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"abstract": "Methotrexate is a highly effective medication that is the mainstay of treatment for numerous complex dermatological and rheumatological disorders. However, its use requires close monitoring as it has serious side effects that could be fatal if not recognized promptly. Herein, we present an interesting case of methotrexate toxicity leading to a prolonged hospital stay with resultant increase in health care cost and patient dissatisfaction. It remains of pivotal importance for primary care physicians and hospitalists to be aware of its side effect profile. As such, early recognition of methotrexate toxicity can result in earlier initiation of goal-directed therapies, leading to improved outcomes and shorter hospital stay. Patient education and effective communication between health care providers and the patient are of utmost importance in ensuring patient safety.",
"affiliations": "Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, USA.;Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, USA.;Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, USA.;Internal Medicine, Sir Ganga Ram Hospital, Lahore, PAK.;Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, USA.",
"authors": "Asghar|Muhammad|M|;Shoaib|Hasan|H|;Kang|Woosun|W|;Tariq|Irfa|I|;Chatterjee|Tulika|T|",
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"doi": "10.7759/cureus.14364",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.14364\nInternal Medicine\nQuality Improvement\nHematology\nMethotrexate Toxicity: A Simple Solution to a Complex Problem\nMuacevic Alexander\nAdler John R\nAsghar Muhammad 1\nShoaib Hasan 1\nKang Woosun 1\nTariq Irfa 2\nChatterjee Tulika 1\n1 Internal Medicine, University of Illinois College of Medicine Peoria, Peoria, USA\n2 Internal Medicine, Sir Ganga Ram Hospital, Lahore, PAK\nMuhammad Asghar noumanasghar1@gmail.com\n8 4 2021\n4 2021\n13 4 e143648 4 2021\nCopyright © 2021, Asghar et al.\n2021\nAsghar et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/54681-methotrexate-toxicity-a-simple-solution-to-a-complex-problem\nMethotrexate is a highly effective medication that is the mainstay of treatment for numerous complex dermatological and rheumatological disorders. However, its use requires close monitoring as it has serious side effects that could be fatal if not recognized promptly. Herein, we present an interesting case of methotrexate toxicity leading to a prolonged hospital stay with resultant increase in health care cost and patient dissatisfaction. It remains of pivotal importance for primary care physicians and hospitalists to be aware of its side effect profile. As such, early recognition of methotrexate toxicity can result in earlier initiation of goal-directed therapies, leading to improved outcomes and shorter hospital stay. Patient education and effective communication between health care providers and the patient are of utmost importance in ensuring patient safety.\n\npatient-centered care\nmethotrexate toxicity\nneutropenia\ndrug rash\ncost-effective\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\n\nThe origin of methotrexate (MTX) can be traced as far back as the year 1947. MTX is closely related to the drug aminopterin, which was used at the time to treat young children with acute leukemia. The patient’s clinical condition improved dramatically; however, just 10 days after the therapy, the patient developed severe stomatitis [1]. MTX is considered the mainstay treatment in many dermatological and systemic disorders and is the first line in the treatment for psoriasis [2]. Although it is clinically effective, MTX has common detrimental side effects such as mucositis and bone marrow suppression; therefore, patient education regarding adequate dosing is essential, and dosing requires close monitoring. Herein, we present a case of a patient who developed severe hematological side effects and dermatological findings after he inadvertently took a higher dose of MTX than prescribed.\n\nCase presentation\n\nA 54-year-old Caucasian male with a past medical history of chronic kidney disease stage III, diastolic heart failure, chronic obstructive pulmonary disease, and plaque psoriasis was admitted with worsening of his psoriatic skin lesions on the extensor surfaces of the elbow and knees along with periumbilical abdominal lesions and a new extensive rash involving the groin along-with mucositis, stomatitis, and balanitis. The patient's vitals were stable on presentation with no fever. The patient has an extensive history of plaque psoriasis and was previously treated with MTX, which was almost resolved. Due to the patient’s psoriasis flaring up, he was started back on MTX at 10 mg per week, but he inadvertently took 10 mg of MTX daily for a total of six days.\n\nOn examination, the patient had swollen, erythematous hands and feet, making activity difficult due to severe pain. The patient also had clearly demarcated, erythematous plaque with silvery scales and pustules involving the periumbilical region, knees, and elbows. Oral examination revealed demarcated painful ulcerations in the oral cavity. The groin region had extensive erosions with desquamation of the involved skin over the erythematous base along with erosive lesions on the glans penis (Figure 1).\n\nFigure 1 Rash involving the periumbilical and groin regions\n\nGiven the extensive nature of his skin lesions, broad-spectrum antibiotic and antifungal coverage was started with piperacillin-tazobactam, vancomycin, and fluconazole. Biopsy of the skin lesions in the groin was performed, which showed epidermal desquamation and ulceration along with dermal infiltrate of eosinophils, which could be seen with a cutaneous rash that would arise secondary to treatment with a cytotoxic drug. Biopsy confirmed our clinical suspicion of MTX toxicity. Cultures from the periumbilical skin lesions were positive for Staphylococcus aureus and diphtheroid due to superimposed infection. Antibacterial were switched to cefepime while fluconazole was continued for fungal infection coverage.\n\nThe patient also developed signs of hematological toxicity associated with MTX overdose. His white blood cell count dropped down to the nadir of 0.69 x 103/microliter with absolute neutrophil count (ANC) of 0.60 x 103/microliter, hemoglobin of 10.1 g/dL, and platelet count of 47 x 103/microliter (Table 1). The bone marrow suppression was treated with granulocyte colony-stimulating injections in our case.\n\nTable 1 Showing trends of WBC, RBC, platelet, absolute neutrophil count, and methotrexate levels\n\nWBC, white blood cell; RBC, red blood cell\n\n \t6/15/2020\t6/16/2020\t6/17/2020\t6/18/2020\t6/19/2020\t6/20/2020\t\nWBC, x103/microliter\t1.10\t1.67\t2.70\t2.33\t1.29\t1.01\t\nRBC, x103/microliter\t3.49\t3.68\t3.89\t3.77\t3.61\t3.75\t\nHemoglobin, g/dL\t10.0\t10.6\t11.2\t10.8\t10.1\t10.1\t\nPlatelet, x103/microliter\t161\t112\t109\t81\t60\t47\t\nAbsolute neutrophil count, x103/microliter\t0.74\t0.82\t1.65\t1.33\t0.29\t0.06\t\nMethotrexate level, umol/L\t0.04\t0.03\t0.03\t0.03\t \t \t\n\nOn admission, MTX was stopped and high-dose leucovorin rescue with 50 mg IV every six hours for two doses followed by 20 mg IV every six hours was initiated. NaHCO3 infusion of 3 liters daily was started for alkalization of urine for better excretion of MTX. MTX blood levels were measured and the patients had a level of 0.04 umol/L; on repeat testing, the MTX level was 0.03 umol/L and remained stable at 0.03 umol/L. A prednisone taper was stated at 20 mg/day for a week, tapering it to half its original dose every week until discontinuation. Given the severity of his skin lesion, cyclosporine 100 mg twice daily was added to his regimen. Adequate pain management was carried out by tylenol along with morphine.\n\nThe patient had improvement in the skin lesions with the resolution of plaques and normalization of the blood counts (Figure 2).\n\nFigure 2 Improvement in the rash after treatment\n\nDiscussion\n\nMTX, a folate analog, is absorbed in the small intestine and mainly excreted renally [3]. MTX inhibits dihydrofolate reductase due to an accumulation of polyglutamate, which prevents the synthesis of purines, pyrimidines, polyamines, and transmethylation of other compounds. Purines and pyrimidines are precursors of DNA and RNA, respectively. At high doses, MTX prevents the proliferation of cells by preventing DNA and RNA production, making it an effective tool against malignancies. The cessation of purine synthesis causes the arrest of the cell cycle in the S phase [4,5].\n\nThe variety and severity of the adverse effects is a conundrum for health care professionals in an otherwise miracle drug. While the different mechanisms of action bring out the benefits of the drug, those same mechanisms also bring out sinister effects of MTX. There is a wide spectrum of adverse effects that can be encountered; while some are reversible and depend on the dose such as stomatitis, others such as pneumonitis and bone marrow suppression are much severe [6]. Our patient presented with stomatitis and balanitis. There is a difference in acute and chronic toxicity of the drug, the latter tends to more severe than the former. Chronic toxicity is mostly considered accidental, which was reported by a study comparing the acute and chronic toxicity of the drug. Chronic toxicity is more likely to be exhibited by older individuals and by patients with renal failure, decreased albumin levels, and polypharmacy [7]. The most common cause of toxicity was due to accidental overdose or physician/pharmacist error. The majority in the chronic group experienced mucosal ulcers followed by skin lesions and gastrointestinal symptoms such as nausea, vomiting, abdominal pain, and gastrointestinal bleed. It makes sense that the group with chronic toxicity also experienced hematological abnormalities, namely thrombocytopenia, anemia, and leukopenia. This group also was a victim of hepatotoxicity due to polyglutamate accumulation [7]. The hematological picture of our patient was quite similar since the lab work showed thrombocytopenia, neutropenia, and leukopenia. The decreased cell counts across all cell lineages was also the most common adverse effect of MTX toxicity among a cohort of 28 patients in the study by Kivity et al. Low-dose toxicity, like our case, can be fatal due to bone marrow suppression [8].\n\nTreating the complexities of the adverse effects of MTX is quite a challenge. Different treatment modalities include administering leucovorin, granulocyte colony-stimulating factor, sodium bicarbonate, and blood products depending on the signs and symptoms of the patient. The guidelines for treating an oral overdose of MTX include gastric lavage, activated charcoal, leucovorin, and sodium bicarbonate [7]. Our treatment plan was quite similar for the patient. The drug levels were monitored, but a cohort study by Kivity et al. did not show any correlation between the drug levels and decreased cell counts [8].\n\nConclusions\n\nOur case shows how a commonly used effective medication can turn into poison if not used properly. The vast side effect profile is well documented in the literature, yet we continue to deal with such cases of MTX toxicity. Most of the cases are due to accidental overdose, where the fault can lie on either side of the aisle. It is exhausting knowing the fact that these cases are preventable, thereby being burdensome to health care and on the patient. The way forward lies in adequate patient education and improvement in communication channels between different health care teams.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study\n==== Refs\nReferences\n\n1 Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid N Engl J Med Farber S Diamond LK 787 793 238 1948 18860765\n2 Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents J Am Acad Dermatol Menter A Korman NJ Elmets CA 451 485 61 2009 https://doi.org/10.1016/j.jaad.2009.03.027 19493586\n3 The human proton-coupled folate transporter: biology and therapeutic applications to cancer Cancer Biol Ther Desmoulin SK Hou Z Gangjee A Matherly LH 1355 1373 13 2012 https://doi.org/10.4161/cbt.22020 22954694\n4 The mechanism of action of methotrexate Rheum Dis Clin North Am Cronstein BN 739 755 23 1997 9361153\n5 Mechanism of action of methotrexate in rheumatoid arthritis, and the search for biomarkers Nat Rev Rheumatol Brown PM Pratt AG Isaacs JD 731 742 12 2016 https://doi.org/10.1038/nrrheum.2016.175 27784891\n6 Methotrexate in rheumatoid arthritis: an update with focus on mechanisms involved in toxicity Semin Arthritis Rheum van Ede AE Laan RF Blom HJ De Abreu RA van de Putte LB 277 292 27 1998 9572710\n7 Acute versus chronic methotrexate poisoning; a cross-sectional study BMC Pharmacol Toxicol Ahmadzadeh A Zamani N Hassanian-Moghaddam H Hadeiy SK Parhizgar P 39 20 2019 31269977\n8 Clinical characteristics and risk factors for low dose methotrexate toxicity: a cohort of 28 patients Autoimmun Rev Kivity S Zafrir Y Loebstein R Pauzner R Mouallem M Mayan H 1109 1113 13 2014 https://doi.org/10.1016/j.autrev.2014.08.027 25172240\n\n",
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"issue": "13(4)",
"journal": "Cureus",
"keywords": "cost-effective; drug rash; methotrexate toxicity; neutropenia; patient-centered care",
"medline_ta": "Cureus",
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"nlm_unique_id": "101596737",
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"pages": "e14364",
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"pmid": "33972915",
"pubdate": "2021-04-08",
"publication_types": "D002363:Case Reports",
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"title": "Methotrexate Toxicity: A Simple Solution to a Complex Problem.",
"title_normalized": "methotrexate toxicity a simple solution to a complex problem"
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"abstract": "A 2-month-old male infant presented for elective repair of inguinal hernias. His preoperative medical history and physical examination were unremarkable. During induction of anesthesia, the infant sustained an adverse cardiac event. The event was characterized by tachycardia, hypotension, and massive ST-segment elevation. Despite vigorous resuscitation, spontaneous hemodynamic stability could not be achieved and extracorporeal membrane oxygenation was required. A transthoracic echocardiogram revealed severe hypoplasia of the ascending aorta. As effective cardiac function did not recover and there was evidence of diffuse ischemic brain injury, life support was withdrawn. Genetic testing performed postoperatively was definitive for Williams syndrome.",
"affiliations": "Department of Clinical Anaesthesia, Riley Hospital for Children, Indianapolis, IN 46202-5200, USA.;Department of Clinical Anaesthesia, Riley Hospital for Children, Indianapolis, IN 46202-5200, USA.;Department of Clinical Anaesthesia, Riley Hospital for Children, Indianapolis, IN 46202-5200, USA.;Department of Clinical Anaesthesia, Riley Hospital for Children, Indianapolis, IN 46202-5200, USA.;Department of Surgery, Riley Hospital for Children, Indianapolis, IN 46202-5200, USA.",
"authors": "Dunlap|Julie D|JD|;Green|Morton C|MC|;Shah|Aali M|AM|;Kibby|Brandon T|BT|;Billmire|Deborah F|DF|",
"chemical_list": "D018685:Anesthetics, Inhalation; D018686:Anesthetics, Intravenous; D000077149:Sevoflurane; D015742:Propofol",
"country": "India",
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"doi": "10.4103/aca.ACA_38_18",
"fulltext": "\n==== Front\nAnn Card AnaesthAnn Card AnaesthACAAnnals of Cardiac Anaesthesia0971-97840974-5181Wolters Kluwer - Medknow India 30971606ACA-22-21010.4103/aca.ACA_38_18Case ReportCardiac Arrest after Induction of Anesthesia in a 2-month-old Infant with Undiagnosed Williams Syndrome Dunlap Julie D Green Morton C Shah Aali M Kibby Brandon T Billmire Deborah F 1Department of Clinical Anaesthesia, Riley Hospital for Children, Indianapolis, IN 46202-5200, USA1 Department of Surgery, Riley Hospital for Children, Indianapolis, IN 46202-5200, USAAddress for correspondence: Dr. Julie D Dunlap, Riley Hospital for Children, Room 2820, 705 Riley Hospital Drive, Indianapolis, IN 46202-5200, USA. E-mail: jdunlap2@iuhealth.orgApr-Jun 2019 22 2 210 212 Copyright: © 2019 Annals of Cardiac Anaesthesia2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.A 2-month-old male infant presented for elective repair of inguinal hernias. His preoperative medical history and physical examination were unremarkable. During induction of anesthesia, the infant sustained an adverse cardiac event. The event was characterized by tachycardia, hypotension, and massive ST-segment elevation. Despite vigorous resuscitation, spontaneous hemodynamic stability could not be achieved and extracorporeal membrane oxygenation was required. A transthoracic echocardiogram revealed severe hypoplasia of the ascending aorta. As effective cardiac function did not recover and there was evidence of diffuse ischemic brain injury, life support was withdrawn. Genetic testing performed postoperatively was definitive for Williams syndrome.\n\nAnesthesiacardiac arrestinductionpediatricWilliams syndrome\n==== Body\nIntroduction\nWilliams syndrome is a multisystem genetic disorder caused by a hemizygous deletion in the long arm of chromosome 7 in the region 7q11.23. Loss of one of the ELN genes from this chromosome band results in a deficiency of elastin.[12] Congenital cardiac defects are common in children with Williams syndrome. These defects include supravalvular aortic stenosis (SVAS), pulmonary artery stenosis, and coronary arterial ostial stenosis.[34] Fusion of the aortic valve leaflets to the aortic wall can produce functional coronary artery stenosis and reduce cardiac blood flow. Stenoses of the abdominal aorta, renal arteries, and intracranial arteries can also occur. Reduced elastin in the large arteries causes increased arterial stiffness that promotes early-onset hypertension.[5] Arterial elasticity is important to cardiac mechanics as energy is stored in the arterial wall during systole and released during diastole. This effect promotes cardiac efficiency, improves peripheral blood flow, reduces left ventricular afterload, and increases coronary blood flow.[67] Elastin deficiency in the myocardium may directly reduce cardiac performance.[89]\n\nNoncardiovascular features of Williams syndrome include elfin facies, growth retardation, endocrine dysfunction, and pulmonary emphysema.[10] The risk of sudden death from cardiomyopathy is 25–100 times greater than the normal population.[11]\n\nThe risk of an adverse cardiac event during anesthesia may be as high as 11%.[12] Focused specialty care may significantly reduce that risk if the diagnosis of Williams syndrome is known before anesthesia.[13] We report a case of cardiac arrest in a 2-month-old infant with undiagnosed Williams syndrome.\n\nWritten permission from the patient's mother and approval from the Indiana University Institutional Review Board for the publication of case report were obtained.\n\nCase Report\nThe patient was a term, 2-month-old male weighing 4.8 kgs, who presented for the elective repair of inguinal hernia. The medical history was unremarkable, and no cardiac murmurs were detected during routine pediatric examinations. Preoperative vital signs were: temperature 36.6°C, heart rate 154/min, blood pressure 107/59, respiratory rate 44/min, and arterial oxygen saturation 100% (room air). No cardiac murmurs were heard.