22 and #29), eculizumab was discontinued after a median of 8 weeks, with no patients showing TMA relapses.\n\nTolerance to eculizumab was excellent with no important side effects recorded. Infectious complications coincidental with eculizumab administration in transplanted patients were attributable to immunosuppressive therapy.\n\nOur study has the limitations inherent to its retrospective design, with a possible bias in the selection of patients and absence of a control group not treated with eculizumab. On the other hand, it has major strengths: the number of recruited patients is large and the work-up tests to exclude other types of TMA was complete, with ADAMTS-13 activity measured in all the patients and the presence of Shiga toxin ruled out in all the cases with gastrointestinal symptoms. Furthermore, renal biopsies and comprehensive genetic and molecular studies were performed in most patients. All the patients received the specific treatment for their aHUS aetiology and plasmapheresis was performed in most of them before eculizumab treatment.\n\nOur findings are consistent with the observation that both primary aHUS, associated with genetic and acquired complement abnormalities, and secondary aHUS are characterized by complement dysregulation. In addition, they suggest that while complement dysregulation is constitutive in the first condition, it is likely temporary in the second and, therefore, both conditions should be considered differently regarding long-term treatment. Based on the results of this study, we suggest that eculizumab could be the first-line treatment in aggressive cases of secondary aHUS who do not respond to other therapies and that a rapid administration of eculizumab would enable an efficient recovery of renal function and complement normalization. Prospective studies are needed to corroborate these findings and to define the ideal duration of eculizumab treatment in secondary aHUS.\n\nSUPPLEMENTARY DATA\n\nSupplementary data are available online at http://ndt.oxfordjournals.org.\n\nSupplementary Material\nSupplementary Data Click here for additional data file.\n\n ACKNOWLEDGEMENTS\nWork in this report was funded by the Instituto de Salud Carlos III: REDinREN (RD 016/009 Feder Funds), the Fondo de Investigaciones Sanitarias (13/02502 and ICI14/00350), the Ministerio de Economia y Competitividad (SAF2015-66287R) and the Autonomous Region of Madrid (S2010/BMD-2316; Grupo de Investigación Complemento-CM). SRdeC is funded by the Seventh Framework Programme European Union Project EURenOmics (305608).\n\nCONFLICT OF INTEREST STATEMENT\nConception, design, data collection and analysis, as well as writing of the study were performed by investigators with no support from pharmaceutical companies. C.R., E.R., A.A., M.B., M.M., M.E., P.A., E.M., M.C., S.R.d.C. and M.P. have received honoraria from Alexion Pharmaceuticals for giving lectures and participating in advisory boards. None of these activities has had any influence on the results or interpretations in this article. Other authors declare no conflicts of interest. The results presented in this article have not been published previously in whole or part, excepting an abstract that has been accepted for oral communication in the Renal Week, American Society of Nephrology 2016.\n==== Refs\nREFERENCES\n1 \nGeorge JN , Nester CM. \nSyndromes of thrombotic microangiopathy . N Engl J Med 2014 ; 371 : 654 –666 25119611 \n2 \nBarbour T , Johnson S , Cohney S \n\nThrombotic microangiopathy and associated renal disorders . Nephrol Dial Transplant 2012 ; 27 : 2673 –2685 22802583 \n3 \nNoris M , Remuzzi G. \nAtypical hemolytic-uremic syndrome . N Engl J Med 2009 ; 361 : 1676 –1687 19846853 \n4 \nBesbas N , Karpman D , Landau D \n\nA classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders . Kidney Int 2006 ; 70 : 423 –431 16775594 \n5 \nCampistol JM , Arias M , Ariceta G \n\nAn update for atypical haemolytic uraemic syndrome: diagnosis and treatment. A consensus document . Nefrologia 2015 ; 35 : 421 –447 26456110 \n6 \nAl-Nouri ZL , Reese JA , Terrell DR \n\nDrug induced thrombotic microangiopathy: a systemic review of published reports . Blood 2015 ; 125 : 616 –618 25414441 \n7 \nIzzedine H , Perazella MA. \nThrombotic microangiopathy, cancer, and cancer drugs . Am J Kidney Dis 2015 ; 66 : 857 –866 25943718 \n8 \nTektonidou MG , Sotsiou F , Nakopoulou L \n\nAntiphospholipid syndrome nephropathy in patients with systemic lupus erythematosus and antiphospholipid antibodies: prevalence, clinical associations, and long-term outcome . Arth Rheum 2004 ; 50 : 2569 –2579 15334471 \n9 \nManadan AM , Harris C , Block JA. \nThrombotic thrombocytopenic purpura in the setting of systemic sclerosis . Semin Arthritis Rheum 2005 ; 34 : 683 –688 15692962 \n10 \nGharbi C , Bourry E , Rouvier P \n\nRapidly progressive lupus nephritis and concomitant thrombotic microangiopathy . Clin Exp Nephrol 2010 ; 14 : 487 –491 20535626 \n11 \nFakhouri F , Vercel C , Frémeaux-Bacchi V. \nObstetric nephrology: AKI and thrombotic microangiopathies in pregnancy . Clin J Am Soc Nephrol 2012 ; 7 : 2100 –2106 22879435 \n12 \nScully M , Thomas M , Underwood M \n\nThrombotic thrombocytopenic purpura and pregnancy: presentation, management, and subsequent pregnancy outcomes . Blood 2014 ; 124 : 211 –219 24859360 \n13 \nLechner K , Obermeier HL. \nCancer-related microangiopathic haemolytic anemia: clinical and laboratory features in 168 reported cases . Medicine 2012 ; 91 : 195 –205 22732949 \n14 \nJodele S , Davies SM , Lane A \n\nDiagnostic and risk criteria for HSCT-associated thrombotic microangiopathy: a study in children and young adults . Blood 2014 ; 124 : 645 –653 24876561 \n15 \nLaskin BL , Goebel J , Davies SM \n\nSmall vessels, big trouble in the kidneys and beyond: hematopoietic stem cell transplantation-associated thrombotic microangiopathy . Blood 2011 ; 118 : 1452 –1462 21596850 \n16 \nAllen U , Kicht C. \nPandemic H1N1 influenza A infection and (atypical) HUS – more than just another trigger . Pediatr Nephrol 2011 ; 26 : 3 –5 21057815 \n17 \nLopes da Silva R. \nViral-associated thrombotic microangiopathies . Hematol Oncol Stem Cell Ther 2011 ; 4 : 51 –59 21727765 \n18 \nManenti L , Gnappi E , Vaglio A \n\nAtypical haemolytic uraemic syndrome with underlying glomerulopathies. A case series and a review of the literature . Nephrol Dial Transplant 2013 ; 28 : 2246 –2259 23787552 \n19 \nSethi S , Fervenza FC. \nPathology of renal diseases associated with dysfunction of the alternative pathway of complement: C3 glomerulopathy and atypical hemolytic uremic syndrome (aHUS) . Semin Thromb Hemost 2014 ; 40 : 416 –421 24799306 \n20 \nMathew RO , Nayer A , Asif A. \nThe endothelium as the common denominator in malignant hypertension and thrombotic microangiopathy . J Am Soc Hypertens 2016 ; 10 : 352 –359 26778772 \n21 \nKalman S , Bakkaloğlu S , Dalgiç B \n\nRecurrent hemolytic uremic syndrome associated with intestinal lymphangiectasia . J Nephrol 2007 ; 20 : 246 –249 17514630 \n22 \nCornec-Le Gall E , Delmas Y , De Parscau L \n\nAdult-onset eculizumab-resistant hemolytic uremic syndrome associated with cobalamin C deficiency . Am J Kidney Dis 2014 ; 63 : 119 –123 24210589 \n23 \nZuber J , Fakhouri F , Roumenina LT \n\nUse of eculizumab for atypical haemolytic uraemic syndrome and C3 glomerulopathies . Nat Rev Nephrol 2012 ; 8 : 643 –657 23026949 \n24 \nLegendre CM , Licht C , Muus P \n\nTerminal complement inhibitor eculizumab in atypical hemolytic-uremic syndrome . N Engl J Med 2013 ; 368 : 2169 –2181 23738544 \n25 \nRodríguez de Córdoba S , Subías M , Pinto S \n\nGenetics of atypical hemolytic uremic syndrome (aHUS) . Semin Thromb Hemost 2014 ; 40 : 422 –430 24799305 \n26 \nNester CM , Barbour T , de Cordoba SR \n\nAtypical aHUS: state of the art . Mol Immunol 2015 ; 67 : 31 –42 25843230 \n27 \nGoodship THJ , Cook TH , Fakhouri F \n\nAtypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference . Kidney Int 2016 (in press); doi: 10.1016/j.kint.2016.10.005\n28 \nNoris M , Mescia F , Remuzzi G. \nSTEC-HUS, atypical HUS and TTP are all diseases of complement activation . Nat Rev Nephrol 2012 ; 8 : 622 –633 22986360 \n29 \nJodele S , Fukuda T , Vinks A \n\nEculizumab therapy in children with severe hematopoietic stem cell transplantation-associated thrombotic microangiopathy . Biol Blood Marrow Transplant 2014 ; 20 : 518 –525 24370861 \n30 \nde Fontbrune FS , Galambrun C , Sirvent A \n\nUse of eculizumab in patients with allogeneic stem cell transplant-associated thrombotic microangiopathy: a study from the SFGM-TC . Transplantation 2015 ; 99 : 1953 –1959 25651309 \n31 \nCanaud G , Kamar N , Anglicheau D \n\nEculizumab improves posttransplant thrombotic microangiopathy due to antiphospholipid syndrome recurrence but fails to prevent chronic vascular changes . Am J Transplant 2013 ; 113 : 2179 –2185 \n32 \nStrakhan M , Hurtado-Sbordoni M , Galeas N \n\n36-year-old female with catastrophic antiphospholipid syndrome treated with eculizumab: a case report and review of literature . Case Rep Hematol 2014 : 704371 ; doi: 10.1155/2014/70437125389502 \n33 \nThomas CP , Nester CM , Phan AC \n\nEculizumab for rescue of thrombotic microangiopathy in PM-Scl antibody-positive autoimmune overlap syndrome . Clin Kidney J 2015 ; 8 : 698 –701 26613027 \n34 \nEl-Husseini A , Hannan S , Awad A \n\nThrombotic microangiopathy in systemic lupus erythematosus: efficacy of eculizumab . Am J Kidney Dis 2015 ; 65 : 127 –130 25446020 \n35 \nBurwick RM , Feingerg BB. \nEculizumab or the treatment of preeclampsia/HELLP syndrome . Placenta 2013 ; 34 : 201 –203 23228435 \n36 \nStarck M , Wendtner CM. \nUse of eculizumab in refractory gemcitabine-induced thrombotic microangiopathy . Br J Haematol 2014 ; 164 : 888 –902 24266453 \n37 \nSafa K , Logan MS , Batal I \n\nEculizumab for drug-induced de novo posttransplantation thrombotic microangiopathy: a case report . Clin Nephrol 2015 ; 83 : 125 –129 24495904 \n38 \nFaguer S , Huart A , Frémeaux-Bacchi V \n\nEculizumab and drug-induced haemolytic uremic syndrome . Clin Kidney J 2013 ; 6 : 484 –485 26120441 \n39 \nKidney Disease: Improving Global Outcomes (KDIGO) . \nAKI definition . Kidney Int Suppl 2012 ; 2 : 19 –36 \n40 \nZakarija A , Bennett C. \nDrug-induced thrombotic microangiopathy . Semin Thromb Hemost 2005 ; 31 : 681 –690 16388419 \n41 \nFrémeaux-Bacchi V , Legendre CM. \nThe emerging role of complement inhibitors in transplantation . Kidney Int 2015 ; 88 : 967 –973 26376132 \n42 \nMorigi M , Galbusera M , Gastoldi S \n\nAlternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis . J Immunol 2011 ; 187 : 172 –180 21642543 \n43 \nOrth D , Khan AB , Naim A \n\nShiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome . J Immunol 2009 ; 182 : 6394 –6400 19414792 \n44 \nRobson WL , Leung AK , Fick GH \n\nHypocomplementemia and leukocytosis in diarrhea-associated hemolytic uremic syndrome . Nephron 1992 ; 62 : 296 –299 1436342 \n45 \nThurman JM , Marians R , Emlen W \n\nAlternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome . Clin J Am Soc Nephrol 2009 ; 4 : 1920 –1924 19820137 \n46 \nRéti M , Farkas P , Csuka D \n\nComplement activation in thrombotic thrombocytopenic purpura . J Thromb Haemost 2012 ; 10 : 791 –798 22372946 \n47 \nRuiz-Torres MP , Casiraghi F , Galbusera M \n\nComplement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies . Thromb Haemost 2005 ; 93 : 443 –452 15735793 \n48 \nLapeyraque AL , Malina M , Fremeaux-Bacchi V \n\nEculizumab in severe Shiga-toxin-associated HUS . N Engl J Med 2011 ; 364 : 2561 –2563 21612462 \n49 \nPecoraro C , Ferretti AV , Rurali E \n\nTreatment of congenital thrombotic thrombocytopenic purpura with eculizumab . Am J Kidney Dis 2015 ; 66 : 1067 –1070 26409664 \n50 \nRenner B , Klawitter J , Goldberg R \n\nCyclosporine induces endothelial cell release of complement-activating microparticles . J Am Soc Nephrol 2013 ; 24 : 1849 –1862 24092930 \n51 \nPeerschke EI , Yin W , Ghebrehiwet B. \nComplement activation on platelets: implications for vascular inflammation and thrombosis . Mol Immunol 2010 ; 47 : 2170 –2175 20621693 \n52 \nAmara U , Flierl MA , Rittirsch D \n\nMolecular intercommunication between the complement and coagulation systems . J Immunol 2010 ; 185 : 5628 –5636 20870944\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0931-0509",
"issue": "32(3)",
"journal": "Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association",
"keywords": "atypical haemolytic uraemic syndrome; complement activation; eculizumab; thrombotic microangiopathies",
"medline_ta": "Nephrol Dial Transplant",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D065766:Atypical Hemolytic Uremic Syndrome; D015267:Churg-Strauss Syndrome; D051056:Complement Inactivating Agents; D003404:Creatinine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007677:Kidney Function Tests; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D010956:Plasmapheresis; D010976:Platelet Count; D012008:Recurrence; D051437:Renal Insufficiency; D012595:Scleroderma, Systemic; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "8706402",
"other_id": null,
"pages": "466-474",
"pmc": null,
"pmid": "28339660",
"pubdate": "2017-03-01",
"publication_types": "D016428:Journal Article",
"references": "20535626;21612462;26376132;22986360;24859360;16775594;26456110;19846853;24370861;1436342;23787552;20621693;23738544;22732949;21057815;22879435;21727765;24799306;24495904;21596850;22802583;25446020;24799305;23026949;24092930;21642543;20870944;15735793;23228435;26613027;15334471;19414792;24876561;25651309;19820137;24210589;26409664;25414441;17514630;16388419;24666021;25119611;25843230;15692962;22372946;26120441;26778772;25389502;27989322;25943718;23763583",
"title": "Eculizumab in secondary atypical haemolytic uraemic syndrome.",
"title_normalized": "eculizumab in secondary atypical haemolytic uraemic syndrome"
} | [
{
"companynumb": "ES-MYLANLABS-2019M1116362",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": n... |
{
"abstract": "Intravascular large B-cell lymphoma (ILBCL) is a subtype of non-Hodgkin's large B-cell lymphoma that is characterised by neoplastic lymphocyte proliferation within the lumen of small blood vessels, which may occur without an extracellular tumour mass or peripheral blood involvement. This report highlights some of the diagnostic issues for ILBCL, and how it can be approached. The two cases described below highlight two significantly different presentations, one with predominately neurological phenomena, and the other with fever of unknown origin for investigation. Both patients were managed with chemotherapy and intercalated intrathecal chemotherapy, with good clinical outcomes, without further evidence of clinical relapse. These cases along with a review of the literature highlight the key learning points in the difficulties in the diagnosis of this condition, and the appropriate use of random skin biopsy in patient suspected of having ILBCL, such as those with constitutional symptoms with otherwise negative malignancy screening, and unexplained neurological phenomena, especially if recurrent in nature.",
"affiliations": "Department of Medicine, The Royal Melbourne Hospital, Melbourne, VIC, Australia jameslbarker90@gmail.com.;Department of Medicine, The Royal Melbourne Hospital, Melbourne, VIC, Australia.;Border Medical Oncology and Haematology, Albury Wodonga Regional Cancer Centre, Albury, NSW, Australia.",
"authors": "Barker|James Llewellyn|JL|http://orcid.org/0000-0001-7579-0535;Swarup|Oshi|O|http://orcid.org/0000-0003-4610-1803;Puliyayil|Anish|A|http://orcid.org/0000-0001-9825-6773",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-244069",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(11)",
"journal": "BMJ case reports",
"keywords": "haematology (incl blood transfusion); medical education",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001706:Biopsy; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D009364:Neoplasm Recurrence, Local; D012867:Skin",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34728502",
"pubdate": "2021-11-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravascular large B-cell lymphoma: representative cases and approach to diagnosis.",
"title_normalized": "intravascular large b cell lymphoma representative cases and approach to diagnosis"
} | [
{
"companynumb": "AU-BAUSCH-BL-2022-009771",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "A 6-year-old girl displayed symptoms of serotonin syndrome after accidental ingestion of Vyvanse (lisdexamfetamine dimesylate). Dexmedetomidine was administered because of persistent neuromuscular hyperactivity and severe agitation despite initial therapy with benzodiazepines. Some children show a paradoxical reaction to benzodiazepines, and dexmedetomidine has a possible role in the treatment of serotonin syndrome.",
"affiliations": "Department of Pediatrics at Tulane Hospital for Children, New Orleans, Louisiana 70112-2632, USA. oakingbo@tulane.edu",
"authors": "Akingbola|Olugbenga A|OA|;Singh|Dinesh|D|",
"chemical_list": "D058647:Adrenergic alpha-2 Receptor Agonists; D014151:Anti-Anxiety Agents; D000697:Central Nervous System Stimulants; D020927:Dexmedetomidine; D008140:Lorazepam; D008874:Midazolam; D000069478:Lisdexamfetamine Dimesylate; D003913:Dextroamphetamine",
"country": "United States",
"delete": false,
"doi": "10.4037/ajcc2012768",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1062-3264",
"issue": "21(6)",
"journal": "American journal of critical care : an official publication, American Association of Critical-Care Nurses",
"keywords": null,
"medline_ta": "Am J Crit Care",
"mesh_terms": "D058647:Adrenergic alpha-2 Receptor Agonists; D014151:Anti-Anxiety Agents; D000697:Central Nervous System Stimulants; D002648:Child; D020927:Dexmedetomidine; D003913:Dextroamphetamine; D062787:Drug Overdose; D005260:Female; D006801:Humans; D000069478:Lisdexamfetamine Dimesylate; D008140:Lorazepam; D008874:Midazolam; D020230:Serotonin Syndrome",
"nlm_unique_id": "9211547",
"other_id": null,
"pages": "456-9",
"pmc": null,
"pmid": "23117910",
"pubdate": "2012-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dexmedetomidine to treat lisdexamfetamine overdose and serotonin toxidrome in a 6-year-old girl.",
"title_normalized": "dexmedetomidine to treat lisdexamfetamine overdose and serotonin toxidrome in a 6 year old girl"
} | [
{
"companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-16-01838",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MIDAZOLAM\\MIDAZOLAM HYDROCHLORIDE"
... |
{
"abstract": "This case illustrates the relationship between gut, hormonal, and brain function in that dietary changes, mindfulness interventions, and detoxification led to resolution of disabling psychiatric symptoms and protracted psychotropic medication withdrawal symptoms.\nA 50-year-old partnered, unemployed, Caucasian female with a history of major depressive disorder, multiple suicide attempts, extensive trauma and abuse, and substance abuse presented for outpatient management. The patient reported limited benefit from over two decades of conventional treatment with psychotropic medications. She presented with depression and symptoms of protracted withdrawal after self-discontinuation of multiple psychiatric medications and was prescribed a dietary, detoxification, and supplementation regimen by the primary author. Additional lifestyle interventions implemented included daily meditation, dry-skin brushing, and coffee enemas.\nThis case exemplifies dramatic clinical remission after cessation of medication treatment and engagement of lifestyle interventions, which include dietary change, meditation, and detoxification. As such, when limited results are achieved by psychotropic medication, tapering combined with dietary interventions as the first-line therapy should be considered. This case is also evidence of the role of lifestyle interventions in treating protracted withdrawal symptoms associated with discontinuing psychotropic medications.",
"affiliations": null,
"authors": "Brogan|Kelly|K|;Jarvi|Alyssa|A|;Anderson|Shelby|S|;Kalen Flynn|Sarah|S|",
"chemical_list": "D000928:Antidepressive Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-3556",
"issue": "34(4)",
"journal": "Advances in mind-body medicine",
"keywords": null,
"medline_ta": "Adv Mind Body Med",
"mesh_terms": "D000928:Antidepressive Agents; D003863:Depression; D003865:Depressive Disorder, Major; D005260:Female; D006801:Humans; D008019:Life Style; D008875:Middle Aged; D019966:Substance-Related Disorders; D013406:Suicide, Attempted; D016896:Treatment Outcome",
"nlm_unique_id": "9813115",
"other_id": null,
"pages": "24-32",
"pmc": null,
"pmid": "33186128",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clinical Remission of Treatment-Resistant Depression, Polysubstance Abuse, and Antidepressant Discontinuation Syndrome Through Engagement of Lifestyle Interventions.",
"title_normalized": "clinical remission of treatment resistant depression polysubstance abuse and antidepressant discontinuation syndrome through engagement of lifestyle interventions"
} | [
{
"companynumb": "US-BAUSCH-BL-2020-035577",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BUPROPION"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nStaphylococcal scalded skin syndrome is an exfoliative skin disease. Reports of this syndrome in newborns caused by methicillin-resistant Staphylococcus aureus are rare but, when present, rapid diagnosis and treatment is required in order to decrease morbidity and mortality.\n\n\nMETHODS\nA premature newly born girl weighing 1,520 g, born with a gestational age of 29 weeks and 4 days, developed staphylococcal scalded skin syndrome on the fifth day of life. Cultures on blood samples collected on the first and fourth days were negative, but Pseudomonas aeruginosa and Enterococcus sp. (vancomycin-sensitive) developed in blood cultures performed on the day of death (seventh day), and Pseudomonas aeruginosa and Serratia marcescens were identified in cultures on nasopharyngeal, buttock and abdominal secretions. In addition to these two Gram-negative bacilli, methicillin-resistant Staphylococcus aureus was isolated in a culture on the umbilical stump (seventh day). The diagnosis of staphylococcal scalded skin syndrome was based on clinical criteria.",
"affiliations": "Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.;Department of Clinical and Toxicological Analyses, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.;Hospital Universitário de Santa Maria, Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.;Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.;Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.;Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.;Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.;Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.;Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.;Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.;Universidade Federal de Santa Maria, Santa Maria, Rio Grande do Sul, Brasil.",
"authors": "Hörner|Andreas|A|;Hörner|Rosmari|R|;Salla|Adenilde|A|;Nunes|Melise Silveira|MS|;Garzon|Litiérri Razia|LR|;Rampelotto|Roberta Filipini|RF|;Martini|Rosiéli|R|;Santos|Silvana Oliveira dos|SO|;Gindri|Lívia|L|;Rodrigues|Mônica de Abreu|Mde A|;Giacomolli|Cláudia|C|",
"chemical_list": null,
"country": "Brazil",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1516-3180",
"issue": "133(5)",
"journal": "Sao Paulo medical journal = Revista paulista de medicina",
"keywords": null,
"medline_ta": "Sao Paulo Med J",
"mesh_terms": "D016470:Bacteremia; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D055624:Methicillin-Resistant Staphylococcus aureus; D013206:Staphylococcal Scalded Skin Syndrome",
"nlm_unique_id": "100897261",
"other_id": null,
"pages": "450-3",
"pmc": null,
"pmid": "26648436",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Staphylococcal scalded skin syndrome in a premature newborn caused by methicillin-resistant Staphylococcus aureus: case report.",
"title_normalized": "staphylococcal scalded skin syndrome in a premature newborn caused by methicillin resistant staphylococcus aureus case report"
} | [
{
"companynumb": "BR-PFIZER INC-2015475413",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXACILLIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPrimary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted.\n\n\nMETHODS\nEBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective.\n\n\nRESULTS\n458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = -6.7%, 95%CI = -13.5%-0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p < 0.001). Non-FN treatment-related hospitalisation occurred in 40/228 (17.5%) of ciprofloxacin patients vs 28/230 (12.2%) of G-CSF patients (p = 0.12). There were no differences in other secondary outcomes. G-CSF was associated with an incremental cost-effectiveness ratio of C$1,760,796 per one quality-adjusted life year gained.\n\n\nCONCLUSIONS\nThe primary endpoint of superiority of G-CSF over ciprofloxacin was not demonstrated. While there were reduced FN rates with G-CSF, there were no differences in chemotherapy dose delays/reductions or discontinuations. With the commonly used willingness to pay value of C$50,000/QALY, G-CSF use was not cost-effective compared to ciprofloxacin and deserves scrutiny from the payer perspective.",
"affiliations": "Department of Medicine, Division of Medical Oncology, The Ottawa Hospital and University of Ottawa, Ottawa, Canada; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada; Clinical Epidemiology Program, Ottawa Hospital Research Institute and School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada. Electronic address: mclemons@toh.ca.;Clinical Epidemiology Program, Ottawa Hospital Research Institute and School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada.;Division of Medical Oncology, Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Canada.;Clinical Epidemiology Program, Ottawa Hospital Research Institute and School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada.;Division of Medical Oncology, Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Canada.;Division of Medical Oncology, Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Canada.;Division of Medical Oncology, Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Canada.;Department of Medicine, Division of Medical Oncology, The Ottawa Hospital and University of Ottawa, Ottawa, Canada.;Division of Medical Oncology, Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Canada.;Department of Medicine, Division of Medical Oncology, The Ottawa Hospital and University of Ottawa, Ottawa, Canada.;Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada.;Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada.;Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada.;Department of Oncology, McMaster University, Hamilton, Canada.;Department of Medicine, Division of Medical Oncology, The Ottawa Hospital and University of Ottawa, Ottawa, Canada.;Department of Medicine, Division of Medical Oncology, The Ottawa Hospital and University of Ottawa, Ottawa, Canada.;Department of Oncology, Northeast Cancer Centre, Sudbury, Canada.;Division of Medical Oncology, Department of Oncology, University of Alberta, Tom Baker Cancer Centre, Calgary, Canada.;Clinical Epidemiology Program, Ottawa Hospital Research Institute and School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada.;Department of Medicine, Division of Medical Oncology, The Ottawa Hospital and University of Ottawa, Ottawa, Canada; Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada.",
"authors": "Clemons|Mark|M|;Fergusson|Dean|D|;Joy|Anil A|AA|;Thavorn|Kednapa|K|;Meza-Junco|Judith|J|;Hiller|Julie Price|JP|;Mackey|John|J|;Ng|Terry|T|;Zhu|Xiaofu|X|;Ibrahim|Mohammed F K|MFK|;Sienkiewicz|Marta|M|;Saunders|Deanna|D|;Vandermeer|Lisa|L|;Pond|Gregory|G|;Basulaiman|Bassam|B|;Awan|Arif|A|;Pitre|Lacey|L|;Nixon|Nancy A|NA|;Hutton|Brian|B|;Hilton|John F|JF|;|||",
"chemical_list": "D000900:Anti-Bacterial Agents; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; D003520:Cyclophosphamide",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.breast.2021.03.012",
"fulltext": "\n==== Front\nBreast\nBreast\nThe Breast : Official Journal of the European Society of Mastology\n0960-9776\n1532-3080\nElsevier\n\nS0960-9776(21)00351-9\n10.1016/j.breast.2021.03.012\nOriginal Article\nA multi-centre study comparing granulocyte-colony stimulating factors to antibiotics for primary prophylaxis of docetaxel-cyclophosphamide induced febrile neutropenia\nClemons Mark mclemons@toh.ca\nabc∗\nFergusson Dean c\nJoy Anil A. d\nThavorn Kednapa c\nMeza-Junco Judith d\nHiller Julie Price d\nMackey John d\nNg Terry a\nZhu Xiaofu d\nIbrahim Mohammed F.K. a\nSienkiewicz Marta b\nSaunders Deanna b\nVandermeer Lisa b\nPond Gregory e\nBasulaiman Bassam a\nAwan Arif a\nPitre Lacey f\nNixon Nancy A. g\nHutton Brian c\nHilton John F. ab\non behalf of the\nREThinking Clinical Trials (REaCT) investigators\na Department of Medicine, Division of Medical Oncology, The Ottawa Hospital and University of Ottawa, Ottawa, Canada\nb Cancer Therapeutics Program, Ottawa Hospital Research Institute, Ottawa, Canada\nc Clinical Epidemiology Program, Ottawa Hospital Research Institute and School of Epidemiology and Public Health, University of Ottawa, Ottawa, Canada\nd Division of Medical Oncology, Department of Oncology, University of Alberta, Cross Cancer Institute, Edmonton, Canada\ne Department of Oncology, McMaster University, Hamilton, Canada\nf Department of Oncology, Northeast Cancer Centre, Sudbury, Canada\ng Division of Medical Oncology, Department of Oncology, University of Alberta, Tom Baker Cancer Centre, Calgary, Canada\n∗ Corresponding author. Division of Medical Oncology Ottawa Hospital Research Institute, 501 Smyth Road, Box 912, Ottawa, Ontario, Canada. mclemons@toh.ca\n01 4 2021\n8 2021\n01 4 2021\n58 4249\n30 11 2020\n23 3 2021\n29 3 2021\n© 2021 The Authors\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground\n\nPrimary febrile neutropenia (FN) prophylaxis with ciprofloxacin or granulocyte-colony stimulating factors (G-CSF) is recommended with docetaxel-cyclophosphamide (TC) chemotherapy for early-stage breast cancer (EBC). A pragmatic randomised trial compared the superiority of G-CSF to ciprofloxacin and a cost-utility analysis were conducted.\n\nMethods\n\nEBC patients receiving TC chemotherapy were randomised to ciprofloxacin or G-CSF. The primary outcome was a composite of FN and non-FN treatment-related hospitalisation. Secondary outcomes included; rates of FN, non-FN treatment-related hospitalisation, chemotherapy dose reductions/delays/discontinuations. Primary analysis was performed with the intention to treat population. Cost-utility analyses were conducted from the Canadian public payer perspective.\n\nResults\n\n458 eligible patients were randomised: 228 to ciprofloxacin and 230 to G-CSF. For the primary endpoint there was non-statistically significant difference (Risk difference = −6.7%, 95%CI = −13.5%–0.1%, p = 0.061) between ciprofloxacin patients (46,20.2%) and G-CSF (31,13.5%). Patients receiving ciprofloxacin were more likely to experience FN (36/228, 15.8% vs 13/230, 5.7%) than patients receiving G-CSF (p < 0.001). Non-FN treatment-related hospitalisation occurred in 40/228 (17.5%) of ciprofloxacin patients vs 28/230 (12.2%) of G-CSF patients (p = 0.12). There were no differences in other secondary outcomes. G-CSF was associated with an incremental cost-effectiveness ratio of C$1,760,796 per one quality-adjusted life year gained.\n\nConclusion\n\nThe primary endpoint of superiority of G-CSF over ciprofloxacin was not demonstrated. While there were reduced FN rates with G-CSF, there were no differences in chemotherapy dose delays/reductions or discontinuations. With the commonly used willingness to pay value of C$50,000/QALY, G-CSF use was not cost-effective compared to ciprofloxacin and deserves scrutiny from the payer perspective.\n\nHighlights\n\n• Primary febrile neutropenia (FN) prophylaxis is indicated for docetaxel-cyclophosphamide (TC) chemotherapy.\n\n• In this multicentre trial 458 breast cancer patients receiving TC chemotherapy were randomised to ciprofloxacin or to G-CSF.\n\n• For the primary endpoint of FN and non-FN treatment-related hospitalizations, G-CSF was not superior over ciprofloxacin.\n\n• While there were reduced FN rates with G-CSF, the incremental cost-effectiveness ratio was C$1,760,796 per one QALYWALY gained.\n\nKeywords\n\nDocetaxel-cyclophosphamide\nBreast cancer\nFebrile neutropenia\nG-CSF\nCiprofloxacin\n==== Body\n1 Introduction\n\nDocetaxel-cyclophosphamide (TC) chemotherapy is commonly used for early stage breast cancer (EBC) [1]. Due to the risk of neutropenia and associated consequences (including febrile neutropenia [FN], non-FN treatment-related hospitalisations, chemotherapy delays/dose reductions/discontinuation), evidence-based guidelines recommend that TC is co-administered with primary FN prophylaxis [[2], [3], [4], [5], [6]]. While ciprofloxacin was mainly used in the definitive trial [1], in clinical practice, granulocyte colony-stimulating factors (G-CSF) (e.g. filgrastim [Neupogen™, Grastofil™] [7] or peg-filgrastim [Neulasta™] are commonly used [1,8,9].\n\nDespite differences in cost, route of administration and toxicity profiles between ciprofloxacin and G-CSF, the optimal choice of agent has never been definitively evaluated [[10], [11], [12]]. In the absence of prospective comparisons, the choice of agent should be based on a full discussion between the patient and health care provider. This discussion should reflect; drug side effects [13,14], subcutaneous administration of G-CSF, and expense (C$ 1920/cycle Neupogen, C$ 1440/cycle Grastofil and C$ 2380/cycle Neulasta™) [15,16]. In practice, however, the choice is usually based on physician preference [10].\n\nWe previously confirmed the feasibility of performing a randomised clinical trial using an oral consent methodology [17] for comparing ciprofloxacin with G-CSF in patients receiving TC [12]. This pilot study was then expanded to compare efficacy outcomes. We report on the expanded study. The primary outcome is a composite endpoint comprised of FN and non-FN treatment-related hospitalisations. This endpoint was chosen as a previous patient survey showed this was the outcome of greatest personal importance [10].\n\n2 Methods\n\nThis open-label, superiority trial was performed at four Canadian cancer centres. Eligible patients had EBC, no prior history of chemotherapy, and were planned to receive 4 cycles of adjuvant TC chemotherapy. Exclusion criteria included contraindications to either G-CSF or ciprofloxacin. Patients were approached for study participation by their oncologist. The study was approved by the local Research Ethics Boards and registered on clinicaltrials.gov (NCT02816112) [18].\n\n2.1 Randomisation\n\nConsented patients were randomised 1:1 to ciprofloxacin (500 mg PO BID for 7–14 days starting 5 days after chemotherapy) or G-CSF (patients, with their physicians, could choose the type, dose, and duration of G-CSF use, including biosimilars) as primary FN prophylaxis for each chemotherapy cycle. Following confirmation of the feasibility of the oral consent methodology [12,19] (Version 28/Aug/2014, NCT02173262, n = 186), a protocol amendment (19/Oct/2016, NCT02816112) allowed study expansion to compare the efficacy of ciprofloxacin with G-CSF. Randomisation was performed using a permuted block design with blocks of variable sizes stratified by centre using a web-based application developed by The Ottawa Methods Centre.\n\nPatients received ciprofloxacin or G-CSF (Neupogen™, Neulasta™: Amgen, Thousand Oaks CA, USA, or Grastofil™, Apotex, Toronto, Canada). Study drugs were funded through either 10.13039/100009142 Cancer Care Ontario (patients over 65) or through third party insurance co-pay programs (Ontario and Alberta). Follow-up visits occurred as per usual care. Outcome data were collected from case report forms and electronic health records.\n\n2.2 Study hypotheses\n\nThe proportion of patients with the composite endpoint of FN or non-FN treatment-related hospitalisations will be lower for patients treated with G-CSF.\n\n2.3 Outcomes\n\nThe primary outcome was the rate of a composite measure of documented, laboratory confirmed FN [20] or non-FN treatment-related hospital admission. Secondary outcomes included; FN rates, non-FN treatment-related hospitalisation rates, proportion of patients who required chemotherapy dose delays/reductions/discontinuation. Rates of laboratory confirmed Clostridium difficile infections or other microbiologic infections were collected.\n\n2.4 Statistical analysis\n\nPatient characteristics and outcomes were summarised using descriptive statistics. All outcomes were assessed from the date of randomisation until 28 days (inclusive) after the last cycle of TC chemotherapy. Primary analysis was based on the intention-to-treat (ITT) principle, which included all patients in the treatment group to which they were allocated, even if they did not receive treatment or were non-compliant. A supportive analysis was performed on the per protocol (PP) population, which included those who received initial treatment as per their randomised allocation. The primary analysis was based on a two-sided, Fisher’s exact test with statistical significance defined at the p = 0.05 level. Absolute risk difference and 95% confidence intervals were calculated between both treatment groups using the Score (Wilson) method. Pre-planned subgroup analyses included: treatment centre (Ottawa vs. others) and age (<65 vs. 65+). Logistic regression analyses, adjusted for stratification factors, were also performed. All statistical analysis was carried out using SAS version-9 or higher for Windows (Cary, NC) or R version 3.2.2 (www.r-project.org). or higher. Of note, the preliminary efficacy data of the feasibility study [12]. was not assessed to ensure the type I error was not impacted.\n\n2.5 Sample size\n\nAn informal survey of medical oncologists from participating centres in February 2016 asked what they felt would be the minimally important effect of G-CSF needed to be deemed superior to ciprofloxacin. The published rates of FN in patients receiving primary FN prophylaxis cited in the survey ranged from 5% to 8% [[10], [11], [12]], thus, if the primary outcome rate in patients administered ciprofloxacin was estimated to be 8%, survey respondents identified that a rate of 2% or less of patients receiving G-CSF would be required to change practice universally. Hence, assuming primary outcome rates of 8% versus 2% for patients administered ciprofloxacin and G-CSF, 80% power and a two-sided alpha of 5%, the required overall sample size was 412 people (206 per treatment group). To account for 5% non-compliance with the protocol, the target sample size was 456 patients (228 per arm).\n\n2.6 Health economic evaluation\n\nWe conducted a cost-utility analysis utilising a decision tree and patient-level data from the trial (Fig. 1 and Supplemental Table 1). The time horizon of the model was three months to align with the trial follow-up, discounting was therefore not required. We did not use a lifetime horizon because G-CSF and ciprofloxacin are supportive care therapies in the breast cancer setting without survival benefits [21,22]. FN and non-FN treatment-related hospitalisations data were taken from the trial. Health outcome was shown as quality-adjusted life year (QALY), that was estimated based on the published health utility values and the area under the curve method. Costs were estimated from the Ontario Ministry of Health perspective and expressed in 2020 Canadian dollars (C$). Our model included the costs of G-CSF, ciprofloxacin, physicians, hospitalisation, inpatient and outpatient FN management. Incremental cost-effectiveness ratios (ICERs) were shown as the incremental cost per QALY gained. We performed a series of one-way and probabilistic sensitivity analyses (PSA) to assess the robustness of study results. A scenario analysis was carried out to assess the impact of the proportion of peg-filgrastim vs. filgrastim.Fig. 1 Decision tree structure.