\n\nAnesthesia was induced with sevoflurane in oxygen to a maximum sevoflurane concentration of 8%, and an intravenous catheter was inserted. Propofol (2 mg/kg intravenous) was administered, and the trachea was intubated with a 3.0 mm internal diameter cuffed tracheal tube. The inspired concentration of sevoflurane was reduced to 3% immediately after intubation. Heart rate at that time was 146 bpm and systolic blood pressure was between 70 and 80 mmHg. Five minutes after intubation, there was a significant change in the electrocardiogram that appeared to be a wide QRS complex tachycardia. As the systolic blood pressure decreased to 58/26, resuscitation was initiated with chest compressions, and repeated doses of epinephrine and sodium bicarbonate. Although epinephrine boluses transiently increased systolic blood pressure but subsequently, it became very low (30-40 mmHg to immeasurable. Over 20 min, nine doses of epinephrine (2–10 μg/kg), four doses of sodium bicarbonate (2–5 mEq/kg), one dose of calcium gluconate (5 mg/kg), one dose of magnesium sulfate (30 mg/kg), and one electrical countershock were administered, and an epinephrine infusion at 50 μg/kg/min was initiated. It became evident that the change in the QRS pattern was actually secondary to massive elevation of the ST segment. Despite aggressive resuscitation efforts, spontaneous circulation could not be restored. Extracorporeal membrane oxygenation (ECMO) was established within 1 h of the arrest, and the patient was transferred to the Intensive Care Unit (ICU). A transthoracic echocardiogram showed moderate-to-severe decreased left ventricular function and a diffusely hypoplastic (4.5 mm, normal 7.5–9 mm[14]) and thickened ascending aorta. The aortic valve was tri-leaflet and normal. Over the next 48 h in the ICU, while on ECMO, the infant suffered a series of seizures. Serial echocardiograms showed no improvement in cardiac function, and cranial computed tomography demonstrated diffuse hypoxic-ischemic injury. Life support was withdrawn. Cytogenetic analysis with fluorescence in situ hybridization was positive for deletion in the Williams syndrome critical region. One chromosome showed signals for ELN, LIMK1, and D7S613. These signals were absent in the other chromosome 7.\n\nDiscussion\nThe increased risk of anesthesia for patients with Williams syndrome has been reported by several sources.[15161718192021] Patients at highest risk are those with SVAS when a decrease in diastolic blood pressure reduces coronary blood flow, leading to myocardial ischemia. Recommendations for anesthesia are similar to those for adults with ischemic heart disease.[222324] These recommendations include maintenance of cardiac preload, myocardial contractility, and systemic vascular resistance (SVR) directed at optimization of coronary blood flow. Although the recommendations for administering an anesthetic that minimizes a reduction of diastolic blood pressure and maintains coronary blood flow are logical, the situation in patients with Williams syndrome may be more complex than that of adult patients with coronary artery disease. Reduced compliance of the aorta due to elastin deficiency in Williams patients can cause marginal blood flow to the subendocardium under normal physiologic conditions. Endocardial perfusion could be further compromised by the effects of anesthetics that are usually well tolerated by normal infants. This may explain the rapidity with which severe hypotension occurs during anesthesia and the poor response to resuscitation in Williams patients. There may be electrophysiologic mechanisms for cardiac arrest such as ventricular dysrhythmia secondary to prolongation of the Q-T interval.[25] Prolongation of the Q-T interval in patients with Williams syndrome resembles the increase in Q-T interval of patients with ischemic heart disease.\n\nThe diagnosis of Williams syndrome in an infant can be difficult as many of the signs of the disease are not present at an early age. Williams patients with SVAS and a cardiac murmur are typically diagnosed at 1–1.5 years of age. Detection, however, may be delayed until 4–5 years of age if SVAS is not present.[26] The cardiovascular pathology of our patient was atypical and different from other reported cases. Most patients with Williams syndrome have SVAS with or without coronary artery anomalies. Our patient had a severely hypoplastic aorta without detectable coronary stenosis and no cardiac murmur. The only preoperative clue may have been the elevated systolic blood pressure of 107 mmHg. Accurate measurement of blood pressure in a young infant, however, is influenced by many variables, and systolic blood pressure of 107 mmHg does not generally cause concern.[27]\n\nWe can only speculate as to the mechanism of the cardiac arrest in our patient. Sevoflurane and propofol both decrease (SVR) and sevoflurane is known to increase the Q-T interval.[28293031] Although the infant tolerated the induction with sevoflurane, a further decrease in SVR caused by propofol could have reduced myocardial blood flow. This is the youngest reported patient with undiagnosed Williams syndrome who suffered a cardiac arrest during anesthesia and underscores the increased risk of anesthesia for these patients.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form, the patient's mother has given his consent for his images and other clinical information to be reported in the journal. The patient's mother understands that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Merla G Brunetti-Pierri N Micale L Fusco C Copy number variants at Williams-Beuren syndrome 7q11. 23 region Hum Genet 2010 128 3 26 20437059 \n2 Heinz A Huertas AC Schräder CU Pankau R Gosch A Schmelzer CE Elastins from patients with Williams-Beuren syndrome and healthy individuals differ on the molecular level Am J Med Genet A 2016 170 1832 42 27311421 \n3 Yuan SM Congenital heart defects in Williams syndrome Turk J Pediatr 2017 59 225 32 29376566 \n4 van Pelt NC Wilson NJ Lear G Severe coronary artery disease in the absence of supravalvular stenosis in a patient with Williams syndrome Pediatr Cardiol 2005 26 665 7 15549615 \n5 Osei-Owusu P Knutsen RH Kozel BA Dietrich HH Blumer KJ Mecham RP Altered reactivity of resistance vasculature contributes to hypertension in elastin insufficiency Am J Physiol Heart Circ Physiol 2014 306 H654 66 24414067 \n6 Collins RT 2nd Cardiovascular disease in Williams syndrome Circulation 2013 127 2125 34 23716381 \n7 Belz GG Elastic properties and Windkessel function of the human aorta Cardiovasc Drugs Ther 1995 9 73 83 7786838 \n8 Jöbsis PD Ashikaga H Wen H Rothstein EC Horvath KA McVeigh ER The visceral pericardium: Macromolecular structure and contribution to passive mechanical properties of the left ventricle Am J Physiol Heart Circ Physiol 2007 293 H3379 87 17933976 \n9 Mizuno T Yau TM Weisel RD Kiani CG Li RK Elastin stabilizes an infarct and preserves ventricular function Circulation 2005 112 I81 8 16159870 \n10 Pober BR Williams-Beuren syndrome N Engl J Med 2010 362 239 52 20089974 \n11 Wessel A Gravenhorst V Buchhorn R Gosch A Partsch CJ Pankau R Risk of sudden death in the Williams-Beuren syndrome Am J Med Genet A 2004 127A 234 7 15150772 \n12 Olsen M Fahy CJ Costi DA Kelly AJ Burgoyne LL Anaesthesia-related haemodynamic complications in Williams syndrome patients: A review of one institution's experience Anaesth Intensive Care 2014 42 619 24 25233176 \n13 Brown ML Nasr VG Toohey R DiNardo JA Williams syndrome and anesthesia for non-cardiac surgery: High risk can be mitigated with appropriate planning Pediatr Cardiol 2018 39 1123 8 29572733 \n14 Kampmann C Wiethoff CM Wenzel A Stolz G Betancor M Wippermann CF Normal values of M mode echocardiographic measurements of more than 2000 healthy infants and children in central Europe Heart 2000 83 667 72 10814626 \n15 Horowitz PE Akhtar S Wulff JA Al Fadley F Al Halees Z Coronary artery disease and anesthesia-related death in children with Williams syndrome J Cardiothorac Vasc Anesth 2002 16 739 41 12486657 \n16 Monfared A Messner A Death following tonsillectomy in a child with Williams syndrome Int J Pediatr Otorhinolaryngol 2006 70 1133 5 16406078 \n17 Pham PP Moller JH Hills C Larson V Pyles L Cardiac catheterization and operative outcomes from a multicenter consortium for children with Williams syndrome Pediatr Cardiol 2009 30 9 14 19052807 \n18 Hornik CP Collins RT 2nd Jaquiss RD Jacobs JP Jacobs ML Pasquali SK Adverse cardiac events in children with Williams syndrome undergoing cardiovascular surgery: An analysis of the Society of Thoracic Surgeons Congenital Heart Surgery Database J Thorac Cardiovasc Surg 2015 149 1516 220 25791950 \n19 Medley J Russo P Tobias JD Perioperative care of the patient with Williams syndrome Paediatr Anaesth 2005 15 243 7 15725324 \n20 Gupta P Tobias JD Goyal S Miller MD Melendez E Noviski N Sudden cardiac death under anesthesia in pediatric patient with Williams syndrome: A case report and review of literature Ann Card Anaesth 2010 13 44 8 20075535 \n21 Latham GJ Ross FJ Eisses MJ Richards MJ Geiduschek JM Joffe DC Perioperative morbidity in children with elastin arteriopathy Paediatr Anaesth 2016 26 926 35 27397140 \n22 Collins Ii RT Collins MG Schmitz ML Hamrick JT Peri-procedural risk stratification and management of patients with Williams syndrome Congenit Heart Dis 2017 12 133 42 28382779 \n23 Matisoff AJ Olivieri L Schwartz JM Deutsch N Risk assessment and anesthetic management of patients with Williams syndrome: A comprehensive review Paediatr Anaesth 2015 25 1207 15 26456018 \n24 Burch TM McGowan FX Jr Kussman BD Powell AJ DiNardo JA Congenital supravalvular aortic stenosis and sudden death associated with anesthesia: What's the mystery? Anesth Analg 2008 107 1848 54 19020129 \n25 Collins RT 2nd Aziz PF Gleason MM Kaplan PB Shah MJ Abnormalities of cardiac repolarization in Williams syndrome Am J Cardiol 2010 106 1029 33 20854969 \n26 Huang L Sadler L O’Riordan MA Robin NH Delay in diagnosis of Williams syndrome Clin Pediatr (Phila) 2002 41 257 61 12041723 \n27 Park MK Menard SM Normative oscillometric blood pressure values in the first 5 years in an office setting Am J Dis Child 1989 143 860 4 2741863 \n28 Kassam SI Lu C Buckley N Lee RM The mechanisms of propofol-induced vascular relaxation and modulation by perivascular adipose tissue and endothelium Anesth Analg 2011 112 1339 45 21543785 \n29 Chang KS Davis RF Propofol produces endothelium-independent vasodilation and may act as a Ca2+ channel blocker Anesth Analg 1993 76 24 32 8418736 \n30 Wodey E Pladys P Copin C Lucas MM Chaumont A Carre P Comparative hemodynamic depression of sevoflurane versus halothane in infants: An echocardiographic study Anesthesiology 1997 87 795 800 9357880 \n31 Kleinsasser A Kuenszberg E Loeckinger A Keller C Hoermann C Lindner KH Sevoflurane, but not propofol, significantly prolongs the Q-T interval Anesth Analg 2000 90 25 7 10624970\n\n",
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"keywords": "Anesthesia; Williams syndrome; cardiac arrest; induction; pediatric",
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"pmc": null,
"pmid": "30971606",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7786838;19020129;20437059;20075535;27311421;16159870;12486657;25791950;20854969;23716381;27397140;9357880;10624970;24414067;12041723;19052807;28382779;26456018;29376566;10814626;16406078;20089974;25233176;15150772;2741863;29572733;17933976;8418736;15549615;21543785;15725324",
"title": "Cardiac arrest after induction of anesthesia in a 2-month-old infant with undiagnosed Williams syndrome.",
"title_normalized": "cardiac arrest after induction of anesthesia in a 2 month old infant with undiagnosed williams syndrome"
} | [
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"abstract": "Golimumab is approved for the treatment of moderate-to-severely active ulcerative colitis. However, there have been no formal trials to assess its utility in Crohn's disease [CD]. Our aim was to determine the efficacy and safety of golimumab in patients with anti-tumour necrosis factor [TNF] refractory CD.\nPatients with CD treated with golimumab between 2010 and 2017 were included in a retrospective observational study. The vast majority of patients failed two anti-TNF agents. Clinical response was defined as a significant reduction in symptoms and biochemical markers of CD, and no requirement for surgery or introduction of immune-suppressants.\nForty-five patients were included, with a median follow-up of 22 months [interquartile range 12-34] following initiation of golimumab. Induction and maintenance regimens were generally higher than standard dosing with first month cumulative doses of 400 mg and above in 75% of the patients. Monthly maintenance doses ≥200 mg were administered in 52% of patients. Clinical response at 3 months was achieved in 35/45 [77.7%] patients. The cumulative probabilities that patients with an initial response maintained their clinical response for 12 and 36 months after introduction of golimumab were 81% and 64%, respectively. Endoscopic improvement and mucosal healing at 12 months was achieved in 73% and 47% of patients, respectively.\nThis study demonstrates the efficacy of golimumab in anti-TNF refractory CD patients. Further studies should be performed in CD to formally assess the efficacy of golimumab in a randomized controlled trial and to establish the optimal dosing regimen.",
"affiliations": "Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, Ontario, Canada; Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada.;Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, Ontario, Canada; Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada.;Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, Ontario, Canada; Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada.;Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital IBD Group, Toronto, Ontario, Canada; Division of Gastroenterology, Department of Medicine, University of Toronto, Toronto, Canada.",
"authors": "Greener|Tomer|T|;Boland|Karen|K|;Steinhart|A Hillary|AH|;Silverberg|Mark S|MS|",
"chemical_list": "D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjx176",
"fulltext": null,
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"issn_linking": "1873-9946",
"issue": "12(4)",
"journal": "Journal of Crohn's & colitis",
"keywords": null,
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal; D003424:Crohn Disease; D016099:Endoscopy, Gastrointestinal; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D060828:Induction Chemotherapy; D000069285:Infliximab; D060046:Maintenance Chemotherapy; D008297:Male; D012074:Remission Induction; D019233:Retreatment; D012189:Retrospective Studies; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101318676",
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"pages": "458-464",
"pmc": null,
"pmid": "29293965",
"pubdate": "2018-03-28",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "The Unfinished Symphony: Golimumab Therapy for Anti-Tumour Necrosis Factor Refractory Crohn's Disease.",
"title_normalized": "the unfinished symphony golimumab therapy for anti tumour necrosis factor refractory crohn s disease"
} | [
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"... |
{
"abstract": "Naegleria fowleri is a thermophilic free-living amoeba that is found in warm, fresh water and causes primary amebic meningoencephalitis (PAM). The following report demonstrates the rapid and destructive clinical features of PAM in an 8-year-old male who presented with severe headaches approximately 12 days after swimming in a hot spring.",
"affiliations": "Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, California.;Department of Infectious Disease, Children's Hospital Los Angeles, California.;Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, California.;Department of Infectious Disease, Children's Hospital Los Angeles, California.;Department of Infectious Disease, Children's Hospital Los Angeles, California.;Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, California.",
"authors": "Vareechon|Chairut|C|;Tarro|Thomas|T|;Polanco|Claudia|C|;Anand|Vikram|V|;Pannaraj|Pia S|PS|;Dien Bard|Jennifer|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofz349",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n31660390\n10.1093/ofid/ofz349\nofz349\nBrief Report\nEight-Year-Old Male With Primary Amebic Meningoencephalitis\nVareechon Chairut 1 Tarro Thomas 23 Polanco Claudia 1 Anand Vikram 23 Pannaraj Pia S 23 Dien Bard Jennifer 13 1 Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, California\n2 Department of Infectious Disease, Children’s Hospital Los Angeles, California\n3 Keck School of Medicine, University of Southern California, Los Angeles\nCorrespondence: J. Dien Bard, PhD, D(ABMM), Director of Microbiology, Department of Pathology and Laboratory Medicine, 4650 Sunset Blvd., Mailstop #32, Los Angeles, CA 90027 (jdienbard@chla.usc.edu).C. V. and T. T. are co-first authors.\n\n\n8 2019 \n29 7 2019 \n29 7 2019 \n6 8 ofz34917 5 2019 26 7 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\n\nNaegleria fowleri is a thermophilic free-living amoeba that is found in warm, fresh water and causes primary amebic meningoencephalitis (PAM). The following report demonstrates the rapid and destructive clinical features of PAM in an 8-year-old male who presented with severe headaches approximately 12 days after swimming in a hot spring.\n\nNaegleria fowleriPAMprimary amebic meningoencephalitis\n==== Body\nCASE PRESENTATION\nAn 8-year-old male with a history of occasional migraines presented to an outside hospital (OSH) complaining of headache that began 2 days before presentation. The headache was severe (10 of 10) and described as constant, pounding pain. The headache was originally frontal and then progressed to involve his entire head. It worsened with movement. Neither acetaminophen nor ibuprofen alleviated the headache. On the day before presentation, the patient began experiencing fevers as high as 39.5°C. He also developed progressive neck-stiffness, photophobia, and multiple episodes of emesis. Subsequently, he developed acute onset delirium followed by a generalized seizure that prompted the family to call emergency services.\n\nUpon presentation to the OSH, the patient was febrile to 40.6°C. He was initiated on antimicrobial therapy for presumed meningitis with vancomycin, ceftriaxone, and acyclovir. He was also given dexamethasone at the time of antimicrobial infusion. Lorazepam was used to effectively control his seizures. A lumbar puncture after the initiation of antibiotic therapy was performed, which produced cloudy, xanthochromic cerebrospinal fluid (CSF). Laboratory studies of the CSF revealed glucose <20 mg/dL and protein 606 mg/dL. Microscopy of the CSF revealed white blood cell count 2624 cells/μL (differential: 91% neutrophils, 4% lymphocytes, 5% monocytes) and negative Gram stain. Both culture and FilmArray Meningitis/Encephalitis (ME) panel were negative. Influenza A/B and respiratory syncytial virus by polymerase chain reaction (PCR) panel were also negative. Brain computed tomography (CT) scan without contrast and chest x-ray were normal. Medical history obtained by the facility was pertinent for the patient being fully immunized without any known ill contacts. Family denied any lifetime travel outside of the United States. However, 2 weeks before the onset of his symptoms, the patient visited his family farm in Bishop, California where he had played with snakes, lizards, and salamanders.\n\nThe patient was transferred to our institution the same day of presentation for a higher level of care. Re-examination of the CSF obtained from the OSH corroborated the initial findings, and fluconazole was initiated for additional antimicrobial coverage. The patient received 1 dose of fluconazole but was discontinued in favor of liposomal amphotericin B because he became comatose with persistent fevers. On day 2 of hospitalization, repeat brain CT scan without contrast showed significant cerebral edema without intracranial hemorrhage. In addition, a wet mount, trichrome stain, and Giemsa stain was performed on the CSF and revealed a potential pathogen (Figure 1). After Giemsa stain examination, the patient was started on azithromycin, posaconazole, rifampin, miltefosine, and dexamethasone in addition to liposomal amphotericin B with no improvement. The patient died on day 3 of hospitalization.\n\nFigure 1. Giemsa stain of the cerebrospinal fluid.\n\nWhat is your diagnosis?