\n\nFig. 1\n\n3 Results\n\nThe trial enrolled from September 18, 2014 to November 19, 2019. Of 458 eligible patients, 228 were randomised to ciprofloxacin and 230 to G-CSF (CONSORT flow diagram, Fig. 2). Of 458 patients, 15 (7 ciprofloxacin; 8 G-CSF) withdrew prior to start of treatment (Fig. 2). In total, 443 (221 ciprofloxacin; 222 G-CSF) patients received treatment as part of this trial. Reasons for discontinuation of study treatments are shown in Fig. 2.Fig. 2 Study CONSORT diagram.\n\nFig. 2\n\nBaseline characteristics of the randomised patients are presented in Table 1. Median age was 58 years (range 30–84). The total number of chemotherapy cycles given were 819 in the ciprofloxacin arm and 849 in the G-CSF arm. Median (interquartile range) durations on study were 90 days (range 46–98) and 92 days (range 68–103) for ciprofloxacin and G-CSF patients, respectively.Table 1 Patient enrolment and baseline characteristics.\n\nTable 1Characteristic\tOverall\tCiprofloxacin\tG-CSF\t\nN\t458\t228\t230\t\nMean age (std dev)\nMedian (range)\t57.7 (10.7)\n58 (30, 84)\t59.0 (10.9)\n60 (30, 84)\t56.4 (10.4)\n57 (31, 81)\t\nType, dose and number of injections of G-CSF∗: n (%)\t–\t–\t147\t\nPegfilgrastim (6 mg)\nFilgrastim (300mcg/5 d)\nFilgrastim (300mcg/7 d)\nFilgrastim (300mcg/10 d)\nFilgrastim (480mcg/5 d)\nFilgrastim (480mcg/7 d)\nFilgrastim (480mcg/10 d)\nDose Unknown\t\t\t4 (2.7)\n79 (53.7)\n34 (23.1)\n26 (17.7)\n1 (0.7)\n1 (0.7)\n2 (1.4)\n83 (36.1)\t\nTotal Cycles of Treatment for all patients\n0\n1\n2\n3\n4\t\n15 (3.3)\n26 (5.7)\n12 (2.6)\n18 (3.9)\n387 (84.5)\t\n7 (3.1)\n14 (6.1)\n8 (3.5)\n9 (4.0)\n190 (83.3)\t\n8 (3.5)\n12 (5.2)\n4 (1.7)\n9 (3.9)\n197 (85.7)\t\nTC = docetaxel/cyclophosphamide.\n\n∗ Data was available on the types of growth factors prescribed at one centre (Ottawa Hospital) only (n = 147). Biosimilar preparations of both filgrastim and pegfilgrastim were allowed.\n\n3.1 Primary outcomes\n\nFN occurred in 36 (15.8%) ciprofloxacin patients and 13 (5.7%) G-CSF patients (RD = −10.1%, 95%CI = −15.7% to −4.5%, p-value<0.001) (Table 2, Fig. 3). There were 40 (17.5%) ciprofloxacin patients who were hospitalised for any reason, compared with 28 (12.2%) G-CSF patients (RD = −5.4%, 95%CI = −11.9%–1.1%, p-value = 0.12). For the primary composite endpoint, a total of 46 (20.2%) ciprofloxacin patients experienced FN or were hospitalised, whereas 31 (13.5%) G-CSF patients experienced FN or were hospitalised. The risk difference was −6.7%, with a 95%CI of −13.5%–0.1%, p-value = 0.061 (Fig. 3, Table 2 and Supplemental Tables 2 and 3). Results were similar in the PP analysis (Supplemental Tables 2 and 3). After adjusting for age (>65 versus ≤ 65) and treatment centre, the odds ratio (95%CI) for developing FN or hospitalisation was 1.52 (95%CI 0.91 to 2.53; p = 0.11) for patients treated with ciprofloxacin. In other words, patients on the ciprofloxacin arm had increased odds of experiencing the primary outcome event, adjusted for stratification factors. Subgroup analyses are presented in Supplemental Tables 3 and 4Table 2 Clinical endpoints, Per Protocol Analysis.\n\nTable 2Outcome\tCiprofloxacin,\nN (%)\tG-CSF\nN (%)\tRisk Difference (95% CI)\tp-value\t\nN\t221\t222\t\t\t\nPrimary Endpoint\t\t\t\t\t\nFN or Treatment-related hospitalisation\t43 (19.5)\t29 (13.1)\t−6.4% (−13.2, 0.5)\t0.073\t\nSecondary Endpoints\t\t\t\t\t\nFebrile Neutropenia\t36 (16.3)\t13 (5.9)\t−10.4% (−16.2, −4.7)\t<0.001\t\nTreatment-related Hospitalisation\t37 (16.7)\t25 (11.3)\t−5.5% (−11.9, 1.0)\t0.10\t\nChemotherapy dose reduction\t23 (10.4)\t21 (9.5)\t−1.0% (−6.5, 4.6)\t0.75\t\nChemotherapy discontinuation\t17 (7.7)\t8 (3.6)\t−4.1% (−8.4, 0.2)\t0.067\t\nChemotherapy dose delay\t8 (3.6)\t9 (4.1)\t0.4% (−3.1, 4.0)\t1.00\t\nMicroinfection\t8 (3.6)\t12 (5.4)\t1.8% (−2.1, 5.7)\t0.49\t\nAny Event\t99 (44.8)\t76 (34.2)\t−10.6% (−19.6, −1.5)\t0.026\t\nFN=Febrile neutropenia.\n\nFig. 3 Forest Plot of clinical endpoints, ITT Population.\n\nFig. 3\n\nOf the 36 patients in the ciprofloxacin group that experienced FN, 30 were hospitalised and 6 had outpatient management. Of 13 patients with FN while on G-CSF, 9 were hospitalised and 4 were managed as outpatients.\n\n3.2 Cycle data\n\nEvents were most frequent during the first cycle of therapy (Table 3). Amongst ciprofloxacin patients, 10.4% and 11.3% respectively experienced FN or non-FN treatment-related hospitalisation during the first cycle, compared with 2.6% and 2.6% in the fourth cycle. Similarly, amongst G-CSF patients, 4.5% and 6.8% experienced FN or non-FN treatment-related hospitalisations during cycle 1, while 1.5% and 1.0% did so during cycle 4.Table 3 Clinical endpoints, by Cycle, ITT Analysis.\n\nTable 3\tCiprofloxacin\tG-CSF\t\nCycle\t1\t2\t3\t4\t1\t2\t3\t4\t\nn (%)\t221\t203\t199\t196\t222\t214\t211\t202\t\nFebrile Neutropenia\t23 (10.4)\t17 (8.4)\t9 (4.5)\t5 (2.6)\t10 (4.5)\t8 (3.7)\t4 (1.9)\t3 (1.5)\t\nTreatment-related Hospitalisation\t25 (11.3)\t10 (4.9)\t4 (2.0)\t5 (2.6)\t15 (6.8)\t8 (3.7)\t7 (3.3)\t2 (1.0)\t\nChemotherapy dose reduction\t0\t19 (9.4)\t12 (6.0)\t6 (3.1)\t0\t18 (8.4)\t12 (5.7)\t9 (4.5)\t\nChemotherapy discontinuation\t18 (8.1)\t4 (2.0)\t3 (1.5)\t8 (4.1)\t8 (3.6)\t3 (1.4)\t5 (2.4)\t9 (4.5)\t\nChemotherapy dose delay\t0\t9 (4.4)\t5 (2.5)\t2 (1.0)\t0\t5 (2.3)\t9 (4.3)\t6 (3.0)\t\nMicroinfection\t5 (2.3)\t5 (2.5)\t2 (1.0)\t1 (0.5)\t6 (2.7)\t6 (2.8)\t1 (0.5)\t1 (0.5)\t\n\n3.3 Secondary outcomes\n\nOverall, 15.7% of patients experienced a dose reduction, 12.7% discontinued chemotherapy, and 7.4% experienced a dose delay. The most common reasons included non-neutropenic fever, peripheral neuropathy, and diarrhoea. No statistically significant difference was observed in the rates of chemotherapy dose reductions (p = 0.90), discontinuations (p = 0.26), dose delays (p = 0.59) or microinfections (p = 0.83) (Fig. 3 and Supplemental Table 3). Events were more common in earlier treatment cycles. In the ITT population, 24/458 (5.2%) patients experienced a laboratory confirmed microinfection. Three patients experienced C. difficile (2-ciprofloxacin; 1-G-CSF) and 1 G-CSF patient grew streptococci.\n\nWhen combining all primary and secondary endpoints, 102/228 patients on ciprofloxacin (44.7%) had at least one primary or secondary endpoint event, compared with 78/230 (33.9%) of G-CSF patients (Fisher’s exact test, RD = −10.8%, 95%CI = −10.8% to −1.9%, p = 0.022) (Fig. 3).\n\n3.4 Cost-utility results\n\nG-CSF was associated with higher cost (C$4005 vs. C$2581) and improved QALYs (0.1783 vs. 0.1774) compared to ciprofloxacin, with an estimated ICER of C$1,760,796/QALY. The estimated ICERs increased with the larger proportions of peg-filgrastim (Table 4). The cost-effectiveness results were highly sensitive to the unit cost of G-CSF, the relative risk of FN, and the relative risk of treatment-related hospitalisation (Fig. 4). The higher cost of G-CSF, the less likely that G-CSF would be cost-effective. By contrast, the greater effectiveness of G-CSF in reducing FN or treatment-related hospitalisation, the more likely that G-CSF would be cost-effective. Results of the PSA show that G-CSF was associated with increased cost and improved QALYs in the majority of the 5000 simulations (Supplemental Fig. 1a). Regardless of the willingness-to-pay values, ciprofloxacin always had the greater probabilities of being a cost-effective option than G-CSF (Supplemental Fig. 1b).Table 4 Cost-utility analysis results.\n\nTable 4Analysis\tTreatment\tAverage\nCost (C$)\tAverage QALYs\tIncremental\nCost (C$)\tIncremental QALYs\tICER, C$/QALY\t\nBase case Pegfilgrastim 2.7%\tG-CSF\t4005\t0.1783\t1424\t0.0008\t1,760,796\t\nCiprofloxacin\t2581\t0.1774\t\nScenario analysis\nPegfilgrastim 0%\tG-CSF\t3881\t0.1784\t1298\t0.0008\t1,608,322\t\nCiprofloxacin\t2583\t0.1776\t\nScenario analysis\nPegfilgrastim 25%\tG-CSF\t4355\t0.1799\t1779\t0.0008\t2,183,394\t\nCiprofloxacin\t2576\t0.1791\t\nScenario analysis\nPegfilgrastim 50%\tG-CSF\t4800\t0.1790\t2232\t0.0008\t2,804,370\t\nCiprofloxacin\t2568\t0.1782\t\nScenario analysis\nPegfilgrastim 75%\tG-CSF\t5221\t0.1790\t2636\t0.0008\t3,232,484\t\nCiprofloxacin\t2585\t0.1782\t\nScenario analysis\nPegfilgrastim 100%\tG-CSF\t5611\t0.1786\t3036\t0.0008\t3,765,911\t\nCiprofloxacin\t2576\t0.1778\t\n\nFig. 4 One-way sensitivity analysis results.\n\nFig. 4\n\n4 Discussion\n\nTC chemotherapy is usually co-administered with primary FN prophylaxis. A systematic review showed FN rates were reduced from 27% to 5% by primary FN prophylaxis [11] but was limited by the retrospective nature of the trials involved. Hence the optimal form of prophylaxis is unknown [[10], [11], [12]]. Indeed, the original study leading to TC approval did not specify whether prophylaxis was used [1] and it was not until a subsequent publication when it became clear that most patients received prophylactic ciprofloxacin [23]. To our knowledge, this is the only randomised trial to prospectively address this important clinical question. In this study the primary outcome of a composite of FN and non-FN treatment-related hospitalisations was chosen because EBC patients have stated that both were the outcomes of greatest importance to them [10]. Our study did not demonstrate the superiority of G-CSF over ciprofloxacin. Our cost-utility analysis also showed that G-CSF was not cost-effective compared to ciprofloxacin at a commonly used willingness-to-pay threshold of C$50,000/QALY.\n\nThese finding are pertinent for several reasons. First, was a recent publication evaluating the omission of peg-filgrastim prophylaxis with the taxane component of dose-dense AC and paclitaxel [24]. In this single arm study omission of routine peg-filgrastim was safe and feasible and associated with a 95.7% reduction in the use of peg-filgrastim. Second, the report from the most recent ASCO Clinical Practice Guideline Update for the Use of WBC Growth Factors [25] states that, \"Prophylactic use of CSFs to reduce the risk of FN is warranted when the risk of FN is approximately 20% or higher and no other equally effective and safe regimen that does not require CSFs is available”. Given that the rate of FN in the current study with ciprofloxacin use was 15%, this is below the 20% threshold stated in this guideline. Finally, with the commonly used willingness to pay value of C$50,000/QALY, the use of G-CSF was not cost-effective compared to ciprofloxacin and deserves great scrutiny from the payer perspective.\n\nIt is challenging to compare our findings with those in the literature, as past studies vary in the type of outcome they report (FN rates, neutropenia rates) and also in the type of analysis reported (by proportion of patients or per cycle of chemotherapy) [[2], [3], [4],9,23,[26], [27], [28], [29]]. As outcome events can be expressed by the rate in the study population overall, and by the total number of chemotherapy cycles received, we chose to present both formats [30]. With respect to study endpoints, TC is not an innocuous regimen even with G-CSF use, as 33.9% of G-CSF patients experienced at least one event related to the primary or secondary endpoint.\n\nThere are limitations with the current trial. Due to the study’s pragmatic nature it did not employ a double-blind design. It might be viewed as both limitations and strengths that the duration of ciprofloxacin was between 7 and 14 days depending on local standards, while the type, dose and duration of G-CSF were left to patient and physician choice. This was done to reflect the realities of clinical practice in a real-world setting. Similarly, many physicians do not adjust the dose of G-CSF based on weight [[31], [32], [33]] or may use shorter durations than identified in prior studies [34]. Some studies cite patient age ≥65 as an important factor for increased risk of FN [3,[26], [27], [28]]. In our study the proportion of patients having FN was 35/339 (10.3%) vs. 14/119 (11.7%) for the <65 and ≥ 65 subgroups (p-value = 0.24), respectively. In the current study, 22.5% of patients were ≥65, compared with 16% in the definitive TC approval trial [1,23]. Our study also allowed patients to receive biosimilar formulations of filgrastim, again making the results more generalisable toward real-world practice.\n\nFuture studies are needed to evaluate primary FN prophylaxis from patient perspective, as there are considerable differences both in terms of toxicity and patient cost between these strategies. Growth factor support is expensive both in terms of direct (costs to the patient and/or the health care system) [6] and indirect (paying health care staff to administer and/or to teach patients to self-administer subcutaneous injections) costs. G-CSF use may also be associated with clinically important adverse effects including local and systemic pain syndrome. In addition, future studies could evaluate the effect of cost effectiveness of different G-CSF products. For example, differences in patients (dose and duration of G-CSF used), between agents (filgrastim vs pegfilgrastim), between biosimilars and non-biosimilars and between insurance companies and Provincial tender-based contracts could give interesting comparisons. Ciprofloxacin, while relatively inexpensive, is associated with its own adverse effects, such as C. difficile infection. With all of these factors considered, the ideal prophylaxis regimen needs to consider not only clinical efficacy but cost and patient comfort/acceptability [35].\n\n5 Conclusion\n\nWe have demonstrated that while our primary outcome of FN and hospitalisations did not reach statistical significance, G-CSF was superior to ciprofloxacin for reducing FN rates. In addition, treatment related hospitalisations also favoured G-CSF, but was not statistically significant. Finally, the gains in clinical benefits of G-CSF did not justify its high cost.\n\nRole of the funding source\n\nThis work was supported by the 10.13039/501100004390 Ottawa Hospital Department of Medicine Patient Quality and Safety Committee PQ&I Project Grant with matched funding from the 10.13039/501100004390 Ottawa Hospital Division of Medical Oncology. Additional funding was obtained from Cancer Care Ontario: Clinical Programs and Quality Initiatives 2017 and 2018 grants to support expansion of REaCT trials to other cancer centres in Ontario and from the Canadian Institute of Health Research: SPOR grant. The Rethinking Clinical Trials (REaCT) Program platform at the 10.13039/501100004390 Ottawa Hospital is also supported by The 10.13039/501100004390 Ottawa Hospital Foundation and its generous donors.\n\nTrial registration\n\nClinicalTrials.gov: NCT02173262, NCT02816112;\n\nAuthor contributions\n\nMC, DF, AAJ, LV, BH and JH designed the study and prepared the protocol. MC, AAJ, JMJ, JPH, JM, XZ, TN, MKFI, MS, DS, BB, AA, LP, NN, JH collected the data. MC acted as principal investigator, MS and DS coordinated data entry and GP did the statistical analysis. KT performed a cost-utility analysis, MC, MS, KT, DS, LV and GP had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. MC, DF, MS, KT, DS, LV and GP wrote the manuscript. All authors were involved in the critical review of the manuscript and approved the final version.\n\nData sharing\n\nThe de-identified dataset is available upon request and approval from the REB Board of Record.\n\nEthics committee approval\n\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of each institutions Research Ethics Board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all trial participants included in the study. All data has been anonymised to protect the identities of subjects involved in the research.\n\nDeclaration of competing interest\n\nMC reports personal fees (honoraria) from 10.13039/100004319 Pfizer . AAJ reports personal fees (honoraria or travel funds) from 10.13039/100016259 Mylan , Teva, 10.13039/100015693 Purdue , 10.13039/100008021 BMS , BI, 10.13039/100008067 Genomic Health , PUMA, 10.13039/100004319 Pfizer , 10.13039/100004337 Roche , Astra Zeneca, 10.13039/100004336 Novartis and Eli 10.13039/100004312 Lilly , outside the submitted work. JPH reports institutional research funds from 10.13039/100004337 Roche and 10.13039/100008021 BMS , outside the submitted work. JM reports personal fees (honorarium) from 10.13039/100004319 Pfizer and share ownership in Pacylex Pharmaceutical Inc, SMHeart Card Inc, and illumiSonics, outside the submitted work. TN reports personal fees (honoraria) from ARIAD, 10.13039/100016040 Takeda and Boehringer-Ingelheim, outside the submitted work. 10.13039/100000957 AA reports personal fees (honorarium for advisory board participation) from 10.13039/100004336 Novartis , outside the submitted work. LP reports personal fees (honorarium from advisory board participation) from Serono Oncology, outside the submitted work. NN reports personal fees (honorarium) from 10.13039/100004337 Roche , and institutional research funds from 10.13039/100004319 Pfizer , outside the submitted work. BH reports consulting fees from Cornerstone Research, outside the submitted work. JFH reports consulting fees from 10.13039/100008021 BMS , 10.13039/100004319 Pfizer , Eli-10.13039/100004312 Lilly , 10.13039/100004336 Novartis and 10.13039/100004334 Merck , outside the submitted work. All other authors declare no competing interests.\n\nAppendix A Supplementary data\n\nThe following are the Supplementary data to this article:Multimedia component 1\n\nMultimedia component 1\n\nMultimedia component 2\n\nMultimedia component 2\n\nAcknowledgements\n\nWe are grateful for patients and their families for their assistance with this study, as well as physicians for approaching patients. Highest accrual by physician was: Clemons (215), Hilton (54), Meza-Junco (29), Price-Hiller (26), Joy (24), Mackey (17), Ng (16), Tonkin (16), Zhu (15), Awan (7), Ibrahim (6) and Verma (5).\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.breast.2021.03.012.\n==== Refs\nReferences\n\n1 Jones S.E. Savin M.A. Holmes F.A. Phase III trial comparing doxorubicin plus cyclophosphamide with docetaxel plus cyclophosphamide as adjuvant therapy for operable breast cancer J Clin Oncol 24 34 2006 5381 5387 17135639\n2 Aapro M.S. Bohlius J. Cameron D.A. Update of EORTC guidelines for the use of granulocyte-colony stimulating factor to reduce the incidence of chemotherapy-induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours Eur J Canc 47 1 2010 8 32 2011\n3 Younis T. Rayson D. Thompson K. Primary G-CSF prophylaxis for adjuvant TC or FEC-D chemotherapy outside of clinical trial settings: a systematic review and meta-analysis Support Care Canc 20 10 2012 2523 2530\n4 Smith T.J. Bohlke K. Lyman G.H. Recommendations for the use of WBC growth factors: American society of clinical Oncology clinical practice guideline update J Clin Oncol 33 28 2015 3199 3212 26169616\n5 National comprehensive cancer network clinical practice guidelines in Oncology (NCCN Guidelines)®: breast cancer version 2 2017 https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf\n6 CCO Drug FormularyGCSF Working Group Cancer care Ontario GCSF recommendations 2016 https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/38561\n7 Amgen Canada Inc. Product monograph (filgrastim) http://pi.amgen.com/∼/media/amgen/repositorysites/pi-amgen-com/neupogen/neupogen_pi_hcp_english.ashx\n8 Amgen Canada Inc. Product monograph (pegfilgrastim) http://pi.amgen.com/∼/media/amgen/repositorysites/pi-amgen-com/neulasta/neulasta_pi_hcp_english.ashx\n9 Altwairgi A.K. Hopman W.M. Mates M. Real-world impact of granulocyte-colony stimulating factor on febrile neutropenia Curr Oncol 20 3 2013 e171 e179 23737687\n10 Hilton J. Vandermeer L. Sienkiewicz M. Filgrastim use in patients receiving chemotherapy for early-stage breast cancer-a survey of physicians and patients Support Care Canc 26 7 2018 2323 2331\n11 Fernandes R. Mazzarello S. Stober C. Optimal primary febrile neutropenia prophylaxis for patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer: a systematic review Breast Canc Res Treat 161 1 2017 1 10\n12 Clemons M. Mazzarello S. Hilton J. Feasibility of using a pragmatic trials model to compare two primary febrile neutropenia prophylaxis regimens (ciprofloxacin versus G-CSF) in patients receiving docetaxel-cyclophosphamide chemotherapy for breast cancer (REaCT-TC) Support Care Canc 27 4 2019 1345 1354\n13 Fernandes R. Mazzarello S. Joy A.A. Taxane acute pain syndrome (TAPS) in patients receiving chemotherapy for breast or prostate cancer: a prospective multi-center study Support Care Canc 26 9 2018 3073 3081\n14 Fernandes R. Mazzarello S. Majeed H. Treatment of taxane acute pain syndrome (TAPS) in cancer patients receiving taxane-based chemotherapy-a systematic review Support Care Canc 24 4 2016 1583 1594\n15 CADTH C.A.D.T.H. Canadian drug expert committee final recommendation: filgrastim (Grastofil - Apotex Inc.) indications: preventions or treatment of neutropenia 2016 CADTH\n16 Neulasta - Board Staff Statement of Allegations (Severed). http://www.pmprb-cepmb.gc.ca/view.asp?ccid=838 (September 28, 2016; [date last accessed)].\n17 Basulaiman B. Awan A.A. Fergusson D. Creating a pragmatic trials program for breast cancer patients: rethinking Clinical Trials (REaCT) Breast Canc Res Treat 2019 10.1007/s10549-019-05274-0\n18 ClinicalTrials.gov. A Multi-Cantre Study to Compare Granulocyte-colony Stimulating Factors to Antibiotics for Primary Prophylaxis of Taxotere/Cyclophosphamide-Induced Febrile Neutropenia REaCT-TC2. https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S0006DI3&selectaction=Edit&uid=U0001VRU&ts=50&cx=-ochws7.\n19 Kim S.Y. Miller F.G. Informed consent for pragmatic trials--the integrated consent model N Engl J Med 370 8 2014 769 772 24552326\n20 de Naurois J. Novitzky-Basso I. Gill M.J. Management of febrile neutropenia: ESMO clinical practice guidelines Ann Oncol 21 Suppl 5 2010 v252 v256 20555092\n21 Sung L. Nathan P.C. Alibhai S.M. Meta-analysis: effect of prophylactic hematopoietic colony-stimulating factors on mortality and outcomes of infection Ann Intern Med 147 6 2007 400 411 17876022\n22 Lyman G. Yau L. Nakov R. Overall survival and risk of second malignancies with cancer chemotherapy and G-CSF support Ann Oncol 29 9 2018 1903 1910 30099478\n23 Jones A. Barlow M. Barrett-Lee P. Management of cardiac health in trastuzumab-treated patients with breast cancer: updated United Kingdom National Cancer Research Institute recommendations for monitoring Br J Canc 100 5 2009 684\n24 Vaz-Luis I. Barroso-Sousa R. Di Meglio A. Avoiding peg-filgrastim prophylaxis during the paclitaxel portion of the dose-dense doxorubicin-cyclophosphamide and paclitaxel regimen: a prospective study J Clin Oncol 2020 10.1200/jco.19.02484:Jco1902484\n25 Smith T.J. Bohlke K. Lyman G.H. Recommendations for the use of WBC growth factors: American society of clinical Oncology clinical practice guideline update J Clin Oncol 33 28 2015 3199 3212 26169616\n26 Madarnas Y. Dent S.F. Husain S.F. Real-world experience with adjuvant fec-d chemotherapy in four Ontario regional cancer centres Curr Oncol 18 3 2011 119 125 21655158\n27 Vandenberg T. Younus J. Al-Khayyat S. Febrile neutropenia rates with adjuvant docetaxel and cyclophosphamide chemotherapy in early breast cancer: discrepancy between published reports and community practice-a retrospective analysis Curr Oncol 17 2 2010 2 3\n28 Soong D. Haj R. Leung M.G. High rate of febrile neutropenia in patients with operable breast cancer receiving docetaxel and cyclophosphamide J Clin Oncol 27 26 2009 e101 e102 19652050\n29 Weycker D. Barron R. Edelsberg J. Risk and consequences of chemotherapy-induced neutropenic complications in patients receiving daily filgrastim: the importance of duration of prophylaxis BMC Health Serv Res 14 2014 189 24767095\n30 Fernandes R. Mazzarello S. Stober C. Primary febrile neutropenia prophylaxis for patients who receive FEC-D chemotherapy for breast cancer: a systematic review J Glob Oncol 4 2018 1 8 10.1200/jgo.2016.008540\n31 Chen B. Nagai S. Armitage J.O. Regulatory and clinical experiences with biosimilar filgrastim in the US, the European Union, Japan, and Canada Oncol 24 4 2019 537\n32 Collins J.M. Fleming G.F. Christ T.N. Comparison of the incidence of febrile neutropenia in obese and normal weight breast cancer patients receiving myelosuppressive chemotherapy and prophylactic pegfilgrastim J Oncol Pharm Pract 25 5 2019 1112 1118 29768957\n33 Buchner A. Lammerich A. Abdolzade-Bavil A. Lipegfilgrastim: pharmacodynamics and pharmacokinetics for body-weight-adjusted and 6 mg fixed doses in two randomized studies in healthy volunteers Curr Med Res Opin 30 12 2014 2523 2533 25251999\n34 Clemons M. Fergusson D. Simos D. A multicentre, randomised trial comparing schedules of G-CSF (filgrastim) administration for primary prophylaxis of chemotherapy-induced febrile neutropenia in early stage breast cancer Ann Oncol 31 7 2020 951 957 32325257\n35 Fraser J. Steele N. Al Zaman A. Are patients in clinical trials representative of the general population? Dose intensity and toxicities associated with FE100C-D chemotherapy in a non-trial population of node positive breast cancer patients compared with PACS-01 trial group Eur J Canc 47 2 2011 215 220\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0960-9776",
"issue": "58()",
"journal": "Breast (Edinburgh, Scotland)",
"keywords": "Breast cancer; Ciprofloxacin; Docetaxel-cyclophosphamide; Febrile neutropenia; G-CSF",
"medline_ta": "Breast",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D002170:Canada; D003520:Cyclophosphamide; D000077143:Docetaxel; D064147:Febrile Neutropenia; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006098:Granulocytes; D006801:Humans",
"nlm_unique_id": "9213011",
"other_id": null,
"pages": "42-49",
"pmc": null,
"pmid": "33901921",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D065007:Pragmatic Clinical Trial; D016449:Randomized Controlled Trial",
"references": null,
"title": "A multi-centre study comparing granulocyte-colony stimulating factors to antibiotics for primary prophylaxis of docetaxel-cyclophosphamide induced febrile neutropenia.",
"title_normalized": "a multi centre study comparing granulocyte colony stimulating factors to antibiotics for primary prophylaxis of docetaxel cyclophosphamide induced febrile neutropenia"
} | [
{
"companynumb": "CA-AMGEN-CANSP2021084964",
"fulfillexpeditecriteria": "2",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": null,
... |
{
"abstract": "Intrauterine devices (IUDs) are rarely associated with serious infections. We report an unusual concomitant infection of group A Streptococcus (GAS) causing toxic shock syndrome and pelvic abscess with Actinomyces odontolyticus associated with an IUD in a healthy 50-year-old patient. The IUD was subsequently removed and the patient recovered on the appropriate antibiotics. This case highlights the importance of clinicians' high index of suspicion of an IUD infection and prompt removal of the infected foreign body to obtain source control.",
"affiliations": "Department of Internal Medicine, The Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.;Department of Infectious Diseases, The Miriam Hospital and Immunology Center, Providence, Rhode Island, USA Department of Infectious Diseases, Providence VA Medical Center, Providence, Rhode Island, USA.",
"authors": "Wu|Carolyn M Yu|CM|;Noska|Amanda|A|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000190:Actinomyces; D000196:Actinomycosis; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007434:Intrauterine Devices; D008875:Middle Aged; D000292:Pelvic Inflammatory Disease; D012772:Shock, Septic; D013290:Streptococcal Infections; D013297:Streptococcus pyogenes; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26965406",
"pubdate": "2016-03-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23394954;24234426;24681126;3292661;25722760;11944185;24774398;8532252;24502071;19577335;335092;7557952;26001364;19395487;4696986;15050180;11314920;20159185;17366042;16818488;19713010;4611218;11447809;11691576;1160788;5950528;15596277;4838895;24790135;15249886;26386777;25986979;19916766;17148065;16548322;6643210;7448549;7432401;17531616;7266960;24126401;6119576;25873798;12172534;20493959",
"title": "Intrauterine device infection causing concomitant streptococcal toxic shock syndrome and pelvic abscess with Actinomyces odontolyticus bacteraemia.",
"title_normalized": "intrauterine device infection causing concomitant streptococcal toxic shock syndrome and pelvic abscess with actinomyces odontolyticus bacteraemia"
} | [
{
"companynumb": "US-BAYER-2021-043256",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo determine the frequency of hypogammaglobulinemia and infections in patients with multiple sclerosis (PwMS) receiving rituximab (RTX).\n\n\nMETHODS\nThis prospective observational study included all consecutive PwMS receiving RTX at the university hospital of Marseille, France, between 2015 and 2020. Patient visits occurred at least every 6 months.\n\n\nRESULTS\nWe included 188 patients (151 with relapsing-remitting MS; the mean age was 43.4 years [SD 12.9], median disease duration 10 years [range 0-36], median Expanded Disability Status Scale 5 [range 0-8], median follow-up 3.5 years [range 1-5.8], and median number of RTX infusions 5 [range 1-9]). Overall, 317 symptomatic infections and 13 severe infections occurred in 133 of 188 (70.7%) and 11 of 188 (5.9%) patients, respectively. After 4 years, 24.4% of patients (95% CI 18.0-33.1) were free of any infection and 92.0% (95% CI 87.1-97.1) had not experienced a severe infection. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 32 of 188 (17%) patients. After RTX, IgG level was <7, <6, <4 and <2 g/L for 83 (44%), 44 (23.4%), 8 (4.2%) and 1 (0.53%) patients, respectively. The risk of infection was associated with reduced IgG levels (multivariate Cox proportional hazards hazard ratio [HR] = 0.86, 95% CI 0.75-0.98, p = 0.03). The risk of reduced IgG level <6 g/L increased with age (HR = 1.36, 95% CI 1.05-1.75, p = 0.01).\n\n\nCONCLUSIONS\nIn PwMS receiving RTX, reduced IgG level was frequent and interacted with the risk of infection.",
"affiliations": "From the Aix Marseille University (M.P., A.M., A.R., C.B., S.D., P.D., J.P., B.A.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; Aix Marseille University (J.-P.S.), APHM, Hôpital de la Timone, Département de Neuroradiologie; Aix Marseille University (A.M., J.-P.S., A.R., C.B., S.D., P.D., J.P., B.A.), CRMBM UMR 7339, CNRS, Marseille, France.;From the Aix Marseille University (M.P., A.M., A.R., C.B., S.D., P.D., J.P., B.A.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; Aix Marseille University (J.-P.S.), APHM, Hôpital de la Timone, Département de Neuroradiologie; Aix Marseille University (A.M., J.-P.S., A.R., C.B., S.D., P.D., J.P., B.A.), CRMBM UMR 7339, CNRS, Marseille, France.;From the Aix Marseille University (M.P., A.M., A.R., C.B., S.D., P.D., J.P., B.A.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; Aix Marseille University (J.-P.S.), APHM, Hôpital de la Timone, Département de Neuroradiologie; Aix Marseille University (A.M., J.-P.S., A.R., C.B., S.D., P.D., J.P., B.A.), CRMBM UMR 7339, CNRS, Marseille, France.;From the Aix Marseille University (M.P., A.M., A.R., C.B., S.D., P.D., J.P., B.A.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; Aix Marseille University (J.-P.S.), APHM, Hôpital de la Timone, Département de Neuroradiologie; Aix Marseille University (A.M., J.-P.S., A.R., C.B., S.D., P.D., J.P., B.A.), CRMBM UMR 7339, CNRS, Marseille, France.;From the Aix Marseille University (M.P., A.M., A.R., C.B., S.D., P.D., J.P., B.A.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; Aix Marseille University (J.-P.S.), APHM, Hôpital de la Timone, Département de Neuroradiologie; Aix Marseille University (A.M., J.-P.S., A.R., C.B., S.D., P.D., J.P., B.A.), CRMBM UMR 7339, CNRS, Marseille, France.;From the Aix Marseille University (M.P., A.M., A.R., C.B., S.D., P.D., J.P., B.A.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; Aix Marseille University (J.-P.S.), APHM, Hôpital de la Timone, Département de Neuroradiologie; Aix Marseille University (A.M., J.-P.S., A.R., C.B., S.D., P.D., J.P., B.A.), CRMBM UMR 7339, CNRS, Marseille, France.;From the Aix Marseille University (M.P., A.M., A.R., C.B., S.D., P.D., J.P., B.A.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; Aix Marseille University (J.-P.S.), APHM, Hôpital de la Timone, Département de Neuroradiologie; Aix Marseille University (A.M., J.-P.S., A.R., C.B., S.D., P.D., J.P., B.A.), CRMBM UMR 7339, CNRS, Marseille, France.;From the Aix Marseille University (M.P., A.M., A.R., C.B., S.D., P.D., J.P., B.A.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; Aix Marseille University (J.-P.S.), APHM, Hôpital de la Timone, Département de Neuroradiologie; Aix Marseille University (A.M., J.-P.S., A.R., C.B., S.D., P.D., J.P., B.A.), CRMBM UMR 7339, CNRS, Marseille, France.;From the Aix Marseille University (M.P., A.M., A.R., C.B., S.D., P.D., J.P., B.A.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; Aix Marseille University (J.-P.S.), APHM, Hôpital de la Timone, Département de Neuroradiologie; Aix Marseille University (A.M., J.-P.S., A.R., C.B., S.D., P.D., J.P., B.A.), CRMBM UMR 7339, CNRS, Marseille, France. bertrand.audoin@ap-hm.fr.",
"authors": "Perriguey|Marine|M|;Maarouf|Adil|A|;Stellmann|Jan-Patrick|JP|;Rico|Audrey|A|;Boutiere|Clemence|C|;Demortiere|Sarah|S|;Durozard|Pierre|P|;Pelletier|Jean|J|;Audoin|Bertrand|B|http://orcid.org/0000-0002-9860-7657",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/NXI.0000000000001115",
"fulltext": "\n==== Front\nNeurol Neuroimmunol Neuroinflamm\nNeurol Neuroimmunol Neuroinflamm\nnnn\nNEURIMMINFL\nNeurology® Neuroimmunology & Neuroinflammation\n2332-7812\nLippincott Williams & Wilkins Hagerstown, MD\n\nNEURIMMINFL2021039267\n10.1212/NXI.0000000000001115\n3\n41\n54\n135\nArticle\nHypogammaglobulinemia and Infections in Patients With Multiple Sclerosis Treated With Rituximab\nPerriguey Marine MD marine.perriguey@ap-hm.fr\n\nMaarouf Adil MD, PhD adil.maarouf@ap-hm.fr\n\nStellmann Jan-Patrick MD jan-patrick.stellmann@ap-hm.fr\n\nRico Audrey MD, PhD audrey.rico@ap-hm.fr\n\nBoutiere Clemence MD clemence.boutiere@ap-hm.fr\n\nDemortiere Sarah MD sarah.demortiere@ap-hm.fr\n\nDurozard Pierre MD pierre.durozard@ap-hm.fr\n\nPelletier Jean MD, PhD jean.pelletier@ap-hm.fr\n\nhttp://orcid.org/0000-0002-9860-7657\nAudoin Bertrand MD, PhD\nFrom the Aix Marseille University (M.P., A.M., A.R., C.B., S.D., P.D., J.P., B.A.), APHM, Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie; Aix Marseille University (J.-P.S.), APHM, Hôpital de la Timone, Département de Neuroradiologie; Aix Marseille University (A.M., J.-P.S., A.R., C.B., S.D., P.D., J.P., B.A.), CRMBM UMR 7339, CNRS, Marseille, France.\nCorrespondence Dr. Audoin bertrand.audoin@ap-hm.fr\nGo to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article.\n\nThe Article Processing Charge was funded by authors.\n\n1 2022\n23 11 2021\n23 11 2021\n9 1 e111508 7 2021\n07 10 2021\nCopyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.\n2021\nAmerican Academy of Neurology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.\n\nBackground and Objectives\n\nTo determine the frequency of hypogammaglobulinemia and infections in patients with multiple sclerosis (PwMS) receiving rituximab (RTX).\n\nMethods\n\nThis prospective observational study included all consecutive PwMS receiving RTX at the university hospital of Marseille, France, between 2015 and 2020. Patient visits occurred at least every 6 months.\n\nResults\n\nWe included 188 patients (151 with relapsing-remitting MS; the mean age was 43.4 years [SD 12.9], median disease duration 10 years [range 0–36], median Expanded Disability Status Scale 5 [range 0–8], median follow-up 3.5 years [range 1–5.8], and median number of RTX infusions 5 [range 1–9]). Overall, 317 symptomatic infections and 13 severe infections occurred in 133 of 188 (70.7%) and 11 of 188 (5.9%) patients, respectively. After 4 years, 24.4% of patients (95% CI 18.0–33.1) were free of any infection and 92.0% (95% CI 87.1–97.1) had not experienced a severe infection. At RTX onset, the immunoglobulin G (IgG) level was abnormal in 32 of 188 (17%) patients. After RTX, IgG level was <7, <6, <4 and <2 g/L for 83 (44%), 44 (23.4%), 8 (4.2%) and 1 (0.53%) patients, respectively. The risk of infection was associated with reduced IgG levels (multivariate Cox proportional hazards hazard ratio [HR] = 0.86, 95% CI 0.75–0.98, p = 0.03). The risk of reduced IgG level <6 g/L increased with age (HR = 1.36, 95% CI 1.05–1.75, p = 0.01).\n\nDiscussion\n\nIn PwMS receiving RTX, reduced IgG level was frequent and interacted with the risk of infection.\n\nOPEN-ACCESSTRUE\n==== Body\npmcB-cell depleting therapy is highly effective against relapsing forms of multiple sclerosis (MS).1,2 Nonetheless, among disease-modifying therapies for MS, B-cell depleting therapy is associated with the highest risk of infection.3 Treatment-induced hypogammaglobulinemia contributes to infections in patients with rheumatologic and hematologic diseases and neuromyelitis optica disorders treated with B-cell depleting therapy.4-6 We do not know whether treatment-induced hypogammaglobulinemia could also be involved and be harmful in patients with MS (PwMS), who are generally younger and with fewer comorbidities than those with other diseases. Pivotal studies1,7 have demonstrated that hypogammaglobulinemia is infrequent in PwMS during the first years of treatment, but little is known about its potential medium-term incidence in nonselected patients nor about its interaction with the risk of infection.\n\nWe report the incidence of hypogammaglobulinemia and infections in PwMS receiving rituximab (RTX) in the MS center of Marseille, France, and followed since their first infusion.\n\nMethods\n\nStudy Population\n\nWe started to use RTX off-label for PwMS in the MS center of Marseille in 2015. All consecutive patients were prospectively included in an observational study. The induction treatment consisted of 1,000 mg infused twice at 2-week intervals. The maintenance regimen consisted of a single infusion of 1,000 mg administered every 6 months until 2018. After 2018, our department changed the clinical practice concerning the dosing interval used for off-label RTX in relapsing-remitting MS (see reference 8 for more details). We extended the interval between 2 infusions beyond 6 months and up to 24 months, maintaining clinical visits every 6 months and MRI monitoring at least annually.\n\nMedical Visits\n\nPatients visited the center for each RTX infusion, in case of relapse or adverse events, and at least every 6 months. In case of fever, patients had to inform our department at any time. All examinations were performed by the same neurologist of our department (A.R., C.B., A.M., J.P., or B.A.) and included a standardized screening for infection, the most frequent potential adverse event associated with RTX. All infections were graded by using the Common Terminology Criteria for Adverse Events v4.0: grade 1, asymptomatic; grade 2, localized or noninvasive intervention indicated; grade 3, intravenous antibiotic, antifungal, or antiviral drugs indicated, interventional radiology or surgical intervention indicated; grade 4, life-threatening events; and grade 5, death. To be retained as a symptomatic infection (grade ≥ 2), a clinical event must be characterized by physical signs suggestive of infection and fever or positive radiographic or positive laboratory findings.\n\nSerum Levels of Immunoglobulins\n\nImmunoglobulin (Ig) levels were measured before RTX onset and at least every 6 months. Four categories of IgG levels were defined: normal level, ≥7 g/L; reduced IgG level 1, 6–7 g/L; reduced IgG level 2, 4–6 g/L; reduced IgG level 3, 2–4 g/L; and reduced IgG level 4, ≤2 g/L. Corresponding levels for IgM were <0.4 g/L and for IgA <0.7 g/L.\n\nStatistical Analysis\n\nMultivariate Cox proportional hazard models for recurrent events were used to assess the risk of symptomatic infection. Variables tested were age, disease duration, Expanded Disability Status Scale (EDSS) score, sex, and levels of Igs. To account for intraindividual correlation of observations, we included patient ID as a cluster variable. We investigated the occurrence of reduced Ig levels during RTX treatment with similar multivariate models. Hazard ratios (HRs) and 95% CIs were computed for the following variables: age, sex, and disease-modifying therapy with an immunosuppressive action before RTX. We used the Schoenfeld test to check for possible violations of the proportional hazard model. R v4.0.2, including the survival package, was used for statistical analysis, and p < 0.05 was considered statistically significant.\n\nStandard Protocol Approvals, Registrations, and Patient Consents\n\nThe authors obtained ethical approval of the institutional review board of the university hospital of Marseille, France (approval no.: RGPD/Ap-Hm 2021-19), to conduct this study.\n\nData Availability\n\nAll data analyzed during this study will be shared anonymized by reasonable request of a qualified investigator to the corresponding author.\n\nResults\n\nStudy Population\n\nIn total, 188 patients received RTX and were followed in our department since 2015; 151 (80.5%) had relapsing-remitting MS, 20 (10.5%) secondary progressive MS, and 17 (9%) primary progressive MS. RTX was used as first-line therapy in 18 patients; 159 (84.6%) patients received at least 1 disease-modifying therapy with an immunosuppressive action before RTX. At RTX onset, the mean age of patients was 43.4 years (SD 12.9), sex ratio 1.7 (F/M; 118/70), median disease duration 10 years (range 0–36), and median EDSS score 5 (range 0–8). The median follow-up after the first RTX infusion was 3.5 years (range 1–5.8), and the median number of RTX infusions 5 (range 1–9).\n\nEleven patients stopped RTX during the follow-up because of severe infection (n = 5), hypogammaglobulinemia (n = 1), psoriasis (n = 1), inflammatory bowel disease (n = 1), stroke (n = 1), myocardial infarction (n = 1), and toxidermia (n = 1). Eight patients were lost to follow-up.\n\nFrequency of Reduced Levels of Igs\n\nBefore and after RTX onset, 32 (17%) and 83 (44%) of the 188 patients showed reduced IgG level <7 g/L, 14 (7.4%) and 44 (23.4%) reduced IgG level <6 g/L, 1 (0.53%) and 8 (4.2%) reduced IgG level <4 g/L, and none and 1 (0.53%) reduced IgG level <2 g/L (Figure). At baseline, 26 (14.1%) patients had an IgM level <0.4 g/L, but no patient had a level <0.2 g/L. During the follow-up, 16 (8.6%) patients had an IgM <0.2 g/L and 67 (35.8%) from 0.2 to 0.4 g/L. Reduced IgA level <0.7 g/L was uncommon at baseline (n = 10, 5.4%) and during the follow-up (n = 23, 12.3%).\n\nFigure Time in Years to First Infection or Hypogammaglobulinemia and Predictors\n\nTime in years to first symptomatic infection (Common Terminology Criteria for Adverse Events v4.0, grade ≥2) (A) first severe infection (grade ≥3), (C) first reduced serum immunoglobulin G (IgG) level <6 g/L, (D) and first reduced serum immunoglobulin M (IgM) level <0.4 g/L in patients with multiple sclerosis treated with rituximab (RTX) (G). Predictors of symptomatic infections, (B) severe infections, (D) hypogammaglobulinemia of IgG and IgM after RTX onset, (F) and (H) respectively. Reduced IgA level <0.7 g/L was uncommon at baseline and during the follow-up (figure not reported). A similar model for IgM did not detect any association between the serum level and infections (figure not reported). Data in B, D, F and H are hazard ratios (HRs) (95% CIs). AgeDec = age per decade; EDSS = Expanded Disability Status Scale score; SEXM = sex male; TRT_IS_preO = treatment with an immunosuppressive action before RTX onset.\n\nFrequency of Infections After RTX Onset\n\nAfter RTX onset, 133 of 188 (70.7%) and 11 of 188 (5.9%) patients had 317 symptomatic infections (grade ≥2) and 13 severe infections (grade ≥3), respectively, with a median number of symptomatic infections per patient of 1 (range 0–16) (Table). Half of the patients had at least one infection after 1.5 years. After 4 years, 24.4% of patients (95% CI 18.0–33.1) were free of any infection and 92.0% (95% CI 87.1–97.1) had not experienced a severe infection.\n\nTable Symptomatic Infections (Common Terminology Criteria for Adverse Events v4.0 grade ≥ 2), Including 13 Severe Infections (grade ≥3), After Rituximab (RTX) Treatment\n\nPredictors of Symptomatic Infection and Hypogammaglobulinemia After RTX\n\nHigh IgG level was associated with the reduced risk of infection (HR = 0.86, 95% CI 0.75–0.98, p = 0.029), with no predictive value of age (HR = 0.89, 95% CI 0.75–1.05, p = 0.162), EDSS score (HR = 0.83, 95% CI 0.64–1.07, p = 0.143), male sex (HR = 0.86, 95% CI 0.60–1.24, p = 0.415), or interaction between IgG level and EDSS score (HR = 1.02, 95% CI 0.99–1.05, p = 0.122). Similar models for IgM did not detect any association between serum levels and infections. The risk of reduced IgG level <6 g/L increased with age (HR = 1.36, 95% CI 1.06–1.75, p = 0.016) but was not associated with sex (HR = 1.05, 95% CI 0.52–2.11, p = 0.902) or history of immunosuppressive treatment (HR = 1.17, 95% CI 0.46–3.02, p = 0.742). IgM level <0.4 g/L was more common in men vs women (HR = 1.98, 95% CI 1.28–3.04, p = 0.002) but was not associated with age (HR = 1.07, 95% CI 0.90–1.28, p = 0.421) or history of immunosuppressive treatment (HR = 1.33, 95% CI 0.69–2.56, p = 0.392). All patients with IgA level <0.7 g/L had a history of immunosuppression, but sex and age were not associated. All HRs were stable over time.\n\nDiscussion\n\nIn our study, 23.4% and 4.2% of PwMS, who received a median number of 5 RTX cycles (range 1–9), showed reduced IgG level <6 and <4 g/L. During this period, 70.7% of patients experienced at least 1 symptomatic infection and 5.9% at least 1 severe infection. Importantly, we demonstrate that IgG level interacted with the risk of infection.\n\nRecently, data were published from the open-label extension of the phase 3 study testing ocrelizumab in relapsing-remitting MS.9 The study revealed that at 5 years, 5.4% of the patients who completed the study had an IgG level <5.68 g/L. However, the authors did not compare the incidence of reduced IgG level between patients who received ocrelizumab from the study onset (5 years) or after 3 years. Moreover, the frequency of hypogammaglobulinemia reported at 5 years may be underestimated owing to a potential high incidence of reduced IgG level in patients who did not complete the study. In a recent retrospective study of a large sample of PwMS receiving RTX or ocrelizumab, 3.7% showed a reduced IgG value < 5 g/L after a mean exposure of 29.7 months (SD 21).10 As we demonstrated, this study found that IgG level interacted with the risk of infection.\n\nThe observational design of this study and the absence of a control group prevent firm conclusions about the incidence of hypogammaglobulinemia and infections directly related to treatment. Moreover, the rather short observation time might have restricted the ability to detect an increase in risk of hypogammaglobulinemia with longer treatment duration. However, the present findings highlight the need to regularly monitor Ig levels in PwMS receiving B-cell depleting therapy to potentially reduce the risk of infection.\n\nStudy Funding\n\nThe authors report no targeted funding.\n\nDisclosure\n\nAll authors report no disclosures relevant to the manuscript. Go to Neurology.org/NN for full disclosures.\n\nAppendix Authors\n\nGlossary\n\nEDSS Expanded Disability Status Scale\n\nHR hazard ratio\n\nIg immunoglobulin\n\nMS multiple sclerosis\n\nPwMS patients with multiple sclerosis\n\nRTX rituximab\n==== Refs\nReferences\n\n1. Hauser SL, Waubant E, Arnold DL, et al. B-cell depletion with rituximab in relapsing–remitting multiple sclerosis. N Engl J Med. 2008;358 (7 ):676-688.18272891\n2. Hauser SL, Bar-Or A, Comi G, et al . Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med. 2017;376 (3 ):221-234.28002679\n3. Luna G, Alping P, Burman J, et al . Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol. 2020;77 (2 ):184-191.31589278\n4. Avouac A, Maarouf A, Stellmann JP, et al . Rituximab-induced hypogammaglobulinemia and infections in AQP4 and MOG antibody-associated diseases. Neurol Neuroimmunol Neuroinflamm. 2021;8 (3 ):e977.33722933\n5. Marcinnò A, Marnetto F, Valentino P, et al . Rituximab-induced hypogammaglobulinemia in patients with neuromyelitis optica spectrum disorders. Neurol Neuroimmunol Neuroinflamm. 2018;5 (6 ):e498.30258855\n6. Barmettler S, Ong MS, Farmer JR, Choi H, Walter J. Association of immunoglobulin levels, infectious risk, and mortality with rituximab and hypogammaglobulinemia. JAMA Netw Open. 2018;1 (7 ):e184169.30646343\n7. Montalban X, Hauser SL, Kappos L, et al . Ocrelizumab versus Placebo in primary progressive multiple sclerosis. N Engl J Med. 2017;376 (3 ):209-220.28002688\n8. Maarouf A, Rico A, Boutiere C, et al. Extending rituximab dosing intervals in patients with MS during the COVID-19 pandemic and beyond? Neurol Neuroimmunol Neuroinflamm. 2020;7 (5 ):e825.32587103\n9. Hauser SL, Kappos L, Arnold DL, et al. Five-years of ocrelizumab in relapsing multiple sclerosis: OPERA studies open-label extension. Neurology. 2020;95 (13):e1854-e1867.32690791\n10. Vollmer BL, Wallach AI, Corboy JR, Dubovskaya K, Alvarez E, Kister I. Serious safety events in rituximab-treated multiple sclerosis and related disorders. Ann Clin Transl Neurol. 2020;7 (9 ):1477-1487.32767531\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2332-7812",
"issue": "9(1)",
"journal": "Neurology(R) neuroimmunology & neuroinflammation",
"keywords": null,
"medline_ta": "Neurol Neuroimmunol Neuroinflamm",
"mesh_terms": null,
"nlm_unique_id": "101636388",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34815322",
"pubdate": "2022-01",
"publication_types": "D016428:Journal Article",
"references": "30646343;33722933;32767531;18272891;30258855;32690791;32587103;28002688;28002679;31589278",
"title": "Hypogammaglobulinemia and Infections in Patients With Multiple Sclerosis Treated With Rituximab.",
"title_normalized": "hypogammaglobulinemia and infections in patients with multiple sclerosis treated with rituximab"
} | [
{
"companynumb": "FR-ROCHE-2971932",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "There are few established treatments for patients with non-small-cell lung cancer (NSCLC) with interstitial lung disease (ILD). The safety and efficacy of albumin-bound paclitaxel (nab-paclitaxel) in combination with carboplatin is uncertain, although the combination of carboplatin and paclitaxel is the most common regimen for treating NSCLC patients with ILD. A total of 9 NSCLC patients with ILD, treated between April 2013 and March 2016, were retrospectively investigated. Carboplatin (AUC 5-6) was administered on day 1 and nab-paclitaxel on days 1, 8 and 15, every 4-6 weeks. The median age of the patients upon initiating chemotherapy was 67 years. The pathological examination revealed 6 patients with squamous cell carcinoma, and 6 patients exhibited the typical pattern of ILD. The response rate was 55.6%, and the median progression-free and overall survival time was 174 and 344 days, respectively. Acute exacerbation of ILD was not observed in any of the patients, and febrile neutropenia developed in 3 patients (3/9, 33.3%). Thus, treatment with carboplatin plus nab-paclitaxel was found to be safe and effective for NSCLC patients with ILD, although management of hematological adverse events, such as febrile neutropenia, was required. However, these encouraging results require confirmation by a large-scale clinical trial.",
"affiliations": "Department of Respiratory Medicine, Kitasato University Hospital, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University Hospital, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University Hospital, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University Hospital, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University Hospital, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University Hospital, Sagamihara, Kanagawa 252-0374, Japan.",
"authors": "Niwa|Hideyuki|H|;Nakahara|Yoshiro|Y|;Yokoba|Masanori|M|;Mitsufuji|Hisashi|H|;Sasaki|Jiichiro|J|;Masuda|Noriyuki|N|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2017.1359",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2049-9450",
"issue": "7(4)",
"journal": "Molecular and clinical oncology",
"keywords": "albumin-bound paclitaxel; carboplatin; interstitial lung disease; non-small-cell lung cancer",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "604-608",
"pmc": null,
"pmid": "28855994",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": "26412456;21623239;21471095;25470694;26375877;19947998;19659650;24388373;28066768;21036764;24836310;17079694;26712084;26124387;25245821;19420811;20493578;19363140;27130459;22547591;15665326;24846037;8404104;16387947;26177183;19692680;11790668;17167137;18337594;25563718",
"title": "Safety and efficacy of carboplatin plus nab-paclitaxel for treating advanced non-small-cell lung cancer with interstitial lung disease.",
"title_normalized": "safety and efficacy of carboplatin plus nab paclitaxel for treating advanced non small cell lung cancer with interstitial lung disease"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-20170901789",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Acute necrotizing encephalopathy (ANE), a fulminant encephalopathy, is often found in childhood. It is still uncertain whether adult patients with ANE display clinical features different from patients with typical pediatric onset. Furthermore, alterations in neuroinflammatory factors in patients with ANE have not been well-characterized. Here, we present an adult patient with ANE, and review all reported adult ANE cases in the literature.\n\n\n\nSerum levels of five cytokines were checked in an adult patient with ANE and compared with gender/age-matched controls. Literature search was performed with PubMed, using the term as \"acute necrotizing encephalopathy\" with the filter of adult 19 + years.\n\n\n\nA total of 13 adult patients were reviewed. Compared with pediatric patients, adult ANE patients had similar clinical symptoms, biochemical data, and neuroimage findings, whereas adult ANE were more female-biased (female:male, 9:4) with a worse prognosis. Elevated cytokine levels in the serum and/or CSF is found in both adult-onset and pediatric-onset ANE. We found significantly elevated serum levels of IL-6 (17.17 pg/mL; healthy control: 1.43 ± 1.22 pg/mL) and VCAM-1 (3033.92 ng/mL; healthy control: 589.71 ± 133.13 ng/mL), and decreased serum TGF-β1 level (14.78 ng/mL, healthy controls: 25.81 ± 6.97 ng/mL) in our patient.\n\n\n\nOur findings clearly delineate the clinical features and further indicate the potential change in cytokine levels in adult patients with ANE, advancing our understanding of this rare disease.",
"affiliations": "Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Department of Neurology, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan.;Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan. Electronic address: gophy5128@cgmh.org.tw.",
"authors": "Lin|Yi-Ying|YY|;Lee|Kuang-Yung|KY|;Ro|Long-Sun|LS|;Lo|Yen-Shi|YS|;Huang|Chin-Chang|CC|;Chang|Kuo-Hsuan|KH|",
"chemical_list": "D016207:Cytokines; D018832:Molecular Chaperones; C508960:TGFB1 protein, human; D053773:Transforming Growth Factor beta1",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bj.2019.01.008",
"fulltext": "\n==== Front\nBiomed JBiomed JBiomedical Journal2319-41702320-2890Chang Gung University S2319-4170(17)30203-210.1016/j.bj.2019.01.008Original ArticleClinical and cytokine profile of adult acute necrotizing encephalopathy Lin Yi-Ying acLee Kuang-Yung bcRo Long-Sun acLo Yen-Shi acHuang Chin-Chang acChang Kuo-Hsuan gophy5128@cgmh.org.twac∗a Department of Neurology, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwanb Department of Neurology, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwanc College of Medicine, Chang Gung University, Taoyuan, Taiwan∗ Corresponding author. Department of Neurology, Chang Gung Memorial Hospital at Linkou, 5, Fusing St., Gueishan, Taoyuan 333, Taiwan. gophy5128@cgmh.org.tw12 7 2019 6 2019 12 7 2019 42 3 178 186 12 6 2017 22 1 2019 © 2019 Chang Gung University. Publishing services by Elsevier B.V.2019Chang Gung UniversityThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Background\nAcute necrotizing encephalopathy (ANE), a fulminant encephalopathy, is often found in childhood. It is still uncertain whether adult patients with ANE display clinical features different from patients with typical pediatric onset. Furthermore, alterations in neuroinflammatory factors in patients with ANE have not been well-characterized. Here, we present an adult patient with ANE, and review all reported adult ANE cases in the literature.\n\nMethods\nSerum levels of five cytokines were checked in an adult patient with ANE and compared with gender/age-matched controls. Literature search was performed with PubMed, using the term as “acute necrotizing encephalopathy” with the filter of adult 19 + years.\n\nResults\nA total of 13 adult patients were reviewed. Compared with pediatric patients, adult ANE patients had similar clinical symptoms, biochemical data, and neuroimage findings, whereas adult ANE were more female-biased (female:male, 9:4) with a worse prognosis. Elevated cytokine levels in the serum and/or CSF is found in both adult-onset and pediatric-onset ANE. We found significantly elevated serum levels of IL-6 (17.17 pg/mL; healthy control: 1.43 ± 1.22 pg/mL) and VCAM-1 (3033.92 ng/mL; healthy control: 589.71 ± 133.13 ng/mL), and decreased serum TGF-β1 level (14.78 ng/mL, healthy controls: 25.81 ± 6.97 ng/mL) in our patient.\n\nConclusions\nOur findings clearly delineate the clinical features and further indicate the potential change in cytokine levels in adult patients with ANE, advancing our understanding of this rare disease.\n\nKeywords\nAcute necrotizing encephalopathyAdultCytokineVCAM-1\n==== Body\nAt a glance of commentary\nScientific background on the subject\nAcute necrotizing encephalopathy (ANE), a fulminant encephalopathy presenting with symmetrical lesions in the thalami, putamina, cerebral and cerebellar white matter, and brain stem tegmentum, is often found in childhood. It is still uncertain whether adult patients with ANE display clinical features different from patients with typical pediatric onset.\n\nWhat this study adds to the field\nWe present an adult patient with ANE, and found high levels of IL-6 and VCAM-1 in the serum of our patient. By studying all reported adult ANE cases in the literature, we further found that adult ANE patients were more female-biased with a worse prognosis compared with classical pediatric ANE patients.\n\n\n\nAcute necrotizing encephalopathy (ANE) is a fulminant encephalopathy characterized by multifocal symmetrical lesions in the thalami and other locations such as cerebral white matter, cerebellar medulla, and brainstem tegmentum [1], [2]. More than 90% of patients had fever and upper airway infection prior to the onset of encephalopathy [1]. Almost all the patients develop seizures and disturbance of consciousness accompanied with decerebrate or decorticate posture [2]. The pathogenesis of ANE could be immune-mediated. It has been reported that cytokines, such as tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-2, IL-6, IL-10, and IL-15, play a role in ANE [3], [4], [5].\n\nANE often affects children younger than 5 years old in the Far East, mostly in Japan, Taiwan, and Korea [1], [2], [6]. Adult cases were seldom reported. It is still uncertain whether adult patients with ANE display clinical features different from patients with typical pediatric onset. Furthermore, alterations in neuroinflammatory factors in patients with ANE have not been well-characterized. Here, we present an adult case in which we examined five common microglia/macrophage-mediated cytokines to reveal potential biomarkers in adult ANE. To clearly delineate the clinical features of adult ANE, we examined reported cases of adult ANE and compared the clinical presentations of our patients with those reported in the literature. Our findings may improve our understanding of this immune-mediated encephalopathy.\n\nMaterial and methods\nReport a case\nWe presented an adult female case of ANE. We diagnosed ANE according to the diagnostic criteria suggested by Mizuguchi M [3]. The criteria are summarized below:1. Rapid conscious change and convulsions following a febrile viral infection.\n\n2. Elevation of protein without pleocytosis in cerebrospinal fluid (CSF).\n\n3. CT or MRI showing symmetric lesions in bilateral thalami; Other locations such as cerebral periventricular white matter, internal capsule, putamen, upper brain stem tegmentum and cerebellar medulla are also common; Except above locations, no other intracranial lesions.\n\n4. Elevation of serum aminotransferases but not ammonia.\n\n5. Exclusion of resembling diseases.\n\n\n\nCytokine, anti-glycolipid and paraneoplastic antibody analysis\nMicroglial activation plays an important role in neuroinflammatory diseases [7]. Therefore, we used enzyme-linked immunosorbent assay (ELISA) Kits to check the serum levels of five common microglia/macrophage-mediated cytokines, including IL-6 (R&D), matrix metalloproteinase (MMP)-9 (R&D), vascular endothelial growth factor (VEGF, R&D), tumor growth factor (TGF)-β1 (R&D) and vascular cell adhesion molecule (VCAM-1 (R&D) [8]. All serum samples were collected before treatment with high-dose steroid. Serum of gender and age-matched controls were recruited from 18 female healthy volunteers (mean age: 37.56 ± 11.51 years). Anti-ganglioside (anti-GD1a, anti-GD1b, anti-GM1, anti-GM2, anti-GM3, anti-GQ1b and anti-GT1b) and paraneoplastic anti-neuronal antigen (anti-TITIN, anti-SOX1, anti-RECOVERIN, anti-Hu, anti-Yo, anti-Ri, anti-Ma2, anti-CV2 and anti-AMPHIPHYSIN) autoantibodies will be tested by immunoblot strip kit (Euroimmun) according to the manufacturer's instruction.\n\nLiterature search and review\nLiterature search was performed with PubMed. We searched the term as “acute necrotizing encephalopathy” with the filter of adult 19 + years. The literature were reviewed from 1979, which is when ANE was first reported [9], until November 2015. We enrolled case reports or case series that had individual information about clinical manifestations, laboratory data, brain images, and outcomes of adult patients with ANE. Twelve adult patients with ANE were identified in the literature [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21]. In total, 13 patients, including this patient, are reviewed and discussed [Table 1].Table 1 Clinical information of adult-onset ANE in 13 patients.\n\nTable 1\tAge/Sex\tClinical symptoms & signs\tLaboratory findings\tCharacteristic finding of images\tTreatment\tOutcome\tReference\t\nSerum\tCSF\tCT (Low-density lesions)\tMRI (Hyperintensity lesions on T2 FLAIR or T2-weighted)\t\n1\t30/F\tfever, flu-like symptoms, CD, convulsive seizure, decerebrate posture, LR (−/−), DTR ↓, BS (+/+)\tLeukopenia, CRP↑, ALT/AST ↑\nIL-6 ↑, VCAM-1 ↑\tNo pleocytosis, protein ↑,\nIgG index ↑\tBil. Th\tBil. Th, CWM, CM, BT; microbleeds on SWI\tAnti-viral, Antimicrobials, PT, PP\tExpired\tour case\t\n2\t80/M\tfever, flu-like symptoms, CD, convulsive seizure, corneal reflex (−/−), VOR (−)\tDIC, acute liver failure, Cr ↑\nInf B (+)\nIL-6 ↑\tNA\tBil. Th\tNA\tAnti-viral,\nPT, IVIG\tExpired\t[11]\t\n3\t23/F\tfever, flu-like symptoms, CD, decerebrate posture, LR (−), cornea reflex (−), DTR ↑\tThrombocytopenia, ALT/AST ↑\tprotein ↑\tNA\tBil. Th, brainstem, and cerebellum; Bil. Th hemorrhage on gradient sequence\tAntimicrobials\tExpired\t[17]\t\n4\t39/F\tdiarrhea, CD, decorticate rigidity, LR (−), BS(+)\tLDH ↑, ALT/AST ↑\tNo pleocytosis, protein ↑\tBil. Th, basal ganglia, CWM, and brainstem\tBil. Th, basal ganglia, CWM, and brainstem\tNA\tPersistent vegetative state\t[19]\t\n5\t40/M\tfever, diarrhea, flu-like symptoms, CD\tLDH ↑, CRP↑,\nALT/AST↑, thrombocytopenia, coagulopathy,\nInf A-H1N1 (+) in nasopharyngeal swabs\tNo pleocytosis, protein ↑\tBil. Th, brainstem\tBil. Th and brainstem; microbleeds on gradient echo\tAnti-viral, Antimicrobials\tLittle improvement\t[20]\t\n6\t27/F\tflu-like symptoms, CD, LR (−), corneal reflex (−)\tInf A RT-PCR (+)\tNo pleocytosis, protein ↑\tdiffuse cerebral white matter edema\tBil Th, CWM, CM, brainstem; microbleeds on gradient echo\tAnti-viral\tExpired\t[13]\t\n7\t76/F\tfever, CD, corneal reflex (−/−), VOR (−), DTR ↓\tLDH ↑, CPK ↑, ALT/AST ↑\nIL-6 ↑, IL-10 ↑\tLymphocytic pleocytosis, protein ↑, IL-6 ↑\tNA\tBil. Th, globus pallidus, caudate head, BT\tPT, IVIG\tLittle improvement\t[18]\t\n8\t22/M\tfever, CD\tALT ↑, Cr ↑\nInf A IgA (+)\tNo pleocytosis, protein ↑\tNA\tBil. Th\tAnti-viral, antimicrobials\tComplete recovery\t[9]\t\n9\t24/F\tfever, vomiting, diarrhea, CD, pathologic reflex (+)\tthrombocytopenia, lactate ↑,\nALT/AST ↑, Cr ↑, coagulopathy\tNo pleocytosis protein ↑\tBil. Th\tBil. Th, CWM, CM\tAnti-viral\tMild cognitive disability\t[12]\t\n10\t27/M\tfever, flu-like symptoms, CD, convulsive seizure, decerebrate rigidity, DTR ↑\tInf A-H3N2 (+)\tNeutrophilic pleocytosis, protein ↑\nIL-1β ↑, IL-6 ↑\tBil. Th\tBil. Th, brainstem, and CWM\tAnti-viral, PT\tWheelchair-bound\t[10]\t\n11\t20/F\tfever, CD, right limbs convulsion, decerebrate posture, pupil dilation, LR (−), DTR ↓, BS (+/−)\tALT ↑\tNA\tNA\tBil. Th, BT\tAnti-viral, steroid,\nIVIG\tLeft hemiparesis, personality change\t[14]\t\n12\t46/F\tfever, CD, convulsion, DTR ↑,\npathologic reflex (+)\tLDH ↑, γ-globulin↑ hypoalbuminemia\tNo pleocytosis protein ↑\tBil. Th\tBil. Th\tPT\tCognitive disability\t[16]\t\n13\t67/F\tdysarthria, dysphagia, ataxia, nystagmus, painful paresthesia, CD, arms rigidly extended\tabnormal liver function\tXanthochromic, protein ↑\tBil. Th, brainstem, cerebellum\tNA\tNA\tExpired\t[15]\t\nAbbreviations: F: female; M: male; CD: disturbance of consciousness; LR: pupillary light reflex; DTR: deep tendon reflex; BS: Babinski sign; VOR: vestibulo-ocular reflex; CSF: cerebrospinal fluid; DIC: disseminated intravascular coagulation; CRP: C-reactive protein; LDH: lactate dehydrogenase; CPK: creatine phosphokinase; Cr: creatinine; Bil.: bilateral; Th: thalami; BT: brainstem tegmentum; CWM: cerebral white matter; CM: cerebellar medulla; NA: not available; T1(+): T1-weighted image post gadolinium enhancement; DWI: Diffusion-weighted images; SWI: Susceptibility weighted images; Anti-viral: Anti-viral agent; PT: steroid pulse therapy; PP: plasmapheresis; IVIG: Intravenous immunoglobulin.\n\n\n\nResults\nReport a case\nA 30-year-old female patient was admitted with Epstein–Barr virus (EBV)-related nasal cavity extranodal NK/T cell lymphoma. She began to develop a spiking fever (up to 40 °C), cough, sore throat, and rhinorrhea following a 3rd round of chemotherapy with a CHOP regimen (Cyclophosphamide 100 mg + Doxorubicin 60 mg + Vincristine 2 mg + Prednisone 1 mg/kg/day). Shortly afterwards, she experienced episodic generalized tonic-convulsive seizures followed by loss of consciousness within 24 h. Physical examination showed reduced consciousness, increased sweating, decerebrate posture, absence of pupillary light reflexes, decreased deep tendon reflex, and bilateral Babinski signs. Hemogram and biochemical studies showed leukopenia (3000/μL), and elevated C-reactive protein (CRP, 71.28 mg/L), aspartate aminotransferase (AST, 106 U/L), alanine aminotransferase (ALT, 43 U/L), and procalcitonin (48.64 ng/mL). The blood levels of glucose, ammonia, bilirubin, alkaline phosphatase, renal function, electrolytes, and thyroid function were within normal limits. Blood autoimmune markers, anti-glycolipids, and paraneoplastic anti-neuronal antibodies were all negative. CSF analysis showed high protein levels (133.5 mg/dL) and IgG index (1.18) without the presence of leukocytes. Her blood EBV genome copy number increased from 331 copies/mL to 779 copies/mL over the course of two months. IgG and IgM to EBV-viral-capsid antigen and IgG to EBV-early antigen were absent in the CSF. Infectious studies for herpes simplex virus, human immunodeficiency virus, Japanese encephalitis virus, cytomegalovirus, and influenza virus A and B were negative. The repeated CSF cytology (2 sessions) were negative for malignancies.\n\nInitial brain computed topography (CT) in the emergency department showed bilateral low-density thalamic lesions [Fig. 1A]. Brain magnetic resonance imaging (MRI), performed 12 h after disease onset, found bilateral thalamic lesions with hypointensities and ring-like contrast enhancement on T1-weighted (T1W) images [Fig. 1B]. In addition, similar contrast-enhanced lesions were also noted in the midbrain, pontine tegmentum, and cerebellum [Fig. 1B]. Water restrictions were detected in the bilateral periventricular white matter and thalami in diffusion-weighted images (DWIs, [Fig. 1C]). Susceptibility weighted images (SWIs) showed bleeding in both thalami [Fig. 1D]. Follow-up brain MRI on day 11 of disease onset revealed bilateral thalamic hyperintensity on T1W images that suggested subacute hemorrhages in the necrotic region [Fig. 2A]. Compared with the 1st MRI, contrast-enhanced lesions over the brainstem tegmentum and cerebellum were no longer apparent [Fig. 2B]. T2-weighted (T2W) images with a fluid attenuation inversion recovery (FLAIR) sequence and DWI showed prominent hyperintensities over the periventricular white matter, thalami, midbrain, pontine tegmentum, and subcortical white matter of the cerebellum bilaterally [Fig. 2C–D]. These lesions were identified as microbleeds on the SWIs [Fig. 2E].Fig. 1 The initial brain CT (A) and brain MRI performed 12 h after disease onset (B, C, D). (A) CT revealed low-density lesions over the bilateral thalami. (B) MRI found bilateral thalamic hypointensities with ring enhancement and hyperintensities in the midbrain, pontine tegmentum, and cerebellum on T1-weighted images with gadolinium enhancement. (C) Water restrictions were detected on bilateral periventricular white matter and thalamus in diffusion-weighted images. (D) Significant bleeding over the bilateral thalami on susceptibility weighted images.\n\nFig. 1Fig. 2 Brain MRI on day 11 of disease onset. (A) Bilateral thalamic hyperintensity on T1-weighted images suggest subacute hemorrhagic change in the central necrotic region. (B) Previous gadolinium enhanced lesions over the brainstem tegmentum and cerebellum are no longer apparent. (C) and (D) T2 FLAIR series and diffusion-weighted images showed progressive hyperintensities over the periventricular white matter, thalami, midbrain, pontine tegmentum, and subcortical white matter of the cerebellum bilaterally. (E) These lesions were identified as microbleeds on susceptibility-weighted images.\n\nFig. 2\n\nLevels of cytokines checked one day after disease onset were shown in [Fig. 3]. As shown in [Fig. 3A–B], serum levels of IL-6 (17.17 pg/mL; healthy controls: 1.43 ± 1.22 pg/mL) and vascular cell adhesion molecule 1 (VCAM-1) (3033.92 ng/mL; healthy controls: 589.71 ± 133.13 ng/mL) in this patient were elevated compared with sex- and age-matched controls. Serum level of TGF-β1 (14.78 ng/mL, healthy controls: 25.81 ± 6.97 ng/mL) was lower than that of control group [Fig. 3C]. Serum levels of MMP-9 (40.31 pg/mL; healthy controls: 90.61 ± 54.39 pg/mL) and VEGF (126.36 pg/mL; healthy controls: 113.58 ± 74.52 pg/mL) were similar to the control group [Fig. 3D–E].Fig. 3 Serum levels of five common microglia-mediated cytokines. Higher serum levels of IL-6 (A) and VCAM-1 (B) were seen in this adult case of ANE compared with control group. Serum level of TGF-β1 (C) was lower, whereas MMP-9 (D), and VEGF (E) were similar to that of the control group.\n\nFig. 3\n\nEmpiric antimicrobial treatment, including vancomycin, cefepime, and metronidazole, as well as acyclovir, were given immediately at admission. Because she had neutropenia, we did not prescribe steroid until 2 weeks later. Methylprednisolone pulse therapy (1 g/day) was started on day 15 of admission for a total course of 5 days. Since there was little improvement in consciousness and clinical condition, two courses of plasmapheresis with five fractions in each were given from day 20–30 and day 37–46. Oral prednisolone (1 mg/kg/day) was initiated on day 20, and was gradually tapered down until stopping treatment on day 46 because of sepsis. The patient died 3 months later because of septic shock.\n\nLiterature review and integration\nDemographic presentation\nAs shown in [Table 1], in thirteen ANE cases (nine females and four males), the median age of onset was 30 years. Eleven cases were patients of Asian origin, and most of whom were Japanese (eight cases).\n\nClinical manifestations\nAll these thirteen patients had disturbance of consciousness and ten of them (77%) had fever. Seven cases (54%) got influenza virus infections or developed flu-like symptoms before change in consciousness. Influenza A and B virus infections were confirmed in four (31%) and one (8%) patient, respectively. Three (23%) cases had symptoms of gastrointestinal tract infection. Cranial nerves palsy were noted in 7 patients (54%), while decerebrate or decorticate postures were noted in 5 patients (38%). Pathological changes of deep tendon reflexes and Babinski's sign were observed in 5 patients (38%).\n\nLaboratory features\nElevated liver enzymes, such as AST, ALT, or lactate dehydrogenase, were reported in 11 of the 13 cases (85%). Thrombocytopenia and/or coagulopathy were also noted in four patients (31%). All 11 patients who received a lumbar puncture demonstrated high protein levels in the CSF. Only two patients (22%) had pleocytosis [11], [19].\n\nCytokine levels in the serum and/or CSF were checked in four cases [11], [12], [19]. All cases showed elevation of IL-6 in the serum or CSF. In addition, elevated serum levels of IL-10 [19] and VCAM-1 (our case), and elevated CSF levels of IL-1β [11], were observed.\n\nBrain MRIs performed in 11 cases showed the characteristic findings of lesions bilaterally in the thalami (100%), brainstem and/or brainstem tegmentum (62%), cerebral white matter (39%), and cerebellum and/or cerebellar medulla (31%). T2W/FLAIR images and DWIs revealed hyperintensities all over these lesions. Bleeding was detected on SWI or gradient echo (31%).\n\nThe results of biopsies in two patients showed symmetric, edematous, and necrotizing lesions over the basal ganglia (including the thalami) and cerebral white matter [12], as well as the midbrain [16]. Edematous lesions were also seen in the cerebral deep white matter, cerebellar dentate nuclei, and dorsolateral tegmentum of the brainstem [16]. Perivascular necrosis with hemorrhages was noted [12], [16]. Notably, lymphocytic or neutrophilic infiltrates were absent [12].\n\nTreatment and outcome\nAnti-viral agents (62%), antimicrobials (31%), high dose steroid (38%), intravenous immunoglobulin (IVIG) (23%), steroid (8%), and plasmapheresis (8%) were used in the treatment of patients with adult ANE. Five patients (39%) died, and three patients (23%) had little or no clinical improvement. Among the five patients with improvement, only one patient completely recovered following treatment. Neurological sequelae persisted in the other four surviving patients. In 11 patients that literature had mentioned about treatment, 6 of them received immune therapy such as high dose steroid, IVIG, or plasmapheresis. Patients with immune therapy (2 patients died, 1 patient had little improvement, and 3 patient had neurological sequelae) displayed similar outcome to those who did not (2 patients died, 1 patient had little improvement, 1 patient had persisted neurological sequelae, and 1 patient had total recovery).\n\nDiscussion\nWe presented an adult case of ANE, a 31-year-old female, whose clinical features, laboratory data, and neuroimages fulfilled the diagnostic criteria of ANE suggested by Mizuguchi M [3]. Other differential diagnoses, such as lymphoma with central nervous system (CNS) involvement, acute disseminated encephalomyelitis (ADEM), and viral encephalitis were not likely. Central nervous system involvement of lymphoma developed in weeks to months [21], [22], [23], but the clinical deterioration of this case was full blown within days. Although elevated serum levels of pro-inflammatory cytokines have been reported in patients with NK/T cell lymphoma [24], repeated cranial CT and MRI further excluded the recurrence of NK/T cell lymphoma. Moreover, negative results of repeated CSF cytology excluded the potential leptomeningeal involvement of lymphoma. However, CHOP treatment may increase the release of IL-6 and contribute to the development of ANE [25]. MRIs of brain in ADEM demonstrate asymmetrical cortical and subcortical lesions [26], [27], whereas the neuroimaging studies of this patient showed symmetrical thalamic and subcortical lesions characteristic of ANE. Cerebrospinal fluid surveys of viral encephalitis including EBV, herpes simplex virus, Japanese encephalitis virus, and cytomegalovirus, were negative. Although we did not get the consent to obtain brain tissues for pathological confirmation, the diagnosis of ANE is still well-established.\n\nIn the literature review, we demonstrated that adult patients with ANE and pediatric ANE had similar clinical presentations, laboratory data, and imaging findings. Both groups of the patients commonly present with antecedent viral infection, fever, disturbance of consciousness, decerebrate or decorticate posture, cranial nerve involvement, and pathologic reflexes. Influenza A infection is the most common infection detected in patients with ANE [2]. Biochemical tests usually reveal elevated liver enzymes, while thrombocytopenia and coagulopathy are occasionally observed in hemograms. High protein levels without pleocytosis are typically observed in the CSF. Bilateral thalamic lesions in CT or MRI exist in all patients with ANE. Other regions, including the brainstem, cerebellum, and cerebral white matter, are also involved [2].\n\nHowever, adult patients with ANE had distinct sex distribution and prognosis from pediatric ones. Pediatric ANE affects boys and girls equally [22], whereas ANE in adults appears to be more prevalent in females than in males (female/male = 2.25). In children, the mortality rate of ANE is approximately 25%, while 60% (33% of all patients) of survivors recover without significant neurological sequelae [2]. In adults, the mortality rate of ANE is approximately 40% and most survivors have significant neurological sequelae. Although the number of adult cases was too small to interpret the data powerfully, we saw the trend that ANE in adult patients struck females more than males and had worse prognosis.\n\nPoor prognosis in adult patients has also been observed in other CNS inflammatory diseases. In acute disseminated encephalomyelitis (ADEM), complete motor recovery was frequently seen in pediatric patients compared with adults [23]. The median time to reach an Expanded Disability Status Scale (EDSS) score of 4 was approximately 10 years longer in pediatric than in adult patients with multiple sclerosis (MS) [26]. Neuromyelitis optica (NMO) in children typically has a monophasic course and many have complete neurological recovery [27], [28], whereas adult NMO frequently occurs as a polyphasic illness that is either fulminant and fatal, or associated with varying degrees of recovery [29]. These features suggest distinct immunological responses and neural repair potentials between pediatric and adult CNS inflammatory diseases.\n\nOur cytokine assays further indicate the potential role of IL-6 and VCAM-1 in the pathogenesis of ANE in adults. Elevation of IL-6 has been previously reported in the serum and CSF of adult [11], [12], [19] and pediatric patients with ANE [3], [4], [30], [31], as well as in other inflammatory and autoimmune diseases such as MS, systemic lupus erythematosus, rheumatoid arthritis, and systemic sclerosis [32]. IL-6 plays a role in the differentiation of B, Th2, and Th17 cells [32], [33]. Overexpression of IL-6 in mouse astrocytes leads to extensive breakdown of the blood–brain barrier and neuroinflammation [34]. Further studies to assess the level of IL-6 in CSF and brain will provide more supports to the role of IL-6 in ANE.