\n\nDISCUSSION\nGiemsa stain of the CSF revealed few Naegleria fowleri trophozoites (Figure 1). Diagnosis of primary amebic meningoencephalitis (PAM) caused by N fowleri was further confirmed by targeted PCR. The patient had been on liposomal amphotericin B, and, based on Giemsa stain examination, the Centers for Disease Control and Prevention (CDC) was contacted. Additional treatment was initiated according to the CDC’s PAM antimicrobial recommendation [1–4] and included the following: azithromycin, posaconazole, rifampin, miltefosine, and dexamethasone. Clinical symptoms did not improve despite therapy, and the patient progressed to brain death on day 3 of hospitalization.\n\n\nNaegleria fowleri is a free-living amoeba that inhabits both soil and fresh water. It is thermophilic and can be found in warm lakes and rivers, geothermal springs, naturally hot untreated water supplies, and warm water discharge from industrial plants. Primary amebic meningoencephalitis is most often associated with human activity in warm, fresh water that results in contaminated water entering the nasal cavity [5]. Infectivity occurs via attachment of the organism to the nasal mucosa, after which the amoeba moves along the olfactory nerve, penetrates the cribriform plate, and reaches the olfactory bulb in the central nervous system [6]. Although exposure to freshwater was initially denied, after preliminary identification and further questioning on day 2 of admission, a family member remembered that the patient and his siblings swam and submerged their heads in a hot spring, approximately 12 days before the onset of symptoms.\n\nOnset of clinical symptoms for PAM present between 1 and 15 days from time of exposure [5]. Initial manifestations of PAM are indistinguishable from bacterial meningitis and symptomatology includes the following: fever, severe headache, photophobia, confusion, seizures, and coma [7]. Cerebrospinal fluid obtained from infected patients is often hazy with hypoglycorrhachia, elevated protein, and pleocytosis with neutrophilic predominance [7]. Rapid diagnosis of PAM can be made by microscopy or PCR. Microscopy methods include wet mount for motile trophozoites or trichrome and Giemsa stain of CSF for identification of the distinctive trophozoite morphology. Giemsa stain is the preferred microscopy method because it best highlights the amoeba’s granularity, its many vacuoles, and its large single nucleus that has a sizable karyosome and lacks peripheral chromatin (Figure 1).\n\nBetween 1962 and 2017, 143 US cases of PAM were reported to the CDC with only 4 survivors [8]. An additional patient in Mexico also survived infection [1]. The first US survivor was thought to be infected with a less virulent strain of N fowleri [9, 10]. Two other patients had full neurologic recovery, which may have been due to early diagnosis, treatment, and the inclusion of miltefosine as a novel therapeutic [2, 4]. The fourth surviving patient from the United States was also treated with miltefosine but did not receive the treatment for several days after onset of symptoms. This patient had permanent neurological sequelae [4]. The sole surviving patient from Mexico was treated immediately with amphotericin B, fluconazole, and rifampicin and had full neurologic recovery [1]. The CDC recommends initiation of antimicrobials as soon as possible; however, effective treatment for infections caused by Naegleria has not been established due to the limited number of survivors. Miltefosine has demonstrated in vitro killing activity against N fowleri when combined with an azole drug [11] and was used to successfully treat 3 patients with PAM. Regardless of treatment regimen, the mortality rate of PAM remains approximately 98% [12].\n\nCONCLUSIONS\nThis case exemplifies the rapid and destructive features of N fowleri-associated PAM. Thorough patient interrogation and prompt identification of the causative agent is paramount to ensure appropriate treatment and management of these patients.\n\nAcknowledgment\n\nPotential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.\n==== Refs\nReferences\n1. \nVargas-Zepeda J , Gómez-Alcalá AV , Vásquez-Morales JA , et al \nSuccessful treatment of Naegleria fowleri meningoencephalitis by using intravenous amphotericin B, fluconazole and rifampicin\n. Arch Med Res 2005 ; 36 :83 –6\n.15900627 \n2. \nLinam WM , Ahmed M , Cope JR , et al \nSuccessful treatment of an adolescent with Naegleria fowleri primary amebic meningoencephalitis\n. Pediatrics 2015 ; 135 :e744 –8\n.25667249 \n3. \nColon BL , Rice CA , Guy RK , Kyle DE \nPhenotypic screens reveal posaconazole as a rapidly acting amebicidal combination partner for treatment of primary amoebic meningoencephalitis\n. J Infect Dis 2019 ; 219 :1095 –103\n.30358879 \n4. \nCope JR , Conrad DA , Cohen N , et al \nUse of the novel therapeutic agent miltefosine for the treatment of primary amebic meningoencephalitis: report of 1 fatal and 1 surviving case\n. Clin Infect Dis 2016 ; 62 :774 –6\n.26679626 \n5. \nYoder JS , Eddy BA , Visvesvara GS , et al \nThe epidemiology of primary amoebic meningoencephalitis in the USA, 1962-2008\n. Epidemiol Infect 2010 ; 138 :968 –75\n.19845995 \n6. \nJarolim KL , McCosh JK , Howard MJ , John DT \nA light microscopy study of the migration of Naegleria fowleri from the nasal submucosa to the central nervous system during the early stage of primary amebic meningoencephalitis in mice\n. J Parasitol 2000 ; 86 :50 –5\n.10701563 \n7. \nCapewell LG , Harris AM , Yoder JS , et al \nDiagnosis, clinical course, and treatment of primary amoebic meningoencephalitis in the United States, 1937-2013\n. J Pediatric Infect Dis Soc 2015 ; 4 :e68 –75\n.26582886 \n8. \nGrace E , Asbill S , Virga K \nNaegleria fowleri: pathogenesis, diagnosis, and treatment options\n. Antimicrob Agents Chemother 2015 ; 59 :6677 –81\n.26259797 \n9. \nSeidel JS , Harmatz P , Visvesvara GS , et al \nSuccessful treatment of primary amebic meningoencephalitis\n. N Engl J Med 1982 ; 306 :346 –8\n.7054710 \n10. \nJohn DT , John RA \nCytopathogenicity of Naegleria fowleri in mammalian cell cultures\n. Parasitol Res 1989 ; 76 :20 –5\n.2622894 \n11. \nSchuster FL , Guglielmo BJ , Visvesvara GS \nIn-vitro activity of miltefosine and voriconazole on clinical isolates of free-living amebas: Balamuthia mandrillaris, Acanthamoeba spp., and Naegleria fowleri\n. J Eukaryot Microbiol 2006 ; 53 :121 –6\n.16579814 \n12. \nMartinez AJ , Visvesvara GS \nFree-living, amphizoic and opportunistic amebas\n. Brain Pathol 1997 ; 7 :583 –98\n.9034567\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "6(8)",
"journal": "Open forum infectious diseases",
"keywords": "Naegleria fowleri; PAM; primary amebic meningoencephalitis",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofz349",
"pmc": null,
"pmid": "31660390",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": "2622894;7054710;26259797;10701563;26679626;26582886;16579814;19845995;15900627;9034567;25667249;30358879",
"title": "Eight-Year-Old Male With Primary Amebic Meningoencephalitis.",
"title_normalized": "eight year old male with primary amebic meningoencephalitis"
} | [
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"abstract": "An 18 years old female patient, who was taking treatment for tinea cruris developed Toxic Epidermal Necrolysis (TEN) due to therapeutic dose of griseofulvin with concomitant use of terbinafine. Both the drugs were stopped; patient's condition was gradually improved after starting the treatment. As per WHO-UMC causality assessment criteria, association between reaction and drug was possible (for both griseofulvin and terbinafine). Griseofulvin and terbinafine, both are widely used as an oral antifungal agent to treat fungal infections, careful monitoring is required in the initial periods of the treatment to prevent such type of serious adverse drug reaction. We report a case of TEN possibly caused by griseofulvin with concomitant use of terbinafine resulting in diagnostic difficulty.",
"affiliations": "Department of Pharmacology, Government Medical College and Sir Takhtsinhji General Hospital, Bhavnagar-364001, Gujarat, India. dharamvir.jadeja@yahoo.com.",
"authors": "Jadeja|Dharamvirsinh|D|;Jaiswal|Chandra S|CS|;Panchasra|Ashwin|A|;Tripathi|Chandrabhanu B|CB|",
"chemical_list": "D000935:Antifungal Agents; D009281:Naphthalenes; D006118:Griseofulvin; D003907:Dexamethasone; D000077291:Terbinafine",
"country": "United Arab Emirates",
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"issn_linking": "1574-8863",
"issue": "11(2)",
"journal": "Current drug safety",
"keywords": null,
"medline_ta": "Curr Drug Saf",
"mesh_terms": "D000293:Adolescent; D000935:Antifungal Agents; D003907:Dexamethasone; D005260:Female; D006118:Griseofulvin; D006801:Humans; D009281:Naphthalenes; D013262:Stevens-Johnson Syndrome; D000077291:Terbinafine",
"nlm_unique_id": "101270895",
"other_id": null,
"pages": "192-4",
"pmc": null,
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"publication_types": "D016428:Journal Article",
"references": null,
"title": "Griseofulvin and/or Terbinafine Induced Toxic Epidermal Necrolysis in an Adult Female Patient - A Case Report.",
"title_normalized": "griseofulvin and or terbinafine induced toxic epidermal necrolysis in an adult female patient a case report"
} | [
{
"companynumb": "IN-GLAXOSMITHKLINE-IN2016093064",
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"activesubstance": {
"activesubstancename": "TERBINAFINE"
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{
"abstract": "Pregabalin, a GABA analogue, binds to the alpha 2 delta subunit of voltage-dependent calcium channels. It is recognised as efficacious in pathologies such as epilepsy, neuropathic pain, and anxiety disorders. Since pregabalin prescriptions have increased worldwide, reports of its abuse have been accumulating, mainly in patients with opioid abuse disorders. The present study investigated potential pregabalin abuse by means of hair analysis, a matrix that provides valuable retrospective information. Half of the pool of 280 susceptible patients had been occasional drug users and were being monitored for driving licence renewals. The other 140 patients had a history of opiate dependency and were monitored to assess compliance with methadone therapy. In view of determining pregabalin in hair samples, it was extracted in methanol, successfully derivatised to give the ethyl chloroformate derivative, and finally pregabalin was analysed by gas chromatography-tandem mass spectrometry. Selectivity, linearity, limit of detection, limit of quantification, recovery, intra- and inter-day precision, and accuracy of the quantification procedure were appraised. Pregabalin limits of detection and quantification were 30 pg/mg and 50 pg/mg, respectively. We found 10.7% of hair samples from methadone patients and 4.29% from occasional drug users were positive to pregabalin without medical prescription. The mean pregabalin concentration in hair was higher than in consumers with medical indications (1.45 ng/mg vs 0.74 ng/mg). These results suggest that pregabalin possesses a significant abuse potential particularly among individuals attending opiate dependence services and that pregabalin abuse is a serious emerging issue, which should be carefully monitored.",
"affiliations": "Drug Chemistry and Technology Section, Department of Pharmaceutics, University of Perugia, Italy.;Forensic and Sports Medicine Section, Department of Surgery and Biomedical Science, University of Perugia, Italy.;Hygiene and Public Health Section, Department of Experimental Medicine, University of Perugia, Italy.;Drug Chemistry and Technology Section, Department of Pharmaceutics, University of Perugia, Italy.;Forensic and Sports Medicine Section, Department of Surgery and Biomedical Science, University of Perugia, Italy.;Forensic and Sports Medicine Section, Department of Surgery and Biomedical Science, University of Perugia, Italy.;Drug Chemistry and Technology Section, Department of Pharmaceutics, University of Perugia, Italy.;Forensic and Sports Medicine Section, Department of Surgery and Biomedical Science, University of Perugia, Italy.",
"authors": "Ianni|Federica|F|http://orcid.org/0000-0003-4293-3100;Aroni|Kyriaki|K|http://orcid.org/0000-0002-7559-4857;Gili|Alessio|A|http://orcid.org/0000-0002-4359-5193;Sardella|Roccaldo|R|http://orcid.org/0000-0001-9856-0230;Bacci|Mauro|M|http://orcid.org/0000-0001-7727-8519;Lancia|Massimo|M|http://orcid.org/0000-0003-2307-470X;Natalini|Benedetto|B|http://orcid.org/0000-0002-7191-1333;Gambelunghe|Cristiana|C|http://orcid.org/0000-0003-2045-9145",
"chemical_list": "D000069583:Pregabalin",
"country": "England",
"delete": false,
"doi": "10.1002/dta.2347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1942-7603",
"issue": "10(6)",
"journal": "Drug testing and analysis",
"keywords": "GC-MS/MS; ethyl chloroformate derivative; hair analysis; pregabalin; pregabalin abuse",
"medline_ta": "Drug Test Anal",
"mesh_terms": "D000328:Adult; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006197:Hair; D006801:Humans; D057230:Limit of Detection; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders; D000069583:Pregabalin; D012680:Sensitivity and Specificity; D015813:Substance Abuse Detection; D053719:Tandem Mass Spectrometry; D055815:Young Adult",
"nlm_unique_id": "101483449",
"other_id": null,
"pages": "968-976",
"pmc": null,
"pmid": "29214743",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "GC-MS/MS detects potential pregabalin abuse in susceptible subjects' hair.",
"title_normalized": "gc ms ms detects potential pregabalin abuse in susceptible subjects hair"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2017-01716",
"fulfillexpeditecriteria": "1",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
... |
{
"abstract": "Despite the decreasing incidence and mortality from gastric cancer, it remains a major health problem worldwide. Ninety percent of cases are adenocarcinomas. Here, we report a case of gastric adenocarcinoma developed after successful treatment of prior primary gastric diffuse large B-cell lymphoma (DLBCL). Our patient was an elderly man with primary gastric DLBCL in whom complete remission was achieved after R-CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone plus rituximab) chemotherapy. Helicobacter pylori infection persisted despite adequate treatment leading to sustained chronic gastritis. The mean time to diagnose metachronous gastric carcinoma was seven years. We believe that a combination of many risk factors, of which chronic H. pylori infection the most important, led to the development of gastric carcinoma following primary gastric lymphoma. In summary, patients who have been successfully treated for primary gastric lymphoma should be followed up at regular short intervals. H. pylori infection should be diagnosed promptly and treated aggressively.",
"affiliations": "Department of Hematology-Oncology, Centre Hospitalier Universitaire Notre Dame des Secours, Byblos, Lebanon.;Department of Hematology-Oncology, Centre Hospitalier Universitaire Notre Dame des Secours, Byblos, Lebanon.;Department of Pathology, Centre Hospitalier Universitaire Notre Dame des Secours, Byblos, Lebanon.;Department of Hematology-Oncology, Hotel Dieu de France Hospital, Universite Saint-Joseph de Beyrouth, Beirut, Lebanon.",
"authors": "Sakr|Riwa|R|;Massoud|Marcel|M|;Aftimos|Georges|G|;Chahine|Georges|G|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5230/jgc.2017.17.e11",
"fulltext": "\n==== Front\nJ Gastric CancerJ Gastric CancerJGCJournal of Gastric Cancer2093-582X2093-5641The Korean Gastric Cancer Association 10.5230/jgc.2017.17.e11Case ReportGastric Adenocarcinoma Secondary to Primary Gastric Diffuse Large B-cell Lymphoma Sakr Riwa 12Massoud Marcel 12Aftimos Georges 34Chahine Georges 51 Department of Hematology-Oncology, Centre Hospitalier Universitaire Notre Dame des Secours, Byblos, Lebanon.2 Department of Hematology-Oncology, Faculty of Medical Sciences, Holy Spirit University of Kaslik, Jounieh, Lebanon.3 Department of Pathology, Centre Hospitalier Universitaire Notre Dame des Secours, Byblos, Lebanon.4 Department of Pathology, Faculty of Medical Sciences, Holy Spirit University of Kaslik, Jounieh, Lebanon.5 Department of Hematology-Oncology, Hotel Dieu de France Hospital, Universite Saint-Joseph de Beyrouth, Beirut, Lebanon.Correspondence to Marcel Antoine Massoud. Department of Hematology-Oncology, Centre Hospitalier Universitaire Notre Dame des Secours, Street 03 St. Charbel Hboub, Byblos, Lebanon. Tel: +961-9-940-400, Fax: +961-9-940-099, marcel.massoud@gmail.com6 2017 22 3 2017 17 2 180 185 07 7 2016 23 11 2016 11 12 2016 Copyright © 2017. Korean Gastric Cancer Association2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Despite the decreasing incidence and mortality from gastric cancer, it remains a major health problem worldwide. Ninety percent of cases are adenocarcinomas. Here, we report a case of gastric adenocarcinoma developed after successful treatment of prior primary gastric diffuse large B-cell lymphoma (DLBCL). Our patient was an elderly man with primary gastric DLBCL in whom complete remission was achieved after R-CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone plus rituximab) chemotherapy. Helicobacter pylori infection persisted despite adequate treatment leading to sustained chronic gastritis. The mean time to diagnose metachronous gastric carcinoma was seven years. We believe that a combination of many risk factors, of which chronic H. pylori infection the most important, led to the development of gastric carcinoma following primary gastric lymphoma. In summary, patients who have been successfully treated for primary gastric lymphoma should be followed up at regular short intervals. H. pylori infection should be diagnosed promptly and treated aggressively.\n\nNeoplasms, second primaryStomach neoplasmsLymphoma\n==== Body\nINTRODUCTION\nDespite the decreasing incidence and mortality from gastric cancer, this entity remains a major health problem worldwide. Gastric cancer is the fourth most common malignancy and the second leading cause of death due to cancer. About 90% of gastric cancers are adenocarcinomas. Many risk factors, such as Helicobacter pylori infection, obesity, gastro-esophageal reflux disease, cigarette smoking, and dietary factors, are implicated in the development of this type of cancer. Other less common factors include pernicious anemia, Epstein-Barr virus infection, radiation, prior gastric surgery for benign conditions, blood type A, and some hereditary syndromes. Here, we report a case of metachronous gastric adenocarcinoma, which developed seven years after successful treatment of the primary gastric diffuse large B-cell lymphoma (DLBCL).\n\nCASE REPORT\nWe report the case of a 73-year-old man who presented with epigastric pain and weight loss in February 2007. No abnormalities were found on physical examination. Contrast-enhanced abdominal computed tomography (CT) scan revealed a 3-cm circumferential gastric wall thickening mainly marked at the fundus and antrum, without contrast enhancement (Fig. 1). Gastric endoscopy showed a congestive and edematous antral mucosa. Biopsies confirmed the diagnosis of malignant DLBCL, and H. pylori infection was detected (Fig. 2). Immunohistochemical analysis revealed most cells to be CD20 positive (Fig. 3). Staging was completed by performing cervical, thoracic, and pelvic CT scans, and the disease was classified as stage I–E according to the Ann Arbor classification system. Adequate therapy comprising proton pump inhibitors and antibiotics was administered to treat the H. pylori infection. Immunochemotherapy was started according to clinical guidelines. The patient received six courses of R-CHOP (cyclophosphamide, adriamycin, vincristine, prednisolone plus rituximab). Four prophylactic intrathecal injections of methotrexate were administered. The patient's treatment ended in July 2007 without major complications. Follow-up endoscopy and imaging (Fig. 4) performed three months later showed complete remission; however, the H. pylori infection persisted despite administering adequate first-line antibiotic treatment. Second-line antibiotic treatment was initiated, and the patient was advised to make follow-up visits to the gastroenterology outpatient clinic.\n\nFig. 1 Abdominal computed tomography scan: 3-cm circumferential wall thickening of the entire stomach, mainly at the fundus and antrum, can be seen. Absence of contrast enhancement.\n\nFig. 2 Diffuse interstitial infiltration by large lymphoid cells, CD20+, CD10−, and cyclin D1 (H&E, ×100).\n\nFig. 3 Tumor cells expressing CD20 (immunohistochemistry, ×100).\n\nFig. 4 Computed tomography scan of the abdomen 4 months after completion of chemotherapy showing complete resolution of the previously noted gastric tumor.\n\nThe patient did not make follow-up visits, but presented to our facility in October 2014 with recurrent epigastric pain along with progressive weight loss. Gastroscopy revealed the presence of ulcerative lesions, indicative of malignancy localized at the fundus. Biopsy confirmed the presence of microfoci of invasive adenocarcinoma of the intestinal type with lymphatic permeation (Fig. 5). Immunohistochemical analysis revealed positive anti-c-erbB2 (score 3+). H. pylori infection was also detected. Initial staging performed with cervical, thoraco-abdominal, and pelvic CT scans showed diffuse peritoneal carcinomatosis without hepatic involvement. Staging laparoscopy was not performed.\n\nFig. 5 Glandular proliferation lined with cylindrical epithelial cells with atypical and hyperchromatic nuclei that are compatible with microfoci of invasive gastric adenocarcinoma of the intestinal type (H&E, ×400).\n\nPlatinum-based chemotherapy was started along with anti-human epidermal growth factor receptor 2 targeted therapy (cisplatin, 5-fluorouracil, trastuzumab). Ten days after the third cycle, the patient was emergently admitted for septic shock, rapid deterioration, and multi-organ failure leading to death.\n\nDISCUSSION\nIn the era of new targeted therapies, the overall survival rate of patients with non-Hodgkin lymphomas has improved; however, there is an increase in the rate of secondary malignancies in survivors. While acute leukemia is the most common secondary malignancy, solid tumors, especially carcinomas, are also common [1].\n\nPrimary gastric lymphoma is one of the most common extra-nodal lymphomas and represents 5% to 10% of all gastric malignancies [23]. Although cases of metachronous gastric adenocarcinoma after primary gastric lymphoma have been described in the literature, it is a very uncommon entity. It has a higher malignant potential as compared to sporadic cases [45]. Many studies have reported a six-fold increase in the incidence of gastric carcinoma in patients treated for gastric lymphoma of mucosa-associated lymphoid tissue as compared to in the general population [25]. The incidence of metachronous gastric adenocarcinoma after gastric lymphoma is 12% according to a retrospective study published by Inaba et al. [5]. The median time from the diagnosis of gastric lymphoma to gastric adenocarcinoma is 3.5 to 34 years [5].\n\nIn fact, most patients with metachronous gastric cancer after primary gastric lymphoma are diagnosed in the advanced stages. This is mainly due to a prolonged pre-diagnostic interval during which patients may not undergo regular follow-up tests [6]. Most patients die within 18 months of diagnosis [6]. However, Nakamura et al. [3] did not report a survival rate in their study.\n\nMany risk factors are implicated, of which H. pylori infection is the most important. Untreated chronic H. pylori infection can lead to the development of chronic gastritis, chronic atrophic gastritis, intestinal metaplasia, and gastric adenocarcinoma [25]. At present, it is still unclear whether treatment of H. pylori infection will prevent the development of gastric cancer as the available data are controversial. In a randomized control trial, Leung et al. [7] showed that eradication of the infection prevented the transformation of premalignant gastric lesions into gastric cancer in 52.9% of the cases. In contrast, in China, Wong et al. [8] showed that the incidence of gastric cancer was similar between patients in whom the infection had been treated and those in whom the infection remained untreated.\n\nOther causes include previous gastric surgery, which results in prolonged exposure of the remaining mucosa to alkaline secretion (bile salts reflux) [4\n910]. Gastroesophageal reflux, adenomatous polyps, and formation of carcinogenic nitrosamines when the gastric pH drops below 5.5 are also involved in the pathophysiology of secondary gastric carcinomas [10]. Inaba et al. [5] also demonstrated, although the significance was marginal (P=0.070), that the incidence of metachronous gastric carcinoma was higher in older populations (age, >60 years), in patients with stage II–IV disease (according to the Ann Arbor classification), in DLBCL subtype and in patients who received chemotherapy [1]. Many drugs are known to have mutagenic and carcinogenic effects [4]. Of these, alkylating agents and topoisomerase II inhibitors are the two families that have been identified by the World Health Organization [11]. These drugs are associated with an increased incidence of hematological malignancies. Further, radiation therapy can induce solid tumors, typically within the radiation field, at doses above 45 Gy [12]. Solid tumors are usually diagnosed 14 to 26 years after radiation therapy [13].\n\nMost patients were treated according to the disease stage, as per conventional guidelines for the treatment of primary gastric adenocarcinomas. In Japan, owing to the increased frequency of follow-ups, the disease is commonly detected in the early stages. A conservative approach, such as endoscopic mucosal resection, is therefore adopted, with more advanced cases being treated with surgery, when indicated, or palliative chemotherapy [1]. Cisplatin, 5-fluorouracil, and mitomycin C regimens in various combinations are commonly used [1].\n\nThere are two theories that could explain how the risk factors contribute to an increased risk of secondary gastric carcinoma following primary gastric lymphoma. The first theory is that the different causative factors (H. pylori infection, chemotherapy, radiation, etc.) damage the gastric mucosa. The second theory is that the carcinoma was probably too small to be detected at the time of the gastric lymphoma diagnosis [4514]. Patients in whom the interval between the development of the two tumors was short might have had a carcinoma that went undetected at the time of the first diagnosis. Whereas, patients in whom the interval was longer would have developed the carcinoma secondary to accumulating risk factors and treatment [3].\n\nThe case described in this report has many common elements. Our patient was an elderly man with primary gastric DLBCL, and complete remission was achieved after treatment with an alkylating agent-based chemotherapy regimen (R-CHOP). H. pylori infection remained active despite administering adequate combined treatment with proton pump inhibitors and antibiotics, which contributed to sustained chronic gastritis. The mean time to diagnose the metachronous gastric carcinoma was seven years, which is similar to what is described in the literature (3.5 to 34 years). In the present case, five of the major risk factors were present. We believe that a combination of many carcinogenic-related risk factors, of which chronic H. pylori infection was the most important, led to the development of gastric carcinoma following primary gastric lymphoma.\n\nIn summary, patients who have achieved complete remission after receiving treatment for primary gastric lymphoma should be followed-up at regular short intervals. Further, H. pylori infection should be diagnosed promptly and treated aggressively. Clinicians should educate their patients about the possible development of secondary gastric cancer, which can be fatal.\n\nConflict of Interest: No potential conflict of interest relevant to this article was reported.\n==== Refs\n1 Coleman CN Williams CJ Flint A Glatstein EJ Rosenberg SA Kaplan HS Hematologic neoplasia in patients treated for Hodgkin's disease N Engl J Med 1977 297 1249 1252 917069 \n2 Ioannidis O Sekouli A Paraskevas G Papadimitriou N Konstantara A Kotronis A Metachronous early gastric adenocarcinoma presenting coinstantaneously with complete remission of stage IV gastric MALT lymphoma Arab J Gastroenterol 2013 14 20 23 23622805 \n3 Nakamura S Aoyagi K Iwanaga S Yao T Tsuneyoshi M Fujishima M Synchronous and metachronous primary gastric lymphoma and adenocarcinoma: a clinicopathological study of 12 patients Cancer 1997 79 1077 1085 9070483 \n4 Hamaloglu E Topaloglu S Ozdemir A Ozenc A Synchronous and metachronous occurrence of gastric adenocarcinoma and gastric lymphoma: a review of the literature World J Gastroenterol 2006 12 3564 3574 16773713 \n5 Inaba K Kushima R Murakami N Kuroda Y Harada K Kitaguchi M Increased risk of gastric adenocarcinoma after treatment of primary gastric diffuse large B-cell lymphoma BMC Cancer 2013 13 499 24159918 \n6 Copie-Bergman C Locher C Levy M Chaumette MT Haioun C Delfau-Larue MH Metachronous gastric MALT lymphoma and early gastric cancer: is residual lymphoma a risk factor for the development of gastric carcinoma Ann Oncol 2005 16 1232 1236 15890667 \n7 Leung WK Lin SR Ching JY To KF Ng EK Chan FK Factors predicting progression of gastric intestinal metaplasia: results of a randomised trial on Helicobacter pylori eradication Gut 2004 53 1244 1249 15306578 \n8 Chow WH Blaser MJ Blot WJ Gammon MD Vaughan TL Risch HA An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma Cancer Res 1998 58 588 590 9485003 \n9 Zorlu AF Atahan IL Gedikoglu G Ruacan S Sayek I Tekuzman G Does gastric adenocarcinoma develop after the treatment of gastric lymphoma J Surg Oncol 1993 54 126 131 8412159 \n10 Pointner R Schwab G Königsrainer A Bodner E Schmid KW Gastric stump cancer: etiopathological and clinical aspects Endoscopy 1989 21 115 119 2743940 \n11 Vardiman JW Harris NL Brunning RD The World Health Organization (WHO) classification of the myeloid neoplasms Blood 2002 100 2292 2302 12239137 \n12 Neglia JP Friedman DL Yasui Y Mertens AC Hammond S Stovall M Second malignant neoplasms in five-year survivors of childhood cancer: childhood cancer survivor study J Natl Cancer Inst 2001 93 618 629 11309438 \n13 Al-Akwaa AM Siddiqui N Al-Mofleh IA Primary gastric lymphoma World J Gastroenterol 2004 10 5 11 14695759 \n14 Haruma K Suzuki T Tsuda T Yoshihara M Sumii K Kajiyama G Evaluation of tumor growth rate in patients with early gastric carcinoma of the elevated type Gastrointest Radiol 1991 16 289 292 1936767\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-1320",
"issue": "17(2)",
"journal": "Journal of gastric cancer",
"keywords": "Lymphoma; Neoplasms, second primary; Stomach neoplasms",
"medline_ta": "J Gastric Cancer",
"mesh_terms": null,
"nlm_unique_id": "101559430",
"other_id": null,
"pages": "180-185",
"pmc": null,
"pmid": "28680723",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports",
"references": "24159918;12239137;9070483;8412159;11309438;9485003;1936767;15306578;23622805;2743940;917069;14695759;16773713;15890667",
"title": "Gastric Adenocarcinoma Secondary to Primary Gastric Diffuse Large B-cell Lymphoma.",
"title_normalized": "gastric adenocarcinoma secondary to primary gastric diffuse large b cell lymphoma"
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"abstract": "Among patients with proximal iliofemoral deep vein thrombosis (DVT) and an elevated Villalta score, anticoagulation therapy alone may not be a sufficient management strategy in select cases. In this article, we report a case of severe bilateral iliofemoral DVT that resisted the standard treatment for DVT, requiring catheter-directed thrombolysis and subsequent mechanical thrombectomy.",
"affiliations": "Baylor Scott and White-The Heart Hospital, Plano, TX, USA.;Baylor Scott and White-The Heart Hospital, Plano, TX, USA.;Baylor Scott and White-The Heart Hospital, Plano, TX, USA.;Baylor Scott and White-The Heart Hospital, Plano, TX, USA.;Baylor Scott and White-The Heart Hospital, Plano, TX, USA.;Baylor Scott and White-The Heart Hospital, Plano, TX, USA.;Baylor Scott and White-The Heart Hospital, Plano, TX, USA.;Baylor Scott and White-The Heart Hospital, Plano, TX, USA.;Baylor Scott and White-The Heart Hospital, Plano, TX, USA.",
"authors": "Hamandi|Mohanad|M|0000-0002-9746-5685;Lanfear|Allison T|AT|0000-0003-3616-4077;Woolbert|Seth|S|;Bolin|Madison L|ML|;Fan|Joy|J|;William|Michael|M|;Khan|Zoheb|Z|;DiMaio|J Michael|JM|;Dib|Chadi|C|",
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"doi": "10.1177/2324709620910288",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620910288\n10.1177_2324709620910288\nCase Report\nChallenging Management of a Patient With Severe Bilateral Deep Vein\nThrombosis\nhttps://orcid.org/0000-0002-9746-5685Hamandi Mohanad MD1 https://orcid.org/0000-0003-3616-4077Lanfear Allison T. 1 Woolbert Seth 1 Bolin Madison L. 1 Fan Joy 1 William Michael MD1 Khan Zoheb 1 DiMaio J. Michael MD1 Dib Chadi MD1 1 Baylor Scott and White—The Heart\nHospital, Plano, TX, USA\nAllison T. Lanfear, Baylor Scott and\nWhite—The Heart Hospital, 1100 Allied Drive, Plano, TX 75093, USA. Email:\nalanfear@bu.edu\n5 3 2020 \nJan-Dec 2020 \n8 23247096209102882 11 2019 18 1 2020 18 1 2020 © 2020 American Federation for Medical\nResearch2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution 4.0 License (https://creativecommons.org/licenses/by/4.0/) which permits\nany use, reproduction and distribution of the work without further\npermission provided the original work is attributed as specified on the SAGE\nand Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Among patients with proximal iliofemoral deep vein thrombosis (DVT) and an\nelevated Villalta score, anticoagulation therapy alone may not be a sufficient\nmanagement strategy in select cases. In this article, we report a case of severe\nbilateral iliofemoral DVT that resisted the standard treatment for DVT,\nrequiring catheter-directed thrombolysis and subsequent mechanical\nthrombectomy.\n\nDVTthrombectomythrombolysisSatish and Yasmin Gupta Family Foundationcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nVenous thromboembolism (VTE) affects 1 in 500 people annually in the United States,\nwith a 13% mortality rate primarily due to pulmonary embolism (PE).1,2 Proximal deep vein thrombosis\n(DVT) mainly involving the femoral and iliac veins carries a much higher risk of PE\nand symptomatic PE when compared with distal DVT.3 Iliofemoral DVT accounts for 39% of all proximal DVT cases and carries a\nhigher risk of recurrent VTE.3,4\nOne third of patients diagnosed with DVT/PE have a recurrence within 10 years, and\nup to 50% develop post-thrombotic syndrome (PTS).5 Anticoagulation therapy is the standard treatment for VTE, as it reduces\nthrombus extension, recurrence, and the risk of PTS.2 Inferior vena cava (IVC) filters, thrombolysis, surgical thrombus removal,\nand compression stockings are also available treatment options.2 In this article, we report a case of severe bilateral iliofemoral DVT that\nresisted the standard treatment for DVT and required catheter-directed thrombolysis\n(CDT) and subsequent mechanical thrombectomy.\n\nCase Summary\nA 56-year-old man with a history of hemochromatosis and noncompliance was referred to\nthe emergency room for bilateral lower extremity (LE) swelling, pain, weeping\nlesions, and difficulty walking. One month prior, the patient was diagnosed with\nbilateral DVT to the superficial femoral veins and managed with oral anticoagulation\ntherapy (rivaroxaban). An IVC filter was implanted due to his history of recurrent\nLE DVT, lack of response to direct oral anticoagulants, and large clot burden at an\noutside hospital. He also has a history of smoking, peripheral vascular disease,\ndiabetes, congestive heart failure, and morbid obesity with a body mass index of\n46.1 kg/m2. He denied any history of coagulopathies or recent travel.\nColor and pulsed Doppler sonography of the bilateral LE deep venous system and\ndistal compression for flow augmentation were performed. Homogenous, hypoechoic,\nlow-level internal echoes filled the lumen of the right and the left common femoral\nveins, extended into the right deep femoral vein, and prevented complete\ncompression. No flow was seen on color and pulsed Doppler evaluation. The\nsuperficial femoral, popliteal, posterior tibial, and peroneal veins were widely\npatent. Computed tomography angiography of the chest showed linear nonocclusive\nfilling defects in the second- and third-order pulmonary arteries supplying the\nright lung consistent with pulmonary emboli, likely chronic. The patient reported\nnoncompliance with rivaroxaban, and on admission to our hospital, his international\nnormalized ratio was found to be 1.5. Rivaroxaban was stopped, and he was started on\nenoxaparin. Enoxaparin was adjusted by 1 mg/kg subcutaneous twice a day.6 His Villalta score was 26. Following examination and review of the case with\nour integrated PERT (pulmonary embolism response team)/DVT team, we decided to\nproceed with intervention. We accessed the right and left distal femoral veins and\nadvanced two 6 Fr sheaths. Venography showed complete occlusion of the proximal\nfemoral veins bilaterally, external, and common iliac veins along with occlusion of\nthe distal IVC up the filter (Figure 1). We then introduced 2 EKOS (EndoWave Infusion Catheter System;\nEKOS Corp, Bothell, WA) catheters in each access site delivering tPA with ultrasonic\nfrequency from the right common femoral vein to the IVC and from the left common\nfemoral vein to the proximal left common iliac vein. After 2 days of therapy, a\nvenogram showed reestablishment of flow in both femoral, external, and common iliac\nveins up to the IVC (Figure\n2). However, a large amount of clot was noted, mostly located in the\nright and left common femoral veins and left external and common iliac vein.\nMechanical thrombectomy was then performed using an 8 Fr Penumbra Indigo catheter in\nboth the right and left lower extremities. Subsequently, there were no filling\ndefects seen angiographically (Figure 3). The patient was discharged on subcutaneous enoxaparin for 3\nmonths to be followed by warfarin with a goal international normalized ratio of 2 to\n3. The patient was also instructed to wear thigh-high 20 to 30 mm Hg gradual\ncompression socks on bilateral LE for life. Continuous education and phone calls\nwere made to ensure compliance with medications. At 3-month follow-up, the patient\nwas doing well; his LE swelling, although present, was not life-limiting, and his\nVillalta score was down to 13.\n\nFigure 1. Venogram of bilateral femoral and iliac veins on admission.\n\nFigure 2. Venogram of bilateral femoral and iliac veins after treatment with EKOS.\n\nFigure 3. Venogram of bilateral femoral and iliac veins after treatment with\nPenumbra.\n\nDiscussion\nDVT is typically found in the LE and seen in 0.1% of people annually.7 This patient’s history of hemochromatosis and increased blood viscosity with\na hemoglobin of 19 likely augmented his risk for acute on chronic DVT. His body mass\nindex of 46.1 kg/m2 is also estimated to increase the risk of DVT by a\nfactor of 2.8,9 Furthermore, his\nlow hemodynamic flow rate caused by his congestive heart failure and the presence of\nan IVC filter may have increased his predisposition for DVT.1,9\n\nAnticoagulation has been the standard treatment approach for DVT; however, in\npatients with iliofemoral DVT and thrombosis extending into the IVC, the choice of\ntherapy remains debatable. It is well established that iliofemoral DVT results in\nmore severe post-thrombotic venous hypertension, more frequent recurrent DVT, and\nmore frequent and severe PTS.10 Although it is difficult to predict PTS occurrence in patients with DVT,\ntreatment that provides rapid resolution of the venous obstruction is essential to\navoid diminished quality of life.