\n\nVCAM-1, one of the adhesion molecules, mediates endothelial function by activation and adhesion of leukocytes [35]. High serum levels of VCAM-1, for the first time, were found in our patient with ANE. Compared with the levels in patients with MS and other non-inflammatory neurological diseases, the CSF levels of VCAM-1 are elevated in patients with NMO [36]. In the rat brain, VCAM-1 co-localizes with the apoptotic marker active caspase-3, indicating the association of VCAM-1 with neuronal apoptosis [37]. VCAM-1 is upregulated by many cytokines such as IL-1β and tumor necrosis factor (TNF)-α [35], [38]. It has been shown that the levels of IL-1β and TNF-α were also elevated in the serum of pediatric patients with ANE [3], [5]. Further studies to assess the levels of IL-1β and TNF-α in blood and CSF will elucidate the regulation of VCAM-1 in adult ANE. In experimental autoimmune encephalomyelitis (EAE) murine model, selective knockout of TGF-β1 in B cells exhibits increased neuroinflammation and demyelination [39]. Administration of TGF-β1 prevented the occurrence of relapses in EAE mice [40]. The finding of low serum TGF-β1 level in our patient further suggests a possible role for TGF-β in the regulation and treatment of ANE.\n\nConclusions\nThis adult patient with ANE showed high serum levels of IL-6 and VCAM-1, and low serum TGF-β1 level. Although these findings are similar to those in pediatric ANE, these cytokine deregulations still provide important information on precision medicine targeting relevant pathways in adult ANE. More systemic surveys of cytokine profiles will be important to elucidate the differences between adult and pediatric ANE. Our literature study demonstrates that adult and pediatric ANE share the similar clinical symptoms, biochemical data, and CT/MRI findings, whereas adult ANE tends to have female preponderance and relatively poor prognosis compared to pediatric ANE. These findings advance our understanding of this rare neuroinflammatory disease in adult patients.\n\nEthics approval and consent to participate\nThis study was performed under a protocol approved by the institutional review boards of Chang Gung Memorial Hospital.\n\nConflicts of interest\nThe authors declare that they have no competing interests.\n\nAcknowledgement\nThis study was sponsored by Chang Gung Medical Foundation (CMRPG 3C1631-33). The funders had no role design of the study and collection, analysis, and interpretation of data and in writing the manuscript.\n\nPeer review under responsibility of Chang Gung University.\n==== Refs\nReferences\n1 Mizuguchi M. Abe J. Mikkaichi K. Noma S. Yoshida K. Yamanaka T. Acute necrotising encephalopathy of childhood: a new syndrome presenting with multifocal, symmetric brain lesions J Neurol Neurosurg Psychiatry 58 1995 555 561 7745402 \n2 Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel form of acute encephalopathy prevalent in Japan and Taiwan Brain Dev 19 1997 81 92 9105653 \n3 Akiyoshi K. Hamada Y. Yamada H. Kojo M. Izumi T. Acute necrotizing encephalopathy associated with hemophagocytic syndrome Pediatr Neurol 34 2006 315 318 16638510 \n4 Kubo T. Sato K. Kobayashi D. Motegi A. Kobayashi O. Takeshita S. A case of HHV-6 associated acute necrotizing encephalopathy with increase of CD56bright NKcells Scand J Infect Dis 38 2006 1122 1125 17148094 \n5 Kansagra S.M. Gallentine W.B. Cytokine storm of acute necrotizing encephalopathy Pediatr Neurol 45 2011 400 402 22115004 \n6 Kim J.H. Kim I.O. Lim M.K. Park M.S. Choi C.G. Kim H.W. Acute necrotizing encephalopathy in Korean infants and children: imaging findings and diverse clinical outcome Korean J Radiol 5 2004 171 177 15467414 \n7 Lee Y.B. Nagai A. Kim S.U. Cytokines, chemokines, and cytokine receptors in human microglia J Neurosci Res 69 2002 94 103 12111820 \n8 Chang K.H. Wu Y.R. Chen Y.C. Chen C.M. Plasma inflammatory biomarkers for Huntington's disease patients and mouse model Brain Behav Immun 44 2015 121 127 25266150 \n9 Mizuta R. Izumi H. Takeuchi S. A case of Reye's syndrome with elevation of influenza A CF antibody Shonika Rinsho 32 1979 2144 2149 \n10 Fasano A. Natoli G.F. Cianfoni A. Ferraro D. Loria G. Bentivoglio A.R. Acute necrotizing encephalopathy: a relapsing case in a European adult J Neurol Neurosurg Psychiatry 79 2008 227 228 17846107 \n11 Iijima H. Wakasugi K. Ayabe M. Shoji H. Abe T. A case of adult influenza A virus-associated encephalitis: magnetic resonance imaging findings J Neuroimaging 12 2002 273 275 12116748 \n12 Ishii N. Mochizuki H. Moriguchi-Goto S. Shintaku M. Asada Y. Taniguchi A. An autopsy case of elderly-onset acute necrotizing encephalopathy secondary to influenza J Neurol Sci 354 2015 129 130 25982501 \n13 Kato H. Hasegawa H. Iijima M. Uchigata M. Terada T. Okada Y. Brain magnetic resonance imaging of an adult case of acute necrotizing encephalopathy J Neurol 254 2007 1135 1137 17294066 \n14 Lee Y.J. Smith D.S. Rao V.A. Siegel R.D. Kosek J. Glaser C.A. Fatal H1N1-related acute necrotizing encephalopathy in an adult Case Rep Crit Care 2011 2011 562516 24826323 \n15 Miyata E. An adult case of acute necrotizing encephalopathy No Shinkei 54 2002 354 355 \n16 Mizuguchi M. Tomonaga M. Fukusato T. Asano M. Acute necrotizing encephalopathy with widespread edematous lesions of symmetrical distribution Acta Neuropathol 78 1989 108 111 2735185 \n17 Nakamura Y. Miura K. Yamada I. Ino H. Mizobata T. A novel adult case of acute necrotizing encephalopathy of childhood with bilateral symmetric thalamic lesions Rinsho Shinkeigaku 40 2000 827 831 11218705 \n18 Narra R. Mandapalli A. Kamaraju S.K. Acute necrotizing encephalopathy in an adult J Clin Imag Sci 5 2015 20 \n19 Saji N. Yamamoto N. Yoda J. Tadano M. Yamasaki H. Shimizu H. Adult case of acute encephalopathy associated with bilateral thalamic lesions and peripheral neuropathy No Shinkei 58 2006 1009 1014 \n20 Shirai T. Fujii H. Ono M. Watanabe R. Shirota Y. Saito S. A novel autoantibody against ephrin type B receptor 2 in acute necrotizing encephalopathy J Neuroinflammation 10 2013 128 24139226 \n21 Ventura E. Summa A. Ormitti F. Picetti E. Crisi G. Influenza a H1N1 related acute necrotizing encephalopathy: radiological findings in adulthood NeuroRadiol J 25 2012 397 401 24029031 \n22 Mizuguchi M. Acute encephalopathy with necrosis of bilateral tha- lami: clinical aspects Neuropathology 13 1993 327 331 \n23 Ketelslegers I.A. Visser I.E. Neuteboom R.F. Boon M. Catsman-Berrevoets C.E. Hintzen R.Q. Disease course and outcome of acute disseminated encephalomyelitis is more severe in adults than in children Mult Scler 17 2011 441 448 21148017 \n24 Cai Q. Huang H.Q. Bai B. Yan G. Li J. Lin S. The serum spectrum of cytokines in patients with NK/T-Cell lymphoma and its cilincial significance in survival Blood 122 2013 1759 \n25 Cheung Y.T. Ng T. Shwe M. Ho H.K. Foo K.M. Cham M.T. Association of proinflammatory cytokines and chemotherapy-associated cognitive impairment in breast cancer patients: a multi-centered, prospective, cohort study Ann Oncol 26 2015 1446 1451 25922060 \n26 Simone I.L. Carrara D. Tortorella C. Liguori M. Lepore V. Pellegrini F. Course and prognosis in early-onset MS: comparison with adult-onset forms Neurology 59 2002 1922 1928 12499484 \n27 Chia W.C. Wang J.N. Lai M.C. Neuromyelitis optica: a case report Pediatr Neonatol 51 2010 347 352 21146800 \n28 Jeffery A.R. Buncic J.R. Pediatric Devic's neuromyelitis optica J Pediatr Ophthalmol Strabismus 33 1996 223 229 8880614 \n29 Wingerchuk D.M. Weinshenker B.G. Neuromyelitis optica: clinical predictors of a relapsing course and survival Neurology 60 2003 848 853 12629245 \n30 Ichiyama T. Endo S. Kaneko M. Isumi H. Matsubara T. Furukawa S. Serum cytokine concentrations of influenza-associated acute necrotizing encephalopathy Pediatr Int 45 2003 734 736 14651552 \n31 Ito Y. Ichiyama T. Kimura H. Shibata M. Ishiwada N. Kuroki H. Detection of influenza virus RNA by reverse transcription-PCR and proinflammatory cytokines in influenza-virus-associated encephalopathy J Med Virol 58 1999 420 425 10421411 \n32 Yao X. Huang J. Zhong H. Shen N. Faggioni R. Fung M. Targeting interleukin-6 in inflammatory autoimmune diseases and cancers Pharmacol Ther 141 2014 125 139 24076269 \n33 Jego G. Palucka A.K. Blanck J.P. Chalouni C. Pascual V. Banchereau J. Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6 Immunity 19 2003 225 234 12932356 \n34 Brett F.M. Mizisin A.P. Powell H.C. Campbell I.L. Evolution of neuropathologic abnormalities associated with blood-brain barrier breakdown in transgenic mice expressing interleukin-6 in astrocytes J Neuropathol Exp Neurol 54 1995 766 775 7595649 \n35 Burne M.J. Elghandour A. Haq M. Saba S.R. Norman J. Condon T. IL-1 and TNF independent pathways mediate ICAM-1/VCAM-1 up-regulation in ischemia reperfusion injury J Leukoc Biol 70 2001 192 198 11493610 \n36 Uzawa A. Mori M. Masuda S. Kuwabara S. Markedly elevated soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1 levels, and blood-brain barrier breakdown in neuromyelitis optica Arch Neurol 68 2011 913 917 21747031 \n37 Zhang D. Yuan D. Shen J. Yan Y. Gong C. Gu J. Up-regulation of VCAM1 relates to neuronal apoptosis after intracerebral hemorrhage in adult rats Neurochem Res 40 2015 1042 1052 25868755 \n38 Zonneveld R. Martinelli R. Shapiro N.I. Kuijpers T.W. Plotz F.B. Carman C.V. Soluble adhesion molecules as markers for sepsis and the potential pathophysiological discrepancy in neonates, children and adults Crit Care 18 2014 204 24602331 \n39 Bjarnadottir K. Benkhoucha M. Merkler D. Weber M.S. Payne N.L. Bernard C.C. B cell-derived transforming growth factor-beta1 expression limits the induction phase of autoimmune neuroinflammation Sci Rep 6 2016 34594 27708418 \n40 Kuruvilla A.P. Shah R. Hochwald G.M. Liggitt H.D. Palladino M.A. Thorbecke G.J. Protective effect of transforming growth factor beta 1 on experimental autoimmune diseases in mice Proc Natl Acad Sci USA 88 1991 2918 2921 2011600\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2319-4170",
"issue": "42(3)",
"journal": "Biomedical journal",
"keywords": "Acute necrotizing encephalopathy; Adult; Cytokine; VCAM-1",
"medline_ta": "Biomed J",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000369:Aged, 80 and over; D001921:Brain; D001927:Brain Diseases; D016207:Cytokines; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018832:Molecular Chaperones; D053773:Transforming Growth Factor beta1",
"nlm_unique_id": "101599820",
"other_id": null,
"pages": "178-186",
"pmc": null,
"pmid": "31466711",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "17148094;24076269;12629245;12116748;8880614;14651552;11493610;25973284;21747031;25982501;17134009;7595649;12111820;11218705;24029031;16638510;21146800;11993167;2735185;15467414;27708418;2011600;9105653;17294066;25922060;21148017;10421411;7745402;24826323;17846107;12932356;12499484;24602331;25266150;22115004;25868755;24139226",
"title": "Clinical and cytokine profile of adult acute necrotizing encephalopathy.",
"title_normalized": "clinical and cytokine profile of adult acute necrotizing encephalopathy"
} | [
{
"companynumb": "TW-PFIZER INC-2019398984",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "Infliximab, a monoclonal antibody directed against tumour necrosis factor, is an effective therapy for moderate-to-severe ulcerative colitis and Crohn's disease. Uncommonly, serious opportunistic infections have occurred in patients after infliximab administration. Here, we describe meningitis caused by Listeria monocytogenes developing in a 37-year-old man with ulcerative colitis refractory to intravenous corticosteroids 10 days after receiving his first infusion of infliximab. With the increasing use of tumour necrosis factor-α-neutralizing agents, clinicians should be aware of the risk of opportunistic infections caused by L. monocytogenes in patients with inflammatory bowel disease following infliximab treatment. The half-life of infliximab is 9.5 days; therefore, patients tend to be more susceptible in the immediate period following infusion. Patients receiving anti-TNF therapy should be advised to avoid foods such as soft cheeses and unpasteurized dairy products.",
"affiliations": "Connolly Hospital Blanchardstown, Dublin, Ireland. vikpar37@yahoo.com.;Connolly Hospital Blanchardstown, Dublin, Ireland.;Connolly Hospital Blanchardstown, Dublin, Ireland.;Connolly Hospital Blanchardstown, Dublin, Ireland.;Connolly Hospital Blanchardstown, Dublin, Ireland.;Connolly Hospital Blanchardstown, Dublin, Ireland.;Connolly Hospital Blanchardstown, Dublin, Ireland.;Connolly Hospital Blanchardstown, Dublin, Ireland.",
"authors": "Parihar|V|V|;Maguire|S|S|;Shahin|A|A|;Ahmed|Z|Z|;O'Sullivan|M|M|;Kennedy|M|M|;Smyth|C|C|;Farrell|R|R|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D006854:Hydrocortisone",
"country": "Ireland",
"delete": false,
"doi": "10.1007/s11845-015-1355-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-1265",
"issue": "185(4)",
"journal": "Irish journal of medical science",
"keywords": "Hydrocortisone; Inflammatory bowel disease; Infliximab; Listeria meningitis",
"medline_ta": "Ir J Med Sci",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D003093:Colitis, Ulcerative; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D006854:Hydrocortisone; D000069285:Infliximab; D008297:Male; D008584:Meningitis, Listeria; D009894:Opportunistic Infections; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "7806864",
"other_id": null,
"pages": "965-967",
"pmc": null,
"pmid": "26358724",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "15138212;12047962;14687847;9321530;11812415;23072245;11596589;10228190;12154220;14699483;12384912;10710107;18294633;12571839;11291675;11280541",
"title": "Listeria meningitis complicating a patient with ulcerative colitis on concomitant infliximab and hydrocortisone.",
"title_normalized": "listeria meningitis complicating a patient with ulcerative colitis on concomitant infliximab and hydrocortisone"
} | [
{
"companynumb": "IE-CMP PHARMA-2017CMP00011",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nPatients presenting with neurogenic bladder often require urological procedures (urodynamic testing and botulinum toxin injections) and a preventive antibiotic therapy. We aimed to assess the efficacy of this little known strategy in a cohort of patients.\n\n\nMETHODS\nAll patients presenting with neurogenic bladder who underwent urological procedure were included in the study. They received an antibiotic therapy in accordance with the urine cytobacteriological examination results. The antibiotic therapy was initiated two days before the procedure and prolonged up until two days after the procedure if the culture was positive. Patients were treated with a single dose of fosfomycin-trometamol in case of a negative culture. The main study outcome was the occurrence of urinary tract infection (UTI), defined by a positive urine culture and symptoms, up until 14 days after the procedure.\n\n\nRESULTS\nA total of 80 urological procedures were performed. Mean patient age was 47±13.1 years (sex ratio 1.22); 59 (73.8%) presented with asymptomatic bacteriuria before the procedure. Nine (11.1%) UTIs were recorded on Day 14, of which one (1.2%) was febrile. Two patients required an additional curative antibiotic therapy. No patient was hospitalized. Overall, 77.8% of UTIs were cured without antibiotic therapy.\n\n\nCONCLUSIONS\nScreening and treating asymptomatic bacteriuria before urological procedures seems unnecessary and vainly exposes this population at high risk of infectious diseases to antibiotic therapies. This data should be confirmed by a randomized clinical trial.",
"affiliations": "AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, unité d'urodynamique, 104, boulevard R.-Poincaré, 92380 Garches, France.;AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, unité des maladies infectieuses, 104, boulevard R.-Poincaré, 92380 Garches, France.;AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, unité d'urodynamique, 104, boulevard R.-Poincaré, 92380 Garches, France.;AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, département de pharmacie, 104, boulevard R.-Poincaré, 92380 Garches, France.;AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, unité des maladies infectieuses, 104, boulevard R.-Poincaré, 92380 Garches, France.;AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, unité des maladies infectieuses, 104, boulevard R.-Poincaré, 92380 Garches, France.;AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, unité des maladies infectieuses, 104, boulevard R.-Poincaré, 92380 Garches, France.;AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, unité des maladies infectieuses, 104, boulevard R.-Poincaré, 92380 Garches, France.;AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, unité d'urodynamique, 104, boulevard R.-Poincaré, 92380 Garches, France.;AP-HP, université Pierre-et-Marie-Curie, hôpital universitaire Pitié Salpêtrière, service d'urologie, 47-83, boulevard de l'Hôpital, 75013 Paris, France.;AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, unité d'urodynamique, 104, boulevard R.-Poincaré, 92380 Garches, France; AP-HP, hôpital universitaire R.-Poincaré, université Versailles-Saint-Quentin, hôpitaux Paris Île-de-France Ouest, unité des maladies infectieuses, 104, boulevard R.-Poincaré, 92380 Garches, France. Electronic address: aurelien.dinh@aphp.fr.",
"authors": "Weglinski|L|L|;Rouzaud|C|C|;Even|A|A|;Bouchand|F|F|;Davido|B|B|;Duran|C|C|;Salomon|J|J|;Perronne|C|C|;Denys|P|P|;Chartier-Kastler|E|E|;Dinh|A|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D019274:Botulinum Toxins, Type A",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0399-077X",
"issue": "46(6)",
"journal": "Medecine et maladies infectieuses",
"keywords": "Bactéries multi-résistantes; Infection urinaire; Multidrug-resistant bacteria; Neurogenic bladder; Prophylaxie; Prophylaxis; Urinary tract infection; Vessie neurologique",
"medline_ta": "Med Mal Infect",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D058070:Asymptomatic Diseases; D001437:Bacteriuria; D019274:Botulinum Toxins, Type A; D055499:Catheter-Related Infections; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D016896:Treatment Outcome; D001750:Urinary Bladder, Neurogenic; D014546:Urinary Catheterization; D014552:Urinary Tract Infections; D014563:Urodynamics; D014946:Wound Infection",
"nlm_unique_id": "0311416",
"other_id": null,
"pages": "300-7",
"pmc": null,
"pmid": "27241225",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Prospective evaluation of antibiotic treatment for urological procedure in patients presenting with neurogenic bladder.",
"title_normalized": "prospective evaluation of antibiotic treatment for urological procedure in patients presenting with neurogenic bladder"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1036282",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BOTULINUM TOXIN TYPE A"
},
"drugadditional": ... |
{
"abstract": "We report a case of ophthalmic artery occlusion (OAO) in a young patient with COVID-19 infection that was on therapeutic anticoagulation with apixaban for deep venous thrombosis (DVT). A 48-year-old man with obesity was hospitalized with a severe form of COVID-19 infection, complicated with acute respiratory failure, septic shock, dilated cardiomyopathy and fungemia. Despite treatment with prophylactic enoxaparin (initial D-Dimer 1.14 µg/ml FEU (normal < 0.05 µg/ml FEU), D-Dimer increased to above 20 µg/ml FEU and patient continued to spike high fevers. This prompted further investigations and upper and lower extremities DVTs were confirmed and managed with enoxaparin 1 mg/kg twice daily. D-dimer level decreased to 4.98 µg/ml FEU while on therapeutic anticoagulation. Three weeks later pending hospital discharge, the anticoagulation was switched to oral apixaban 10 mg twice daily. Patient developed acute severe right eye visual loss of no light perception and was diagnosed with incomplete OAO. D-Dimer was elevated at 2.13 µg/ml FEU. Stroke etiological work-up found no embolic sources, resolution of the dilated cardiomyopathy and negative antiphospholipid antibodies. Treatment was changed to enoxaparin and no thrombotic events were encountered to date. Ocular vascular complications have not yet been reported in COVID-19. Controversy exists on the best management algorithm for the hypercoagulable state associated to COVID-19 Either direct oral anticoagulants or low-molecular-weight-heparin are considered appropriate at discharge for patients with venous thromboembolism. The optimum regimen for ischemic stroke prevention and the significance of D-Dimer for anticoagulation monitoring in COVID-19 remain unclear.",
"affiliations": "Department of Neurology, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd, A6302, Los Angeles 90048, CA, United States. Electronic address: oana.dumitrascu@cshs.org.;Department of Pathology, Cedars-Sinai Medical Center, Los Angeles, CA, United States. Electronic address: oksana.volod@cshs.org.;Department of Ophthalmology, Cedars-Sinai Medical Center, Los Angeles, CA, United States. Electronic address: boseneuroeye@gmail.com.;Department of Ophthalmology, Cedars-Sinai Medical Center, Los Angeles, CA, United States. Electronic address: wangx699@gmail.com.;Department of Ophthalmology, Emory University School of Medicine, Atlanta, GA, United States; Department of Neurology, Emory University School of Medicine, Atlanta, GA, United States; Department of Neurological surgery, Emory University School of Medicine, Atlanta, GA, United States. Electronic address: vbiouss@emory.edu.;Department of Neurology, Cedars-Sinai Medical Center, 127 S. San Vicente Blvd, A6302, Los Angeles 90048, CA, United States. Electronic address: patrick.lyden@cshs.org.",
"authors": "Dumitrascu|Oana M|OM|;Volod|Oksana|O|;Bose|Swaraj|S|;Wang|Yao|Y|;Biousse|Valérie|V|;Lyden|Patrick D|PD|",
"chemical_list": "D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2020.104982",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "29(8)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Anticoagulation; COVID-19; Ophthalmic artery occlusion; Stroke",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D001157:Arterial Occlusive Diseases; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D057915:Drug Substitution; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D000076662:Host Microbial Interactions; D006801:Humans; D008297:Male; D008875:Middle Aged; D009880:Ophthalmic Artery; D058873:Pandemics; D011024:Pneumonia, Viral; D011720:Pyrazoles; D011728:Pyridones; D012307:Risk Factors; D000086402:SARS-CoV-2; D016896:Treatment Outcome; D020246:Venous Thrombosis",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "104982",
"pmc": null,
"pmid": "32689586",
"pubdate": "2020-08",
"publication_types": "D002363:Case Reports",
"references": "32302462;32320517;32232433;32311448;32268022;32329044;32343504;32336042;26064103;32616524;32073213",
"title": "Acute ophthalmic artery occlusion in a COVID-19 patient on apixaban.",
"title_normalized": "acute ophthalmic artery occlusion in a covid 19 patient on apixaban"
} | [
{
"companynumb": "US-ROCHE-2633559",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Chronic subdural hematoma (CSDH) is one of the most common neurological diseases, which mainly occurs among elderly people and usually develop after minor head injuries. Over the years, a simple burr hole evacuation of the hematoma has been accepted as the widespread method for most cases of CSDH, but acute parenchymal hemorrhage is a rare and deadly complication after surgery. We report three elderly cases of post-operative parenchymal hemorrhage and analyse the underlying factors and formulate relevant strategies in this article. Three advanced age patients had been admitted to our department with gradually increasing headache and limb activity disorder urgently and underwent an emergency operation of burr hole drainage of CSDH in frontal-temporal region after preoperative evaluations and examinations. Unfortunately, acute post-operative parenchymal hemorrhage occurred in three advanced age patients. Ultimately, the patients achieved satisfying outcome with no significant neurological deficit through conservative treatment. The exact mechanism of such uncommon complications are difficult to explain and remain poorly understood. Advanced age, hypertension, amyloidosis, high perfusion triggered by rapid hematoma release, cerebrospinal fluid (CSF) loss, oral anticoagulant, primary disease aggravation were the main mechanisms which were speculated in our report. Simultaneously, positive measures could be adopt to prevent this rare complication.",
"affiliations": "Department of Neurosurgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, 17 Lujiang Road, Hefei 230001, China.;Department of Neurosurgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, 17 Lujiang Road, Hefei 230001, China.",
"authors": "Wang|Yang|Y|;Wei|Xiangping|X|",
"chemical_list": null,
"country": "Uganda",
"delete": false,
"doi": "10.11604/pamj.2018.31.140.13982",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-31-14010.11604/pamj.2018.31.140.13982Case ReportAcute parenchymal hemorrhage of three cases report after burr hole drainage of chronic subdural hematoma Wang Yang 1Wei Xiangping 1&1 Department of Neurosurgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, 17 Lujiang Road, Hefei 230001, China& Corresponding author: Xiangping Wei, Department of Neurosurgery, Anhui Provincial Hospital Affiliated to Anhui Medical University, 17 Lujiang Road, Hefei 230001, China25 10 2018 2018 31 14026 9 2017 19 10 2018 © Yang Wang et al.2018The Pan African Medical Journal - ISSN 1937-8688. 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 work is properly cited.Chronic subdural hematoma (CSDH) is one of the most common neurological diseases, which mainly occurs among elderly people and usually develop after minor head injuries. Over the years, a simple burr hole evacuation of the hematoma has been accepted as the widespread method for most cases of CSDH, but acute parenchymal hemorrhage is a rare and deadly complication after surgery. We report three elderly cases of post-operative parenchymal hemorrhage and analyse the underlying factors and formulate relevant strategies in this article. Three advanced age patients had been admitted to our department with gradually increasing headache and limb activity disorder urgently and underwent an emergency operation of burr hole drainage of CSDH in frontal-temporal region after preoperative evaluations and examinations. Unfortunately, acute post-operative parenchymal hemorrhage occurred in three advanced age patients. Ultimately, the patients achieved satisfying outcome with no significant neurological deficit through conservative treatment. The exact mechanism of such uncommon complications are difficult to explain and remain poorly understood. Advanced age, hypertension, amyloidosis, high perfusion triggered by rapid hematoma release, cerebrospinal fluid (CSF) loss, oral anticoagulant, primary disease aggravation were the main mechanisms which were speculated in our report. Simultaneously, positive measures could be adopt to prevent this rare complication.\n\nAcute parenchymal hemorrhagechronic subdural hematomaburr hole drainage\n==== Body\nIntroduction\nChronic subdural haematoma (CSDH) is one of the most common neurosurgical conditions and is especially prevalent among elderly individuals [1]. Behavioural disturbance and neurological deficits are the most common first symptoms. Head trauma, advanced age, coagulopathies, and therapeutic anticoagulation are considered as risk factors [2]. In addition, intracranial hypotension due to cerebrospinal fluid (CSF) loss and the age-related increase of subdural space and subarachnoid cisterns may also accelerate CSDH formation [3]. Current management strategies of CSDH remain widely controversial. These strategies include surgical techniques such as single burr-hole drainage under local anesthesia, double burr-hole evacuation technique, formal craniotomy. Burr-hole craniectomy combined with subdural drainage is a relatively safe and effective management option [4, 5]. Neuroendo-scopic techniques have also been proposed for multiloculated or septated haematomas, but are rarely recommended routinely [6]. In our institution, bur hole craniostomy under local anesthesia has been the treatment of choice for patients with CSDH. Postoperative CSDH complications include recurrence, acute subdural hematoma, acute intracranial bleeding, chronic subdural collection of fluid, epilepsy, subdural empyema and tension pneumocephalus [7-9]. Previous reports have indicated acute parenchymal hemorrhage may occur in routine craniotomy and is related to a poor clinical outcome [10]. In our report, acute parenchymal hemorrhage all occurred in 3 cases after burr hole drainage. In our research, 135 CSDH patients?33 cases were over 70 years old) who admitted to Department of Neurosurgery, Anhui Provincial Hospital Affiliated to Anhui Medical University from August 2015 to October 2016 were retrospectively analysed. Unfortunately, acute post-operative and parenchymal hemorrhage occurred in advanced age patients, with an incidence of 9.9%. This study was done to investigate the causes of this uncommon complications and formulate relevant therapeutic strategies.\n\nPatient and observation\nCase 1: An 71-year-old male patient had been admitted to our department with two-week history of gradually increasing headache and slight limb activity disorder and a 2-month history of minor head trauma as a result of fall to the ground. Cranial CT revealed bilateral CSDH. There was hypertension and multiple lacunar infarction were the systemic diseases which were under normal control (Table 1). Chest radiography, electrocardiogram and the blood system examinations were completed preoperatively. Fortunately, the major data was not exceptional remarkably and preoperative coagulation parameters were within normal limits. The patient underwent an urgent operation of burr hole drainage of CSDH in bilateral frontal-temporal region. During the operation, subdural hematoma launched from bone hole after the opening of the dura in spite of over high intracranial pressure (ICP). The procedure was completed without any obvious accident and the vital signs remained stable during operation. Eventually, a subdural closed system of drainage was placed when intracranial pneumatosis was eliminated absolutely. Because of the exacerbation of conscious disturbance, emergent CT scan was taken at 2 hours postoperatively and revealed multiple parenchymal hemorrhage. Postoperative recovery was uneventful. Surgical intervention was not adopted, and the patient kept to conservative treatment including continuous neurological observation for 6 days in the NICU. The hospitalization time was prolonged to 20 days because of mental disturbance after the operation which was corrected successfully in that interval. Finally, the patient was discharged from hospital with no neurological deficit except for slight language barriers. At 2-month follow-up no abnormality was noted, and the CT scan revealed hematoma was absorbed completely (Figure 1).\n\nTable 1 pre-operative and post-operative data of 3 cases\n\nItems\tCase 1\tCase 2\tCase 3\t\nAge\t75y\t81y\t83y\t\nGender\tMale\tMale\tMale\t\nSide\tBilateral\tRight\tRight\t\nPresention\tHeadache, limb, activity disorder\tLimbs weakness\tDizziness and Headache\t\nPrimary disease\tHypertension, lacunar infarction\tCerebral infarction, coronary heart disease\tHypertension, COPD, asthma, ischemic heart disease\t\nAnticoagulant\tNone\tRivaroxaban\tNone\t\nOperation method\tBurr hole drainage\tBurr hole drainage\tBurr hole drainage\t\nDrainage amount (ml)\t700\t500\t750\t\nExtubation time (day)\t4\t4\t5\t\nHospitalization time (day)\t20\t12\t30\t\nCSDH: chronic subdural hematoma; COPD: chronic obstructive pulmonary disease\n\nFigure 1 Preoperative CT showed bilateral CSDH (chronic subdural hematoma); postoperative CT show multiple parenchymal hemorrhage; follow-up CT show hematoma absorption\n\nCase 2: in case 2 we reported an 82-years-old man had been admitted to our department due to limbs weakness presented progressive aggravation with undergoing frequent falls in the previous month and a history of cerebral infarction, arterial hypertension and coronary heart disease with long-term oral rivaroxaban. The CT scan showed a right equi-density subdural hematoma and brain tissue compression. The neurologic evaluation revealed slow response and weakness of the left limbs (Table 1). The urgent evacuation of the subdural hematoma was performed with a single parietal burr-hole craniectomy on the right side without discontinuing oral rivaroxaban. A subdural drainage catheter was positioned in prefrontal region routinely. Surprisingly, we observed right visual field defect the following day and vital signs was remained within normal range all the time. The post-operative CT scan showed a bit of prefrontal pneumocephalus and right occipital lobe hemorrhage and no acute bleedings in ipsilateral subdural space. The drainage tube removal was delayed to the fourth day. Meanwhile, the CT findings occipital hematoma appeared absorbed gradually and did not require surgical intervention. The neurologic evaluation revealed a slight postural instability and for this reason that the patient was arranged to physical therapy. At two-month follow-up, the patient was able to walk unaided, and the review CT scan was normal (Figure 2).\n\nFigure 2 Preoperative CT showed a right equidensity CSDH (chronic subdural hematoma) and brain tissue compression; postoperative CT right occipital lobe hemorrhage; follow-up CT show hematoma absorption\n\nCase 3: in case 3 we reported an 80-years-old man had been admitted to our department due to moderate dizziness and headache for 20 days with a history of hypertension, ischemic heart disease, chronic obstructive pulmonary disease (COPD) and asthma. Neurological assessment confirmed mental confusion and gait imbalance without focal deficits. The CT scan revealed a sizeable right chronic subdural hematoma which caused midline left shift (Table 1). The patient underwent an instant single burr-hole craniectomy and the right subdural hematoma evacuation was satisfactory largely. A subdural drainage apparatus was positioned routinely. On the second day after surgery, sudden airways spasm occurred and blood oxygen saturation presented unstable within a short time. Emergency tracheal incubation was implemented to maintain vital signs. Simultaneously, the drainage device was closed and a emergent CT scan was performed and revealed the presence of a small area occipital intraparenchymal hemorrhage. On the third day, the patient was transferred to the ICU and assisted respiration with ventilator postoperatively. Subsequently, the patient was required tracheotomy due to difficulty of removing trachea cannula within a short time. The drainage tube removal was delayed to the fifth day postoperatively. After one week, the patient successfully detached from the respirator and returned to general ward to continue anti-infective treatment for 10 days. Finally, the patient discharged from hospital with mild pulmonary inflammation, but therapeutic process was uneventful, and the total hospitalization time was up to one month. The two-month follow-up showed the patient was in good conditions and life-independent. The CT scan of the head revealed no recurrence (Figure 3).\n\nFigure 3 Preoperative CT showed a sizeable right CSDH (chronic subdural hematoma) which caused midline left shift; postoperative CT a small area occipital intraparenchymal hemorrhage; follow-up CT show hematoma absorption\n\nDiscussion\nPostoperative parenchymal hemorrhage generally occurs in operative region after tumor resection or hematoma clearance, mostly on account of inexact hemostasis. Subdural hematoma after drilling drainage operation of CSDH is the most common type of postoperative bleeding [11]. However, acute parenchymal hemorrhage occurrence after supratentorial burr hole drainage of CSDH is a kind of uncommon complications, which are difficult to explain and remain poorly understood at present [12, 13]. Moreover, what is amazing is that 3 cases we reported are all advanced age patients. Advanced age, hypertension, amyloidosis, high perfusion triggered by rapid hematoma release, CSF loss, oral anticoagulant, primary disease aggravation are the conceivable mechanisms currently debated. There was no doubt that the rate of multiple intracranial hemorrhage being similar to this condition in case 1 after burr hole evacuation of CSDH was percussive. The total hematoma volume was summed up to 40ml approximately without apparent midline shift and hematoma clearance combined with decompressive craniotomy should not be adopted under these circumstances due to mild disturbance of consciousness and neurologic defect. Although the actual pathophysiological mechanism still remained unclear, several possible causative factors have been considered, such as severe hypertension, amyloid degeneration, rapid brain decompression, shift of the intracranial contents during surgery and loss of CSF though analysing the whole process of diagnosis and treatment. Consequently, surgical procedure and occasion caused our attention. Blood pressure control, slow and concurrent evacuation of bilateral subdural hematoma was beneficial to prevent high perfusion and shift of the intracranial contents triggered by rapid hematoma release for bilateral CSDH patients. Once parenchymal hemorrhage occurred postoperatively, subdural drainage tube was raised or shut timely to stop hematoma expanding further. In addition, moderate dehydrator and coagulants application rather than hematoma evacuation was possible optimal choice for multifocal cerebral hemorrhage [14]. It goes without saying that therapeutic process was destined to be uneventful on condition that postoperative complications appeared, such as pulmonary infection and epileptic seizure. Fortunately, the therapeutic effect of this patient was satisfactory and discharged from hospital with no neurological deficit except for slight language barriers. It was well known that blood coagulopathy was suggested as a causative factor of postoperative intracranial bleeding all the time [15]. However, although there was no evident coagulation abnormality in pre-operative examination in case 2, we could not eliminate the underlying impact of oral anticoagulant drug, especially some new anticoagulants which are not acquainted so far absolutely.\n\nIn our case 2, there was no coagulation abnormality but a history of recent use of new anticoagulant [16]. Rivaroxaban, a new kind of direct inhibitors of factor Xa equipped with these advantages including fast acting time, short half-life and the low incidence of bleeding [17]. Most importantly, coagulation function monitoring was omitted during the period of oral drugs. Unfortunately, relevant deficiency was investigated in few literatures and rivaroxaban administration was not discontinued before surgery due to preoperative coagulation parameters being within normal limits. The assumption of coagulopathy caused by new anticoagulants should be considered as a risk factor resulting in ipsilateral occipital lobe hemorrhage. Therefore, when we encountered the CSDH patients with oral administration new anticoagulants, the specific procedures should be formulated. To begin with, the type and last medication time were realized, the necessity of emergency surgery was filtered strictly, and the mean time of drug discontinuance should be extended as long as possible for elective surgery [18]. Afterwards, laboratory examination, including APTT, PT, dTT and coagulation factors activities analysis were completed as quickly as possible and evaluated comprehensively [19]. Finally, blood products preparation, tranexamic acid, vitamin K1 application and supplement of PPSB were recommended regardless of existence of coagulation parameters abnormality [20]. To avoid infarction formation, new oral anticoagulants should be resumed as soon as possible after intracranial condition was stable.