\n\nTo diagnose and categorize the severity of PTS, the Villalta scoring system is often\nused. This score uses a point system that tracks 5 symptoms (pain, cramps,\nheaviness, paresthesia, pruvitis) and 6 clinical signs (pretibial edema, skin\ninduration, hyperpigmentation, redness, venous ectasia, pain on calf compression)\nassociated with PTS. For each symptom and sign, a score is assigned on a scale of 0\nfor absent to 3 for severe. These numbers are then summed to give the final Villalta score.11 A score of 5 or greater confirms the diagnosis of PTS; a score of 5 to 9\ncharacterizes mild PTS, 10 to 14 moderate PTS, and 15 or greater severe PTS.11 This score has also been shown to correlate with patient-perceived quality of\nlife and can be used to assess the effectiveness of treatment.\n\nFollowing insufficient lysis of the thrombi in our patient’s right and left LE, CDT\nwas pursued. The goal was to reduce the clot burden as much as possible in order to\nimprove long-term outcomes.12 Most techniques rely on the use of thrombolytic agents, either through\nsystemic or catheter-directed infusion.13 In the CaVenT study, a 14.5% decrease in the incidence of PTS at 24 months in\npatients with acute iliofemoral DVT who received CDT treatment compared with those\nwho received anticoagulation treatment was observed.14 In our patient, CDT in the form of an EKOS ultrasound-accelerated\nthrombolysis (UAT) catheter (EKOS Corp) was introduced with tPA infusion. The EKOS\nUAT catheter is a method of CDT that delivers ultrasonic energy to the thrombus\nwhile tPA is infused through the catheter. This method of thrombolysis has been\nshown to provide a 50% reduction of thrombi through standard use in more than 90% of patients.15 It is interesting to note that the results of the BERNUTIFUL trial showed\nthat there was no significant difference between EKOS and conventional CDT with\nregard to vascular patency or PTS occurrence.16 However, we decided to pursue UAT as this patient had a history of what\nappears to be an acute on chronic DVT, and we thought that the addition of the\nultrasonic energy would enhance thrombolysis in this specific setting. Following 48\nhours of EKOS therapy, moderate clot burden was still seen in specific areas.\n\nMechanical thrombectomy using the Penumbra Indigo CAT8 system was then chosen, given\nthe added benefit of an increased directional suction power. Mechanical thrombectomy\nis primarily used in patients at high risk of bleeding with tPA as these techniques\ndo not inherently introduce pharmaceutical agents to thrombi.17 The 2 most commonly used devices in interventional mechanical thrombectomy\nare the AngioJet system (Possis Medical, Minneapolis, MN) and the Trellis device\n(Bacchus Vascular, Santa Clara, CA).13 The latter device was recently taken off the market. All mechanical\nthrombectomy techniques implement a method of thrombus fragmentation, and usually, a\nmethod of evacuation. However, this mechanical technique does come with the risks of\nvalvular and vessel wall injury, as well as PE. The Penumbra Indigo mechanical\nthrombectomy system (Penumbra, Inc, Alameda, CA) is a new, minimally invasive device\nthat implements continuous suction to evacuate thrombi and emboli from VTE.18 The device functions by applying external suction through the catheter to the\nthrombus and uses an accompanying separator device to make sure the site of\nevacuation remains unobstructed by the fragmented thrombi. The Indigo system was\nreported to resolve >70% of thrombi in patients with acute iliofemoral DVT,\nwithout the need for postoperative CDT or other endovascular treatments.19 The ClotTriever Inari device is the most recent emerging mechanical\nthrombectomy that is currently being investigated in the CLOUT registry.20 This device offers the promise of a single setting clot removal using a 13 Fr\nsheath and should, in theory, reduce the amount of time patients would spend in the\nintensive care unit.\n\nPharmocomechanical catheter-directed thrombolysis (PCDT) techniques combining CDT\nwith mechanical thrombectomy have also been used in the treatment of acute proximal\nDVT. The results of the ATTRACT trial (n = 692) showed no significant difference\nbetween patients who received PCDT treatment and those who received anticoagulation\ntherapy alone with regard to the occurrence of PTS 6 to 24 months following therapy.21 The ATTRACT trial, however, included a large number of patients with\nfemoropopliteal DVT, which made the results difficult to apply to patients with more\nproximal disease. In a subsequent subgroup analysis of patients with DVT involving\nmainly the deep femoral and iliac veins, PCDT significantly reduced early leg\nsymptoms along with PTS severity scores over 24 months and, more important, reduced\nthe number of patients who developed moderate-or-severe PTS on follow-up resulting\nin improved quality of life scores.21 It should also be noted that 80% of the patients included in the ATTRACT\ntrial had a Villalta score of <15, and almost 50% of them had a Villalta score of\n<10, which is very different when compared with our patient.21\n\nOverall, in patients with symptomatic iliofemoral DVT, available clinical studies\nsupport the clinical importance of early thrombus resolution in the prevention of PTS.3 On admission, our patient’s PTS was categorized as severe with a Villalta\nscore of 26. Three months following treatment, the patient’s Villalta score\ndecreased by half to 13, recategorizing his PTS as moderate, suggesting that\ntreatment was effective.\n\nConclusion\nIn select cases of patients with proximal iliofemoral DVT and an elevated Villalta\nscore, anticoagulation therapy alone may not be a sufficient management strategy.\nMultiple interventional treatment options have emerged as safe and effective\nalternatives and should be considered depending on patients’ specific clinical\ncharacteristics.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the\nresearch, authorship, and/or publication of this article: This study was\nsupported by a generous grant from the Satish and Yasmin Gupta Family\nFoundation.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient for their anonymized\ninformation to be published in this article.\n\nORCID iDs: Mohanad Hamandi \nhttps://orcid.org/0000-0002-9746-5685\n\nAllison T. Lanfear \nhttps://orcid.org/0000-0003-3616-4077\n==== Refs\nReferences\n1 \nKarande GY Hedgire SS Sanchez Y , et al\nAdvanced imaging in acute\nand chronic deep vein thrombosis\n. Cardiovasc Diagn\nTher .\n2016 ;6 :493 -507\n.28123971 \n2 \nKruger PC Eikelboom JW Douketis JD Hankey GJ. \nDeep vein thrombosis: update on diagnosis and\nmanagement\n. Med J Aust .\n2019 ;210 :516 -524\n.31155730 \n3 \nJaff MR McMurtry MS Archer SL , et al\nManagement of massive and\nsubmassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic\nthromboembolic pulmonary hypertension: a scientific statement from the\nAmerican Heart Association\n. Circulation .\n2011 ;123 :1788 -1830\n.21422387 \n4 \nVedantham S Grassi CJ Ferral H , et al\nReporting standards for\nendovascular treatment of lower extremity deep vein\nthrombosis\n. J Vasc Interv Radiol .\n2006 ;17 :417 -434\n.16567667 \n5 \nCenter for Disease Control and Prevention . Data\nand statistics on venous thromboembolism\n. https://www.cdc.gov/ncbddd/dvt/data.html. Accessed\nAugust 11, 2019 .\n6 \nBalla SR Cyr DD Lokhnygina Y , et al\nRelation of risk of stroke\nin patients with atrial fibrillation to body mass index (from patients\ntreated with rivaroxaban and warfarin in the rivaroxaban once daily oral\ndirect factor Xa inhibition compared with Vitamin K Antagonism for\nPrevention of Stroke and Embolism Trial in Atrial Fibrillation\nTrial)\n. Am J Cardiol .\n2017 ;119 :1989 -1996\n.28477860 \n7 \nKesieme E Kesieme C Jebbin N Irekpita E Dongo A. \nDeep vein thrombosis: a clinical review\n.\nJ Blood Med .\n2011 ;2 :59 -69\n.22287864 \n8 \nModi S Deisler R Gozel K , et al\nWells criteria for DVT is a\nreliable clinical tool to assess the risk of deep venous thrombosis in\ntrauma patients\n. World J Emerg Surg .\n2016 ;11 :24 .27279896 \n9 \nBevis PM Smith FC. \nDeep vein thrombosis\n. Surgery .\n2016 ;34 :159 -164\n.\n10 \nComerota AJ Kearon C Gu CS , et al\nEndovascular thrombus\nremoval for acute iliofemoral deep vein thrombosis\n.\nCirculation .\n2019 ;139 :1162 -1173\n.30586751 \n11 \nSoosainathan AS Moore HM Gohel MS Davies AH. \nScoring systems for the post-thrombotic syndrome\n.\nJ Vasc Surg .\n2013 ;57 :254 -261\n.23182156 \n12 \nYoo T Aggarwal R Wang TF Satiani B Haurani MJ. \nPresence and degree of residual venous obstruction on serial\nduplex imaging is associated with increased risk of recurrence and\nprogression of infrainguinal lower extremity deep venous\nthrombosis\n. J Vasc Surg Venous Lymphat\nDisord .\n2018 ;6 :575 -583.e1\n.29945822 \n13 \nLin PH Ochoa LN Duffy P. \nCatheter-directed thrombectomy and thrombolysis for symptomatic\nlower-extremity deep vein thrombosis: review of current interventional\ntreatment strategies\n. Perspect Vasc Surg Endovasc\nTher .\n2010 ;22 :152 -163\n.21098496 \n14 \nEnden T Haig Y Kløw NE , et al\nLong-term outcome after\nadditional catheter-directed thrombolysis versus standard treatment for\nacute iliofemoral deep vein thrombosis (the CaVenT study): a randomised\ncontrolled trial\n. Lancet .\n2012 ;379 :31 -38\n.22172244 \n15 \nKohi MP Kohlbrenner R Kolli KP Lehrman E Taylor AG Fidelman N. \nCatheter directed interventions for acute deep vein\nthrombosis\n. Cardiovasc Diagn Ther .\n2016 ;6 :599 -611\n.28123980 \n16 \nEngelberger RP Spirk D Willenberg T , et al\nUltrasound-assisted versus\nconventional catheter-directed thrombolysis for acute iliofemoral deep vein\nthrombosis\n. Circ Cardiovasc Interv .\n2015 ;8 :e002027 .25593121 \n17 \nMurphy KD. \nMechanical thrombectomy for DVT\n. Tech\nVasc Interv Radiol .\n2004 ;7 :79 -85\n.15252764 \n18 \nPenumbra . Indigo® system\n.\nhttps://www.penumbrainc.com/peripheral-device/indigo-system/.\nAccessed August 11, 2019 .\n19 \nLopez R DeMartino R Fleming M Bjarnason H Neisen M. \nAspiration thrombectomy for acute iliofemoral or central deep\nvenous thrombosis\n. J Vasc Surg Venous Lymphat\nDisord .\n2019 ;7 :162 -168\n.30639411 \n20 \nClinicalTrials.gov . ClotTriever Outcomes (CLOUT)\nRegistry\n. https://clinicaltrials.gov/ct2/show/NCT03575364. Published July\n2, 2018. Accessed August 11, 2019 .\n21 \nWeinberg I Vedantham S Salter A , et al\nRelationships between the\nuse of pharmacomechanical catheter-directed thrombolysis, sonographic\nfindings, and clinical outcomes in patients with acute proximal DVT: results\nfrom the ATTRACT Multicenter Randomized Trial\n. Vasc\nMed .\n2019 ;24 :442 -451\n.31354089\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "DVT; thrombectomy; thrombolysis",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D005268:Femoral Vein; D006801:Humans; D007084:Iliac Vein; D008297:Male; D008875:Middle Aged; D017131:Thrombectomy; D015912:Thrombolytic Therapy; D016896:Treatment Outcome; D014654:Vascular Patency; D020246:Venous Thrombosis",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709620910288",
"pmc": null,
"pmid": "32131636",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "28123980;29945822;21422387;22287864;22172244;30586751;28477860;25593121;27279896;31354089;21098496;15252764;23182156;28123971;31155730;16567667;30639411",
"title": "Challenging Management of a Patient With Severe Bilateral Deep Vein Thrombosis.",
"title_normalized": "challenging management of a patient with severe bilateral deep vein thrombosis"
} | [
{
"companynumb": "US-JNJFOC-20200344890",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
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"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
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... |
{
"abstract": "We describe an episode of Leptotrichia trevisanii bacteraemia in a neutropenic hemato-oncology patient receiving chemotherapy for Refractory Anemia with Excess Blasts-2 (RAEB-2). Although Leptotrichia spp. colonize the oral cavity and genitourinary tract, serious episodes of bacteraemia might occur in immunocompromised patients, particularly in those with severe neutropenia. Therefore, microbiologists should consider the possibility of Leptotrichia spp. septicemia in patients with blood cultures positive for gram negative bacilli, when routine microbiology tests fail to reveal a correct identification of the organism.",
"affiliations": "Department of Microbiology, GZA Sint-Augustinus, Wilrijk, Belgium. cooremansarah@hotmail.com",
"authors": "Cooreman|S|S|;Schuermans|C|C|;Van Schaeren|J|J|;Olive|N|N|;Wauters|G|G|;Verhaegen|J|J|;Jeurissen|A|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.anaerobe.2010.12.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-9964",
"issue": "17(1)",
"journal": "Anaerobe",
"keywords": null,
"medline_ta": "Anaerobe",
"mesh_terms": "D016470:Bacteremia; D004358:Drug Therapy; D064420:Drug-Related Side Effects and Adverse Reactions; D045825:Fusobacteriaceae Infections; D019337:Hematologic Neoplasms; D006801:Humans; D016867:Immunocompromised Host; D045183:Leptotrichia; D008297:Male; D008875:Middle Aged; D009503:Neutropenia",
"nlm_unique_id": "9505216",
"other_id": null,
"pages": "1-3",
"pmc": null,
"pmid": "21184838",
"pubdate": "2011-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bacteraemia caused by Leptotrichia trevisanii in a neutropenic patient.",
"title_normalized": "bacteraemia caused by leptotrichia trevisanii in a neutropenic patient"
} | [
{
"companynumb": "BE-MYLANLABS-2018M1071027",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IDARUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTacrolimus is recommended for the treatment of steroid-refractory ulcerative colitis (UC). Concomitantly started purine analogues (PAs) are used for the maintenance of remission, though their therapeutic relevance remains uncertain. Here we studied the role of PAs in the long-term outcome of steroid-refractory UC after tacrolimus treatment.\n\n\nMETHODS\nIn five centres, charts of tacrolimus-treated UC patients with a steroid-refractory moderate to severe course were reviewed. Long-term efficacy was determined by colectomy rates and clinical remission in cases of colectomy-free survival for 3 months.\n\n\nRESULTS\nWe identified 156 patients (median age 34 years) with a median Lichtiger score of 12 (4-17) and pancolitis (E3) in 65% (101). The Kaplan-Meier curve for colectomy-free survival after month 3 showed a benefit in the PA group (p = 0.02). In patients treated with PA clinical remission was achieved in 82% (65/79) vs 67% (39/58) in those not treated with PA (p = 0.02). Time to colectomy was 2 years (median, 0.7-5.8) in the PA group and 0.8 years (0.3-4.7) in the group not treated with PAs (p = 0.02). Time to relapse was 1.2 years (median, 0.3-6.2) in patients with PA treatment and 0.5 years (0.3-3.9) in those without PA treatment (p = 0.05). Overall, clinical remission was achieved in 67% (104/156) of patients. Colectomy was performed in 29% (45/156) 0.5 years (median, 0.04-5.79) after initiation of tacrolimus. Ten (6%) patients had to stop tacrolimus due to adverse events and two (without PA treatment) died.\n\n\nCONCLUSIONS\nOur study supports the efficacy of tacrolimus in steroid-refractory UC. Purine analogues appear to be beneficial for the long-term outcome of these patients.",
"affiliations": "Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany.;Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany.;Department of Internal Medicine I, Agaplesion Markus Hospital, Frankfurt, Germany.;Department of Gastroenterology and Hepatology, Charite Medical School, Humboldt University of Berlin, Berlin, Germany.;Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany.;Department of Gastroenterology, Hepatology and Endocrinology, Robert Bosch Hospital, Stuttgart, Germany.;Department of Internal Medicine I, Asklepios Klinik Nord, Hamburg, Germany.;Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany.;Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Lübeck, Germany juergen.buening@uk-sh.de.",
"authors": "Schmidt|K J|KJ|;Müller|N|N|;Dignass|A|A|;Baumgart|D C|DC|;Lehnert|H|H|;Stange|E F|EF|;Herrlinger|K R|KR|;Fellermann|K|K|;Büning|J|J|",
"chemical_list": "D007166:Immunosuppressive Agents; D013256:Steroids; D015122:Mercaptopurine; D016559:Tacrolimus",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjv175",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-9946",
"issue": "10(1)",
"journal": "Journal of Crohn's & colitis",
"keywords": "Ulcerative colitis; tacrolimus; purine analogues",
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000328:Adult; D000368:Aged; D015331:Cohort Studies; D003082:Colectomy; D003093:Colitis, Ulcerative; D003113:Colonoscopy; D016208:Databases, Factual; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005858:Germany; D006801:Humans; D007166:Immunosuppressive Agents; D007413:Intestinal Mucosa; D053208:Kaplan-Meier Estimate; D008297:Male; D015122:Mercaptopurine; D008875:Middle Aged; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D018709:Statistics, Nonparametric; D013256:Steroids; D015996:Survival Rate; D016559:Tacrolimus; D013997:Time Factors; D016896:Treatment Outcome; D014945:Wound Healing; D055815:Young Adult",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "31-7",
"pmc": null,
"pmid": "26419459",
"pubdate": "2016-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Long-term Outcomes in Steroid-refractory Ulcerative Colitis Treated with Tacrolimus Alone or in Combination with Purine Analogues.",
"title_normalized": "long term outcomes in steroid refractory ulcerative colitis treated with tacrolimus alone or in combination with purine analogues"
} | [
{
"companynumb": "DE-MYLANLABS-2016M1047155",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCurrently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort.\n\n\nMETHODS\nClinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment.\n\n\nRESULTS\n4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn's disease (CD) underwent SOT (p = 2.69 x 10(-6), UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26-84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%).\n\n\nCONCLUSIONS\nSOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.",
"affiliations": "Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany; Department of Preventive Dentistry and Periodontology, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Medicine IV Nephrology-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Medicine IV Nephrology-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany; Transplantation Center-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Transplantation Center-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Max-Planck-Institute of Psychiatry, Munich, Germany.;Max-Planck-Institute of Psychiatry, Munich, Germany.;Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Transplantation Center-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany; Transplantation Center-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Transplantation Center-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany; Department of Surgery-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Gastroenterology, Hospital Barmherzige Brüder, Munich, Germany.;Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany; Transplantation Center-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.;Department of Medicine II-Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany.",
"authors": "Schnitzler|Fabian|F|;Friedrich|Matthias|M|;Stallhofer|Johannes|J|;Schönermarck|Ulf|U|;Fischereder|Michael|M|;Habicht|Antje|A|;Karbalai|Nazanin|N|;Wolf|Christiane|C|;Angelberger|Marianne|M|;Olszak|Torsten|T|;Beigel|Florian|F|;Tillack|Cornelia|C|;Göke|Burkhard|B|;Zachoval|Reinhart|R|;Denk|Gerald|G|;Guba|Markus|M|;Rust|Christian|C|;Grüner|Norbert|N|;Brand|Stephan|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0135807",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2628818710.1371/journal.pone.0135807PONE-D-14-54050Research ArticleSolid Organ Transplantation in Patients with Inflammatory Bowel Diseases (IBD): Analysis of Transplantation Outcome and IBD Activity in a Large Single Center Cohort IBD and Solid Organ TransplantationSchnitzler Fabian \n1\nFriedrich Matthias \n1\n\n2\nStallhofer Johannes \n1\nSchönermarck Ulf \n3\nFischereder Michael \n3\n\n4\nHabicht Antje \n4\nKarbalai Nazanin \n5\nWolf Christiane \n5\nAngelberger Marianne \n1\nOlszak Torsten \n1\nBeigel Florian \n1\nTillack Cornelia \n1\nGöke Burkhard \n1\nZachoval Reinhart \n4\nDenk Gerald \n1\n\n4\nGuba Markus \n4\n\n6\nRust Christian \n7\nGrüner Norbert \n1\n\n4\n\n‡\nBrand Stephan \n1\n\n‡\n*\n1 \nDepartment of Medicine II—Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany\n\n2 \nDepartment of Preventive Dentistry and Periodontology, Ludwig-Maximilians-University (LMU), Munich, Germany\n\n3 \nDepartment of Medicine IV Nephrology—Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany\n\n4 \nTransplantation Center—Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany\n\n5 \nMax-Planck-Institute of Psychiatry, Munich, Germany\n\n6 \nDepartment of Surgery—Grosshadern, Ludwig-Maximilians-University (LMU), Munich, Germany\n\n7 \nDepartment of Gastroenterology, Hospital Barmherzige Brüder, Munich, Germany\nHeimesaat Markus M. Editor\nCharité, Campus Benjamin Franklin, GERMANY\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: FS SB. Performed the experiments: FS SB. Analyzed the data: FS CW. Contributed reagents/materials/analysis tools: FS JS US M. Friedrich AH NK CW MA TO FB CT M. Fischereder BG RZ GD MG CR NG SB. Wrote the paper: FS M. Friedrich SB.\n\n‡ These authors are shared senior authors on this work.\n\n* E-mail: stephan.brand@med.uni-muenchen.de19 8 2015 2015 10 8 e01358078 12 2014 27 7 2015 © 2015 Schnitzler et al2015Schnitzler 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 properly credited.Background\nCurrently, limited data of the outcome of inflammatory bowel disease (IBD) in patients after solid organ transplantation (SOT) are available. We aimed to analyze effects of SOT on the IBD course in a large IBD patient cohort.\n\nMethods\nClinical data from 1537 IBD patients were analyzed for patients who underwent SOT (n = 31) between July 2002 and May 2014. Sub-analyses included SOT outcome parameters, IBD activity before and after SOT, and efficacy of IBD treatment.\n\nResults\n4.74% of patients with ulcerative colitis (UC) and 0.84% of patients with Crohn’s disease (CD) underwent SOT (p = 2.69 x 10−6, UC vs. CD). 77.4% of patients with SOT underwent liver transplantation (LTx) with tacrolimus-based immunosuppressive therapy after SOT. All LTx were due to primary sclerosing cholangitis (PSC) or PSC overlap syndromes. Six patients (19.4%) required renal transplantation and one patient (3.2%) heart transplantation. A survival rate of 83.9% after a median follow-up period of 103 months was observed. Before SOT, 65.0% of patients were in clinical remission and 5 patients received immunosuppressive therapy (16.1%). After SOT, 61.0% of patients were in remission (p = 1.00 vs. before SOT) and 29.0% required IBD-specific immunosuppressive or anti-TNF therapy (p = 0.54 vs. before SOT). 42.9% of patients with worsening of IBD after SOT were at higher risk of needing steroid therapy for increased IBD activity (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26–84.06). Four patients (13.0%) needed anti-TNF therapy after SOT (response rate 75%).\n\nConclusions\nSOT was more common in UC patients due to the higher prevalence of PSC-related liver cirrhosis in UC. Despite mainly tacrolimus-based immunosuppressive regimens, outcome of SOT and IBD was excellent in this cohort. In this SOT cohort, concomitant immunosuppressive therapy due to IBD was well tolerated.\n\nS. Brand was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (BR1912/6-1) and the Else-Kröner-Fresenius-Stiftung (Else Kröner-Exzellenzstipendium 2010_EKES.32). F. Beigel was supported by DFG (BE 4490/2-1). C. Tillack was supported by a grant of Ludwig-Maximilians-University Munich (FöFoLe program). T. Olszak was supported by a grant from Deutsche Forschungsgemeinschaft (DFG, OL/324-1) and by a grant from the Ludwig-Maximilians-University Munich (FöFoLe program). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nIntroduction\nThe clinical course of inflammatory bowel diseases (IBD) such as ulcerative colitis (UC) and Crohn’s disease (CD) is typically characterized by alternating episodes of flares and remission. In up to one third of IBD patients, extraintestinal manifestations such as primary sclerosing cholangitis (PSC) or renal dysfunction (e.g., due to amyloidosis) are found [1–3].\n\nPSC is a chronic cholestatic liver disease with chronic inflammation and fibrosis of hepatic bile ducts, resulting in liver cirrhosis and progressive impairment of liver function and consecutive liver failure in a subgroup of PSC patients [3, 4]. Liver transplantation is currently the only curative therapy for PSC as medical treatments are limited and non-curative in PSC [5]. PSC is more frequent in UC patients than in CD patients with prevalence rates of PSC ranging from 0.76% to 5.4% in UC patients and from 1.2% to 3.4% in CD patients [1, 6–8]. Most IBD patients with PSC display a characteristic disease course compared to IBD patients without cholestatic liver diseases [4, 8–17]. Furthermore, the frequency of pancolitis is higher in UC-PSC patients with more right-sided colitis; and more of these patients have rectal sparing and backwash ileitis, although the course of UC is often mild [4, 9–12, 14, 15, 18]. In contrast, the risk of malignancies including colorectal cancer (CRC) and cholangiocarcinoma is significantly increased in UC patients with concomitant PSC, independently from the underlying risk of CRC in UC alone [13, 16, 17, 19]. In addition, the risk of pouchitis was reported to be high after proctocolectomy with ileal pouch-anal anastomosis (IPAA) [9].\n\nGiven the high prevalence of PSC among IBD patients, PSC is the most frequent cause for liver transplantation (LTx) in IBD patients. Another less frequent cause for solid organ transplantation (SOT) in IBD patients is renal insufficiency, e.g., due to amyloidosis [2, 20]. In IBD patients undergoing SOT, the disease course is highly variable after SOT and data on the subsequent IBD course after SOT are conflicting [2, 3, 9–18, 20–31]. A recently published meta-analysis included a total of 609 IBD patients of 14 clinical studies and investigated the natural history of IBD after LTx in patients with PSC/UC. Among these IBD patients, one third (31%) showed improvement of IBD activity after LTx, 39% of patients displayed no significant change of IBD activity, whereas in 30% of patients the IBD activity worsened after LTx with need for treatment intensification after LTx [5]. Similarly, after renal transplantation, approximately 30% of patients develop IBD flares and one fifth of patients have to undergo colectomy after renal transplantation [32–35]. Therefore, for approximately one third of IBD patients treatment has to be adapted due to the increasing activity of IBD after SOT.\n\nAnti-tumour necrosis factor alpha (TNF-α) therapy has proven to be an effective therapeutic option in patients with refractory IBD in numerous clinical trials. Therefore, anti-TNF-α therapy represents a treatment option in IBD patients who underwent SOT. However, clinical experience of anti-TNF-α therapy in IBD patients after SOT is very limited. To date, a total of 21 IBD patients including patients with UC, CD, indeterminate colitis and pouchitis, have been treated with infliximab or adalimumab after LTx [36–40]. Some case reports were published on anti-TNF-α therapy in IBD patients after renal transplantation but no data exist on anti-TNF-α therapy in IBD after heart transplantation [41, 42].\n\nGiven the rare incidence of SOT in IBD patients, our large IBD patient cohort enabled us to perform a large single center study (n = 31 SOT cases) on the IBD disease course and anti-TNF-treatment efficacy before and after SOT in a well-characterized IBD cohort.\n\nOne aim was to investigate the outcome of SOT in IBD patients and to evaluate the course of IBD before and after SOT. In addition, we aimed to analyze the treatment outcome of anti-TNF therapy among these patients. These data were finally compared to other available clinical trials and analyses of SOT in IBD patients.\n\nMaterials and Methods\nEthical Statement\nAll individuals gave their written, informed consent prior to study inclusion. The study was approved by the local Ethics committee (Ludwig-Maximilians-University Munich) and adhered to the ethical principles for medical research involving human subjects of the Helsinki Declaration.\n\nStudy population\nAll IBD patients were recruited from the IBD outpatient department of the University Hospital Munich-Grosshadern and from our Center for Solid Organ Transplantation (Ludwig-Maximilians-University Munich, Germany). Databases of all IBD patients who were followed at the IBD outpatient department and of all patients who underwent SOT at the University Hospital Munich-Grosshadern or were followed after SOT at our Center for Solid Organ Transplantation, respectively, were merged to identify IBD patients who underwent SOT. Two senior gastroenterologists viewed relevant data of the 31 IBD patients who underwent SOT between July 2002 and May 2014. Clinical data was collected prospectively. However, data analysis was performed retrospectively. Two senior gastroenterologists analyzed the data which were recorded by patients’ chart analysis and a detailed questionnaire based on an interview at time of enrolment. All patients were regularly seen at the IBD outpatient department and at the Center for Solid Organ Transplantation at the University Hospital Munich—Grosshadern. The diagnosis of UC and CD was based on the Montréal classification including endoscopic, radiological, and histopathological parameters [43]. IBD activity was evaluated clinically before and after SOT and was based on endoscopic findings before and after SOT. Endoscopic assessment for UC was based on the Mayo endoscopic subscore with (0) for inactive disease, (1) for mild disease with erythema, decreased vascular pattern, mild friability, (2) for moderate disease with marked erythema, absent vascular pattern, friability, erosions and (3) for severe disease with spontaneous bleeding and ulcerations. For CD, endoscopic activity was defined as “remission”in case of the absence of erosions, ulcers and stenosis and fistulas, respectively and “mild”in case of signs of inflammation with erosions and absence of ulcers, stenosis and fistulas, respectively, and “severe”in case of ulcerations, stenosis or fistulas. For clinical assessment of CD, the Crohn's Disease Activity Index (CDAI) was used; a score of < 150 points was defined as clinical remission. For UC, the Clinical Activity Index (CAI, Lichtiger score) was used; a CAI of ≤ 4 points was defined as clinical remission. For endoscopic activity, the last endoscopy before SOT and the first endoscopy after SOT were analyzed. Steroid treatment after SOT for IBD was defined as daily steroid treatment > 10 mg prednisolone due to high IBD activity.\n\nStatistical analysis\nData were described with proportions for categorical variables and median with range for continuous variables. Crude associations between categorical variables were assessed with the Chi-square test or the Fisher’s exact test, where appropriate. Quantitative variables were compared between subgroups using Student’s t-test. All tests were two-tailed and p-values < 0.05 were considered as significant.\n\nResults\nSolid organ transplantation in IBD patients\nOut of a total IBD cohort of 1073 CD patients and 464 UC patients analyzed in this study, 31 patients (2.0% of all IBD patients) underwent SOT during the study period (between July 2002 and May 2014). Among the 31 IBD patients were 22 UC patients (71.0%) and 9 CD patients (29.0%). Therefore, 0.84% of all 1073 CD patients and 22 of all 464 UC patients (4.74%) underwent SOT, confirming the increased incidence of SOT among UC patients compared to CD patients (p = 2.69 x 10−6, UC vs. CD). Twenty-four IBD patients underwent LTx (77.4%), six IBD patients underwent kidney transplantation (19.4%) and one patient underwent heart transplantation (3.2%; Table 1, Fig 1).\n\n10.1371/journal.pone.0135807.t001Table 1 Shown are the clinical characteristics of the 31 IBD patients who underwent solid organ transplantation (SOT).\nGiven are sex, age, anti-reject immunosuppressive regimen, malignancies before/after organ transplantation, re-transplantation and reason for re-transplantation and severe complications after SOT, IBD activity before and after SOT, medical treatment of IBD and history of CD-related surgeries. The diagnosis and classification of UC and CD was based on the Montreal classification including endoscopic, radiological, and histopathological parameters [43].\n\nPatient\tAge\tsex\tIBD type\tMontreal classi-fication\tIndication for SOT\tImmuno-suppression after SOT\tIBD activity before SOT\tIBD activity after SOT\tIBD acti-vity change\tIBD treatment before SOT\tIBD treatment after SOT\tsurgery before SOT\tsurgery after SOT\tMalignancy before SOT\tMalignancy after SOT\tRe-Trans-plantation\tReason for Re-Tx\tSOT compli-cations\tFollow-up months\t\n\nIBD patients with liver transplantation (n = 24)\n\t\n1\t53\tm\tUC\tE2\tPSC\ttac, steroids\tremission\tmild\tworse\t5-ASA\tno treatment\tnone\tnone\tnone\tnone\tno\tn. a.\tnone\t102\t\n2\t35\tm\tUC\tE1\tPSC\ttac\tremission\tremission\tno\t5-ASA\tno treatment\tnone\tnone\tnone\tnone\tyes(4x LTx)\tischemic Tx organ injury\tdeath because of septic complications /GI bleeding\t138\t\n3\t46\tf\tCD\tn. a.\tPSC\ttac\tremission\tremission\tno\tAZA\tAZA\tnone\tnone\tnone\tadeno-carcinoma of the Papilla of Vater\tno\tn. a.\tnone\t98\t\n4\t56\tm\tUC\tE3\tPSC\ttac, MMF, steroids\tsevere\tremission\tbetter\t5-ASA\t5-ASA\tnone\tnone\tnone\tnone\tno\tn. a.\tdeath because of acute Ischemic Tx organ failure\t16\t\n5\t44\tf\tUC\tE3\tPSC\ttac, steroids\tremission\tsevere\tworse\t5-ASA, steroids\t5-ASA, steroids\tnone\tnone\tnone\tnone\tno\tn. a.\tnone\t103\t\n6\t32\tm\tUC\tE3\tPSC\ttac\tsevere\tmild\tbetter\tAZA\t5-ASA, IFX\tnone\tnone\tnone\tnone\tno\tn. a.\tnone\t82\t\n7\t70\tm\tUC\tE3\tPSC\ttac, steroids\tremission\tremission\tno\t5-ASA, steroids\tno treatment\tnone\tnone\tmeso-thelioma\tnone\tno\tn. a.\tnone\t141\t\n8\t34\tf\tUC\tE3\tPSC/AIH overlap\ttac, MMF\tsevere\tremission\tbetter\t5-ASA, steroids\tno treatment\tprocto-colec-tomy J-pouch\tnone\tnone\tnone\tno\tn. a.\tnone\t56\t\n9\t53\tm\tCD\tL2/B1\tPSC\ttac, steroids\tmild\tremission\tbetter\tno treatment\tno treatment\tnone\tnone\tnone\tnone\tno\tn. a.\tnone\t143\t\n10\t48\tf\tUC\tE2\tPSC\ttac, steroids\tremission\tn. a.\tn. a.\tno treatment\tno treatment\tnone\tnone\tCCC\tnone\tno\tn. a.\tnone\t13\t\n11\t32\tm\tUC\tE3\tPSC\ttac, steroids\tremission\tmild\tworse\t5-ASA\t5-ASA, ADA\tnone\tnone\tnone\tnone\tyes\tischemic Tx organ injury (split-liver)\tnone\t140\t\n12\t59\tm\tUC\tE3\tPSC\ttac, steroids\tmild\tmild\tno\t5-ASA, steroids\tno treatment\tnone\tnone\tHCC\tnone\tno\tn. a.\tnone\t127\t\n13\t43\tm\tUC\tE3\tPSC\ttac, steroids\tsevere\tremission\tbetter\t5-ASA, steroids\tno treatment\tprocto-colectomy J-pouch (DALM)\tnone\tDALM (procto-colectomy J-pouch)\tnone\tno\tn. a.\tnone\t50\t\n14\t33\tm\tUC\tE3\tPSC/AIH overlap\ttac, steroids\tmild\tremission\tbetter\t5-ASA, steroids\tno treatment\tnone\tnone\tnone\tnone\tno\tn. a.\tnone\t145\t\n15\t44\tf\tUC\tE3\tPSC\ttac, MMF, steroids\tmild\tmild\tno\t5-ASA\t5-ASA\tnone\tnone\tnone\tnone\tno\tn. a.\tnone\t115\t\n16\t60\tm\tUC\tE3\tPSC\ttac, steroids\tremission\tremission\tno\t5-ASA\tno treatment\tnone\tnone\tnone\tnone\tyes\tischemic Tx organ injury\tnone\t9\t\n17\t65\tm\tUC\tE3\tPSC\ttac\tmild\tmild\tno\t5-ASA, steroids\tIFX\tnone\tProcto-colec-tomy, J-pouch\tnone\tnone\tno\tn. a.\tnone\t157\t\n18\t44\tm\tUC\tE3\tPSC/ hemo-chromatosis\ttac, steroids\tremission\tmild\tworse\t5-ASA, steroids\tsteroids, AZA\tnone\tnone\tnone\tnone\tyes\tchronic Tx organ failur\tnone\t154\t\n19\t44\tm\tCD\tL1/B1\tPSC\ttac, CyA, steroids\tremission\tremission\tno\tsteroids\tno treatment\tnone\tnone\tCCC\tnone\tno\tn. a.\tdeath because of septic complications /bleeding\t7\t\n20\t53\tf\tUC\tE2\tPSC\ttac, steroids\tremission\tremission\tno\tno treatment\t5-ASA\tnone\tnone\tnone\tnone\tno\tn. a.\tdeath because of acute ischemic Tx organ failure\t41\t\n21\t65\tm\tUC\tE2\tPSC\ttac, steroids\tremission\tremission\tno\t5-ASA\t5-ASA\tnone\tnone\tnone\tnone\tno\tn. a.\tdeath because of acute ischemic Tx organ failure\t15\t\n22\t44\tm\tUC\tE2\tPSC\ttac\tremission\tremission\tno\t5-ASA\t5-ASA\tnone\tnone\tnone\tnone\tno\tn. a.\tnone\t139\t\n23\t49\tf\tUC\tE3\tPSC\ttac, steroids\tsevere\tremission\tbetter\tno treatment\tno treatment\tprocto-colec-tomy J-pouch\tnone\tnone\tnone\tno\tn. a.\tnone\t155\t\n24\t56\tm\tUC\tE3\tPSC\ttac\tremission\tremission\tno\tno treatment\tno treatment\tleft-sided hemi-colec-tomy, rectal resection for colon cancer\tnone\tsigmoid colon carcinoma\tnone\tno\tn. a.\tacute cardiac failure\t86\t\n\nIBD patients with renal transplantation (n = 6)\n\t\n25\t48\tf\tUC\tE3\tCRF due to IgA nephropathy\tCyA, steroids\tremission\tmild\tworse\tno treatment\t5-ASA, steroids\tnone\tnone\tnone\tnone\tno\tn. a.\tnone\t102\t\n26\t63\tm\tCD\tL3/B1\tCRF unknown etiology\tCyA, MMF, steroids\tremission\tremission\tno\tno treatment\tno treatment\tnone\tnone\tnone\tnone\tno\tn. a.\tnone\t112\t\n27\t54\tm\tCD\tn. a.\tCRF due to HUS\tCyA, steroids\tremission\tremission\tno\tno treatment\tno treatment\tnone\tnone\tnone\tpost-transplant lympho-proliferative disorder (PTLD)\tyes\tischemic Tx organ injury\tnone\t181\t\n28\t45\tm\tCD\tL3/B3p\tCRF due to AA amyloidosis\ttac, MMF\tremission\tremission\tno\t5-ASA, steroids, 6-MP\tsteroids, 6-MP\tileocecal resection, fistula surgery\tnone\tnone\tnone\tno\tn. a.\tnone\t108\t\n29\t48\tm\tCD\tL3/B3p\tCRF due to AA amyloidosis\ttac, steroids\tremission\tmild\tno\tsteroids, AZA\tno treatment\tileocecal resection, fistula surgery\tnone\tnone\trenal cell carcinoma of the Tx kidney\tno\tn. a.\tnone\t13\t\n30\t67\tm\tCD\tL3/B3p\tCRF due to oxalate nephropathy\tCyA, steroids\tremission\tremission\tno\t6-MP\t6-MP\tileocecal resection, re-resection of anastomosis-stenosis, fistula surgery\tnone\tnone\tnone\tno\tn. a.\tnone\t159\t\n\nIBD patient with heart transplantation (n = 1)\n\t\n31\t37\tm\tCD\tL2/B2\tcongestive heart failure because of ischemic dilatative cardio-myopathy\ttac, MMF, steroids\tmild\tremission\tbetter\tno treatment\tIFX\tright-sided hemi-colec-tomy\tnone\tnone\tnone\tno\tn. a.\tnone\t81\t\nDisease classification was performed as detailed in the Materials and Methods section (n. a., not applicable; DALM, dysplasia-associated lesion or mass; 5-ASA, 5-aminosalicylic acid; AZA, azathioprine; 6-MP, 6-mercaptopurine; ADA, adalimumab; IFX, infliximab; LTx, liver transplantation; Tx, transplantation; PSC, primary sclerosing cholangitis; AIH, autoimmune hepatitis; DALM, Dysplasia-associated lesion or mass; HCC, hepatocellular carcinoma; CCC, cholangio-cellular carcinoma; CRF, chronic renal failure; MMF, mycophenolate mofetil; CyA, cyclosporine A; tac, tacrolimus).\n\n10.1371/journal.pone.0135807.g001Fig 1 Indication for solid organ transplantation (SOT).\nA total of 31 patients (22 UC patients and 9 CD patients underwent SOT between July 2002 and May 2014). Twenty-four IBD patients (21 UC patients and 3 CD patients) underwent orthotopic LTx (77.4%) and 6 IBD patients (1 UC patient and 5 CD patients) underwent renal transplantation (19.4% off all SOT) and one CD patient underwent heart transplantation (3.2% of all SOT) (PSC, primary sclerosing cholangitis; AIH, autoimmune hepatitis; HUS, acute hemolytic uremic syndrome; CRF, chronic renal failure; LTx, liver transplantation; UC, ulcerative colitis; CD, Crohn’s disease).