\n\nIn case 3, acute parenchymal hemorrhage took place followed by serious airways spasm exceeding our expectation. However, surgery acquired a success in this case sometimes, but the postoperative complications or primary diseases deterioration often make poor prognosis and the perioperative management of advanced age patients with CSDH brings us a challenge. Therefore, positive therapy of primary diseases, the management of respiratory tract, prophylactic drug use, early postoperative function exercise and multidisciplinary consultation can be prevented acute parenchymal bleeding induced by unexpectedly condition occurrence for advanced age patients. Despite all these analytical mechanisms are discussed through the above cases, no exact mechanisms have been confirmed to explain its occurrence properly. Although we cannot prevent bleeding events occurrence certainly after CSDH operation, we can decrease the incidence rate of acute parenchymal hemorrhage for hyper-aged CSDH patients which can't stand secondary brain injury provided that we conformed to normalized procedures.\n\nConclusion\nWe reported three cases of uncommon intraparenchymal hemorrhage after burr hole craniotomy for CSDH. They are probably associated with Advanced age, hypertension, amyloidosis, high perfusion triggered by rapid hematoma release, cerebrospinal fluid (CSF) loss, oral anticoagulant, primary disease aggravation. Although CSDH drainage is considered as a minimally invasive surgical approach, neurosurgeons must be aware of this rare and deadly event. Correction of coagulation function, control of blood pressure and treatment of primary diseases are essential in order to prevent such complications before operation. Careful and gentle evacuation of the subdural hematoma without excessive head rotation is suggested to avoid rapid shift of intracranial contents and local hyper transfusion during operation. Continuous electrocardiograph monitoring, repeated evaluation of neurologic conditions, prompt radiological assessment, positive therapy of primary disease, volume of drainage control strictly and the height of drainage tube adjustment are mandatory after operation. Above all, when the uncommon complication occurs, conservative treatment is recommended intensively unless enormous intracranial hematoma make the patients unconsciousness, even brain hernia. Unfortunately, evacuation of hematoma and decompressing craniotomy were only adopted to save lives accompanied by poor prognosis.\n\nCompeting interests\nThe authors declare no competing interests.\n\nAcknowledgments\nWe acknowledge all the staff of department of Neurosurgery in Anhui Provincial Hospital for their support.\n\nAuthors’ contributions\nYang Wang is responsible for collecting data and writing the manuscript. Xiangping Wei is responsible for its drafting and revision. The authors read and approved the final manuscript.\n==== Refs\nReferences\n1 Kolias AG Chari A Santarius T Hutchinson PJ Chronic subdural haematoma: modern management and emerging therapies Nat Rev Neurol 2014 10 10 10 570 8 25224156 \n2 Ahn JH Jun HS Kim JH Oh JK Analysis of risk factor for the development of chronic subdural hematoma in patients with traumatic subdural hygroma J Korean Neurosurg Soc 2016 11 59 6 622 627 27847577 \n3 Kristof RA Grimm JM Stoffel-Wagner B Cerebrospinal fluid leakage into the subdural space: possible influence on the pathogenesis and recurrence frequency of chronic subdural hematoma and subdural hygroma J Neurosurg 2008 2 108 2 275 80 18240922 \n4 Ducruet AF Grobelny BT Zacharia BE Hickman ZL The surgical management of chronic subdural hematoma Neurosurg Rev 2012 4 35 2 155 69 21909694 \n5 Javadi SA Naderi F Javadi AM The optimal surgical approach for treatment of chronic subdural hematoma: questionnaire assessment of practice in Iran and review of literature Acta Med Iran 2015 10 53 10 617 21 26615373 \n6 Májovský M Masopust V Netuka D Benes V Flexible endoscope-assisted evacuation of chronic subdural hematomas Acta Neurochir (Wien) 2016 10 158 10 1987 92 27473394 \n7 Qian Z Yang D Sun F Sun Z Risk factors for recurrence of chronic subdural hematoma after burr hole surgery: potential protective role of dexamethasone Br J Neurosurg 2017 2 31 1 84 88 27899031 \n8 Huang YH Yang TM Lin YJ Tsai NW Risk factors and outcome of seizures after chronic subdural hematoma Neurocrit Care 2011 4 14 2 253 9 21286854 \n9 Ihab Z Pneumocephalus after surgical evacuation of chronic subdural hematoma: is it a serious complication Asian J Neurosurg 2012 4 7 2 66 74 22870154 \n10 Pang CH Lee SE Kim CH Kim JE Acute intracranial bleeding and recurrence after bur hole craniostomy for chronic subdural hematoma J Neurosurg 2015 7 123 1 65 74 25679282 \n11 Ivamoto HS Lemos HP Jr Atallah AN Surgical treatments for chronic subdural hematomas: a comprehensive systematic review World Neurosurg 2016 2 86 399 418 26485412 \n12 Gürbüz MS Karaarslan N Gök S Soyalp C Remote cerebellar haemorrhage after burr hole drainage of chronic subdural haematoma: a case report J Clin Diagn Res 2016 5 10 5 PD01 2 \n13 Rusconi A Sangiorgi S Bifone L Balbi S Infrequent hemorrhagic complications following surgical drainage of chronic subdural hematomas J Korean Neurosurg Soc 2015 5 57 5 379 85 26113968 \n14 Chen S Zeng L Hu Z Progressing haemorrhagic stroke: categories, causes, mechanisms and managements J Neurol 2014 11 261 11 2061 78 24595959 \n15 Szczygielski J Gund SM Schwerdtfeger K Steudel WI Factors affecting outcome in treatment of chronic subdural hematoma in ICU patients: impact of anticoagulation World Neurosurg 2016 8 92 426 33 27241090 \n16 Bengtson LG Lutsey PL Chen LY MacLehose RF Comparative effectiveness of dabigatran and rivaroxaban versus warfarin for the treatment of non-valvular atrial fibrillation J Cardiol 2017 6 69 6 868 876 27889397 \n17 Arnao V Riolo M Tuttolomondo A Pinto A New frontiers in anticoagulation: non vitamin-K oral anticoagulants in stroke prevention Expert Rev Neurother 2017 6 17 6 539 552 27911120 \n18 Becattini C Sembolini A Paciaroni M Resuming anticoagulant therapy after intracerebral bleeding Vascul Pharmacol 2016 9 84 15 24 27260938 \n19 Riley TR Gauthier-Lewis ML Sanchez CK Douglas JS Role of agents for reversing the effects of target-specific oral anticoagulants Am J Health Syst Pharm 2017 1 74 2 54 61 27895055 \n20 Amano T Takahara K Maehara N Shimogawa T Optimal perioperative management of antithrombotic agents in patients with chronic subdural hematoma Clin Neurol Neurosurg 2016 12 151 43 50 27770654\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "31()",
"journal": "The Pan African medical journal",
"keywords": "Acute parenchymal hemorrhage; burr hole drainage; chronic subdural hematoma",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D002543:Cerebral Hemorrhage; D006259:Craniocerebral Trauma; D004322:Drainage; D006261:Headache; D020200:Hematoma, Subdural, Chronic; D006801:Humans; D008297:Male; D011183:Postoperative Complications; D012307:Risk Factors",
"nlm_unique_id": "101517926",
"other_id": null,
"pages": "140",
"pmc": null,
"pmid": "31037200",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "18240922;21286854;21909694;22870154;24595959;25224156;25679282;26113968;26485412;26615373;27241090;27260938;27437296;27473394;27770654;27847577;27889397;27895055;27899031;27911120",
"title": "Acute parenchymal hemorrhage of three cases report after burr hole drainage of chronic subdural hematoma.",
"title_normalized": "acute parenchymal hemorrhage of three cases report after burr hole drainage of chronic subdural hematoma"
} | [
{
"companynumb": "CN-JNJFOC-20190613947",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": null,
... |
{
"abstract": "Myoclonus is an abnormal involuntary movement that has been previously reported with administration of high doses of opioids for prolonged periods of time. In this case, however, we report an acute myoclonic reaction and review the literature on the possible causative pathophysiology. We report the case of a 24-year-old woman who was admitted for postdated cesarean section. She started to have abnormal involuntary movements after administration of an epidural anesthesia containing 700 μg of fentanyl with 115 mL (0.5) bupivacaine and 40 mL (2%) lidocaine. Upon examination, the patient was conscious, alert, and oriented. Her vital signs were stable. Her movements can be described as generalized, sudden, involuntary, jerking movements, involving the upper limbs, head, torso as well as the lower limbs. The frequency of these jerks was about every 1-2 min lasting for 10 s. There was no change in level of consciousness during these abnormal movements. The rest of the neurological examination was normal. Laboratory values showed normoglycemia and normal serum biochemistry. A routine electroencephalogram showed no epileptiform activity. Brain imaging was normal. Based on history, examination, and laboratory findings, we made the diagnosis of drug-induced myoclonus, which in this clinical scenario was secondary to fentanyl. We discontinued fentanyl and, gradually, the intensity and frequency of the abnormal movements decreased and disappeared after a few hours. A clear definitive explanation of the acute effect of opioids is still to be reached. It involves an interaction of complex neuroanatomical pathways and neurophysiological receptors. Nonetheless, a unanimous effort is needed to raise awareness about the role of opioids in the development of abnormal movements and their clinical management, to insure that they do not go unnoticed in the clinical scenarios, and to further add more scientific content that could help in reaching an explanatory theory.",
"affiliations": "College of Medicine, Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.;Department of Obstetrics and Gynecology, King Fahd Hospital of the University, Al-Khobar, Saudi Arabia.;Department of Neurology, King Fahd Hospital of the University, Al-Khobar, Saudi Arabia.",
"authors": "Almedallah|Dana Khaled|DK|;Alshamlan|Dana Yousef|DY|;Shariff|Erum Mubbashir|EM|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000486891",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1662-680X",
"issue": "10(2)",
"journal": "Case reports in neurology",
"keywords": "Fentanyl; Myoclonus; Opioids; Toxicity",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "130-134",
"pmc": null,
"pmid": "29928219",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "15353098;3090905;8656710;2988772;4003808;16844959;1742831;9060031;7486124;1562337;10202603;7673770;7149296;9514554;1919900;2531560;10960295",
"title": "Acute Opioid-Induced Myoclonic Reaction after Use of Fentanyl as an Anesthetic Drug for an Emergency Cesarean Section.",
"title_normalized": "acute opioid induced myoclonic reaction after use of fentanyl as an anesthetic drug for an emergency cesarean section"
} | [
{
"companynumb": "SA-MYLANLABS-2018M1083661",
"fulfillexpeditecriteria": "1",
"occurcountry": "SA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": "1",
... |
{
"abstract": "Hyperbaric oxygen (HBO2 ) therapy is infrequently reported as a treatment for poison-induced retinal damage. We describe a case in which HBO2 therapy was used to treat suspected retinal toxicity induced by quinine.\nWe present a case in which HBO2 was used to treat visual disturbances thought to be caused by quinine-induced retinal damage. The patient intentionally ingested undisclosed amounts of citalopram and quinine. Following a complicated hospital course, including profound shock requiring treatment with four vasopressors and a peripheral left-ventricular assist device, the patient, once extubated, reported visual abnormalities consistent with those described from quinine-induced retinal toxicity. Visual disturbances seemed to show improvement following HBO2 treatment. Several months following hospitalization visual defects continued to be present on examination. However, with corrective lenses the patient's visual acuity was normal. No adverse events were attributed to the use of HBO2.\nHBO2 for treatment of quinine-induced retinal damage is infrequently reported or studied. In the reported case, use of HBO2 appeared to be associated with substantial improvement in visual disturbances occurring in the setting of an overdose of quinine. The patient's improvement is remarkable, given her retinas were also jeopardized by her profound shock. Additional data are needed to understand the risks and benefits of this procedure, but due to limited treatment options for poison-induced retinal toxicity and the low likelihood for implementation of a controlled randomized trial of HBO2 in this population, the procedure may be considered in quinine-induced retinal toxicity.",
"affiliations": "Minnesota Poison Control System, Hennepin County Medical Center, Minneapolis, Minnesota U.S.;Department Center for Hyperbaric Medicine, Hennepin County Medical Center, Minneapolis, Minnesota.;Minnesota Poison Control System, Hennepin County Medical Center, Minneapolis, Minnesota U.S.",
"authors": "Laes|JoAn R|JR|;Hendriksen|Stephen|S|;Cole|Jon B|JB|",
"chemical_list": "D000962:Antimalarials; D011803:Quinine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1066-2936",
"issue": "45(4)",
"journal": "Undersea & hyperbaric medicine : journal of the Undersea and Hyperbaric Medical Society, Inc",
"keywords": " cardiovascular drugs ; drug overdose ; hyperbaric medicine ; quinine ; shock ",
"medline_ta": "Undersea Hyperb Med",
"mesh_terms": "D000962:Antimalarials; D005260:Female; D006801:Humans; D006931:Hyperbaric Oxygenation; D008875:Middle Aged; D011803:Quinine; D012164:Retinal Diseases; D014786:Vision Disorders",
"nlm_unique_id": "9312954",
"other_id": null,
"pages": "457-461",
"pmc": null,
"pmid": "30241126",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of hyperbaric oxygen therapy in quinine-associated visual disturbances.",
"title_normalized": "use of hyperbaric oxygen therapy in quinine associated visual disturbances"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2018GMK037621",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CITALOPRAM HYDROBROMIDE"
},
"... |
{
"abstract": "Headache disorders attributed to low and high intracranial pressure are commonly encountered in specialty headache practices and may occur more frequently than realized. While the headaches resulting from intracranial pressure disorders have what are conventionally thought of as defining characteristics, a substantial minority of patients do not manifest the \"typical\" features. Moreover, patients with intracranial pressure disorders may also have a preexisting primary headache disorder. Heightening the complexity of the presentation, the headaches of intracranial pressure disorders can resemble the phenotype of a primary disorder. Lastly, patients with so-called intracranial \"hypotension\" often have normal CSF pressure and neuroimaging studies. Thus, a high index of suspicion is needed. The published literature has inherent bias as many types of specialists evaluate and treat these conditions. This article reviews the key points to emphasize the history, examination, and laboratory evaluation of patients with intracranial pressure disorders from a neurologist's perspective.\n\n\n\nLumbar puncture opening pressure in patients with spontaneous intracranial hypotension was low enough to meet diagnostic criteria (≤60 mm CSF) in only 34% of patients in one study. Most patients had an opening pressure in the low normal to normal range, and 5% had an opening pressure of 200 mm CSF or more. Diskogenic microspurs are a common cause of this syndrome. The Idiopathic Intracranial Hypertension Treatment Trial found that most participants had a headache phenotype resembling migraine or tension-type headache. No \"typical\" or characteristic headache phenotype was found, and headache-related disability was severe at baseline. Headache disability did not correlate with the lumbar puncture opening pressure at baseline or at the 6-month primary outcome period. Although participants who were randomly assigned to acetazolamide had a lower mean CSF opening pressure at 6 months, headache disability in that group was similar to the group who received placebo.\n\n\n\nSignificant overlap is seen in the symptoms of high and low CSF pressure disorders and in those of primary headache disorders. Neurologists are frequently challenged by patients with headaches who lack the typical clinical signs or imaging features of the pseudotumor cerebri syndrome or spontaneous intracranial hypotension. Even when characteristic symptoms and signs are initially present, the typical features of both syndromes tend to lessen or resolve over time; consider these diagnoses in patients with long-standing \"chronic migraine\" who do not improve with conventional headache treatment. While the diagnostic criteria for pseudotumor cerebri syndrome accurately identify most patients with the disorder, at least 25% of patients with spontaneous intracranial hypotension have normal imaging and over half have a normal lumbar puncture opening pressure. Detailed history taking will often give clues that suggest a CSF pressure disorder. That said, misdiagnosis can lead to significant patient morbidity and inappropriate therapy.",
"affiliations": null,
"authors": "Friedman|Deborah I|DI|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1212/CON.0000000000000623",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1080-2371",
"issue": "24(4, Headache)",
"journal": "Continuum (Minneapolis, Minn.)",
"keywords": null,
"medline_ta": "Continuum (Minneap Minn)",
"mesh_terms": "D000328:Adult; D005260:Female; D006261:Headache; D006801:Humans; D019586:Intracranial Hypertension; D019585:Intracranial Hypotension; D007427:Intracranial Pressure",
"nlm_unique_id": "9509333",
"other_id": null,
"pages": "1066-1091",
"pmc": null,
"pmid": "30074550",
"pubdate": "2018-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Headaches Due to Low and High Intracranial Pressure.",
"title_normalized": "headaches due to low and high intracranial pressure"
} | [
{
"companynumb": "US-JNJFOC-20180833351",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": "2",
"... |
{
"abstract": "A number of clinical trials demonstrated that tigecycline was effective and well tolerated in the treatment of patients with various bacterial infections, but few literatures had shown the coagulopathy induced by tigecycline. To address this concern, we performed a retrospective analysis to assess the impact of tigecycline treatment on coagulation parameters in 50 patients with bacterial infections in our hospital (Shandong Provincial Hospital, China). These patients were treated with tigecycline at Shandong Provincial Hospital in 2015-2016 at either a recommended (50 mg q12h) or a higher dose (100 mg q12h). Coagulation parameters, including Fibrinogen (FIB) levels, prothrombin time (PT), activated partial thromboplastin time (aPTT), platelet count (PLT) and D-dimer, were evaluated in order to assess the impact of tigecycline treatment in these severely infected patients. What we found was that the plasma fibrinogen (FIB) level was 4.63 ± 1.56 g/L before tigecycline treatment, and decreased to 2.92 ± 1.23 g/L during treatment, which was statistically significant (p < 0.001). The mean values of aPTT and PT were significantly increased from 39.58 ± 8.72 to 44.05 ± 10.45 s (p = 0.002), and from 15.37 ± 1.53 to 16.37 ± 2.64 s (p = 0.004), respectively. This study demonstrates that treatment of tigecycline could reduce FIB, prolong aPTT and PT. In conclusion, we advise that it is necessary for practitioners routinely monitor coagulation level in at-rick patient populations treated with tigecycline.",
"affiliations": "Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University.;Centre for Heart Lung Innovation, St. Paul's Hospital and Department of Pathology and Laboratory Medicine, University of British Columbia.;Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University.;Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University.;Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University.;Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong University.",
"authors": "Leng|Bing|B|;Xue|Yuan Chao|YC|;Zhang|Wen|W|;Gao|Tian Tian|TT|;Yan|Gen Quan|GQ|;Tang|Hui|H|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000078304:Tigecycline",
"country": "Japan",
"delete": false,
"doi": "10.1248/cpb.c18-00844",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-2363",
"issue": "67(3)",
"journal": "Chemical & pharmaceutical bulletin",
"keywords": "assess; coagulation parameter; infection; retrospective analysis; tigecycline",
"medline_ta": "Chem Pharm Bull (Tokyo)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D001424:Bacterial Infections; D001777:Blood Coagulation; D001780:Blood Coagulation Tests; D005260:Female; D006801:Humans; D007668:Kidney; D008099:Liver; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000078304:Tigecycline",
"nlm_unique_id": "0377775",
"other_id": null,
"pages": "258-264",
"pmc": null,
"pmid": "30828002",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Retrospective Analysis of the Effect of Tigecycline on Coagulation Function.",
"title_normalized": "a retrospective analysis of the effect of tigecycline on coagulation function"
} | [
{
"companynumb": "CN-PFIZER INC-2019422392",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TIGECYCLINE"
},
"drugadditional": "1",
... |
{
"abstract": "On Dec 31, 2019, China reported a cluster of cases of pneumonia in people at Wuhan, Hubei Province. The responsible pathogen is a novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We report the relevant features of the first cases in Europe of confirmed infection, named coronavirus disease 2019 (COVID-19), with the first patient diagnosed with the disease on Jan 24, 2020.\n\n\n\nIn this case series, we followed five patients admitted to Bichat-Claude Bernard University Hospital (Paris, France) and Pellegrin University Hospital (Bordeaux, France) and diagnosed with COVID-19 by semi-quantitative RT-PCR on nasopharyngeal swabs. We assessed patterns of clinical disease and viral load from different samples (nasopharyngeal and blood, urine, and stool samples), which were obtained once daily for 3 days from hospital admission, and once every 2 or 3 days until patient discharge. All samples were refrigerated and shipped to laboratories in the National Reference Center for Respiratory Viruses (The Institut Pasteur, Paris, and Hospices Civils de Lyon, Lyon, France), where RNA extraction, real-time RT-PCR, and virus isolation and titration procedures were done.\n\n\n\nThe patients were three men (aged 31 years, 48 years, and 80 years) and two women (aged 30 years and 46 years), all of Chinese origin, who had travelled to France from China around mid-January, 2020. Three different clinical evolutions are described: (1) two paucisymptomatic women diagnosed within a day of exhibiting symptoms, with high nasopharyngeal titres of SARS-CoV-2 within the first 24 h of the illness onset (5·2 and 7·4 log10 copies per 1000 cells, respectively) and viral RNA detection in stools; (2) a two-step disease progression in two young men, with a secondary worsening around 10 days after disease onset despite a decreasing viral load in nasopharyngeal samples; and (3) an 80-year-old man with a rapid evolution towards multiple organ failure and a persistent high viral load in lower and upper respiratory tract with systemic virus dissemination and virus detection in plasma. The 80-year-old patient died on day 14 of illness (Feb 14, 2020); all other patients had recovered and been discharged by Feb 19, 2020.\n\n\n\nWe illustrated three different clinical and biological types of evolution in five patients infected with SARS-CoV-2 with detailed and comprehensive viral sampling strategy. We believe that these findings will contribute to a better understanding of the natural history of the disease and will contribute to advances in the implementation of more efficient infection control strategies.\n\n\n\nREACTing (Research & Action Emerging Infectious Diseases).",
"affiliations": "Department of Infectious and Tropical Diseases, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France.;Medical and Infectious Diseases Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France.;Department of Infectious Diseases and Tropical Medicine, University Hospital of Bordeaux, Bordeaux, France; INSERM U1219, University of Bordeaux, Bordeaux, France.;Department of Infectious and Tropical Diseases, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France.;Medical and Infectious Diseases Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France.;National Reference Center for Respiratory Viruses, Molecular Genetics of RNA Viruses, CNRS-UMR 3569, The Institut Pasteur, Paris, France.;National Reference Center for Respiratory Viruses, Department of Virology, Infective Agents Institute, North Hospital Network, Lyon, France; Virpath Laboratory, International Center of Research in Infectiology, INSERM U1111, CNRS-UMR 5308, École Normale Supérieure de Lyon, Université Claude Bernard Lyon, Lyon University, Lyon, France.;National Reference Center for Respiratory Viruses, Department of Virology, Infective Agents Institute, North Hospital Network, Lyon, France; Virpath Laboratory, International Center of Research in Infectiology, INSERM U1111, CNRS-UMR 5308, École Normale Supérieure de Lyon, Université Claude Bernard Lyon, Lyon University, Lyon, France.;National Reference Center for Respiratory Viruses, Molecular Genetics of RNA Viruses, CNRS-UMR 3569, The Institut Pasteur, Paris, France.;Department of Virology, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France.;National Reference Center for Respiratory Viruses, Molecular Genetics of RNA Viruses, CNRS-UMR 3569, The Institut Pasteur, Paris, France; Mutualized Platform of Microbiology, Pasteur International Bioresources Network, The Institut Pasteur, Paris, France.;Department of Virology, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France.;National Reference Center for Respiratory Viruses, Department of Virology, Infective Agents Institute, North Hospital Network, Lyon, France; Virpath Laboratory, International Center of Research in Infectiology, INSERM U1111, CNRS-UMR 5308, École Normale Supérieure de Lyon, Université Claude Bernard Lyon, Lyon University, Lyon, France.;Santé Publique France, Saint Maurice, France.;Infection Control Unit, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France.;Department of Epidemiology, Biostatistics and Clinical Research, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France.;Center for Clinical Investigation, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France.;Department of Virology, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France.;Department of Infectious Diseases and Tropical Medicine, University Hospital of Bordeaux, Bordeaux, France; INSERM U1219, University of Bordeaux, Bordeaux, France.;Medical and Infectious Diseases Intensive Care Unit, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France.;National Reference Center for Respiratory Viruses, Department of Virology, Infective Agents Institute, North Hospital Network, Lyon, France; Virpath Laboratory, International Center of Research in Infectiology, INSERM U1111, CNRS-UMR 5308, École Normale Supérieure de Lyon, Université Claude Bernard Lyon, Lyon University, Lyon, France.;National Reference Center for Respiratory Viruses, Molecular Genetics of RNA Viruses, CNRS-UMR 3569, The Institut Pasteur, Paris, France.;Department of Infectious and Tropical Diseases, Assistance Publique-Hôpitaux de Paris, Bichat-Claude Bernard University Hospital, Paris, France; Infections Antimicrobials Modelling Evolution (IAME) UMR 1137, University of Paris, Paris, France. Electronic address: yazdan.yazdanpanah@aphp.fr.",
"authors": "Lescure|Francois-Xavier|FX|;Bouadma|Lila|L|;Nguyen|Duc|D|;Parisey|Marion|M|;Wicky|Paul-Henri|PH|;Behillil|Sylvie|S|;Gaymard|Alexandre|A|;Bouscambert-Duchamp|Maude|M|;Donati|Flora|F|;Le Hingrat|Quentin|Q|;Enouf|Vincent|V|;Houhou-Fidouh|Nadhira|N|;Valette|Martine|M|;Mailles|Alexandra|A|;Lucet|Jean-Christophe|JC|;Mentre|France|F|;Duval|Xavier|X|;Descamps|Diane|D|;Malvy|Denis|D|;Timsit|Jean-François|JF|;Lina|Bruno|B|;van-der-Werf|Sylvie|S|;Yazdanpanah|Yazdan|Y|",
"chemical_list": "D012367:RNA, Viral",
"country": "United States",
"delete": false,
"doi": "10.1016/S1473-3099(20)30200-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-3099",
"issue": "20(6)",
"journal": "The Lancet. Infectious diseases",
"keywords": null,
"medline_ta": "Lancet Infect Dis",
"mesh_terms": "D000328:Adult; D000369:Aged, 80 and over; D000073640:Betacoronavirus; D001769:Blood; D000086382:COVID-19; D002681:China; D018352:Coronavirus Infections; D005243:Feces; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D009305:Nasopharynx; D058873:Pandemics; D011024:Pneumonia, Viral; D012367:RNA, Viral; D000086402:SARS-CoV-2; D014195:Travel; D014556:Urine; D019562:Viral Load",
"nlm_unique_id": "101130150",
"other_id": null,
"pages": "697-706",
"pmc": null,
"pmid": "32224310",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "31995857;31992387;28659436;23727167;32004427;24551142;24355025;31774950;32074444;31986264;14709637;32007143;32091533;31986261;32031570;32020029;15158632;19430490;31924756;32052846;27344959;14707219;26763967",
"title": "Clinical and virological data of the first cases of COVID-19 in Europe: a case series.",
"title_normalized": "clinical and virological data of the first cases of covid 19 in europe a case series"
} | [
{
"companynumb": "FR-PFIZER INC-2020238576",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "COLISTIN SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND Cancer is the second leading cause of death internationally, resulting in millions of deaths each year. While treatment in the past has heavily relied on surgery and radiotherapy, chemotherapy and immunotherapy are being increasingly utilized depending on disease presentation. CASE REPORT A 56-year-old male presented to the Emergency Department with a 3-week history of a rapidly enlarging left supraclavicular neck mass. Computed tomography scan revealed a 12×13 cm mass extending from the angle of the mandible to the supraclavicular area. A biopsy confirmed advanced stage squamous cell carcinoma of the head and neck. The patient was started on a chemotherapy regimen of docetaxel, cisplatin, and 5-fluorouracil (TCF). The tumor progressed through chemotherapy, which was switched to cetuximab; however, this therapy was discontinued after an anaphylactic reaction. Palliative radiation treatment was begun along with pembrolizumab. Pembrolizumab was continued, and after 9 cycles, the patient's cancer was almost in complete remission. Three months later, disease progression was once again noted with pembrolizumab treatment, which was subsequently discontinued. The patient was started on paclitaxel and carboplatin chemotherapy regimen as a last resort, despite failure of prior TCF treatment, and the patient responded, this time with complete remission in 4 months. CONCLUSIONS This case demonstrates a unique outcome in which a patient who previously was resistant to chemotherapy, later responded to chemotherapy after a trial of radiation therapy and immunotherapy. Immunotherapy may have a synergistic effect with radiation therapy and play a role in tumor sensitivity to chemotherapy in head and neck cancer treatment.",
"affiliations": "College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;School of Medicine, St. Matthew's University, Grand Cayman, Cayman Islands.;Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.;College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.;Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.",
"authors": "Atiq|Saad O|SO|;Atiq|Osman O|OO|;Atiq|Mohammad O|MO|;Phillips|Kara C|KC|;Jacks|Blake B|BB|;Moreno|Mauricio|M|;Maraboyina|Sanjay|S|;Atiq|Omar T|OT|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.910224",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3033347410.12659/AJCR.910224910224ArticlesThe Role of Immunotherapy and Radiation Therapy in Tumor Chemosensitivity in Advanced Head and Neck Cancer Atiq Saad O. ABCDEFG1Atiq Osman O. BEF2Atiq Mohammad O. EG3Phillips Kara C. EF1Jacks Blake B. BE4Moreno Mauricio ABCD5Maraboyina Sanjay ABCD5Atiq Omar T. ABCD5\n1 College of Medicine, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.\n2 School of Medicine, St. Matthew’s University, Grand Cayman, Cayman Islands\n3 Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, U.S.A.\n4 Department of Radiology, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.\n5 Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, U.S.A.Authors’ 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: Saad O. Atiq, e-mail: saadatiq47@gmail.com2018 18 10 2018 19 1241 1244 26 3 2018 31 7 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 56\n\nFinal Diagnosis: Advanced stage squamous cell carcinoma of the head and neck\n\nSymptoms: Rapidly enlarging mass in left neck\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Oncology\n\nObjective:\nUnusual clinical course\n\nBackground:\nCancer is the second leading cause of death internationally, resulting in millions of deaths each year. While treatment in the past has heavily relied on surgery and radiotherapy, chemotherapy and immunotherapy are being increasingly utilized depending on disease presentation.\n\nCase Report:\nA 56-year-old male presented to the Emergency Department with a 3-week history of a rapidly enlarging left supraclavicular neck mass. Computed tomography scan revealed a 12×13 cm mass extending from the angle of the mandible to the supraclavicular area. A biopsy confirmed advanced stage squamous cell carcinoma of the head and neck. The patient was started on a chemotherapy regimen of docetaxel, cisplatin, and 5-fluorouracil (TCF). The tumor progressed through chemotherapy, which was switched to cetuximab; however, this therapy was discontinued after an anaphylactic reaction. Palliative radiation treatment was begun along with pembrolizumab. Pembrolizumab was continued, and after 9 cycles, the patient’s cancer was almost in complete remission. Three months later, disease progression was once again noted with pembrolizumab treatment, which was subsequently discontinued. The patient was started on paclitaxel and carboplatin chemotherapy regimen as a last resort, despite failure of prior TCF treatment, and the patient responded, this time with complete remission in 4 months.\n\nConclusions:\nThis case demonstrates a unique outcome in which a patient who previously was resistant to chemotherapy, later responded to chemotherapy after a trial of radiation therapy and immunotherapy. Immunotherapy may have a synergistic effect with radiation therapy and play a role in tumor sensitivity to chemotherapy in head and neck cancer treatment.\n\nMeSH Keywords:\nChemoradiotherapy, AdjuvantHead and Neck NeoplasmsImmunotherapy, Active\n==== Body\nBackground\nCancer is the second leading cause of death internationally, resulting in millions of deaths each year [1]. Head and neck cancers account for approximately 6% of all cancers, with major risk factors including alcohol and tobacco use, sun exposure, human papilloma virus infection, and more. The risk of patients developing a secondary primary cancer is 4% per year. Five-year survival varies based on initial staging, with 91% in stage I disease, 77% in stage II, 61% in stage III, 32% in stage IVA, 25% in stage IVB, and <4% in stage IVC disease [2]. While treatment in the past has heavily relied on surgery and radiotherapy, chemotherapy and immunotherapy are being increasingly utilized depending on disease presentation [3]. This case demonstrates a unique outcome in which a patient who previously was resistant to chemotherapy, later responded to chemotherapy after a trial of radiation therapy and immunotherapy.\n\nCase Report\nA 56-year-old male presented to the Emergency Department with a 3-week history of a rapidly enlarging left supraclavicular neck mass suspicious of malignancy. Computed tomography (CT) scan revealed a 12×13 cm mass extending from the angle of the mandible to the supraclavicular area. A biopsy confirmed advanced stage squamous cell carcinoma of the head and neck. Due to the size and aggressive growth of the tumor at the time of diagnosis, resection was not an option. The patient was started on a chemotherapy regimen of docetaxel, cisplatin, and 5-fluorouracil (TCF). He was also referred to Radiation Oncology. A single session of 2000 cGy high dose radiation was performed for de-bulking. The tumor progressed through chemotherapy (Figure 1) and the regimen was switched to cetuximab; however, the patient had an anaphylactic reaction, and cetuximab was discontinued. Palliative radiation treatment was begun along with pembrolizumab. Radiation therapy was administered at 4750 cGy in 20 fractions over a 1-month period. Pembrolizumab was continued, and after 9 cycles (one infusion every 3 weeks), the patient’s cancer was almost in complete remission (Figure 2). Three months later, disease progression was once again noted with pembrolizumab treatment (Figure 3), which was subsequently discontinued. The patient was in good health otherwise, and therefore, he was started on paclitaxel and carboplatin chemotherapy regimen as a last resort, despite failure of prior TCF treatment. The patient responded to chemotherapy this time with complete remission in 4 months (Figure 4).\n\nDiscussion\nCancer incidence is expected to rise by 70% over the next 2 decades [1]. Approximately 644 000 cases of head and neck cancer are diagnosed each year, with greater than 90% being of squamous cell origin [4]. Mainstays of cancer treatment are surgical resection, radiotherapy, chemotherapy, and immunotherapy. Treatment is tailored depending on the patient’s disease presentation and response. For advanced stage head and neck cancer that cannot be resected, chemoradiotherapy is the first-line treatment. The platinum-based chemotherapy regimen used is a combination of docetaxel, cisplatin, and 5-fluorouracil [4]. Second-line treatment is with radiation and the epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab [5]. For cases that show progression after these treatments, the FDA-approved nivolumab and pembrolizumab, anti-PD-1 antibodies [6].\n\nMany head and neck cancers were found to express high levels of PD-L1. This was shown to be a negative prognostic indicator, with these patients showing reduced overall survival time [7]. However, PD-L1 expression was found to be variable over time and to display intratumor heterogeneity, which limits the efficacy of measuring these levels in head and neck cancer patients [8]. Additionally, both patients with and without PD-L1 expression in their tumors have been shown to benefit from anti-PD-1 antibody treatment, further demonstrating the value of immunotherapy in head and neck cancer patients [9].\n\nAnti-PD-1/PD-L1 antibody has been shown to enhance the effect of EGFR antibodies such as cetuximab [10]. Likewise, cetuximab has been shown to improve the efficacy of treatment in patients receiving radiotherapy for head and neck cancers [11]. Less studied, however, are the effects of immunotherapy on tumor sensitivity to chemotherapy regimens, and the possibility of radiosensitization with immunotherapy. Concomitant administration of immunotherapy and radiotherapy in mice showed superior antitumor immunity than either treatment alone [12]. The concurrent treatment in humans has not been well-documented. The previously presented patient did not initially respond to chemotherapy; however, following a trial of immunotherapy with pembrolizumab and concurrent palliative radiation therapy, the patient’s disease did respond to treatment with chemotherapy. As demonstrated in this case, immunotherapy may have a synergistic effect with radiation therapy and play a role in tumor sensitivity to chemotherapy in head and neck cancer treatment. Further studies would need to be undertaken with respect to this possible synergism.\n\nConclusions\nThis case demonstrates a unique outcome in which a patient who previously was resistant to chemotherapy, later responded to chemotherapy after a trial of radiation therapy and immunotherapy. Immunotherapy may have a synergistic effect with radiation therapy and play a role in tumor sensitivity to chemotherapy in head and neck cancer treatment.\n\nFigure 1. Computed tomography image demonstrating progression with chemotherapy. Arrows denoting tumor borders.\n\nFigure 2. Computed tomography image demonstrating remission after immunotherapy/radiation. Arrows denoting remaining tumor.\n\nFigure 3. Computed tomography image demonstrating disease recurrence. Arrows denoting growing tumor.\n\nFigure 4. Computed tomography image demonstrating complete remission with chemotherapy. Arrows denoting area previously occupied by tumor.\n==== Refs\nReferences:\n1. Cancer [Internet] World Health Organization. World Health Organization; [cited 2018Jan22]. Available from: http://www.who.int/mediacentre/factsheets/fs297/en/ \n2. Lefebvre J-L Current clinical outcomes demand new treatment options for SCCHN Ann Oncol 2005 16 vi7 vi12 15987995 \n3. Keir JA Whiteside OJ Winter SC Outcomes in squamous cell carcinoma with advanced neck disease Ann R Coll Surg Engl 2007 89 703 8 17959009 \n4. Marur S Forastiere AA Head and neck cancer: Changing epidemiology, diagnosis, and treatment Mayo Clin Proc 2008 83 489 501 18380996 \n5. Argiris A Karamouzis MV Raben D Ferris RL Head and neck cancer Lancet 2008 371 1695 709 18486742 \n6. Nigro CL Denaro N Merlotti A Merlano M Head and neck cancer: Improving outcomes with a multidisciplinary approach Cancer Manag Res 2017 9 363 71 28860859 \n7. Müller T Braun M Dietrich D PD-L1: A novel prognostic biomarker in head and neck squamous cell carcinoma Oncotarget 2017 8 32 52889 900 28881780 \n8. Bauml JM Cohen RB Aggarwal C Immunotherapy for head and neck cancer: Latest developments and clinical potential Ther Adv Med Oncol 2016 8 168 75 27239235 \n9. Fuereder T Immunotherapy for head and neck squamous cell carcinoma Magazine of European Medical Oncology 2016 9 66 69 27429658 \n10. Ran X Yang K Inhibitors of the PD-1/PD-L1 axis for the treatment of head and neck cancer: current status and future perspectives Drug Des Devel Ther 2017 11 2007 14 \n11. Goel A Singh D Radiosensitization of head and neck cancer by targeting the epidermal growth factor receptor Indian J Med Paediatr Oncol 2009 30 3 92 20838543 \n12. Deng L Liang H Burnette B Irradiation and anti–PD-L1 treatment synergistically promote antitumor immunity in mice J Clin Invest 2014 124 2 687 95 24382348\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "19()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D006258:Head and Neck Neoplasms; D006801:Humans; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "1241-1244",
"pmc": null,
"pmid": "30333474",
"pubdate": "2018-10-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17959009;27429658;28860859;27239235;24382348;28721019;18380996;28881780;18486742;20838543;15987995",
"title": "The Role of Immunotherapy and Radiation Therapy in Tumor Chemosensitivity in Advanced Head and Neck Cancer.",
"title_normalized": "the role of immunotherapy and radiation therapy in tumor chemosensitivity in advanced head and neck cancer"
} | [
{
"companynumb": "US-009507513-1811USA001159",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Efavirenz (Sustiva®) is used for the treatment of human immunodeficiency virus (HIV) type 1 infection. Hepatoxicity is a known potential adverse drug event with efavirenz; however, to our knowledge, vanishing bile duct syndrome (VBDS), a type of liver injury, has not been reported with this therapy.\nWe report the case of a 48-year-old male with HIV and VBDS secondary to antiretroviral therapy. The patient was started on efavirenz, emtricitabine, and tenofovir disoproxil fumarate (Atripla®). Four weeks later, the patient presented with complaints of poor appetite, nausea with emesis, dark urine, and malaise. Labs obtained supported the diagnosis of acute hepatitis, and a liver biopsy confirmed a diagnosis of VBDS. The Naranjo adverse drug reaction probability scale showed that it was probable (score of 7) that the VBDS was related to drug therapy. Efavirenz was assessed to be the most likely cause of VBDS, end-stage liver disease, and the eventual need for liver transplantation.\nTo our knowledge, this is the first reported case of probable efavirenz-induced VBDS in a patient living with HIV. Recognition and awareness of this adverse drug reaction by clinicians for quick diagnosis, discontinuation of therapy, and management are important in patients receiving this regimen.",
"affiliations": "15473Mercer University College of Pharmacy, Atlanta, GA, USA.;15473Mercer University College of Pharmacy, Atlanta, GA, USA.;Department of Medicine, Emory Decatur Hospital, Decatur, GA, USA.",
"authors": "Nwaesei|Angela Shogbon|AS|;Moye-Dickerson|Pamela M|PM|https://orcid.org/0000-0002-9737-3123;Dretler|Robin Henry|RH|",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D000068679:Emtricitabine; C098320:efavirenz",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190019868358",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "34(2)",
"journal": "Journal of pharmacy practice",
"keywords": "HIV; antiretroviral; drug-induced; efavirenz; vanishing bile duct syndrome",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D001652:Bile Ducts; D002779:Cholestasis; D003521:Cyclopropanes; D000068679:Emtricitabine; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "319-324",
"pmc": null,
"pmid": "31451051",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Efavirenz-Induced Vanishing Bile Duct Syndrome: A Case Report.",
"title_normalized": "efavirenz induced vanishing bile duct syndrome a case report"
} | [
{
"companynumb": "GB-MACLEODS PHARMACEUTICALS US LTD-MAC2021030774",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
... |
{
"abstract": "Purpose To assess the efficacy and safety of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who experienced disease progression during or after trastuzumab-based therapy and received a prior taxane. Patients and Methods Patients were randomly assigned to arm A: trastuzumab 8 mg/kg → 6 mg/kg once every 3 weeks plus capecitabine 1,250 mg/m2 twice a day (2 weeks on, 1 week off, every 3 weeks); or arm B: pertuzumab 840 mg → 420 mg once every 3 weeks plus trastuzumab at the same dose and schedule as arm A plus capecitabine 1,000 mg/m2 on the same schedule as arm A. The primary end point was independent review facility-assessed progression-free survival (IRF PFS). Secondary end points included overall survival (OS) and safety. Hierarchical testing procedures were used to control type I error for statistical testing of IRF PFS, OS, and objective response rate. Results Randomly assigned (intent-to-treat) populations were 224 and 228 patients in arms A and B, respectively. Median IRF PFS at 28.6 and 25.3 months' median follow-up was 9.0 v 11.1 months (hazard ratio, 0.82; 95% CI, 0.65 to 1.02; P = .0731) and interim OS was 28.1 v 36.1 months (hazard ratio, 0.68; 95% CI, 0.51 to 0.90). The most common adverse events (all grades; incidence of ≥ 10% in either arm and ≥ 5% difference between arms) were hand-foot syndrome, nausea, and neutropenia in arm A, and diarrhea, rash, and nasopharyngitis in arm B. Conclusion The addition of pertuzumab to trastuzumab and capecitabine did not significantly improve IRF PFS. An 8-month increase in median OS to 36.1 months with pertuzumab was observed. Statistical significance for OS cannot be claimed because of the hierarchical testing of OS after the primary PFS end point; however, the magnitude of OS difference is in keeping with prior experience of pertuzumab in metastatic breast cancer. No new safety signals were identified.",
"affiliations": "Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.;Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.;Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.;Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.;Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.;Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.;Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.;Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.;Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.;Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.;Ander Urruticoechea, Onkologikoa Foundation, San Sebastián; Ander Urruticoechea, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, GEICAM; Montserrat Muñoz, Translational Genomics and Targeted Therapeutics in Solid Tumors and Hospital Clínic, Barcelona, GEICAM; Antonio Carlos Sánchez Ruiz, Hospital Universitario Puerta de Hierro, Madrid, Spain; Mohammed Rizwanullah, Beatson West of Scotland Cancer Centre, Glasgow; Hannah Douthwaite and Sarah Heeson, Roche, Welwyn Garden City, United Kingdom; Seock-Ah Im, Seoul National University Hospital, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea; István Láng, National Institute of Oncology, Budapest, Hungary; Gianluca Tomasello, ASST di Cremona - Ospedale di Cremona, Cremona, Italy; Tanja Badovinac Crnjevic, F Hoffmann-La Roche, Basel, Switzerland; and Jennifer Eng-Wong, Genentech, South San Francisco, CA.",
"authors": "Urruticoechea|Ander|A|;Rizwanullah|Mohammed|M|;Im|Seock-Ah|SA|;Ruiz|Antonio Carlos Sánchez|ACS|;Láng|István|I|;Tomasello|Gianluca|G|;Douthwaite|Hannah|H|;Badovinac Crnjevic|Tanja|T|;Heeson|Sarah|S|;Eng-Wong|Jennifer|J|;Muñoz|Montserrat|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000069287:Capecitabine; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; C485206:pertuzumab; D000068878:Trastuzumab",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2016.70.6267",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "35(26)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000069287:Capecitabine; D018450:Disease Progression; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D018719:Receptor, ErbB-2; D000068878:Trastuzumab",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "3030-3038",
"pmc": null,
"pmid": "28437161",
"pubdate": "2017-09-10",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Randomized Phase III Trial of Trastuzumab Plus Capecitabine With or Without Pertuzumab in Patients With Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Who Experienced Disease Progression During or After Trastuzumab-Based Therapy.",
"title_normalized": "randomized phase iii trial of trastuzumab plus capecitabine with or without pertuzumab in patients with human epidermal growth factor receptor 2 positive metastatic breast cancer who experienced disease progression during or after trastuzumab based therapy"
} | [
{
"companynumb": "ES-MYLANLABS-2017M1068295",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMyelin oligodendrocyte glycoprotein immunoglobulin G1 (MOG-IgG1)-associated disease is suggested as a separate disease entity distinct from multiple sclerosis and neuromyelitis optica spectrum disorder. Nonetheless, the optimal treatment regimen for preventing relapses in MOG-IgG1-associated disease remains unclear.\n\n\nMETHODS\nWe describe the case of a 45-year-old man with MOG-IgG1-positive highly relapsing optic neuritis who had experienced 5 attacks over 21 months and had monocular blindness despite prednisolone and azathioprine therapy. He began treatment with rituximab, which reduced the rate of relapse markedly. Following discontinuation of rituximab, however, the patient experienced two successive optic neuritis attacks 2 and 4 months after B-lymphocyte restoration.\n\n\nCONCLUSIONS\nHighly relapsing MOG-IgG1-associated disease can be prevented with rituximab even when the MOG-IgG1 titers are relatively stationary. Discontinuation of rituximab and restoration of B-lymphocytes may be associated with the rebound of disease activity.",
"affiliations": "Department of Neurology, Inha University Hospital, Incheon, Republic of Korea.;Department of Neurology, Seoul National University Hospital, 101, Daehak-Ro Jongno-Gu, Seoul, 03080, Republic of Korea.;Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Neurology, Seoul National University Hospital, 101, Daehak-Ro Jongno-Gu, Seoul, 03080, Republic of Korea. sueh916@gmail.com.;Department of Neurology, Seoul National University Hospital, 101, Daehak-Ro Jongno-Gu, Seoul, 03080, Republic of Korea.",
"authors": "Choi|Seok-Jin|SJ|;Kim|Boram|B|;Lee|Haeng-Jin|HJ|;Kim|Seong-Joon|SJ|;Kim|Sung-Min|SM|;Sung|Jung-Joon|JJ|",
"chemical_list": "D001323:Autoantibodies; D007074:Immunoglobulin G; D007155:Immunologic Factors; D063308:Myelin-Oligodendrocyte Glycoprotein; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-018-1222-1",
"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 122210.1186/s12883-018-1222-1Case ReportRebound of relapses after discontinuation of rituximab in a patient with MOG-IgG1 positive highly relapsing optic neuritis: a case report Choi Seok-Jin seokjin83@gmail.com 1Kim Boram boram217@gmail.com 2Lee Haeng-Jin leehaengjin@hanmail.net 3Kim Seong-Joon ophjun@gmail.com 3Kim Sung-Min +82-2-2072-4902sueh916@gmail.com 2Sung Jung-Joon jjsaint@snu.ac.kr 21 0000 0004 0648 0025grid.411605.7Department of Neurology, Inha University Hospital, Incheon, Republic of Korea 2 0000 0001 0302 820Xgrid.412484.fDepartment of Neurology, Seoul National University Hospital, 101, Daehak-Ro Jongno-Gu, Seoul, 03080 Republic of Korea 3 0000 0001 0302 820Xgrid.412484.fDepartment of Ophthalmology, Seoul National University Hospital, Seoul, Republic of Korea 21 12 2018 21 12 2018 2018 18 2166 3 2018 9 12 2018 © The Author(s). 2018Open 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\nMyelin oligodendrocyte glycoprotein immunoglobulin G1 (MOG-IgG1)-associated disease is suggested as a separate disease entity distinct from multiple sclerosis and neuromyelitis optica spectrum disorder. Nonetheless, the optimal treatment regimen for preventing relapses in MOG-IgG1-associated disease remains unclear.\n\nCase presentation\nWe describe the case of a 45-year-old man with MOG-IgG1-positive highly relapsing optic neuritis who had experienced 5 attacks over 21 months and had monocular blindness despite prednisolone and azathioprine therapy. He began treatment with rituximab, which reduced the rate of relapse markedly. Following discontinuation of rituximab, however, the patient experienced two successive optic neuritis attacks 2 and 4 months after B-lymphocyte restoration.\n\nConclusions\nHighly relapsing MOG-IgG1-associated disease can be prevented with rituximab even when the MOG-IgG1 titers are relatively stationary. Discontinuation of rituximab and restoration of B-lymphocytes may be associated with the rebound of disease activity.\n\nKeywords\nMOG-IgG1Optic neuritisHighly relapsingRituximabhttp://dx.doi.org/10.13039/501100003710Korea Health Industry Development InstituteHI17C0335HI17C0789Kim Sung-Min issue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nMyelin oligodendrocyte glycoprotein immunoglobulin G1 (MOG-IgG1)-associated disease is suggested as a separate disease entity distinct from multiple sclerosis and neuromyelitis optica spectrum disorder (NMOSD) with anti-aquaporin-4 IgG (AQP4-IgG); it has a predilection for the optic nerve rather than spinal cord, perineural enhancement extending to adjacent soft tissues on magnetic resonance imaging (MRI), and a less unfavorable prognosis than NMOSD [1]. Recent studies with a sufficient number of patients and duration of follow-up have indicated that a considerable number of patients with MOG-IgG1 have relapsing attacks in the central nervous system followed by neurological deficits [2, 3]. Nonetheless, the optimal treatment regimen for preventing relapses in patients with MOG-IgG1-associated disease has only recently begun to be studied [4]. Here, we describe a patient with highly relapsing optic neuritis (ON) associated with MOG-IgG1, whose ON attacks were relatively well-prevented with rituximab (RTX) treatment. However, the patient experienced rebounds of repeated ON attacks shortly after the restoration of B-cells following discontinuation of RTX.\n\nCase presentation\nA 45-year-old man presented with decreased right visual acuity (VA) accompanied by periocular pain lasting for 1 week. Ophthalmological examination revealed that the patient’s right eye was only able to perceive light (best-corrected VA, light perception/0.9 in decimals, measured using a Snellen chart) and had relative afferent pupillary defect of grade 3, diffuse disc swelling, and inferior disc hemorrhage. Neurological examination showed normal muscle strength in all extremities, no sensory deficits, normoactive deep tendon reflexes, and no signs of bladder or bowel dysfunction. Orbit MRI revealed T2 high signal intensities and diffuse contrast enhancement along the right anterior and posterior optic nerve, as well as perineural enhancement [1] (Fig. 1-a and b). The results of cerebrospinal fluid (CSF) analysis showed a red blood cell count of 0/μL, a white blood cell count of 1/μL, and a protein level of 27 mg/dL. CSF oligoclonal band measured by isoelectric focusing was negative and IgG index was 0.64. The result of a serum AQP4-IgG flow cytometry assay using AQP4-M23-expressing live cells was negative [5]. Right ON was suspected, and intravenous methylprednisolone (1000 mg pulse therapy) for 5 days followed by oral prednisolone (60 mg daily) were prescribed. The right VA of the patient was improved to 0.5 (visual Functional System score improved to 2 from 5).Fig. 1 (a) Axial and (b) coronal T1-weighted magnetic resonance images demonstrating diffuse gadolinium enhancement and swelling along the right anterior and posterior optic nerve. c Longitudinal clinical course of recurrent optic neuritis. d Change of CD19+ B-lymphocytes (%) during rituximab treatment. e Change of MOG-IgG1 titers measured by a geometric mean fluorescence (G-mean) ratio of the MOG-expressing cells that bound to IgG1 using in-house flow cytometry (G-mean ratio = G-mean values of the patient’s sera / G-mean values of the healthy control)\n\n\n\nThe second right ON attack (0.15/1.0) occurred 4 months after the first ON when the prednisolone dose had been tapered to 10 mg daily. Thus, azathioprine 50 mg twice per day was started in a remission state between the second and third ON (4 months prior to the third ON). The average thickness of a retinal nerve fiber layer measured by spectral-domain optical coherence tomography was decreased in the right eye (right 51 μm and left 105 μm) (Fig. 2-a). The third (hand movement/0.9) and fourth (finger count/1.2) right ON attacks occurred 6 and 10 months after the second ON, respectively, while the prednisolone dose was maintained at 5 mg daily and azathioprine was 75 mg twice per day. Following these attacks, the patient developed left central serous chorioretinopathy (0.15/0.9) associated with long-term steroid use. The 25 mg dose of prednisolone was thus tapered out at this point. Nevertheless, right ON recurred 2 months later for a fifth time (hand movement/0.9) when the patient was under azathioprine treatment only. At this time, the patient developed monocular blindness. The pattern-reversal visual evoked potential showed an abnormal waveform in the right eye with diminished amplitude. The left eye presented a relatively preserved response with prolonged P100 latency (118 ms) (Fig. 2-b). Serum from the patient sampled at the time of the fifth ON attack was tested for MOG-IgG1 using a cell-based assay utilizing full-length human MOG (Radcliffe Hospital, Oxford, UK) [6]. The result of this test was positive.Fig. 2 a (Remission state after the second optic neuritis) the average retinal nerve fiber layer thickness measured by spectral-domain optical coherence tomography was decreased in the right eye (right 51 μm and left 105 μm), with preferential thinning of the superior, temporal, and inferior quadrants. b (During fifth optic neuritis) the pattern-reversal visual evoked potential showed an abnormal waveform in the right eye with diminished amplitude. The left eye presented a relatively preserved response with prolonged P100 latency (118 ms)\n\n\n\nDespite continued immunosuppressive treatment and due to the repeated ON attacks and the side effect of the steroid (chorioretinopathy), the patient was administered RTX (375 mg/m2, 3 weekly infusion for induction and 3 maintenance doses under CD19+ B-cell monitoring over 29 months). Although one mild ON attack (no light perception/1.2) occurred in the patient’s right eye during RTX treatment, the rate of relapse decreased markedly and the patient’s visual function was well-maintained. However, 32 months after the initiation of RTX treatment, we became unable to maintain RTX treatment due to insurance issues (denial for reimbursement). As a result, the treatment was switched to mycophenolate mofetil (250 mg twice per day) combined with oral prednisolone (5 mg every other day). The patient’s CD19+ B-lymphocyte level was restored to 2 and 4% at 9 and 11 months after the last RTX infusion, respectively. Subsequently, 2 more left ON attacks (hand movement/1.0 and hand movement/0.15) occurred within a one-month interval (Fig. 1-c and 1-D). The titer of MOG-IgG1 was measured by a geometric mean fluorescence (G-mean) ratio of the MOG-expressing cells bound to IgG1 using in-house flow cytometry. The G-mean ratio was calculated for each sera as followings: G-mean values of the patient’s sera / G-mean values of the healthy control. The titer was not associated with the continuation or cessation of the RTX treatment (Fig. 1-e).\n\nDiscussion and conclusions\nHere, we describe the longitudinal clinical course and treatment response to RTX therapy in a patient with MOG-IgG1-positive highly relapsing ON. We found that 1) highly relapsing MOG-IgG1-associated disease can be prevented with RTX even when the MOG-IgG1 titers are relatively preserved, and 2) discontinuation of RTX in patients with this condition can cause rebound of disease activity with restoration of B-lymphocytes.\n\nInitial reports regarding MOG-IgG1-associated disease indicated that it typically has a monophasic and benign disease course [7]. However, recent multicenter studies have shown that a considerable proportion of patients have a relapsing course of disease, and some have significant neurological deficits [2, 3]. More recently, RTX was reported to reduce the rate of relapse in some cases of MOG-IgG1-associated disease [4]. Nevertheless, the results of studies comparing the patient’s condition before vs. after the treatment should be interpreted with caution because the disease may have a naturally decreasing relapse rate in the later stages, as in NMOSD [8], and also the statistical phenomenon of regression towards the mean. In this regard, the present case, wherein we observed a restoration of B-lymphocytes and a subsequent rebound of relapses after discontinuation of RTX treatment, implies that long-term RTX maintenance therapy may be helpful in patients with highly relapsing MOG-IgG1-associated disease.\n\nDespite initial treatment with azathioprine and prednisolone, the patient had a high relapse rate of 0.238/year (5 attacks over 21 months) and subsequent unilateral visual loss in the right eye. After initiating RTX treatment, his relapse rate markedly decreased to 0.031/year (1 attack over 32 months). However, the patient experienced 2 ON attacks over 4 months following cessation of RTX treatment and restoration of B-lymphocytes.\n\nIn summary, the case described here illustrates that RTX can be a good treatment option for preventing relapses in MOG-IgG1-associated disease. The treatment effect was observed despite the relatively unchanged MOG-IgG1 titers during the treatment period. Finally, cessation of RTX treatment and restoration of B-lymphocytes may be associated with the rebound of disease activity. RTX may serve as an effective treatment regimen in MOG-IgG1-associated disease, especially in patients with high relapse rates.\n\nAbbreviations\nAQP4anti-aquaporin-4\n\nCSFcerebrospinal fluid\n\nIgGimmunoglobulin G\n\nMOGmyelin oligodendrocyte glycoprotein\n\nMRImagnetic resonance imaging\n\nNMOSDneuromyelitis optica spectrum disorder\n\nONoptic neuritis\n\nRTXrituximab\n\nVAvisual acuity\n\nAcknowledgements\nNone.\n\nFunding\nThis work was supported by grant no. HI17C0335 and HI17C0789 from the Korea Health Industry Development Institute Research fund. The funders had no role in the design of the study, interpretation of data and in writing the manuscript. They had contributed to the data collection and analysis of AQP4-IgG and MOG-IgG1 antibodies.\n\nAvailability of data and materials\nAll data have been presented within the manuscript and in the form of images.\n\nAuthors’ contributions\nS-MK conceived of the study. S-JC and S-MK analyzed and interpreted the data, and involved in drafting and revising the manuscript. BK contributed to acquisition and analysis of the data, and involved in revising the manuscript critically. J-JS contributed to interpretation of the data, and involved in revising the manuscript critically. H-JL and S-JK made substantial contributions to interpretation of ophthalmological data and also involved in revising the manuscript critically; as a result, this manuscript came to have more intellectual content on ophthalmology. All listed authors have participated sufficiently in the work to take public responsibility for appropriate portions of the content, and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nEthics approval and consent to participate\nThis study was approved by the ethics committee of Seoul National University Hospital (IRB no. 1005–023-317).\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Kim SM, Woodhall MR, Kim JS, Kim SJ, Park KS, Vincent A, Lee KW, Waters P. Antibodies to MOG in adults with inflammatory demyelinating disease of the CNS. Neurol Neuroimmunol Neuroinflamm. 2015;2(6):e163.\n2. Jurynczyk M, Messina S, Woodhall MR, Raza N, Everett R, Roca-Fernandez A, Tackley G, Hamid S, Sheard A, Reynolds G, et al. Clinical presentation and prognosis in MOG-antibody disease: a UK study. Brain. 2017;140(12):3128-38.\n3. Cobo-Calvo A, Ruiz A, Maillart E, Audoin B, Zephir H, Bourre B, Ciron J, Collongues N, Brassat D, Cotton F, et al. Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study. Neurology. 2018;90(21):e1858-e1869.\n4. Ramanathan S, Mohammad S, Tantsis E, Nguyen TK, Merheb V, Fung VSC, White OB, Broadley S, Lechner-Scott J, Vucic S, et al. Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination. J Neurol Neurosurg Psychiatry. 2018;89(2):127-137.\n5. Yang J, Kim SM, Kim YJ, Cheon SY, Kim B, Jung KC, Park KS. Accuracy of the Fluorescence-Activated Cell Sorting Assay for the Aquaporin-4 Antibody (AQP4-Ab): Comparison with the Commercial AQP4-Ab Assay Kit. PLoS One. 2016;11(9):e0162900.\n6. Waters P, Woodhall M, O'Connor KC, Reindl M, Lang B, Sato DK, Jurynczyk M, Tackley G, Rocha J, Takahashi T, et al. MOG cell-based assay detects non-MS patients with inflammatory neurologic disease. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e89.\n7. Kitley J, Woodhall M, Waters P, Leite MI, Devenney E, Craig J, Palace J, Vincent A. Myelin-oligodendrocyteglycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology. 2012;79(12):1273-1277.\n8. Kim SM, Park J, Kim SH, Park SY, Kim JY, Sung JJ, Park KS, Lee KW. Factors associated with the time to next attack in neuromyelitis optica: accelerated failure time models with random effects. PLoS One. 2013;8(12):e82325.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "18(1)",
"journal": "BMC neurology",
"keywords": "Highly relapsing; MOG-IgG1; Optic neuritis; Rituximab",
"medline_ta": "BMC Neurol",
"mesh_terms": "D001323:Autoantibodies; D002908:Chronic Disease; D006801:Humans; D007074:Immunoglobulin G; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D063308:Myelin-Oligodendrocyte Glycoprotein; D009902:Optic Neuritis; D012008:Recurrence; D000069283:Rituximab",
"nlm_unique_id": "100968555",
"other_id": null,
"pages": "216",
"pmc": null,
"pmid": "30577778",
"pubdate": "2018-12-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22914827;24358171;25821844;26516628;27658059;29136091;29142145;29695592",
"title": "Rebound of relapses after discontinuation of rituximab in a patient with MOG-IgG1 positive highly relapsing optic neuritis: a case report.",
"title_normalized": "rebound of relapses after discontinuation of rituximab in a patient with mog igg1 positive highly relapsing optic neuritis a case report"
} | [
{
"companynumb": "VISTAPHARM, INC.-VER201901-000006",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3... |
{
"abstract": "Congenital thrombocytopenia can easily be misdiagnosed as immune thrombocytopenic purpura, as is illustrated by this case of a woman and her two children. Doubts arose when steroid/IVIG therapy failed in the mother and the thrombocytopenia in the children persisted. By means of next-generation sequencing, two missense variants in cis in the ACTN1 gene of the affected family members were identified, both of unknown significance. We conclude, after further analysis of these mutations with, among others, in silico prediction tools, that the thrombocytopenia has a genetic cause, in particular the ACTN1 mutations, and is not immune mediated.",
"affiliations": "Department of Pediatric Hematology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands.;Department of Laboratory Medicine, University Medical Center Groningen, Groningen, the Netherlands.;Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.;Department of Hematology, Van Creveldkliniek, University Medical Center Utrecht, Utrecht, the Netherlands.;Department of Laboratory Medicine, University Medical Center Groningen, Groningen, the Netherlands.;Department of Pediatric Hematology, Beatrix Children's Hospital, University Medical Center Groningen, Groningen, the Netherlands.",
"authors": "Kanhai|Danny|D|;Mulder|René|R|;Ploos van Amstel|Hans Kristian|HK|;Schutgens|Roger|R|;Lukens|Michael|M|;Tamminga|Rienk Y J|RYJ|",
"chemical_list": "C526905:ACTN1 protein, human; D000185:Actinin",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27418",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "65(12)",
"journal": "Pediatric blood & cancer",
"keywords": "ACTN1; ITP; actinin 1; congenital macrothrombocytopenia; next-generation sequencing",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000185:Actinin; D002648:Child; D003951:Diagnostic Errors; D005260:Female; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D016553:Purpura, Thrombocytopenic, Idiopathic; D013921:Thrombocytopenia",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27418",
"pmc": null,
"pmid": "30124235",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Familial macrothrombocytopenia due to a double mutation in cis in the alpha-actinin 1 gene (ACTN1), previously considered to be chronic immune thrombocytopenic purpura.",
"title_normalized": "familial macrothrombocytopenia due to a double mutation in cis in the alpha actinin 1 gene actn1 previously considered to be chronic immune thrombocytopenic purpura"
} | [
{
"companynumb": "NL-MYLANLABS-2019M1031307",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Docetaxel, cisplatin, and 5-FU(DCF)chemotherapy for esophageal cancer has been reported to be highly effective, but often causes serious adverse events, including severe bone marrow suppression. We report the successful treatment of a 67- year-old man with highly advanced esophageal cancer with invasion of the left bronchus and broad lymph node metastases. He received induction chemotherapy with DCF therapy, and prophylactic administration of pegfilgrastim. He safely completed 5 courses of DCF therapy without serious adverse events, such as neutropenia and febrile neutropenia. The size of the primary tumor and lymph node metastases remarkably reduced after the third course of DCF. He underwent thoracoscopic esophagectomy with three-field lymph node dissection and reconstruction with a gastric tube. The pathological findings of the resected specimen showed no viable malignant cells in the primary lesion and the pathological effect after chemotherapy was judged as Grade 3. Viable cancer cells still remained in 10 lymph nodes in the dissected field. DCF therapy with prophylactic administration of pegfilgrastim may be an effective and safe treatment for advanced esophageal cancer.",
"affiliations": "Dept. of Gastroenterological Surgery, Graduate School of Medical Science, Kanazawa University.",
"authors": "Gunjigake|Katsuya|K|;Okamoto|Koichi|K|;Gabata|Ryosuke|R|;Yamaguchi|Takahisa|T|;Ninomiya|Itasu|I|;Fushida|Sachio|S|;Ohta|Tetsuo|T|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim; D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(1)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D000077143:Docetaxel; D004938:Esophageal Neoplasms; D000069585:Filgrastim; D005472:Fluorouracil; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols; D043823:Taxoids",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "61-63",
"pmc": null,
"pmid": "30765644",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Advanced Esophageal Cancer with DCF Chemotherapy and Pegfilgrastim.",
"title_normalized": "successful treatment of advanced esophageal cancer with dcf chemotherapy and pegfilgrastim"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-213708",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"dr... |
{
"abstract": "Topical 5- Fluorouracil (5-FU) is used more frequently to treat actinic keratosis. We are presenting a skin reaction as a side effect of this medication. Treatment for such cases of 5-FU-induced skin reactions is based on proper skin care and treatment of any superimposed infections. Medical providers should be aware of such side effects to provide their patients with proper instructions to avoid complications.",
"affiliations": "Department of Internal Medicine, Hurley Medical Center, Michigan, USA.;Department of Internal Medicine, Hurley Medical Center, Michigan, USA.;Department of Internal Medicine, Hurley Medical Center, Michigan, USA.;Department of Internal Medicine, Hurley Medical Center, Michigan, USA.",
"authors": "Chughtai|Komal|K|;Gupta|Rahul|R|;Upadhaya|Sunil|S|;Al Hadidi|Samer|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omx043",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omx043omx043Clinical ImageTopical 5-Fluorouracil associated skin reaction Chughtai Komal 1Gupta Rahul 1Upadhaya Sunil 1Al Hadidi Samer 1\n1 \nDepartment of Internal Medicine, Hurley Medical Center, Michigan, USA* Correspondence address. Department of Internal Medicine, Hurley Medical Center, Michigan, USA. E-mail: salhadi1@hurleymc.com8 2017 10 8 2017 10 8 2017 2017 8 omx04316 3 2017 14 6 2017 20 6 2017 © The Author 2017. Published by Oxford University Press.2017This 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 non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nTopical 5- Fluorouracil (5-FU) is used more frequently to treat actinic keratosis. We are presenting a skin reaction as a side effect of this medication. Treatment for such cases of 5-FU-induced skin reactions is based on proper skin care and treatment of any superimposed infections. Medical providers should be aware of such side effects to provide their patients with proper instructions to avoid complications.\n==== Body\nA 76-year-old female presented to an outpatient dermatologist’s office with facial actinic keratosis (AK). Skin biopsy revealed nonspecific verrucous squamous hyperplasia. She was prescribed 5% 5-fluorouracil (5-FU) cream, and asked to apply it to the face twice a day for 2 weeks. Instead, the patient reported that she was applying it seven times a day. She then presented to the emergency department with blistering, peeling and painful erythema of the face focused around the forehead, eyes and cheeks (Fig. 1). There was no involvement of mucosal surfaces. She was noted to have a small area of honey-colored crusting on her right cheek.\n\n\nFigure 1: Erythema of the face around the forehead, eyes and cheeks. Small area of honey-colored crusting on right cheek.\n\nSkin damage can result from topical 5-FU which inhibits thymidylate synthetase. Topical 5-FU was shown to decrease AK counts and the need for spot treatments for longer than 2 years [1]. In addition to superficial discomfort, 5-FU can lead to skin erosion, desquamation and re-epithelialization. This may increase the risk of superimposed skin infections. About 5% 5-FU is associated with higher frequency of skin side effects mainly skin irritation [2].\n\nTreatment for such cases of 5-FU-induced skin reactions are based on proper skin care and treatment of any superimposed infections. In our case, 5-FU cream was discontinued, and patient was educated on suitable skin care with liberal application of petroleum jelly. She was treated with antibiotics for impetigo. Regular follow-up on an outpatient basis is important to ensure that the skin is healing appropriately. One week follow-up in outpatient clinic showed healing skin with resolved infection (Fig. 2).\n\n\nFigure 2: Resolving erythema and honey-colored crusting.\n\nCONFLICT OF INTEREST STATEMENT\nNone declared.\n==== Refs\nREFERENCES\n1 \nPomerantz H , Hogan D , Eilers D , Swetter SM , Chen SC , Jacob SE , et al \nLong-term efficacy of topical fluorouracil cream, 5%, for treating actinic keratosis: a randomized clinical trial . JAMA Dermatol 2015 ;151 :952 .25950503 \n2 \nLevy S , Furst K , Chern W \nA pharmacokinetic evaluation of 0.5% and 5% fluorouracil topical cream in patients with actinic keratosis . Clin Ther 2001 ;23 :908 .11440290\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2017(8)",
"journal": "Oxford medical case reports",
"keywords": null,
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
"other_id": null,
"pages": "omx043",
"pmc": null,
"pmid": "28845237",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": "11440290;25950503",
"title": "Topical 5-Fluorouracil associated skin reaction.",
"title_normalized": "topical 5 fluorouracil associated skin reaction"
} | [
{
"companynumb": "US-BAUSCH-BL-2018-029469",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "1",
... |
{
"abstract": "Epidermal growth factor receptor (EGFR)-targeted therapy has become standard of care in advanced stages EGFR-mutant non-small cell lung cancer. Acquired resistance to first-line EGFR-tyrosine kinase inhibitor (TKI) and subsequent disease progression is a common problem and mostly due to a secondary mutation (T790M) in EGFR. We report a case of a patient with EGFR-mutated lung adenocarcinoma who developed a complex resistance profile: T790M mutation, HER2 mutation and HER2 amplification after first-line EGFR-TKI. This patient was safely treated with a combination of osimertinib and trastuzumab and achieved a clinically meaningful and clear molecular response. This is the first reported case of acquired resistance to first-line EGFR-TKI based on three resistance mechanisms, treated with molecular targeted combination therapy.",
"affiliations": "Department of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium.;Department of Pathology and Molecular Biology, Jessa Hospital, Hasselt, Belgium.;Department of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium.;Department of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium.;Department of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium.",
"authors": "Ralki|Mike|M|;Maes|Brigitte|B|;Pat|Karin|K|;Wynants|Jokke|J|;Cuppens|Kristof|K|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000502214",