\n\nOutcome of liver transplantation in IBD patients\nTwenty-four IBD patients including 21 UC patients and 3 CD patients underwent LTx for PSC or PSC/AIH overlap syndrome; one UC patient had concomitant PSC and hemochromatosis (Fig 1, Table 1). The median age at first diagnosis of liver disease was 27.2 years (range 12.5–56.0 years), compared to a median age of 21.2 years at first IBD diagnosis (range 9.1–50.0 years). The median age at first LTx was 41.2 years (range 27.1–66.0 years). Therefore, the median interval from first diagnosis of liver disease to LTx was 156.8 months (range 10.1–418.0 months).\n\nAll patients with LTx received immunosuppressive therapy with tacrolimus after transplantation, five patients received tacrolimus in combination with mycophenolate mofetil (MMF) (20.8% of all LTx patients), 17 patients received concomitant steroid treatment (70.8%) and one UC patient received consecutively cyclosporine A and then tacrolimus (4.2%, Table 1). Three of the 24 IBD patients (12.5%) needed re-transplantation because of acute ischemic organ failure after first LTx; one of them (4.2%) required even a total of four LTx due to recurrent acute ischemic organ failures after transplantation (Table 1). One UC patient (4.2%) needed a second LTx one month after first SOT because of organ failure after recurrent cholangitis and intra-hepatic bleeding complications. Another UC/PSC patient (4.2%) needed re-transplantation three years after first LTx because of chronic vascular complications resulting in a chronic ischemic organ failure (Table 1).\n\nOutcome of renal transplantation in IBD patients\nSix IBD patients out of 1537 IBD patients analyzed (0.4%), including five CD patients (0.47% of all CD patients) and one UC patient (0.22% of all UC patients) underwent renal transplantation for terminal renal failure (Fig 1, Table 1). Two out of these six patients (33%) were diagnosed with AA amyloidosis resulting in chronic renal failure. Another UC patient (16.7%) was diagnosed with IgA nephropathy. One CD patient (16.7%) was diagnosed with oxalate nephropathy and consecutive chronic renal failure needing hemodialysis followed by renal transplantation. Another CD patient (16.6%) developed an acute hemolytic uremic syndrome with acute renal failure and underwent renal transplantation (Table 1). In one CD patient with chronic renal failure, the cause for renal failure could not been diagnosed (Table 1). Median age at first diagnosis of renal disease was 35.8 years (range 14.4–56.9 years) compared to a median age at first diagnosis of IBD of 27.1 years (range 8.4–43.0 years). The median age at first renal transplantation was 43.6 years (range 28.5–66.3 years). Therefore, the median interval from first diagnosis of kidney disease to renal transplantation was 101.0 months (range 0.0–177.1 months). Three of the six IBD patients (50.0%) received cyclosporine A (CyA) after renal transplantation (one patient with CyA mono therapy, one CyA with steroids, and one CyA with MMF treatment, Table 1). Two IBD patients (33.3%) received tacrolimus after kidney transplantation (one patient with combination therapy with steroids and one patient with concomitant MMF treatment, Table 1). Another IBD patient received MMF and steroid treatment after renal transplantation. In summary, five of the six IBD patients (83.3%) had concomitant steroid treatment after transplantation.\n\nOutcome of solid organ transplantation in the IBD patient with heart transplantation\nOne CD patient out of 1537 IBD patients analyzed (0.07%) underwent heart transplantation because of ischemic dilatative cardiomyopathy with consecutive congestive heart failure at age of 29 years (Fig 1, Table 1). This patient was diagnosed with CD at age of 22 years and received tacrolimus, MMF and steroid treatment after heart transplantation. The time from diagnosis of heart failure to heart transplantation was 15 months.\n\nIBD activity and medical treatment before and after solid organ transplantation\nClinical characteristics of UC and CD based on the Montreal classification, disease activity before and after SOT, as well as history of IBD-related surgery and IBD-related medical treatment before and after SOT are given for the 22 UC patients and 9 CD patients in Table 1. All 31 IBD patients underwent endoscopy within a median of 16.5 months before SOT; they underwent also endoscopy within a median of 24.4 months after SOT.\n\nOverall, 20 of the 31 IBD patients were clinically and endoscopically in remission before SOT (64.5%). Six IBD patients had mild disease activity before SOT (19.4%) and five IBD patients had severe IBD activity before SOT (16.1%, Table 1, Fig 2A). After SOT, no activity of IBD was endoscopically seen in 19 of the 31 IBD patients (61.3%), while nine IBD patients had mild disease activity after SOT (29.0%) and three patients (9.7%) had severe disease activity (Table 1, Fig 2B).\n\n10.1371/journal.pone.0135807.g002Fig 2 Endoscopic disease activity seen (A) before single organ transplantation (SOT) and (B) after SOT.\nOverall, 20 of the 31 IBD patients were endoscopically in remission before SOT (64.5%) compared to six IBD patients with mild disease activity before SOT (19.4%) and five IBD patients with severe IBD activity before SOT (16.1%). After SOT, no activity of IBD was endoscopically seen in 19 of the 31 IBD patients (61.3%) versus nine IBD patients with mild disease activity after SOT (29.0%) and severe disease activity in three IBD patients (9.7%).\n\nHistory of medical treatment before and after SOT is given in Table 1 and Fig 3. Sixteen UC patients (out of 22 UC patients with SOT; 72.8%) received 5-amino-salicylic acid (5-ASA) treatment pre-SOT, eight patients received steroids (36.4%) and one patient with severe pancolitis received azathioprine (4.5%), while five UC patients had no maintenance treatment before SOT (22.7%, Table 1, Fig 3). After SOT, nine of the 22 UC patients received 5-ASA treatment (40.9%), three patients needed steroid treatment (13.6%) and two UC patients had immunosuppressive therapy with azathioprine after SOT (9.1%, Table 1, Fig 3). Two UC patients (9.1%) were treated with infliximab after SOT and another UC patient was treated with adalimumab 2.5 years after SOT (Table 1, Fig 3).\n\n10.1371/journal.pone.0135807.g003Fig 3 Medical treatment for IBD before and after single organ transplantation (n = 31).\nGiven are the total number of patients and proportion of patients for the relevant IBD treatment. (5-ASA, aminosalicylates; AZA, azathioprine; 6-MP, 6-mercaptopurine; IFX, infliximab; ADA, adalimumab). * excludes short-term steroid treatment for SOT.\n\nFour of the nine CD patients had no maintenance treatment before SOT (44.4%, Table 1, Fig 3), two CD patients had immunosuppressive therapy with azathioprine (22.2%) and two other CD patients received 6-mercaptopurine (22.2%). Three CD patients had steroid treatment with two of them receiving concomitant immunosuppressive treatment with azathioprine and 6-mercaptopurine, respectively, and 5-ASA in one of these patients (33.3%, Table 1, Fig 3). After SOT, one CD patient was treated with infliximab (Table 1 and Fig 3). One patient received steroid treatment after SOT because of increased CD activity (11.1%), 3 patients had immunosuppressive therapy with azathioprine after SOT (33.3%) and five patients (55.6%) had no IBD-specific treatment after SOT (Table 1, Fig 3).\n\nIBD activity changes after solid organ transplantation\nA change of disease activity was seen in twelve of the 31 IBD patients after single organ transplantation (39%), while in 19 patients (61%) no significant influence of SOT on IBD activity was observed. Worsening of disease activity after SOT was seen in 7 patients (23%), while IBD activity decreased in five patients after SOT (16%; Table 1, Fig 4).\n\n10.1371/journal.pone.0135807.g004Fig 4 Change of IBD activity in our cohort of 31 IBD patients.\nUnivariate analysis revealed that requirement of additional corticosteroid therapy (defined as prednisolone equivalent of 10 mg or greater for IBD activity and not for therapy of transplant rejection) was a good predictor for worsening IBD activity after SOT (p = 0.03; relative risk (RR): 10.29; 95% CI 1.26–84.06; Table 2).\n\n10.1371/journal.pone.0135807.t002Table 2 Comparison of IBD-SOT patients with unchanged or improved IBD activity (n = 24) and IBD-SOT patients with worsened IBD activity (n = 7; univariate analysis).\nSteroid treatment for IBD after SOT was significantly associated with worsening of disease activity (p = 0.028). However, this association may be most likely explained by the fact that IBD patients with worsening of IBD activity after SOT will be primarily treated with steroid treatment rather than steroid treatment being an independent risk factor for worsening of IBD activity after SOT.\n\nVariable\tDisease activity unchangedor improved after SOT(n = 24)\tWorsening of diseaseactivity after SOT(n = 7)\tOR\t95% CI\tp value\t\nMale sex\t18/24 (75.0%)\t5/7 (71.4%)\t1.193\t0.091/10.112\t1.000\t\nAge < 20 years at diagnosis of IBD\t7/24 (29.2%)\t4/7 (57.1%)\t0.322\t0.037/2.449\t0.210\t\nSmoking at date of SOT\t1/24 (4.2%)\t1/7 (14.3)\t0.276\t0.003/23.864\t0.406\t\nIBD in remission before SOT\t13/20 (65.0%)\t7/20 (35.0%)\t3.337\t0.794/15.458\t0.113\t\nDiagnosis UC\t17/24 (70.8%)\t5/7 (71.4%)\t0.972\t0.076/7.954\t1.000\t\nDiagnosis CD\t7/24 (29.2%)\t2/7 (28.6%)\t1.028\t0.126/13.243\t1.000\t\nAminosalicylates before SOT\t14/24 (58.3%)\t3/7 (43.0%)\t1.829\t0.248/15.396\t0.671\t\nSteroid treatment before SOT\t8/24 (33.3%)\t3/7 (43.0%)\t0.676\t0.088/5.757\t0.676\t\nAzathioprine before SOT\t5/24 (20.8%)\t1/7 (14.3%)\t1.558\t0.13/86.917\t1.000\t\nTacrolimus after SOT\t22/24 (91.7%)\t5/7 (71.4%)\t4.135\t0.245/70.752\t0.212\t\nCyclosporine A after SOT\t2/24 (8.3%)\t2/7 (28.6%)\t0.242\t0.014/4.075\t0.212\t\nAminosalicylates after SOT\t6/24 (25.0%)\t3/7 (42.9%)\t0.457\t0.057/4.032\t0.384\t\nAzathioprine after SOT\t4/24 (16.7%)\t1/7 (14.3%)\t1.193\t0.091/68.793\t1.000\t\nAnti-TNF (infliximab or adalimumab) after SOT\t3/24 (12.5%)\t1/7 (14.3%)\t0.862\t0.056/52.407\t1.000\t\nSteroid treatment for IBD after SOT\t1/24 (4.2%)\t3/7 (42.9%)\t0.058\t0.0048/0.7062\t\n0.028\n\t\nMycophenlate mofetil (MMF) after SOT\t8/24 (33.3%)\t2/7 (28.6%)\t1.241\t0.155/15.778\t1.000\t\nSevere complications after solid organ transplantation\nOverall, there was a survival rate of 83.9% after a mean follow-up period of 33.3 months (range 0.1–242.4 months) after SOT. During a total follow-up time of 103.0 months (range 7.0–182.0 months) and a median follow-up of 33.3 months (range 0.1–242.4 months) after SOT, a total of 6 IBD patients who underwent SOT died (16.1%) at a median age of 49.0 years (range 34.6–57.2 years, Table 1). All patients who died during the follow-up interval were male patients.\n\nThree male UC patients who underwent LTx for PSC (9.7%) died because of acute ischemic failure of the transplanted liver after a median of 5.8 months (range 3.6–8.9 months). One male CD-PSC patient (3.2%) died one year after LTx because of septic and bleeding complications at an age of 35 years. This patient received MMF, steroids and tacrolimus as immunosuppressive regimen after SOT. Another male UC patient who underwent a total of four LTx because of recurrent acute ischemic organ failures died six years after the last LTx because of septic complications and gastro-intestinal bleeding complications at an age of 35 years with concomitant immunosuppressive therapy with tacrolimus (3.2%, Table 1). Two years after LTx, another male UC-PSC patient died because of congestive heart failure (3.2%, Table 1). Despite incomplete data regarding the cytomegalovirus (CMV) infection status before SOT, none of the 31 IBD patients with SOT developed infectious complications related to CMV or CMV reactivation.\n\nMalignancies in IBD patients before and after SOT\nAlmost one third of the 31 IBD-SOT patients were diagnosed with malignancies or dysplasia (n = 9, 29%). Six IBD patients (19.4%) were diagnosed with malignancy or dysplasia before SOT (6/9 patients, 66.7%: one male UC patient with abdominal cutaneous malignant mesothelioma; one female UC patient with cholangiocellular carcinoma diagnosed in the explanted liver; one male UC patient with hepatocellular carcinoma diagnosed in the explanted liver; one male UC patient with severe pancolitis was diagnosed with high-grade dysplasia-associated lesions (DALM); one male CD patient with cholangiocellular carcinoma diagnosed in the explanted liver and one UC patient with colorectal cancer before SOT; Table 1).\n\nThree IBD patients (9.7%) were diagnosed with malignancies after SOT (one female UC patient with adenocarcinoma of the papilla of Vater; one male CD patient with post-transplant lymphoproliferative disease (PTLD) and male CD patient with papillary renal cell carcinoma in the transplanted kidney; Table 1).\n\nDiscussion\nThe aim of this study was to analyze the effect of SOT on the IBD course. Only a minority of 2% of all IBD patients (31 out of 1537 IBD patients) needed SOT in our IBD cohort demonstrating that this is an overall rare event in IBD, especially in CD patients. Importantly, significantly more UC patients underwent SOT in our study cohort compared to CD patients due to the higher prevalence of PSC-related liver cirrhosis in UC (4.74% of all UC patients vs. 0.84% of all CD patients, p = 2.69 x 10−6). All LTx were performed due to PSC or PSC overlap syndromes. Epidemiologic data from Northern European countries demonstrated a lifetime risk of 5% for developing PSC in IBD patients [6]. Also in Northern European countries, PSC is a major indication for LTx constituting approximately 17% of all indications for LTx in the general population (including IBD patients) [21].\n\nOverall, outcome of SOT in the 31 patients was favourable in our cohort. The survival rate was 84% (n = 26) during a total follow-up of 103.0 months (range 7.0–182.0 months) and a median follow-up period of 33.3 months after SOT (Table 1). Five male IBD patients who underwent SOT died (16%) at a median age of 49.0 years. Most common complications were ischemic organ failure of the transplanted liver, septic complications as well as uncontrollable bleeding complications.\n\nRenal failure is a rare complication especially in patients with CD [20]. Age and duration of IBD have been identified as independent risk factors to develop renal failure [44]. Systemic AA amyloidosis is associated with IBD and at least 1% of IBD patients will develop amyloidosis [45]. Two of our CD patients needed renal transplantation for AA amyloidosis and had favourable long-term outcomes. An association between IgA nephropathy and IBD seems possible [46] and there is an between oxalate nephropathy and IBD since the prevalence of calcium-oxalate urolithiasis is up to five-fold higher in CD than in the general population [47]. Hemolytic-uremic syndrome (HUS) is characterized by microangiopathic hemolytic anemia, impaired renal function and excessive platelet consumption leading to thrombocytopenia especially related to gastrointestinal tract infections with Shiga toxin-producing Escherichia coli (STEC) [48]. CD seems to be a likely predisposing factor for HUS because of recurrent gastrointestinal tract infections [49].\n\nImportantly, the majority of IBD patients in our cohort received a tacrolimus-based anti-reject treatment regimen after SOT (87.1%). In some studies, this immunosuppressive treatment regimen was associated with an unfavourable outcome in IBD patients who underwent SOT with an up to four-fold higher risk of post-LTx IBD relapse [5, 50–52]. However, we could not confirm this unfavourable outcome in IBD patients with tacrolimus-based anti-reject treatment regimen post-SOT as in 61% of patients disease activity was not influenced by SOT (and SOT-associated immunosuppressive therapy) and 16% of patients had even improvement of disease activity after SOT.\n\nCyclosporine-based anti-reject regimens after SOT were not associated with worsening of disease activity in patients with IBD [52, 53]. However, only four of our 31 IBD patients (13.0%, 3 CD patients and one UC patient) had cyclosporine-based immunosuppression after SOT (Table 1). Disease activity did not change in two of these patients after start of cyclosporine A; two patients had mild activity after SOT while all patients were clinically and endoscopically in remission before SOT. However, our subgroup of patients with cyclosporine A treatment after SOT is too small to draw definite conclusions. These observations were confirmed by univariate analysis of risk factors, demonstrating no association between tacrolimus or cyclosporine treatment after SOT with worsening of disease activity.\n\nSteroid treatment for IBD after SOT was associated with active disease in this univariate analysis (p = 0.028, Table 2). This association may be most likely explained by the fact that patients with active IBD after SOT will be primarily started with steroid treatment to control disease activity considering the limited experience with other treatment options for IBD maintenance therapy after SOT such as anti-TNF treatment. Therefore, steroid therapy is not necessarily a predictor of disease worsening after SOT but rather an indicator for active IBD following SOT.\n\nBased on the results of a large Scandinavian meta-analysis with unfavourable outcomes of IBD under tacrolimus-based anti-reject treatment regimen after liver transplantation, Jørgensen et al. suggested a shift of immunosuppressive treatment to cyclosporine as potentially beneficial [5, 21]. However, tacrolimus-based anti-reject therapy seems superior to cyclosporine-based anti-reject treatment regimen by significantly reducing the risk of acute rejection and steroid-resistant rejection as well as the risk of graft loss [54]. For every 100 LTx patients treated with tacrolimus instead of cyclosporine, rejection and graft loss could be avoided in 9 and 5 patients, respectively [54]. None of the IBD patients in our cohort had severe episodes of acute rejection after SOT or loss of the transplant due to acute rejection reaction. Therefore, our data cannot support unfavourable outcomes of the IBD course in tacrolimus-treated patients. Taking the lower risk of acute rejection and steroid-resistant rejection as well as the lower risk of graft loss in patients with tacrolimus treatment into account, a switch to cyclosporine in IBD patients with SOT cannot be recommended considering the results of our study.\n\nAlthough calcineurin inhibitors (CNIs) are the main anti-reject treatment after LTx, CNI treatment is associated with unfavourable side effects such as worsening of renal dysfunction, neurotoxicity, and diabetes in patients following LTx. The use of mammalian target of rapamycin (mTOR) inhibitors after liver transplantation has been associated with favourable benefits on renal function but with efficacy comparable to CNIs and therefore would be a good alternative in IBD patients following LTx [55]. However, data on mTOR treatment for IBD are very limited and currently not established to control disease activity in patients with IBD [55].\n\nData on the prevalence of colectomy after SOT are conflicting. Whereas a progressive PSC with a consecutive need for LTx seems to be associated with a decrease of disease activity in some IBD/PSC patients, other clinical trials report a prevalence of colectomy of up to 35% in UC patients after LTx [56, 57]. In our cohort, only one patient needed colectomy after SOT because of refractory pancolitis despite anti-TNF maintenance treatment with infliximab.