"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 10.1159/000502214cro-0012-0625Case ReportTriple Trouble: A Case of Multiple Resistance Mechanisms after First Generation EGFR-TKI in NSCLC Ralki Mike a*Maes Brigitte bPat Karin cWynants Jokke cCuppens Kristof caDepartment of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, BelgiumbDepartment of Pathology and Molecular Biology, Jessa Hospital, Hasselt, BelgiumcDepartment of Pulmonology and Thoracic Oncology, Jessa Hospital, Hasselt, Belgium*Mike Ralki, MD, Department of pulmonology and thoracic oncology, Jessa Hospital, Stadsomvaart 11, BE-3500 Hasselt (Belgium), E-Mail mike.ralki@jessazh.beMay-Aug 2019 6 8 2019 6 8 2019 12 2 625 630 11 7 2019 11 7 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This 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.Epidermal growth factor receptor (EGFR)-targeted therapy has become standard of care in advanced stages EGFR-mutant non-small cell lung cancer. Acquired resistance to first-line EGFR-tyrosine kinase inhibitor (TKI) and subsequent disease progression is a common problem and mostly due to a secondary mutation (T790M) in EGFR. We report a case of a patient with EGFR-mutated lung adenocarcinoma who developed a complex resistance profile: T790M mutation, HER2 mutation and HER2 amplification after first-line EGFR-TKI. This patient was safely treated with a combination of osimertinib and trastuzumab and achieved a clinically meaningful and clear molecular response. This is the first reported case of acquired resistance to first-line EGFR-TKI based on three resistance mechanisms, treated with molecular targeted combination therapy.\n\nKeywords\nResistanceEGFRHER2Non-small cell lung cancerCase report\n==== Body\nIntroduction\nEpidermal growth factor receptor (EGFR)-targeted therapy has become standard of care in advanced stages EGFR-mutant non-small cell lung cancer (NSCLC). However, most patients eventually develop disease progression due to acquired resistance to EGFR-tyrosine kinase inhibitor (TKI). A secondary mutation (T790M) in EGFR accounts for resistance in more than half of these cases. Other known resistance mechanisms include non-T790M secondary mutations in EGFR (1%), activation of parallel pathways mostly by HER2 amplification (10–15%) or MET amplification (5%), activating mutations in the common downstream pathway (1%), and phenotypic transformation (10%) [1].\n\nCase Presentation\nA 60-year-old male, never smoker, presented with cough and neck pain after which he was diagnosed with an EGFR-mutated (L858R) bone metastasized lung adenocarcinoma. Mutation and HER2 amplification analyses were carried out on diagnosis biopsy (Fig. 1). All mutation analyses in this case were performed by Next Generation Sequencing (TruSeq Custom Amplicon on MiSeq, 24 genes, Illumina) and all HER2 amplification analyses were performed by HER2 Fluoresence In Situ Hybridization (PathVysion HER2 DNA Probe Kit, Abbott). Our patient was treated with first generation EGFR-TKI gefitinib 250mg/day and this resulted in deep partial remission.\n\nSix months after treatment initiation, disease progression occurred. Rebiopsy of the primary tumor revealed emergence of EGFR T790M resistance mutation (allele frequency 92%), HER2 S310Y mutation (allele frequency 32%) and HER2 amplification (HER2/CEP ratio 3.49), all not present at diagnosis (Fig. 2). After discussion on the multidisciplinary molecular pathology board, both T790M and HER2 alterations were considered to contribute to the emergence of resistance. Hence, second-line treatment with third generation EGFR-TKI osimertinib 80 mg/day in combination with HER2-receptor blocker trastuzumab (loading dose 4 mg/kg followed by 2 mg/kg weekly, off-label) was initiated and excellently tolerated. No signs of toxicity were noted, in particular no cardiotoxicity on routine echocardiography. This treatment resulted in disease stabilization.\n\nDisease progression occurred four months later. Biopsy of pleural metastases showed persistence of EGFR L858R and T790M mutation (the latter at a lower allele frequency of 4%) and absence of HER2 mutation and amplification (Fig. 3). Treatment with osimertinib and trastuzumab was discontinued and platinum-based combination chemotherapy was initiated.\n\nDiscussion\nIn this case, we report the simultaneous presence of three resistance mechanisms (EGFR T790M mutation, HER2 S310Y mutation and HER2 amplification) after first-line EGFR-TKI treatment. Although multiple resistance mechanisms have already been identified, the simultaneous presence of these three resistance mechanisms is a unique feature. Moreover, the presence of HER2 mutation on top of HER2 amplification as resistance mechanism has not been reported before to our knowledge. Interestingly, the observed HER2 mutation is not the common HER2 exon 20 insertion, but an activating point mutation in the extracellular domain, that has been confirmed to be oncogenic both in vitro and in vivo [2, 3, 4].\n\nThe additional presence of HER2 alterations led to association of trastuzumab to osimertinib, as the principal pathway of resistance was unclear and the aim was to inhibit both EGFR and HER2 pathways. No such combination therapy for this resistance profile has been reported.\n\nTo date, experience with HER2 inhibition in HER2 mutated NSCLC is limited: case series suggest a response rate of 50% for trastuzumab in combination with chemotherapy and 18% for trastuzumab in combination with afatinib [5, 6, 7, 8]. A recent phase II basket trial showed a response rate of 44% for emtansine-conjugated trastuzumab [9]. To date, there is no prospective evidence of trastuzumab alone or in combination with EGFR-TKI in HER2 mutated NSCLC.\n\nIn this case, treatment with osimertinib and trastuzumab was excellently tolerated and resulted in a clinically meaningful although not long-lasting stable disease. Interestingly, a clear molecular response was observed with disappearance of the HER2 mutated clone and HER2 amplification. Data about molecular response after HER2 inhibition are not available in previously published cases.\n\nThe course of this case should however be interpreted in the context of certain limitations. First, we cannot exclude that tumor heterogeneity rather than treatment is responsible for the observed molecular changes. Indeed, rebiopsy at the time of second progression was performed on pleural metastases rather than on the primary tumor because this was the predominant site of progression, and we have no liquid biopsy data for this particular case. Second, it is not impossible that osimertinib alone, which has also minor in vitro HER2 inhibitory effects [10], may have had the same molecular effect as the combination of osimertinib and trastuzumab. In this case, we combined osimertinib with trastuzumab, which is a far more potent HER2 inhibitor than osimertinib, assuming that maximal HER2 inhibition could lead to better clinical response. This remains of course unproven.\n\nConclusion\nThis is the first reported case of acquired resistance to first-line EGFR-TKI based on three resistance mechanisms. Second-line molecular based treatment with osimertinib and trastuzumab resulted in a clinically meaningful and clear molecular response in this patient. Targeting multiple (resistance) pathways might be a useful therapeutic option in patients with a complex EGFR resistance pattern and merits further investigation.\n\nStatement of Ethics\nThis research complies with the guidelines for human studies and was conducted in accordance with the World Medical Association Declaration of Helsinki. Written informed consent to publish was obtained and can be requested anytime.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThe authors received no specific funding for this work.\n\nAuthor Contributions\nAll authors (MR, BM, KP, JW and KC) contributed equally to this manuscript and approved the final manuscript.\n\nAcknowledgement\nNot applicable.\n\nFig. 1 Radiological and molecular status (HER2 FISH assay) at diagnosis.\n\nFig. 2 Radiological and molecular (HER2 FISH assay) status at disease progression 6 months after the start of gefitinib.\n\nFig. 3 Radiological and molecular (HER2 FISH assay) status at disease progression 4 months after the start of osimertinib and trastuzumab.\n==== Refs\nReferences\n1 Westover D Zugazagoita J Cho BC Lovly CM Paz-Ares L Mechanisms of acquuired resistance to first- and second-generation EGFR tyrosine kinase inhibitors Ann Oncol 2018 29 (suppl_1) i10 i19 29462254 \n2 Greulich H Kaplan B Mertins P Chen TH Tanaka KE Yun CH Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2 Proc Natl Acad Sci USA 2012 9 109 (36) 14476 81 22908275 \n3 Wang J Wen Y Ding G Ding P Zhang L Liu J Efficacy generated by afatinib in a lung adenocarcinoma patient harboring HER2 S310Y mutation Cancer Biol Ther 2018 6 19 (6) 450 3 29561699 \n4 Gao Y Zheng A Zhu X Song J Xue Q Clinical benefit from afatinib in an advanced squamous cell lung carcinoma patient harboring HER2 S310Y mutation: a case report OncoTargets Ther 2018 12 11 8705 10 \n5 Cappuzzo F Bemis L Varella-Garcia M HER2 mutation and response to trastuzumab therapy in non-small-cell lung cancer N Engl J Med 2006 6 354 (24) 2619 21 16775247 \n6 Mazières J Peters S Lepage B Cortot AB Barlesi F Beau-Faller M Lung cancer that harbors an HER2 mutation: epidemiologic characteristics and therapeutic perspectives J Clin Oncol 2013 6 31 (16) 1997 2003 23610105 \n7 Mazières J Barlesi F Filleron T Besse B Monnet I Beau-Faller M Lung cancer patients with HER2 mutations treated with chemotherapy and HER2-targeted drugs: results from the European EUHER2 cohort Ann Oncol 2016 2 27 (2) 281 6 26598547 \n8 De Grève J Teugels E Geers C Decoster L Galdermans D De Mey J Clinical activity of afatinib (BIBW 2992) in patients with lung adenocarcinoma with mutations in the kinase domain of HER2/neu Lung Cancer 2012 4 76 (1) 123 7 22325357 \n9 Li BT Shen R Buonocore D Olah ZT Ni A Ginsberg MS Ado-trastuzumab emtansine in patients with HER2 mutant lung cancers: results from a phase II basket trial J Clin Oncol 2018 8 36 (24) 2532 7 29989854 \n10 Liu S Li S Hai J Wang X Chen T Quinn MM Targeting HER2 Aberrations in Non-Small Cell Lung Cancer with Osimertinib Clin Cancer Res 2018 6 24 (11) 2594 604 29298799\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "12(2)",
"journal": "Case reports in oncology",
"keywords": "Case report; EGFR; HER2; Non-small cell lung cancer; Resistance",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "625-630",
"pmc": null,
"pmid": "31543779",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "16775247;22325357;22908275;23610105;26598547;29298799;29462254;29561699;29989854;30584328",
"title": "Triple Trouble: A Case of Multiple Resistance Mechanisms after First Generation EGFR-TKI in NSCLC.",
"title_normalized": "triple trouble a case of multiple resistance mechanisms after first generation egfr tki in nsclc"
} | [
{
"companynumb": "BE-AMGEN-BELSP2019155215",
"fulfillexpeditecriteria": "2",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OSIMERTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Pancreatoblastoma is a rare malignant tumor in children. Surgical resection of the tumor is necessary for cure; however, due to its aggressive nature, it is often unresectable at presentation due to tumor size, local invasion, and/or metastasis. Because it is a rare tumor, there is currently no standard treatment regimen. We report a case of a 4-year-old boy who presented with metastatic pancreatoblastoma with multiple large metastases involving all four sectors of the liver. We began treatment with chemotherapy (cisplatin, 5FU, vincristine, and doxorubicin), which significantly reduced the tumor burden in both the pancreas and liver. We then performed a staged subtotal pancreatectomy, complete hepatectomy, and living donor left lateral segment liver transplant. This was followed by postoperative adjuvant chemotherapy. Our patient is alive and healthy and has now been tumor-free for 7 years with no tumor relapse.",
"affiliations": "University of Utah School of Medicine, Salt Lake City, UT, USA.;Division of Pediatric Gastroenterology, Department of Pediatrics, University of Utah, Salt Lake City, UT, USA.;Division of Pediatric Surgery, Department of Surgery, University of Utah, Salt Lake City, UT, USA.",
"authors": "Ghaffarian|A A|AA|;Book|L|L|;Meyers|R L|RL|0000-0003-3901-8307",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13098",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "22(1)",
"journal": "Pediatric transplantation",
"keywords": "hepatoblastoma; liver transplant; pancreatoblastoma",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002675:Child, Preschool; D018572:Disease-Free Survival; D006498:Hepatectomy; D006801:Humans; D008113:Liver Neoplasms; D016031:Liver Transplantation; D008297:Male; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29235221",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Liver transplant for metastatic pancreatoblastoma: 7-year event-free survival after chemotherapy, pancreatectomy, complete hepatectomy, and liver transplant.",
"title_normalized": "liver transplant for metastatic pancreatoblastoma 7 year event free survival after chemotherapy pancreatectomy complete hepatectomy and liver transplant"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201803702",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "VINCRISTINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nFibrosing interstitial lung disease is the poor prognostic non-infectious lung disease by unknown etiology. Here, we present one case developing interstitial pneumonia with fibrosis after treatment of pneumocystis pneumonia (PCP) in newly diagnosed HIV-1 infected case.\n\n\nMETHODS\nA previously healthy 63-year old male was referred to our institute because of protracted dyspnea on effort in 2 weeks after pneumocystis pneumonia treatment. At referral, arterial blood oxygen pressure was within normal range (93.5 mmHg) at rest, but decreased rapidly 30 s after a slow walk (44.5 mmHg). Respiratory function tests showed severe restrictive ventilator impairment (vital capacity = 36.5%; forced expiratory volume in 1 s = 107.4%). Chest computed tomography showed severe fibrotic changes at bilateral basal parts and diffuse fibrotic changes in which PCP lesions were seen initially in previous images although β-D glucan was not elevated and P. jirovecii was not detected in saliva at referral. Other etiologies of fibrotic IP including infectious and/or autoimmune diseases were excluded by serology. Fibrotic lesion did not expand thereafter although it had not responded to the high-dose corticosteroid therapy.\n\n\nCONCLUSIONS\nWe report the first case of fibrosing interstitial lung disease triggered by HIV-related PCP.",
"affiliations": "AIDS Clinical Center, National Center of Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;Department of respiratory medicine, National Center of Global Health and Medicine, Tokyo, Japan.;AIDS Clinical Center, National Center of Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;AIDS Clinical Center, National Center of Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;AIDS Clinical Center, National Center of Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;AIDS Clinical Center, National Center of Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan.;AIDS Clinical Center, National Center of Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655, Japan. kwatanab@acc.ncgm.go.jp.",
"authors": "Suzuki|Tetsuya|T|;Shimoda|Yukiko|Y|;Teruya|Katsuji|K|;Gatanaga|Hiroyuki|H|;Kikuchi|Yoshimi|Y|;Oka|Shinichi|S|;Watanabe|Koji|K|http://orcid.org/0000-0002-3190-8439",
"chemical_list": "D047071:beta-Glucans; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "England",
"delete": false,
"doi": "10.1186/s12890-019-0831-9",
"fulltext": "\n==== Front\nBMC Pulm MedBMC Pulm MedBMC Pulmonary Medicine1471-2466BioMed Central London 83110.1186/s12890-019-0831-9Case ReportCase report: new development of fibrosing interstitial lung disease triggered by HIV-related pneumocystis pneumonia Suzuki Tetsuya tesuzuki@hosp.ncgm.go.jp 14Shimoda Yukiko yushimoda@hosp.ncgm.go.jp 2Teruya Katsuji kteruya@acc.ncgm.go.jp 1Gatanaga Hiroyuki higatana@acc.ncgm.go.jp 13Kikuchi Yoshimi yoshik@acc.ncgm.go.jp 1Oka Shinichi oka@acc.ncgm.go.jp 13http://orcid.org/0000-0002-3190-8439Watanabe Koji kwatanab@acc.ncgm.go.jp 11 0000 0004 0489 0290grid.45203.30AIDS Clinical Center, National Center of Global Health and Medicine, 1-21-1 Toyama, Shinjuku-ku, Tokyo, 162-8655 Japan 2 0000 0004 0489 0290grid.45203.30Department of respiratory medicine, National Center of Global Health and Medicine, Tokyo, Japan 3 0000 0001 0660 6749grid.274841.cCenter for AIDS Research, Kumamoto University, Kumamoto, Japan 4 0000 0004 0489 0290grid.45203.30Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan 18 3 2019 18 3 2019 2019 19 6519 2 2018 13 3 2019 © The Author(s). 2019Open 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\nFibrosing interstitial lung disease is the poor prognostic non-infectious lung disease by unknown etiology. Here, we present one case developing interstitial pneumonia with fibrosis after treatment of pneumocystis pneumonia (PCP) in newly diagnosed HIV-1 infected case.\n\nCase presentation\nA previously healthy 63-year old male was referred to our institute because of protracted dyspnea on effort in 2 weeks after pneumocystis pneumonia treatment. At referral, arterial blood oxygen pressure was within normal range (93.5 mmHg) at rest, but decreased rapidly 30 s after a slow walk (44.5 mmHg). Respiratory function tests showed severe restrictive ventilator impairment (vital capacity = 36.5%; forced expiratory volume in 1 s = 107.4%). Chest computed tomography showed severe fibrotic changes at bilateral basal parts and diffuse fibrotic changes in which PCP lesions were seen initially in previous images although β-D glucan was not elevated and P. jirovecii was not detected in saliva at referral. Other etiologies of fibrotic IP including infectious and/or autoimmune diseases were excluded by serology. Fibrotic lesion did not expand thereafter although it had not responded to the high-dose corticosteroid therapy.\n\nConclusion\nWe report the first case of fibrosing interstitial lung disease triggered by HIV-related PCP.\n\nKeywords\nHIVPneumocystis pneumoniaFibrosing interstitial lung diseasePulmonary fibrosisInterstitial pneumoniahttp://dx.doi.org/10.13039/100009619Japan Agency for Medical Research and Development15Afk0410017h0001Teruya Katsuji issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nFibrosing interstitial lung disease is the poor prognostic non-infectious lung disease by unknown etiology. Here, we present one case developing interstitial pneumonia with fibrosis after treatment of pneumocystis pneumonia (PCP) in newly diagnosed HIV-1 infected case.\n\nCase report\nA previously healthy Japanese 63-year-old male was referred to the AIDS Clinical Center, National Center for Global Health and Medicine (Tokyo, Japan; day 0) because of protracted dyspnea on effort (DOE) after pneumocystis pneumonia (PCP) treatment.\n\nFifty-seven days before referral (day − 57), he was admitted to a local hospital for progressive dyspnea of one month duration with diffuse interstitial infiltration in bilateral lung fields (chest computed tomography (CT), Fig. 1a, b). Human immunodeficiency virus (HIV) infection was first pointed out upon initial blood examination, and the non-acute phase of HIV-1 infection was confirmed by western blotting. Cluster of differentiation-4 counts and HIV-RNA loads were 45/μL (7.3%) and 56,000 copies/mL, respectively. Bronchoscopy identified Pneumocystis jirovecii in bronchoalveolar lavage fluid, and levels of β-D glucan in serum was increased (> 300 pg/mL) at that time point. With a diagnosis of HIV-related PCP, trimethoprim-sulfamethoxazole (TMP-SMX) was initiated with corticosteroids at that hospital (day − 47). Hypoxia under rest was improved rapidly, but DOE remained 2 weeks after completion of PCP treatment (day − 12). He was referred to our hospital for the further examination and treatment (day 0). Physical examination revealed “Velcro rales” in bilateral lower back auscultation, whereas no other abnormalities were identified by a review of systems (including neurologic examination). Arterial blood oxygen pressure was within normal range (93.5 mmHg) at rest, but decreased rapidly 30 s after a slow walk (44.5 mmHg). Respiratory function tests showed severe restrictive ventilator impairment (vital capacity = 36.5%; forced expiratory volume in 1 s = 107.4%). Re-examination of chest CT showed severe fibrotic changes at bilateral basal parts and diffuse fibrotic changes (Fig. 1c, d) in which PCP lesions were seen initially in previous images. Levels of SP-D (214.2 ng/mL), KL-6 (2249 IU/mL) and lactate dehydrogenase (234 IU/L) were increased, but β-D glucan was not elevated (14.8 pg/mL) and P. jirovecii was not detected in saliva at referral. Cytomegalovirus DNA in plasma and surrogate markers of autoimmune diseases (anti-centromere antibody, anti-Jo-1 antibody, c-ANCA, p-ANCA, anti-nuclear antibody, anti-RNP antibody, anti-SS-A antibody, anti-SS-B antibody, anti-Scl-70 antibody, anti-CCP antibody) was negative. The drug-induced lymphocyte stimulation test (DLST) against TMP-SMX was negative, but we changed secondary prophylaxis of PCP to atovaquone. We initiated combination antiretroviral therapy (cART) comprising dolutegravir, tenofovir alafenamide and emtricitabine at day 2, and added tacrolimus at day 16, but respiratory function and imaging findings were not improved. Corticosteroids (methylprednisolone [1000 mg/day, p.o.] for 3 days followed by prednisolone [1 mg/kg/day, p.o.]) were re-initiated at day 37. However, we stopped corticosteroid therapy because it caused mediastinal emphysema without eliciting any positive effects upon lung fibrosis. We started nintedanib at day 48, and are following up symptoms carefully. Oxygen requirement until the last follow-up date (day 120) was unchanged, that is 2 L/min at rest or 4 L/min at light labor.Fig. 1 High-resolution computed tomography of the chest before (a and b, day − 56) and after (c and d, day 14) treatment of pneumocystis pneumonia\n\n\n\nDiscussion and conclusions\nFibrosing interstitial lung disease, especially non-specific interstitial pneumonia (NSIP) and lymphoid interstitial pneumonitis, is more common among HIV-positive individuals than among HIV-negative ones, and cART could be effective in some cases [1, 2]. Drugs and autoimmune diseases can also induce acute lung damage that mimics NSIP [3, 4]. In our case, PCP was diagnosed initially by identification of P. jirovecii at a local hospital. Thereafter, fibrotic changes progressed despite successful treatment for PCP. Organ damage other than bilateral lung fields was not identified by imaging (contrast-enhanced CT from the neck to the abdomen; magnetic resonance imaging of the brain) or physical examination. Serological tests for autoimmune diseases were within normal ranges. We cannot completely exclude the possibility that drugs induced interstitial pneumonia, but DLST against TMP-SMX was negative, and fibrosis was not improved by cessation of treatment with TMP-SMX or corticosteroids. Furthermore, fibrotic changes spread in accordance with those seen for PCP lesions with severe restrictive ventilatory impairment. cART or corticosteroids had no beneficial effects on fibrosis. We diagnosed fibrosing interstitial lung disease by PCP from these clinical courses even though a pathologic diagnosis using expanded lung biopsy samples under surgery was not made due to severe restrictive ventilatory impairment. Another possible etiology was that PCP induced acute exacerbations of undiagnosed idiopathic pulmonary fibrosis which was present asymptomatically for a long time before PCP. However, our patient underwent annual health checks, and we confirmed that chest radiography was normal about one year before PCP onset. Furthermore, pulmonary fibrosis was limited within PCP lesions and did not progress after completion of PCP treatment.\n\nIn conclusion, we report the first case of fibrosing interstitial lung disease triggered by HIV-related PCP.\n\nAcknowledgements\nWe thank all the staff at the Department of Respiratory Medicine and at the AIDS Clinical Center for their help in completion of this study. We also thank Arshad Makhdum, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.\n\nFunding\nThis work was supported by the “Study on appropriate management of opportunistic illnesses in the era of early and prolonged ART of Japan” (#15Afk0410017h0001) from the Japan Agency for Medical Research and Development. The funders had no role in the collection or interpretation of data.\n\nAvailability of data and materials\nAll data discussed in the manuscript are included within this published article.\n\nAuthors’ contributions\nST writes first version of the manuscript, and WK completed all documents. ST, SY, TK, and WK were responsible for the treatment of the patients. GH, KY, and OS supervised the treatment and the completion of this case report. All atuhors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent for publication of case report was obtained from the patient.\n\nCompeting interests\nThe authors report no conflicts of interest.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. George MP, Singh V, Gladwin MT. Noninfectious and nonneoplastic conditions associated with human immunodeficiency virus infection. Semin Respir Crit Care Med 2016;37(2):289–302. doi: 10.1055/s-0036-1572560.\n2. Doffman SR Miller RF Interstitial lung diseases in HIV Clin Chest Med 2013 34 2 293 306 10.1016/j.ccm.2013.01.012 23702178 \n3. American Thoracic Society; European Respiratory Society. American Thoracic Society/European Respiratory Society international multidisciplinary consensus classification of the idiopathic interstitial pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001 Am J Respir Crit Med 2002;165(2):277–304.\n4. Travis WD Hunninghake G King TE Jr Lynch DA Colby TV Galvin JR Idiopathic nonspecific interstitial pneumonia: report of an American Thoracic Society project Am J Respir Crit Care Med 2008 177 12 1338 1347 10.1164/rccm.200611-1685OC 18388353\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2466",
"issue": "19(1)",
"journal": "BMC pulmonary medicine",
"keywords": "Fibrosing interstitial lung disease; HIV; Interstitial pneumonia; Pneumocystis pneumonia; Pulmonary fibrosis",
"medline_ta": "BMC Pulm Med",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D005541:Forced Expiratory Volume; D015658:HIV Infections; D006801:Humans; D016867:Immunocompromised Host; D008168:Lung; D017563:Lung Diseases, Interstitial; D008297:Male; D008875:Middle Aged; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D014057:Tomography, X-Ray Computed; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D047071:beta-Glucans",
"nlm_unique_id": "100968563",
"other_id": null,
"pages": "65",
"pmc": null,
"pmid": "30885173",
"pubdate": "2019-03-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11790668;18388353;23702178;26974305",
"title": "Case report: new development of fibrosing interstitial lung disease triggered by HIV-related pneumocystis pneumonia.",
"title_normalized": "case report new development of fibrosing interstitial lung disease triggered by hiv related pneumocystis pneumonia"
} | [
{
"companynumb": "JP-PFIZER INC-2019148665",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS\\TACROLIMUS ANHYDROUS"
},
"drugadd... |
{
"abstract": "Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are prescribed widely for the treatment of depression, anxiety disorders and other psychiatric disorders. Although antidepressants are considered as a safety drug category but unexpected cardiovascular events have been reported as the most serious complications. The aim of this study was to introduce a case presentation on bradycardia due to the drug interference of venlafaxine and cyclosporine.\nThe patient was a 38-year old woman diagnosed with systemic lupus erythematosus 5 years ago, who was admitted to a general educational hospital in northern Iran due to intensified rheumatologic symptoms and complaining about abdominal pain. Cyclosporine tab were administered to the patient, 50 mg twice daily. Two weeks after the administration of cyclosporine, the level of blood cyclosporine was checked. The patient became bradycardic after starting a single dose of venlafaxine (heart rate 52 ppm). Cardiac assessment showed no reason for bradycardia and it subsided after a drop of venlafaxine.\nAs a result of the potential adverse drug interactions between cyclosporine and antidepressants such as venlafaxine, physicians should be aware of the possibility of bradycardia in the simultaneous prescription of these drugs in cases.",
"affiliations": "Sexual and Reproductive Health Research Center, Nasibeh Nursing and Midwifery Faculty, Mazandaran University of Medical Sciences, Sari, Iran.;Department of Psychiatry, Psychiatry and Behavioral Sciences Research Center and addiction Institute, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.;Department of Internal Medicine, Orthopedic Research Center, Mazandaran University of Medical Sciences, Sari, Iran.",
"authors": "Azizi|Marzieh|M|;Elyasi|Forouzan|F|;Niksolat Roodposhti|Fatemeh|F|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": "10.22088/cjim.10.4.463",
"fulltext": "\n==== Front\nCaspian J Intern MedCaspian J Intern MedCJIMCaspian Journal of Internal Medicine2008-61642008-6172Babol University of Medical Sciences Babol, Iran 10.22088/cjim.10.4.463Case ReportBradycardia caused by interaction of venlafaxine and cyclosporine: A case report Azizi Marzieh MSc1Elyasi Forouzan MD*2Niksolat Roodposhti Fatemeh MD3\n1 Sexual and Reproductive Health Research Center, Nasibeh Nursing and Midwifery Faculty, Mazandaran University of Medical Sciences, Sari, Iran\n2 Department of Psychiatry, Psychiatry and Behavioral Sciences Research Center and addiction Institute, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran\n3 Department of Internal Medicine, Orthopedic Research Center, Mazandaran University of Medical Sciences, Sari, Iran* Correspondence: Forouzan Elyasi, Department of Psychiatry, Psychiatry and Behavioral Sciences Research Center and addiction Institute, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. E-mail: Forouzan.el@gmail.com, Tel: 0098 1133285109, Fax: 0098 1133285109Autumn 2019 10 4 463 467 15 12 2017 21 12 2018 20 2 2019 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nSelective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are prescribed widely for the treatment of depression, anxiety disorders and other psychiatric disorders. Although antidepressants are considered as a safety drug category but unexpected cardiovascular events have been reported as the most serious complications. The aim of this study was to introduce a case presentation on bradycardia due to the drug interference of venlafaxine and cyclosporine.\n\nCase presentation:\nThe patient was a 38-year old woman diagnosed with systemic lupus erythematosus 5 years ago, who was admitted to a general educational hospital in northern Iran due to intensified rheumatologic symptoms and complaining about abdominal pain. Cyclosporine tab were administered to the patient, 50 mg twice daily. Two weeks after the administration of cyclosporine, the level of blood cyclosporine was checked. The patient became bradycardic after starting a single dose of venlafaxine (heart rate 52 ppm). Cardiac assessment showed no reason for bradycardia and it subsided after a drop of venlafaxine.\n\nConclusion:\nAs a result of the potential adverse drug interactions between cyclosporine and antidepressants such as venlafaxine, physicians should be aware of the possibility of bradycardia in the simultaneous prescription of these drugs in cases.\n\nKey Words\nBradycardiaVenlafaxineCyclosporineSerotonin-Norepinephrine reuptake inhibitorsSelective serotonin reuptake inhibitors.\n==== Body\nSelective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) are prescribed widely for the treatment of depression, anxiety disorders and other psychiatric disorders (1). The cause of the widespread use of SSRIs and SNRIs drugs include relative safety, appropriate tolerability and low toxicity (2). Although antidepressants are considered as safety drugs but unexpected cardiovascular events such as arrhythmia or sudden heart arrest or cardiac death even in an individual with no history of cardiac problems have been reported as the most serious complications of these drugs (3, 4). SNRIs elevated norepinephrine and serotonin levels, can accelerate the activity of the cardiac sympathetic system and lead to a mild increase in heart rate and systemic blood pressure. Epidemiological studies showed that blood pressure monitoring is proposed for patients receiving SNRIs, especially venlafaxine. This drug with blocking sodium channels may show QTc wave prolongation in electrocardiogram results (5, 6). Even though tachycardia is more common in patients with venlafaxine, some studies showed bradycardia, as a result of venlafaxine consumption (7, 8). A case report has been reported on drug interactions resulting from the simultaneous consumption of cyclosporine and antidepressants such as nefazodone and venlafaxine which led to an increase in serum creatinine levels and increased levels of cyclosporine metabolism in the blood. Both nefazodone and venlafaxine led to inhibitors of CYP3A3 /4 isoenzyme (9). \n\nGiven the awareness of the inhibitory effects of SNRIs agents on hepatic cytochrome isoenzymes, it may predict the probability of a potential drug interaction between SNRIs and cyclosporine. The aim of this study was to introduce a case presentation on bradycardia due to the drug interference of venlafaxine and cyclosporine.\n\nCase presentation\nThe patient was a 38 year old woman, married, third grade middle school, unemployed, diagnosed with systemic lupus erythematosus 5 years ago, and was admitted to a general educational hospital in northern Iran due to chronic rheumatologic symptoms and complaining about abdominal pain. The patient mentioned that this pain was not related to eating and defecation and was not exacerbated by her activities. The results of initial laboratory tests and sonography were normal. \n\nCyclosporine tab 50 mg twice daily were administered to the patient. Two weeks after cyclosporine was prescribed, the blood cyclosporine level was checked. She had a history of treatment with sertraline, trazodone, quetiapine and duloxetine due to mood disorders. The patient also mentioned a history of suicidal attempts in the past. At that time, she used quetiapine 100 mg nightly. In the psychiatric examination, she was oriented, alert, had a dysphoric mood and was able to communicate well. The patient mentioned that she had attempted suicide twice due to marital conflicts but her children prevented the final action to suicide. In the period of her hospitalization, she had no suicidal thoughts. Quetiapine continued and venlafaxine was started at 37.5 mg per day. For 2 days, the patient received only cyclosporine, and had no bradycardia (figure 1) but after prescribing a single dose of venlafaxine, the patient became bradycardic (heart rate 52 ppm) (figure 2). In cardiac counseling, a 24-h Holter monitoring was done for the patient and the left ventricular ejection fraction (LVEF) was 55. Also, for assessment of QTc prolongation, daily electrocardiography (ECG) was requested 72 h later. Due to bradycardia, it was advised to discontinue venlafaxine and quetiapine. Also, the rheumatologist discontinued cyclosporine prescription. Psychiatric counseling was requested as a result of continuing psychiatric symptoms and she was visited by the psychiatrist twice a day for 72 h. Within 48 h of discontinuation (venlafaxine and cyclosporine), bradycardia was gradually eliminated.\n\nFigure 1 The patient's ECG before prescription of venlafaxine which showed no bradycardia\n\nFigure 2 The patient's ECG before prescription of Venlafaxine which showed bradycardia\n\nDiscussion\nIn this study, the patient showed bradycardia due to venlafaxine. The Naranjo adverse drug reactions (ADR) probability scale is shown in table 1. According to the results of this scale, venlafaxine with a probable ADR (score 8) was considered as the cause of bradycardia in this patient (13).\n\nVenlafaxine is a relatively new and commonly prescribed antidepressant from the SNRIs category and it is mainly approved and prescribed in the case of a major depressive disorder and general anxiety disorder (7). Studies have shown that this drug causes a reuptake of both serotonin and norepinephrine receptors and also has a weak effect on histamine and alpha-adrenergic receptors (14, 15). According to literatures, this drug is a relatively safe agent and patients treated with venlafaxine compared to other drugs such as tricyclic antidepressants (TCAs) showed a lower risk of drug's interactions. Hence, it is considered as an appropriate selection in the elderly or patients with disabilities (16) but cardiac abnormalities such as changing on QTc prolongation because of increased concentrations of venlafaxine has been reported in some cases. These changes can be explained through blocking the fast current of sodium in ventricular myocytes (17). \n\nIt is only contraindicated in patients with an identified risk of a serious cardiac ventricular arrhythmia or with uncontrolled hypertension. Also, it has been shown that compared to other effective antidepressants, venlafaxine is associated with the greatest risk of death from overdose (18). Results about this negative effect on cardiovascular system were controversial such that in a retrospective study, elderly patients who received venlafaxine were not only low to moderate in doses of this drug. Although there were no adverse cardiovascular problems, but they showed a lower risk of heart failure compared to SSRIs drugs such as sertraline (19).\n\nTable 1 The Naranjo adverse drug reaction probability scale: To assess the adverse drug reaction\n\n\t\nYes\n\t\nNo\n\t\nDon’t \n\n\n Know\n\t\nScore\n\t\n1.Are there previous conclusive report on this reaction\t✔\t\t\t+1\t\n2. Did the adverse event occur after the suspected drug was administered?\t✔\t\t\t+2\t\n3. Did the adverse reaction improve when the drug was continued or a specific antagonist was administered?\t\t✔\t\t0\t\n4. Did the adverse reaction reappear when the drug was readministered?\t\t\t✔\t0\t\n5. Are there alternative causes (other than the drug) that could have on their own caused the reaction?\t\t✔\t\t+2\t\n6. Did the reaction reappear when a placebo was given?\t\t\t✔\t0\t\n7. Was the blood detected in the blood (or other fluids) in concentrations known to be toxic?\t\t✔\t\t+1\t\n8. Was the reaction more severe when the dose was increased or less severe when the dose was decreased?\t✔\t\t\t+1\t\n9. Did the patient have a similar reaction to the same or similar drugs in any previous exposure?\t\t\t✔\t0\t\n10. Was the adverse events confirmed by any objective evidence?\t✔\t\t\t+1\t\nCyclosporine is an immunosuppressive agent which is used as a proper drug for the treatment of many autoimmune diseases (20). In a case report study in which the patient underwent allogeneic hematopoietic stem cell transplantation, cyclosporine 60 mg/kg was administered for two days and after continuous infusion of cyclosporine, 3mg/kg was prescribed with maintained checking of cyclosporine serum between 250-400 ng/dl. On day 23, serum cyclosporine increased to 450 ng/dl, heart rate decreased to 30-40/min and ECG showed sinus bradycardia. This study showed that there was a significant relationship between the dose of cyclosporine used and the occurrence of bradycardia in the patient (21). \n\nTwo probable mechanisms for bradycardia were considered as induced by the use of cyclosporine. In the first proposed mechanism, Cyclosporine may suppress the sinus node automatically and sinus bradycardia was reported in cases with cyclosporine prescription but this abnormality in the sinus node diminished after discontinuation of this drug (22). The second possible mechanism is that cyclosporine may lead to bradycardia by provoking the parasympathetic nervous system but studies have suggested that the second possible mechanism is less likely (21, 23). \n\nA study which assessed the adverse effect of cyclosporine on baroreflexes through the inhibition of testosterone receptors of cardiac vagal control showed that short term cyclosporine treatment led to decreased plasma testosterone level, impaired baroreflexes function, reduced its sensitivity and overall caused to reflex bradycardia (23). The selection of antidepressants depends on many factors such as the current drug prescribed for the patient, and the probable drugs interactions. Most antidepressants are metabolized in the liver through the isoenzyme P450 cytochrome system. The inhibition of this isoenzyme by drugs affect other drugs which need an isoenzyme for metabolism or transformation (14). \n\nAmong the various isoenzymes of P450, CYP3A3/4, plays the most important role in the metabolism of cyclosporine and inhibition of this system leads to decreased cyclosporine metabolism and increased cyclosporine level which cause toxicity in patients. Venlafaxine and nefazodone have the strongest inhibitory action on the CYP3A3/4 isoenzyme and decreased cyclosporine metabolism (9, 16). In this case report, maybe venlafaxine and cyclosporine drug interaction caused bradycardia but it was not specifically clear that which drugs creates bradycardia. Because patient showed no bradycardia during drug consumption of cyclosporine and after adding a single dose of venlafaxine patient showed bradycardia in her ECG and also bradycardia disappeared after discontinuation of venlafaxine, it is probably attributed to single dose of venlafaxine. Clinical studies have shown that the adverse interactions of these drugs depend on many factors such as the concentration of the isoenzyme inhibitor, amount of participation of active metabolites in the isoenzyme inhibitory activity and the level of toxicity of prescribed drugs (9). As a result of the potential adverse drug interactions between cyclosporine and antidepressants such as venlafaxine, physicians should be aware of the possibility of bradycardia in simultaneous prescription of these drugs in cases. Also, it has been proposed that ECG control should be continued during therapy, especially in patients with cardiovascular abnormalities or disorders. \n\nFunding:\nWe sincerely appreciate Mazandaran University of Medical Sciences and Sexual and Reproductive Health Research Center. \n\nConflict of Interest:\n None declared.\n==== Refs\nReferences\n1 Ozdilek B Escitalopram-induced bradycardia in elderly individuals: a case series report Klinik Psikofarmakoloji Bülteni Bull Clin Psychopharmacol 2015 25 183 5 \n2 Favre MP Sztajzel J Bertschy G Bradycardia during citalopram treatment: a case report Pharmacol Res 1999 39 149 50 10072706 \n3 Hamer M Batty GD Seldenrijk A Kivimaki M Antidepressant medication use and future risk of cardiovascular disease: the Scottish Health Survey Eur Heart J 2010 32 437 42 21118851 \n4 Waring WS Clinical use of antidepressant therapy and associated cardiovascular risk Drug Healthc Patient Saf 2012 4 93 101 22936860 \n5 Howell C Wilson AD Waring W Cardiovascular toxicity due to venlafaxine poisoning in adults: a review of 235 consecutive cases Br J Clin Pharmacol 2007 64 192 7 17298480 \n6 Mbaya P Alam F Ashim S Bennett D Cardiovascular effects of high dose venlafaxine XL in patients with major depressive disorder Hum Psychopharmacol 2007 22 129 33 17397100 \n7 Gründer G Wetzel H Schlösser R Benkert O Subchronic antidepressant treatment with venlafaxine or imipramine and effects on blood pressure and heart rate: assessment by automatic 24-hour monitoring Pharmacopsychiatry 1996 29 72 8 8741025 \n8 Agelink M Zeit T Klieser E Prolonged bradycardia complicates antidepressive treatment with venlafaxine and ECT Br J Psychiatry 1998 173 441 5 \n9 Vella JP Sayegh MH Interactions between cyclosporine and newer antidepressant medications Am J Kidney Dis 1998 31 320 3 9469504 \n10 Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 7249508 \n11 Masand PS Gupta S Long-term side effects of newer-generation antidepressants: SSRIS, venlafaxine, nefazodone, bupropion, and mirtazapine Ann Clin Psychiatry 2002 14 175 82 12585567 \n12 Béïque JC Montigny C Blier P Debonnel G Blockade of 5‐Hydroxytryptamine and noradrenaline uptake by venlafaxine: a comparative study with paroxetine and desipramine Br J Pharm 1998 125 526 32 \n13 Ereshefsky L Drug-drug interaction involving antidepressants: Focus on Venlafaxine J Clin Psychopharmacol 1996 16 37s 50s 8784647 \n14 Letsas K Korantzopoulos P Pappas L QT interval prolongation associated with venlafaxine administration Int J Cardiol 2006 109 116 7 16574528 \n15 National Institute for Health and Care Excellent What is the antidepressant of choice in coronary heart disease? NICE Available at: www.evidence.nhs.uk \n16 Nezafati MH Vojdanparast M Nezafati P Antidepressants and cardiovascular adverse events: A narrative review ARYA Atheroscler 2015 11 295 304 26715935 \n17 Scherrer U Vissing SF Morgan BJ Cyclosporine-induced sympathetic activation and hypertension after heart transplantation New Engl J Med 1990 323 693 9 2388667 \n18 Fujisaki G Kami M Murashige N Sinus bradycardia associated with cyclosporine following allogeneic hematopoietic stem cell transplantation Bone Marrow Transplant 2005 35 211 2 15531900 \n19 Griffith BP Bando K Hardesty RL A prospective randomized trial of FK506 versus cyclosporine after human pulmonary transplantation Transplantation 1994 57 848 51 7512292 \n20 El-Mas MM Afify EA Omar AG Sharabi FM Cyclosporine adversely affects baroreflexes via inhibition of testosterone modulation of cardiac vagal control J Pharmacol Exp Ther 2002 301 346 11907192\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2008-6164",
"issue": "10(4)",
"journal": "Caspian journal of internal medicine",
"keywords": "Bradycardia; Cyclosporine; Selective serotonin reuptake inhibitors.; Serotonin-Norepinephrine reuptake inhibitors; Venlafaxine",
"medline_ta": "Caspian J Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101523876",
"other_id": null,
"pages": "463-467",
"pmc": null,
"pmid": "31814947",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "21118851;22936860;9806336;7249508;15531900;9469504;16574528;2388667;8784647;11907192;9926067;17397100;10072706;7512292;26715935;8741025;17298480;12585567",
"title": "Bradycardia caused by interaction of venlafaxine and cyclosporine: A case report.",
"title_normalized": "bradycardia caused by interaction of venlafaxine and cyclosporine a case report"
} | [
{
"companynumb": "IR-PRINSTON PHARMACEUTICAL INC.-2019PRN00902",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugaddi... |
{
"abstract": "Acute metabolic acidosis is rarely associated with a reduced or negative anion gap (AG), but several case reports have described such an abnormality occurring in the setting of acute salicylate intoxication. The underlying cause of this phenomenon is unclear.\n\n\n\nIn this retrospective cohort study, we reviewed our institutional database to identify all patients admitted for salicylate intoxication at Mayo Clinic (Rochester, MN, USA) from January 2010 through December 2012. Serum chloride was measured with the Cobas INTEGRA 400 plus electrode (expedited laboratory test) or Cobas 6000 (routine laboratory test). We compared blood chloride levels measured by the 2 devices in the presence of positive blood salicylate level.\n\n\n\nTwelve adult patients with salicylate levels >20 mg/dL had markedly elevated chloride concentrations. The median (interquartile range) chloride level at admission was 120 (107-145) mmol/L on their initial laboratory studies, resulting in reduced or even negative AGs. None of the patients had bromide toxicity, nor did they have any other identifiable cause of hyperchloremia or decreased AG. Further testing of the same blood samples with an alternative measurement system (Roche Cobas 6000) yielded normal chloride values, indicating that falsely elevated chloride values with the initial testing led to the diminished or negative AG values.\n\n\n\nCirculating levels of salicylate can interfere with chloride measured by using routine techniques, resulting in spurious hyperchloremia outcomes and erroneous AG values. In patients with acute metabolic acidosis and abnormally reduced or negative AG, salicylate interference with chloride measurement should be suspected.",
"affiliations": "Division of Nephrology and Hypertension, Rochester, Minnesota, USA.;Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota, USA.;Division of Nephrology and Hypertension, Rochester, Minnesota, USA.",
"authors": "Kashani|Kianoush B|KB|;Steuernagle Iv|Jon H|JH|;Qian|Qi|Q|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D001965:Bromides; D002712:Chlorides; D012459:Salicylates; D001241:Aspirin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000484636",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1660-8151",
"issue": "138(3)",
"journal": "Nephron",
"keywords": "Hyperchloremia; Salicylate toxicity; Spurious",
"medline_ta": "Nephron",
"mesh_terms": "D000138:Acidosis; D000293:Adolescent; D000328:Adult; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001241:Aspirin; D001965:Bromides; D002712:Chlorides; D015331:Cohort Studies; D016208:Databases, Factual; D005189:False Positive Reactions; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012459:Salicylates; D014883:Water-Electrolyte Imbalance; D055815:Young Adult",
"nlm_unique_id": "0331777",
"other_id": null,
"pages": "186-191",
"pmc": null,
"pmid": "29131112",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spurious Hyperchloremia in the Presence of Elevated Plasma Salicylate: A Cohort Study.",
"title_normalized": "spurious hyperchloremia in the presence of elevated plasma salicylate a cohort study"
} | [
{
"companynumb": "US-NOVAST LABORATORIES, LTD-US-2018NOV000188",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN\\CARISOPRODOL"
},
... |
{
"abstract": "BACKGROUND\nIn the chronic phase of Hemiconvulsion-Hemiplegia-Epilepsy (HHE) syndrome, developing epilepsy may be intractable. Herein, we report a case where adrenocorticotropic hormone (ACTH) ceased an intractable habitual partial seizure in a patient with HHE syndrome.\n\n\nMETHODS\nA developmentally normal one-year-old girl presented with left focal motor status epilepticus in the clinical course of rotavirus infection. She was diagnosed with HH syndrome. At 4 months after status epilepticus, she developed partial seizures that occurred daily, and which resulted in a stooped posture, head rotation to the right, and contraction of both upper limbs predominantly in the left arm. At this time, she was diagnosed with idiopathic HHE syndrome. Her seizures were not reduced by sodium valproate, clonazepam, clobazam, zonisamide, phenytoin, phenobarbital, topiramate, lamotrigine, or liposteroid. At the age of 7, ACTH therapy was performed. On the 10th day of ACTH therapy, the habitual seizure was ceased. However, partial seizures characterized by left arm contraction then developed. Treatment with 350 mg/day lamotrigine prevented this emerging seizure. She has been free of both seizure types for more than one year, with no serious adverse effects of ACTH therapy.\n\n\nCONCLUSIONS\nWe suggest that ACTH therapy may be useful for patients with HHE, although further studies are required.",
"affiliations": "Department of Pediatrics, Osaka Medical College, Takatsuki, Osaka, Japan. Electronic address: ZVQ10523@nifty.com.;Department of Pediatrics, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Pediatrics, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Pediatrics, Osaka Medical College, Takatsuki, Osaka, Japan.;Department of Pediatrics, Hirakata Municipal Hospital, Hirakata, Osaka, Japan.;Department of Pediatric Neurology, Tanabe Children's Clinic, Hirakata, Osaka, Japan.;Department of Pediatrics, Osaka Medical College, Takatsuki, Osaka, Japan.",
"authors": "Shimakawa|Shuichi|S|;Nomura|Shohei|S|;Ogino|Motoko|M|;Fukui|Miho|M|;Kashiwagi|Mitsuru|M|;Tanabe|Takuya|T|;Tamai|Hiroshi|H|",
"chemical_list": "D000324:Adrenocorticotropic Hormone",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": "37(7)",
"journal": "Brain & development",
"keywords": "Adrenocorticotropic hormone therapy; Hemiconvulsion–Hemiplegia–Epilepsy syndrome; Lamotrigine; Treatment",
"medline_ta": "Brain Dev",
"mesh_terms": "D000324:Adrenocorticotropic Hormone; D001921:Brain; D002675:Child, Preschool; D000069279:Drug Resistant Epilepsy; D004569:Electroencephalography; D004828:Epilepsies, Partial; D005260:Female; D006429:Hemiplegia; D006801:Humans; D008279:Magnetic Resonance Imaging",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "733-7",
"pmc": null,
"pmid": "25476246",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "ACTH therapy on intractable epilepsy in Hemiconvulsion-Hemiplegia-Epilepsy syndrome.",
"title_normalized": "acth therapy on intractable epilepsy in hemiconvulsion hemiplegia epilepsy syndrome"
} | [
{
"companynumb": "JP-RANBAXY-2014R1-90487",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nTreatment for malignant embryonal brain tumors in young children usually employs cycles of standardly dosed cisplatinum followed by high-dose carboplatinum-containing conditioning with single or tandem autologous stem cell rescue (HDC-ASCR). High-dose carboplatin is potentially nephrotoxic, and additive platinum exposure may acutely impact renal function. Aiming to determine if decrease in renal function during conditioning assessed prior to each carboplatin dose was associated with acute increases in creatinine, requirement for dialysis or transplant-related mortality (TRM). This was a retrospective study of consecutive patients with medulloblastoma (n = 15) / atypical teratoid/rhabdoid tumor (AT/RT, n = 5) receiving HDC-ASCR. Fifteen patients underwent 1 HDC-ASCR (carboplatin × 3 doses/ etoposide/ thiotepa) and 5 patients underwent at least 1 of 3 planned tandem HDC-ASCR (carboplatin × 2 doses/ thiotepa). Renal function was assessed by daily creatinine and nuclear medicine glomerular filtration rate (GFR)/ creatinine clearance before each carboplatin dose.\n\n\nRESULTS\nIn this cohort of 20 patients, 3 had doses of carboplatin omitted due to decreases in GFR: 1 did not develop nephrotoxicity, 1 experienced nephrotoxicity without need for dialysis, and 1 required dialysis temporarily but recovered renal function. Two patients did not have GFR changes but developed post-ASCR renal failure requiring dialysis and TRM.\n\n\nCONCLUSIONS\nDaily assessment of renal function by GFR, prior each dose of carboplatin during HDC-ASCR, will help in protecting the kidney in heavily treated population of oncology/HSCT patients. Although the study had a small number of patients which is a major limitation of the study, but it points to a serious transplant-related morbidity and mortality. So, larger scale studies are needed to clarify the best approach to carboplatin dosing to insure the optimal balance between efficacy and toxicity.",
"affiliations": "Pediatric Stem Cell Transplantation Unit, Dana Farber/Children's Cancer and Blood Disorders Center, Boston, MA, USA. yasser.elborai@cu.edu.eg.;Pediatric Immunology and Stem Cell Transplant Unit, Queen Rania Children's Hospital/King Hussein Medical Center/Royal Medical Services, Amman, Jordan.;Department of Pediatric Hematology Oncology, Nicklaus Children's Hospital, Miami, FL, USA.;Pediatric Oncology Department, National Cancer Institute (NCI), Cairo University, Cairo, Egypt.;Pediatric Stem Cell Transplantation Unit, Dana Farber/Children's Cancer and Blood Disorders Center, Boston, MA, USA.;Pediatric Stem Cell Transplantation Unit, Dana Farber/Children's Cancer and Blood Disorders Center, Boston, MA, USA.",
"authors": "Elborai|Yasser|Y|http://orcid.org/0000-0002-5528-0025;Almutereen|Mohammad|M|;Maher|Ossama M|OM|;Hafez|Hanafy|H|;Lee|Michelle A|MA|;Lehmann|Leslie|L|",
"chemical_list": "D005047:Etoposide; D013852:Thiotepa; D003404:Creatinine; D016190:Carboplatin; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1186/s43046-020-00024-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1110-0362",
"issue": "32(1)",
"journal": "Journal of the Egyptian National Cancer Institute",
"keywords": "Autologous stem cell transplant (ASCT); Brain tumor; Carboplatin; GFR; Renal toxicity",
"medline_ta": "J Egypt Natl Canc Inst",
"mesh_terms": "D058186:Acute Kidney Injury; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D016190:Carboplatin; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin; D003404:Creatinine; D004305:Dose-Response Relationship, Drug; D005047:Etoposide; D005260:Female; D005919:Glomerular Filtration Rate; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D008527:Medulloblastoma; D012189:Retrospective Studies; D018335:Rhabdoid Tumor; D013724:Teratoma; D013852:Thiotepa; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous; D016896:Treatment Outcome",
"nlm_unique_id": "9424566",
"other_id": null,
"pages": "9",
"pmc": null,
"pmid": "32372349",
"pubdate": "2020-02-18",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Changes in glomerular filtration rate and clinical course after sequential doses of carboplatin in children with embryonal brain tumors undergoing autologous stem cell transplantation.",
"title_normalized": "changes in glomerular filtration rate and clinical course after sequential doses of carboplatin in children with embryonal brain tumors undergoing autologous stem cell transplantation"
} | [
{
"companynumb": "NVSC2020US096072",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
"dru... |
{
"abstract": "Calcinosis cutis is a rare disorder resulting from the precipitation and deposition of insoluble calcium and phosphate salts (hydroxyapatite crystals) in the dermis and subcutaneous tissue. It is generally divided into four main groups on the basis of etiology and pathogenesis. Clinical presentation of cutaneous calcinosis cutis varies according to the diagnosis and the underlying process. We report a case of calcinosis cutis of the heel in which both the extravasation of a calcium gluconate infusion and renal failure could have promoted the development of calcinosis cutis.",
"affiliations": "University of Bologna. alma.ismaili@yahoo.it.",
"authors": "Vaccari|Sabina|S|;Ismaili|Alma|A|;Barisani|Alessia|A|;Neri|Iria|I|;Patrizi|Annalisa|A|",
"chemical_list": "D002125:Calcium Gluconate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "19(9)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D002114:Calcinosis; D002125:Calcium Gluconate; D002406:Catheterization, Peripheral; D020405:Dermis; D004890:Erythema; D005119:Extravasation of Diagnostic and Therapeutic Materials; D005260:Female; D005533:Foot Dermatoses; D016523:Foot Ulcer; D006801:Humans; D054559:Hyperphosphatemia; D007008:Hypokalemia; D007223:Infant; D007262:Infusions, Intravenous; D007676:Kidney Failure, Chronic; D009392:Nephrectomy; D010530:Peritoneal Dialysis; D017044:Polycystic Kidney, Autosomal Recessive; D011183:Postoperative Complications; D011859:Radiography",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": "19617",
"pmc": null,
"pmid": "24050291",
"pubdate": "2013-09-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Solitary erythematous, tender plaque of the heel in a young infant.",
"title_normalized": "solitary erythematous tender plaque of the heel in a young infant"
} | [
{
"companynumb": "IT-FRESENIUS KABI-FK201503774",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CALCIUM GLUCONATE"
},
"drugadditional": ... |
{
"abstract": "A 66-year-old Japanese woman who was diagnosed with synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome presented with bilateral blurred vision 4 months prior to visiting our hospital. She had visited a local ophthalmology clinic first. She was diagnosed with conjunctivitis and was prescribed antibacterial eye drops. The symptoms persisted in spite of treatment. She was then referred to our hospital. At her initial visit, the visual acuities were 0.6 in both eyes. A slit-lamp examination revealed bilateral shallow anterior chamber, and intraocular pressures of 18 mm Hg in the right eye and 16 mm Hg in the left eye. There were no cells in the anterior chamber. Fundus examination revealed bilateral annular choroidal detachment and serous retinal detachment. Fluorescein angiography showed leakage of dye from the retinal pigment epithelium (RPE) and indocyanine green angiography showed focal choroidal hypoperfusion. Optical coherence tomography showed wavy RPE line and blurry thick choroid. Systemic investigation by the physician demonstrated bilateral pleural effusions of unknown origin. The patient had a past history of breast cancer; however, no metastasis was identified via malignant cells through cytology, laboratory findings, radiographs, CT, and MRI. After the diagnosis of Vogt-Koyanagi-Harada (VKH) disease was made, the patient was treated with local and systemic steroid including high-dose intravenous corticosteroids, and 150 mg of cyclosporine per day. Seventy days after the second high-dose of intravenous corticosteroids, these medications brought a complete resolution of both choroidal and retinal detachment. VKH disease associated with SAPHO syndrome is rare. The combination of immunosuppressive drug and steroid might be helpful for severe cases of VKH disease.",
"affiliations": "Aichi Medical University, Department of Ophthalmology, Nagakute City, Japan.;Aichi Medical University, Department of Ophthalmology, Nagakute City, Japan.;Aichi Medical University, Department of Ophthalmology, Nagakute City, Japan.;Aichi Medical University, Department of Ophthalmology, Nagakute City, Japan.;Aichi Medical University, Department of Ophthalmology, Nagakute City, Japan.",
"authors": "Hasegawa|Miyuki|M|;Fukutomi|Akira|A|;Jinno|Akiko|A|;Fujita|Kyoko|K|;Kamei|Motohiro|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000487226",
"fulltext": "\n==== Front\nCase Rep OphthalmolCase Rep OphthalmolCOPCase Reports in Ophthalmology1663-2699S. 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 10.1159/000487226cop-0009-0202Case ReportUnusual Case of Vogt-Koyanagi-Harada Disease Associated with SAPHO Syndrome: A Case Report Hasegawa Miyuki Fukutomi Akira Jinno Akiko Fujita Kyoko *Kamei Motohiro Aichi Medical University, Department of Ophthalmology, Nagakute City, Japan*Kyoko Fujita, 1-1, Karimata, Yazako, Nagakute-shi, Aichi-ken, 480-1195 (Japan), fujita.kyouko.249@mail.aichi-med-u.ac.jpJan-Apr 2018 29 3 2018 29 3 2018 9 1 202 208 31 10 2017 26 1 2018 Copyright © 2018 by S. Karger AG, Basel2018This 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 66-year-old Japanese woman who was diagnosed with synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome presented with bilateral blurred vision 4 months prior to visiting our hospital. She had visited a local ophthalmology clinic first. She was diagnosed with conjunctivitis and was prescribed antibacterial eye drops. The symptoms persisted in spite of treatment. She was then referred to our hospital. At her initial visit, the visual acuities were 0.6 in both eyes. A slit-lamp examination revealed bilateral shallow anterior chamber, and intraocular pressures of 18 mm Hg in the right eye and 16 mm Hg in the left eye. There were no cells in the anterior chamber. Fundus examination revealed bilateral annular choroidal detachment and serous retinal detachment. Fluorescein angiography showed leakage of dye from the retinal pigment epithelium (RPE) and indocyanine green angiography showed focal choroidal hypoperfusion. Optical coherence tomography showed wavy RPE line and blurry thick choroid. Systemic investigation by the physician demonstrated bilateral pleural effusions of unknown origin. The patient had a past history of breast cancer; however, no metastasis was identified via malignant cells through cytology, laboratory findings, radiographs, CT, and MRI. After the diagnosis of Vogt-Koyanagi-Harada (VKH) disease was made, the patient was treated with local and systemic steroid including high-dose intravenous corticosteroids, and 150 mg of cyclosporine per day. Seventy days after the second high-dose of intravenous corticosteroids, these medications brought a complete resolution of both choroidal and retinal detachment. VKH disease associated with SAPHO syndrome is rare. The combination of immunosuppressive drug and steroid might be helpful for severe cases of VKH disease.\n\nKeywords\nVogt-Koyanagi-Harada diseaseSAPHO syndromeChoroidal detachmentSerous retinal detachmentCyclosporine\n==== Body\nIntroduction\nSynovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome is a rare but clinically important disease characterized by pustular skin lesions and non-pyogenic osteoarticular lesions [1]. The etiology of SAPHO syndrome remains unclear, but neutrophil activation is suggested to contribute to the pathophysiology of this disease [2]. Ocular inflammation associated with SAPHO syndrome is rare. In this report, we describe an unusual case of Vogt-Koyanagi-Harada (VKH) disease manifesting bilateral annular choroidal detachment and exudative retinal detachment in a patient with SAPHO syndrome.\n\nCase Report\nA 66-year-old Japanese woman presented with bilateral blurred vision 4 months prior to visiting our hospital. She had been diagnosed with conjunctivitis and prescribed antibacterial eye drops by a local ophthalmology clinic. While undergoing therapy, she developed general fatigue and lumbar pain. She visited a private clinic, and was diagnosed with bilateral exudative pleural effusions. She was then referred to our hospital for further investigation and treatment. After admission to our hospital, complete physical examinations were done. Her exudative pleural effusion was of unknown origin. The patient had a past history of breast cancer 2 years ago, but no malignant cells were observed in cytology examination, and no malignancy was detected by CT and MRI. In pleural fluid examination, the specific gravity was 1.304, cell count 397/µL (neutrophils 4.0%, lymphocyte 62.0%, macrophage 34.0%), lactate dehydrogenase 105 U/L, adenosine deaminase 8.7 U/L, total protein 4.4 g/dL, rheumatoid factor < 10.0 IU/mL, antinuclear antibodies (±), and negative cultures. The cause of lumbar pain was also examined by the orthopedic department, and she was diagnosed with multiple spondylitis. Findings of an MRI of the spine and bone scintigraphy are shown in Figure 1. She also had palmoplantar pustulosis beginning several years ago. Based on the findings of spondylitis and palmoplantar pustulosis, she was diagnosed with SAPHO syndrome by both orthopedists and dermatologists, and was prescribed antibiotics and nonsteroidal anti-inflammatory drugs (NSAIDs). Seven days after admission, she was referred to ophthalmology for investigation of the cause of her blurred vision. At presentation, her best-corrected visual acuity (BCVA) was 0.6 in both eyes. Intraocular pressure was 18 mm Hg in the right eye and 16 mm Hg in the left eye. Slit-lamp examination demonstrated bilateral shallow anterior chambers. There were no keratic precipitates in both corneas, and no cells in the anterior chambers. Fundus examination revealed bilateral annular choroidal detachment with exudative serous retinal detachment involving the macula. Optical coherence tomography (OCT) showed subretinal fluid with a wavy retinal pigment epithelium (RPE) line and thicker choroid in both eyes. Fluorescein angiography (FA) depicted multiple areas of pinpoint dye leakage from the RPE. Indocyanine green angiography (ICGA) showed multiple areas of choroidal hypoperfusion in both eyes (Fig. 2). B-scan ultrasonography confirmed choroidal detachment with no associated scleral thickening or masses affecting the choroid and sclera. Although the patient did not meet all the diagnostic criteria for VKH disease, differential diagnosis showed no evidence of diseases such as uveal effusion syndrome, posterior scleritis, or choroidal metastasis, and laboratory markers of other types of uveitis including sarcoidosis, syphilis, and tuberculosis were negative. Moreover, autoimmune diseases such as rheumatoid arthritis and antineutrophil cytoplasmic antibody-associated vasculitis, which are often accompanied by uveitis, were also unlikely because of the absence of antibodies specific to these diseases. Her clinical findings including FA, ICGA, and OCT indicated VKH disease. Treatment was begun with a subtenon injection of triamcinolone acetonide in both eyes, while internists continued investigations to rule out other diseases. After 7 days, when internists finished the diagnostic workup with no additional findings, high-dose intravenous corticosteroids were given for 3 days. Treatment was continued with a slowly tapering course of oral prednisolone to 30 mg per day for 8 days. Because the choroidal and retinal detachments persisted in spite of steroid therapy, the patient was prescribed immunosuppressive medication of cyclosporine 150 mg twice daily. Two weeks after starting cyclosporine, cellulitis occurred in the left leg and C-reactive protein (CRP) increased to 23.5 mg/dL. Cyclosporine was discontinued, and prednisolone was further tapered to 10 mg per day. Because of this episode, ocular findings persisted and worsened. Ten days after discontinuing cyclosporine, her general condition improved and CRP level decreased to within the normal limit. Treatment was resumed with high dose (1 g) of intravenous corticosteroids for 3 days and cyclosporine 150 mg twice daily. Seventy days after the second course of high-dose intravenous corticosteroids, choroidal and retinal detachments were resolved completely, and BCVA was 0.5 in the right eye and 0.7 in the left eye (Fig. 3). Bilateral pleural effusions were also resorbed, and her general condition improved.\n\nDiscussion\nFirst described by Chamot and associates [1] in 1987, SAPHO syndrome is a disease characterized by pustular skin lesions and nonpyogenic osteoarticular lesions. At present, SAPHO syndrome is regarded as a rare disease with an estimated prevalence of less than 1 in 10,000 [2]. Furthermore, ocular inflammation associated with SAPHO syndrome is rare. Fernández-Melón and associates [3] reviewed 394 patients with uveitis having spondyloarthropathies and reported only one patient with SAPHO syndrome. Yabe and associates [4] reported two cases of SAPHO syndrome accompanied by Behçet's disease. Tanaka and associates [5] reported a case of scleritis associated with SAPHO syndrome. There are no reports of VKH disease with exudative choroidal and retinal detachments associated with SAPHO syndrome. In this report, we describe an unusual case of VKH disease-associated SAPHO syndrome.\n\nThe ocular findings in our case, such as annular choroidal detachment, were uncommon compared to typical VKH disease. There are a few reports of VKH disease with annular choroidal detachment [6, 7]. Yamamoto and associates [6] reported a case of annular choroidal detachment without retinal detachment associated with VKH disease. Elaraoud and associates [7] reported a similar case. Our case did not manifest overt retinal detachment or disc swelling but showed multiple areas of fluorescein leakage from the RPE on FA and choroidal hypoperfusion areas on ICGA. OCT revealed increased choroidal thickness and a wavy RPE line. Ultimately, we diagnosed the patient with VKH disease associated with SAPHO syndrome.\n\nAlthough several factors have been speculated to be possible etiologies of the SAPHO syndrome, such as infection, genetic predisposition, and immunological dysfunction, they remain controversial. The relationship between SAPHO syndrome and VKH disease is also unclear. Several studies have demonstrated that HLA-DR4 is strongly associated with VKH disease [8, 9]. On the other hand, there is no report of HLA-DR4-positive individuals with SAPHO syndrome. However, the association of HLA types with diseases remains controversial, because there are many questions regarding HLA typing for those diseases. VKH disease is a granulomatous inflammation related to T cell-mediated autoimmune disease targeting melanocyte self-antigens [10]. Grosjean and associates [11] have reported that autoantibodies were found in 20 patients (22.2%) with SAPHO syndrome, and they mentioned a link between autoimmunity and SAPHO syndrome. The mechanism of overlapping multiple autoimmune disorders is unknown. Infections or stress factors presumably activate humoral immunity, and the development of multiorgan immune disease is a possibility.\n\nOur case did not respond to steroids alone, and immunosuppression therapy with cyclosporine was considered. NSAID is regarded as the first-line treatment for SAPHO syndrome [12]. For patients who respond insufficiently to NSAIDs, addition of corticosteroids, bisphosphonates, and disease-modifying anti-rheumatic drugs such as methotrexate, sulfasalazine, and cyclosporine can be considered [12, 13]. Moreover, biologics such as tumor necrosis factor inhibitors may be used in the case of refractory disease [12, 14]. In our case, steroid therapy was suspended due to complication with cellulitis during treatment. We must always keep in mind systemic conditions and the adverse effects of steroids. In our case, although ophthalmic findings and general conditions did not improve with NSAIDs and steroids, both were improved by combination with cyclosporine.\n\nIn conclusion, we reported a rare case of VKH disease associated with SAPHO syndrome. Combined therapy of immunosuppressive drugs with steroids was effective in resolving choroidal and retinal detachments.\n\nFig. 1 a MRI T2-weighted image of the spine shows hyperintensity in Th7, Th8, L2, and L3. b Bone scintigraphy shows abnormal uptake in sternoclavicular joint, C7, Th1, Th7, Th8, Th12, and L3.\n\nFig. 2 Color fundus photographs (a, b) and optical coherence tomography images (c, d) at initial visit. Fundus photographs show annular choroidal detachment and serous retinal detachment in both eyes. Optical coherence tomography images show a wavy retinal pigment epithelium and thick choroid in both eyes. Fluorescein angiography and indocyanine green angiography findings. Early-phase fluorescein angiogram of right eye (e) shows dye leakage from retinal pigment epithelium. Late-phase fluorescein angiogram (f) shows slightly increased dye leakage. Dye pooling is not seen. Early- and late-phase indocyanine green angiograms (g and h, respectively) of right eye show focal hypoperfusion areas. Similar changes were seen in the left eye.\n\nFig. 3 Color fundus photographs (a, b) and optical coherence tomography images (c, d) at 70 days after initial treatment. Fundus color photographs show resolved annular choroidal detachment and serous retinal detachment in both eyes. Optical coherence tomography images show resolved serous retinal detachment.\n==== Refs\nReferences\n1 Chamot AM Benhamou CL Kahn MF Beraneck L Kaplan G Prost A Acne-pustulosis-hyperostosis-osteitis syndrome. Results of a national survey. 85 cases Rev Rhum Mal Osteoartic 1987 54 187 196 2954204 \n2 Magrey M Khan MA New insights into synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome Curr Rheumatol Rep 2009 11 329 333 19772827 \n3 Fernández-Melón J Muñoz-Fernández S Hidalgo V Bonilla-Hernán G Schlincker A Fonseca A Vieitez J Martín-Mola E Uveitis as the initial clinical manifestation in patients with spondyloarthropathies J Rheumatol 2004 31 524 527 14994399 \n4 Yabe H Takano Y Nomura E Nakayama M Kihara M Miyakawa S Horiuchi Y Two cases of SAPHO syndrome accompanied by classic features of Behcet's disease and review of the literature Clin Rheumatol 2008 27 133 135 17717714 \n5 Tanaka R Sakurai K Kaburaki T Scleritis associated with SAPHO syndrome: a case report Ocul Immunol Inflamm 2017 6 1 3 \n6 Yamamoto N Naito K Annular choroidal detachment in a patient with Vogt-Koyanagi-Harada disease Graefes Arch Clin Exp Ophthalmol 2004 242 355 358 14963715 \n7 Elaraoud I Andreatta W Jiang L Damer K Al-Ibrahim J A mystery of bilateral annular choroidal and exudative retinal detachment with no systemic involvement: is it part of Vogt-Koyanagi-Harada disease spectrum or a new entity? Case Rep Ophthalmol 2017 16 1 6 \n8 Shindo Y Inoko H Yamamoto T Ohno S HLA-DRB1 typing of Vogt-Koyanagi-Harada's disease by PCR-RFLP and the strong association with DRB1*0405 and DRB1*0410 Br J Ophthalmol 1994 78 223 226 7908535 \n9 Shi T Lv W Zhang L Chen J Chen H Association of HLA-DR4/HLA-DRB1*04 with Vogt-Koyanagi-Harada disease a systematic review and meta-analysis Sci Rep 2014 4 6887 25382027 \n10 Moorthy RS Inomata H Rao NA Vogt-Koyanagi-Harada syndrome Surv Ophthalmol 1995 39 265 292 7725227 \n11 Grosjean C Hurtado-Nedelec M Nicaise-Roland P Ferreyra-Dillon R Bollet C Quintin E Dieude P Palazzo E Wattiaux MJ Kahn MF Meyer O Chollet-Martin S Hayem G Prevalence of autoantibodies in SAPHO syndrome a single-center study of 90 patients J Rheumatol 2010 37 639 643 20110527 \n12 Rukavina I SAPHO syndrome: a review J Child Orthop 2015 9 19 27 25585872 \n13 Yabe H Ohshima H Takano Y Koyanagi T Usui H Nojiri K Ochi K Kihara M Horiuchi Y Mucosal lesions may be a complication of SAPHO syndrome: a study of 11 Japanese patients with SAPHO syndrome Rheumatol Int 2010 30 1277 1283 19774382 \n14 Moll C Hernández MV Cañete JD Gómez-Puerta JA Soriano A Collado A Sanmartí R Ilium osteitis as the main manifestation of the SAPHO syndrome: response to infliximab therapy and review of the literature Semin Arthritis Rheum 2008 37 299 306 17976692\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1663-2699",
"issue": "9(1)",
"journal": "Case reports in ophthalmology",
"keywords": "Choroidal detachment; Cyclosporine; SAPHO syndrome; Serous retinal detachment; Vogt-Koyanagi-Harada disease",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "202-208",
"pmc": null,
"pmid": "29681837",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "19774382;2954204;17976692;17717714;20110527;14963715;28203189;28060551;19772827;25585872;7908535;25382027;14994399;7725227",
"title": "Unusual Case of Vogt-Koyanagi-Harada Disease Associated with SAPHO Syndrome: A Case Report.",
"title_normalized": "unusual case of vogt koyanagi harada disease associated with sapho syndrome a case report"
} | [
{
"companynumb": "JP-BAUSCH-BL-2018-024588",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "1",
... |
{
"abstract": "A 40-year-old woman developed therapy-related acute myeloid leukemia (t-AML) with inv(16)(p13.1q22) and a rare type D form of core-binding factor β-subunit gene-myosin heavy chain 11 gene (CBFB-MYH11) fusion transcript approximately 2.5 years after receiving chemoradiotherapy for uterine cervical cancer. t-AML with inv(16)(p13.1q22) and rare non-type A CBFB-MYH11 typically develops after exposure to a topoisomerase II inhibitor, with a short period of latency of one to five years. As the patient had no history of exposure to topoisomerase II inhibitors, among her previously used chemotherapeutics, the topoisomerase I inhibitor, irinotecan, was speculated to be the most plausible cause of t-AML in this case. The present case suggests that irinotecan may cause t-AML resembling that associated with topoisomerase II inhibitors.",
"affiliations": "Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.",
"authors": "Akiyama|Hiroki|H|;Yamamoto|Masahide|M|;Sakashita|Chizuko|C|;Umezawa|Yoshihiro|Y|;Kurosu|Tetsuya|T|;Murakami|Naomi|N|;Miura|Osamu|O|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; C095514:CBFbeta-MYH11 fusion protein; D015514:Oncogene Proteins, Fusion; D000077146:Irinotecan; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.3535",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(6)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000328:Adult; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D059248:Chemoradiotherapy; D002885:Chromosomes, Human, Pair 16; D005260:Female; D006801:Humans; D000077146:Irinotecan; D015470:Leukemia, Myeloid, Acute; D015514:Oncogene Proteins, Fusion; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "651-5",
"pmc": null,
"pmid": "25786458",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Therapy-related leukemia with Inv(16)(p13.1q22) and type D CBFB/MYH11 developing after exposure to irinotecan-containing chemoradiotherapy.",
"title_normalized": "therapy related leukemia with inv 16 p13 1q22 and type d cbfb myh11 developing after exposure to irinotecan containing chemoradiotherapy"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP02822",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.