\n\nIn the literature, a total of 21 patients with anti-TNF treatment after SOT are reported to date [36–40]. The majority of these patients showed good response rates after start of anti-TNF treatment. With the exception of one study [37], which demonstrated in several patients infectious complications and a case of post-transplant lymphoproliferative disorder, there was also an overall good safety outcome (Table 3). Considering the patient number of these studies combined (n = 21), the clinical experience of anti-TNF-treated IBD patients with SOT is still very limited. In addition, the overall incidence of SOT in IBD is rare; therefore, very large studies are needed to draw definitive conclusions on the safety of anti-TNF therapies in SOT patients.\n\n10.1371/journal.pone.0135807.t003Table 3 Given is an overview of publications on IBD patients who received anti-TNF therapy after solid organ transplantation including the 4 anti-TNF-treated patients of this study.\nAuthor\tNumber of patients treated with anti-TNF therapy\tAnti-TNF treatment (IFX, ADA)\tClinical outcome, Response rate (%)\tEndoscopic outcome, mucosal healing(%)\tAdverse events\t\nSandhu et al. [36]\t6\t6 patients with IFX\t67\tn/a\tSystemic lupus erythematosus, Colorectal cancer\t\nMohabbat et al. [37]\t8\t4 patients with IFX 2 patients with ADA after IFX, 2 patients with ADA\t87.5\t42.9\tOral candidiasis, Clostridium difficile colitis, Bacterial pneumonia, Cryptosporidiosis,Epstein-Barr virus-positive post-transplant lympho-proliferative disorder\t\nLal et al. [38]\t1\t1 patient with IFX\t100\t100\tNone\t\nEl-Nachef et al. [39]\t2\t1 patient with IFX1 patient with ADA\t100\tn/a\tNone\t\nIndriolo et al. [40]\t4\t4 patients with IFX\t75\t33\tMolluscum contagiosum\t\nSchnitzler et al. (Own data)\t4\t3 patients with IFX, one patient with ADA\t75\t75\tNone\t\nA total of 21 IBD patients received anti-TNF therapy after SOT, including 17 patients who received IFX and 4 IBD patients who received ADA treatment after organ transplantation (n/a, not applicable; IFX, infliximab; ADA, adalimumab).\n\nIn our cohort, four patients (13.0%) received anti-TNF treatment after SOT, including one CD patient after heart transplantation. This patient suffered from an inflammatory intestinal stenosis before heart transplantation. After start of infliximab, this patient was clinically in remission; endoscopically no signs of inflammation were seen. No side effects occurred. This is to our knowledge the first report of an IBD patient with infliximab treatment after heart transplantation. Overall, outcome of anti-TNF treatment was good in our cohort, although the number of patients is small. None of the four anti-TNF treated patients developed infectious complications; in one UC patient infliximab treatment was stopped prophylactically because of recurrent episodes of cholangitis most likely caused by stenosis of the biliary-enteric anastomosis. Despite the limited data on anti-TNF therapy, anti-TNF treatment seems effective and safe in IBD patients post-SOT and refractory to conventional treatment [36–40]. Only one UC patient needed surgery after SOT with proctocolectomy and ileal pouch-anal anastomosis for treatment-refractory UC. Tacrolimus-based reject therapy after solid organ transplantation had a favourable outcome in patients with IBD. The risk for colorectal cancer was low in our IBD cohort, only one UC patient (3%) was diagnosed with colorectal cancer before SOT and none of the IBD patients were diagnosed with colorectal cancer after SOT. However, given that the majority of patients were PSC-IBD patients with a high risk for developing colorectal cancer, annual screening colonoscopies were performed in most patients, likely contributing to the low number of colorectal cancers.\n\nOur study represents one of the largest single-center experiences on SOT outcomes in IBD patients. A major limitation of our study was the limited number of patients included in the analysis; e.g., the subgroup of anti-TNF-treated patients included only four patients. However, considering that the total number of all anti-TNF-treated IBD-SOT patients in the medical literature is only n = 21, this study adds important information to our knowledge of how to treat IBD patients after SOT.\n\nIn conclusion, due to the stronger association of PSC-associated liver cirrhosis with UC (compared to CD), SOT is significantly more often required in UC (4.74% of our patients) than in CD (0.84% of our patients; p = 2.69 x 10−6, UC vs. CD). The overall outcome of SOT in our IBD cohort was favourable with a survival rate of 84%. Anti-TNF treatment was effective and safe in all IBD patients who underwent SOT. This suggests good safety aspects of anti-TNF-treatment in IBD after SOT, although larger, multi-center cohort analyses are needed to confirm these findings.\n==== Refs\nReferences\n1 \nGizard E , Ford AC , Bronowicki JP , Peyrin-Biroulet L . Systematic review: The epidemiology of the hepatobiliary manifestations in patients with inflammatory bowel disease . Alimentary pharmacology & therapeutics . 2014 ;40 (1 ):3 –15 . .24815622 \n2 \nOikonomou K , Kapsoritakis A , Eleftheriadis T , Stefanidis I , Potamianos S . Renal manifestations and complications of inflammatory bowel disease . Inflammatory bowel diseases . 2011 ;17 (4 ):1034 –45 . .20842645 \n3 \nRust C , Brand S . 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"fulltext_license": "CC BY",
"issn_linking": "1932-6203",
"issue": "10(8)",
"journal": "PloS one",
"keywords": null,
"medline_ta": "PLoS One",
"mesh_terms": "D000328:Adult; D000368:Aged; D003093:Colitis, Ulcerative; D003424:Crohn Disease; D005260:Female; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D015996:Survival Rate; D016559:Tacrolimus; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101285081",
"other_id": null,
"pages": "e0135807",
"pmc": null,
"pmid": "26288187",
"pubdate": "2015",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "24815622;20740366;20002354;7590655;11867174;17394153;16151544;23333218;9621299;22094024;22616981;18671816;20186355;16827858;11826412;23371008;24262508;12085034;1995269;9824344;23689806;22407885;20445523;9484758;21769176;23827861;19491858;16292093;16496231;23896954;19295408;16686766;10423073;1632681;23706934;21094876;15591511;12840678;9430887;20842645;2013375;21456044;24707135;12907911;22103794;17301656;12848624;23496317;9106695;22366809;21561875;23622632;25518055;22428731;18567077;22779779;7680144",
"title": "Solid Organ Transplantation in Patients with Inflammatory Bowel Diseases (IBD): Analysis of Transplantation Outcome and IBD Activity in a Large Single Center Cohort.",
"title_normalized": "solid organ transplantation in patients with inflammatory bowel diseases ibd analysis of transplantation outcome and ibd activity in a large single center cohort"
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"companynumb": "DE-ACCORD-033431",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "CYCLOSPORINE"
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"abstract": "Fibrosing mediastinitis (FM) is a rare disorder resulting from abnormal immunological-mediated fibro-proliferative reaction in the mediastinum. Here, we describe a case of a 46-year-old female with an incidentally found 11×9 cm posterior mediastinal mass. Multiple biopsies of this unresectable, 18-fluorodeoxyglucose avid mass revealed marked fibrosis without any evidence of malignancy, suggesting idiopathic fibrosing mediastinitis as our initial diagnosis. Multiple interventions including a trial of steroids, fluconazole, and azathioprine to target fibrosing mediastinitis were not successful. Repeat biopsy was consistent with primary mediastinal follicular dendritic cell sarcoma. The manuscript highlights the heightened need for suspecting occult malignancies in cases of FM presenting with an indeterminate cause.",
"affiliations": "Department of Internal Medicine, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA.;Department of Pathology and Translational Pathobiology, Louisiana State University Health Sciences Center Shreveport, Shreveport, Louisiana, USA.;Center for Molecular Imaging and Therapy, Biomedical Research Foundation of Northwest Louisiana, Shreveport, Louisiana, USA.;Department of Hematology and Oncology, Lousiana State University Health, Shreveport, Shreveport, Louisiana, USA.",
"authors": "Cingam|Shashank Reddy|SR|;Al Shaarani|Majd|M|;Takalkar|Amol|A|;Peddi|Prakash|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-218889",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Cardiothoracic surgery; Pathology; Surgical oncology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D054740:Dendritic Cell Sarcoma, Follicular; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008480:Mediastinitis; D008482:Mediastinum; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D012598:Sclerosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28611161",
"pubdate": "2017-06-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11353121;11395549;15252304;1544676;17373675;22033450;22228355;23755890;2420185;24476636;24720374;24966952;26722384;26910224;27318412;28920202;7660343;8091258",
"title": "Follicular dendritic sarcoma masquerading as fibrosing mediastinitis.",
"title_normalized": "follicular dendritic sarcoma masquerading as fibrosing mediastinitis"
} | [
{
"companynumb": "US-PFIZER INC-2017301945",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "PREDNISONE"
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... |
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"abstract": "The prognosis of diffuse large B-cell lymphoma (DLBCL) patients depends on lymphoma- and patient-related risk factors and is best estimated by the international prognostic index (IPI). The aim of the study was to determine whether the average relative dose intensity (ARDI) of an anthracycline-containing regimen could predict DLBCL outcome independently from the IPI. We analyzed 223 white Caucasian DLBCL patients who completed at least four cycles of first-line immunochemotherapy with rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R-CHOP). The ARDI was calculated by specially developed software in each individual patient, simultaneously with the chemotherapy prescription, which instantly revealed all causes of its decrease. The relevance of the ARDI for progression-free/overall survival (PFS/OS) was evaluated. Prolonged intervals between cycles of immunochemotherapy-the most common cause of decreased ARDI (49.3%, 110/223)-were due to neutropenia (absolute neutrophil count <1.0 × 109 /L) and infections. Reductions in cytostatic doses were observed in 19.7% (44/223) of patients, mainly as the consequence of cardiotoxicity (23/223, 10.3%). The OS varied significantly when the ARDI was >90% (P < 0.00001). Multivariate analysis confirmed that an ARDI>90% was an IPI-independent predictor of prolonged PFS (HR = 0.31; 95%CI: 0.20-0.47; P < 0.00001) and OS (HR = 0.32; 95%CI: 0.21-0.48; P < 0.00001). With an analytic tool allowing real-time ARDI assessment, it was possible to maintain an ARDI above 90% in 161 of 223 patients (72%). DLBCL patients with an ARDI >90% have significantly better outcome regardless of the IPI; therefore, our official recommendation is an adequate dose density through efficient neutropenia prophylaxis and cardiac protection.",
"affiliations": "Department of Haematology, Jagiellonian University, Krakow, Poland.;Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre, Otwock, Poland.;Department of Haematology, Jagiellonian University, Krakow, Poland.;Department of Haematology, Jagiellonian University, Krakow, Poland.;Department of Haematology, Jagiellonian University, Krakow, Poland.",
"authors": "Długosz-Danecka|Monika|M|;Szmit|Sebastian|S|0000-0002-3075-1943;Ogórka|Tomasz|T|;Skotnicki|Aleksander B|AB|;Jurczak|Wojciech|W|",
"chemical_list": "D015415:Biomarkers; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.2008",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 10.1002/cam4.2008CAM42008Original ResearchClinical Cancer ResearchOriginal ResearchThe average relative dose intensity of R‐CHOP is an independent factor determining favorable overall survival in diffuse large B‐cell lymphoma patients DŁUGOSZ‐DANECKA et al.Długosz‐Danecka Monika \n1\nSzmit Sebastian http://orcid.org/0000-0002-3075-1943s.szmit@gmail.com \n2\nOgórka Tomasz \n1\nSkotnicki Aleksander B. \n1\nJurczak Wojciech \n1\n\n1 \nDepartment of Haematology\nJagiellonian University\nKrakow\nPoland\n\n2 \nDepartment of Pulmonary Circulation\nThromboembolic Diseases and Cardiology\nCentre of Postgraduate Medical Education\nEuropean Health Centre\nOtwock\nPoland\n* Correspondence\n\nSebastian Szmit, Department of Pulmonary Circulation, Thromboembolic Diseases and Cardiology, Centre of Postgraduate Medical Education, European Health Centre, Otwock, Poland\n\nEmail: s.szmit@gmail.com\n10 2 2019 3 2019 8 3 10.1002/cam4.2019.8.issue-31103 1109 09 9 2018 13 1 2019 15 1 2019 © 2019 The Authors. Cancer Medicine 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.Abstract\nThe prognosis of diffuse large B‐cell lymphoma (DLBCL) patients depends on lymphoma‐ and patient‐related risk factors and is best estimated by the international prognostic index (IPI). The aim of the study was to determine whether the average relative dose intensity (ARDI) of an anthracycline‐containing regimen could predict DLBCL outcome independently from the IPI. We analyzed 223 white Caucasian DLBCL patients who completed at least four cycles of first‐line immunochemotherapy with rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R‐CHOP). The ARDI was calculated by specially developed software in each individual patient, simultaneously with the chemotherapy prescription, which instantly revealed all causes of its decrease. The relevance of the ARDI for progression‐free/overall survival (PFS/OS) was evaluated. Prolonged intervals between cycles of immunochemotherapy—the most common cause of decreased ARDI (49.3%, 110/223)—were due to neutropenia (absolute neutrophil count <1.0 × 109/L) and infections. Reductions in cytostatic doses were observed in 19.7% (44/223) of patients, mainly as the consequence of cardiotoxicity (23/223, 10.3%). The OS varied significantly when the ARDI was >90% (P < 0.00001). Multivariate analysis confirmed that an ARDI>90% was an IPI‐independent predictor of prolonged PFS (HR = 0.31; 95%CI: 0.20‐0.47; P < 0.00001) and OS (HR = 0.32; 95%CI: 0.21‐0.48; P < 0.00001). With an analytic tool allowing real‐time ARDI assessment, it was possible to maintain an ARDI above 90% in 161 of 223 patients (72%). DLBCL patients with an ARDI >90% have significantly better outcome regardless of the IPI; therefore, our official recommendation is an adequate dose density through efficient neutropenia prophylaxis and cardiac protection.\n\naverage relative dose intensitycardiotoxicitychemotherapydiffuse large B‐cell lymphomaneutropenia source-schema-version-number2.0component-idcam42008cover-dateMarch 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.1 mode:remove_FC converted:26.03.2019\n\n\nDługosz‐Danecka \nM \n, \nSzmit \nS \n, \nOgórka \nT \n, \nSkotnicki1 \nAB \n, \nJurczak \nW \n. The average relative dose intensity of R‐CHOP is an independent factor determining favorable overall survival in diffuse large B‐cell lymphoma patients . Cancer Med . 2019 ;8 :1103 –1109 . 10.1002/cam4.2008\n==== Body\n1 INTRODUCTION\nThe CHOP chemotherapy regimen, consisting of doxorubicin, cyclophosphamide, vincristine, and prednisone, remains the first‐line standard of care in diffuse large B‐cell lymphoma (DLBCL).1 Adding rituximab, an anti‐CD20 monoclonal antibody, was the only major modification thus far and has improved treatment efficacy.2 A correlation between the dose intensity and the therapeutic effect remains undefined.3, 4, 5, 6, 7\n\n\nDose intensity (DI) reflects the dose of the administered drug per unit of time (ie, expressed in mg/m2 per week). DI has been considered in the treatment of solid tumors, and recently, it was also considered in lymphoma therapy.8, 9 The relative dose intensity (RDI) expresses the amount of drug administered per unit of time compared to the planned amount of drug at the scheduled time. The intensity of the entire chemotherapy regimen is better defined by the average relative dose intensity (ARDI), which is a calculation of the mean values of the RDI of all drugs used in a chemotherapy cycle.\n\nThe optimal dose intensity of chemotherapy may be a specific challenge in aggressive lymphomas. Overall survival (OS) was significantly shorter when the RDI of doxorubicin and cyclophosphamide was below 80%.8 The effect of DI on the outcome of non‐Hodgkin's lymphoma patients was carefully evaluated for different chemotherapy regimens,10, 11 and the importance of an RDI of adriamycin >75% was also defined as the single most important predictor of survival in DLBCL.9 None of the mentioned trials have analyzed the effect of the ARDI in different international prognostic index (IPI) subgroups.\n\nThe aim of the current study was to determine whether the lymphoma treatment intensity expressed by the ARDI could be an IPI‐independent predictive and prognostic factor.\n\n2 METHODS\n2.1 Study cohort\nThe study group comprised 223 white, Caucasian, histopathologically confirmed treatment‐naive DLBCL patients who received immunochemotherapy including rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisone (R‐CHOP) between 2005 and 2013. The IPI prognostic index was calculated for all patients at diagnosis.12 Efficacy and survival analyses were performed separately in low‐, intermediate‐ ,and high‐risk groups (with IPI: 0‐1, 2‐3, and 4‐5, respectively). The clinical stage of lymphoma was assessed by using the Ann Arbor classification with Cotswolds revision 1988.13, 14 The characteristics and demographics of patients are summarized in Table 1.\n\nTable 1 Characteristics of patients in a study cohort: risk factor distribution and IPI analysis\n\nRisk factor\tNumber of cases n (%)\t\nAge\t\n≤60 y\t133 (59,64)\t\n>60 y\t90 (40,36)\t\nECOG performance status\t\n<2\t209 (93,72)\t\n≥2\t14 (6,28)\t\nClinical stage according to Ann Arbor scale\t\nI/II\t73 (32,74)\t\nIII/IV\t150 (67,26)\t\nNumber of extranodal sites\t\n0‐1\t99 (44,39)\t\n>1\t124 (55,61)\t\nSerum LDH activity\t\nN\t97 (43,50)\t\n>N\t126 (56,50)\t\nIPI\t\n0\t19 (8,52)\t\n1\t47 (21,08)\t\n2\t70 (31,39)\t\n3\t50 (22,42)\t\n4\t34 (15,25)\t\n5\t3 (1,35)\t\nIPI risk groups\t\nLow risk (L, IPI: 0‐1)\t66 (29,60)\t\nIntermediate risk (I, IPI: 2‐3)\t120 (53,81)\t\nHigh risk (H, IPI: 4‐5)\t37 (16,59)\t\nJohn Wiley & Sons, Ltd2.2 Oncological status, treatment, and dose intensity parameters\nThe ARDI was evaluated in a specially developed OWID® computer program (dosage intensity assessment). The ARDI was calculated for all cycles of R‐CHOP immunochemotherapy based on the body surface area (BSA) of the patient, planned and actually administered doses of drugs, and planned and actual dates of chemotherapy cycles. The DI and RDI of each intravenously administered drug were assessed. R‐CHOP immunochemotherapy was to be repeated every 21 days for six cycles. None of the cases with fewer than four cycles was included, as including these cases would not allow a reliable assessment of the treatment DI.\n\nAll patients received supportive treatment, including prevention of tumor lysis syndrome, prophylactic antibacterial, antiviral and antifungal therapy, and transfusions of red blood cells, platelets, or other blood products, as required. Primary prophylaxis of neutropenia by granulocyte colony‐stimulating factor (G‐CSF) was not applied, and secondary prophylaxis was implemented according to local standards.\n\n2.3 Response to treatment\nResponse to treatment was evaluated according to the Cheson criteria based on computed tomography (CT) and positron emission tomography (PET).15, 16 The progression‐free survival (PFS) time, which is defined as the time from the onset of R‐CHOP immunochemotherapy to lymphoma progression or death, was assessed. OS was calculated as the time from the beginning of treatment to death, regardless of the cause.\n\n2.4 Statistical analysis\nKaplan‐Meier curves were used to determine PFS and OS. Univariate and multivariate analyses of the risk of lymphoma progression or death were carried out using the Cox proportional hazards model. The results were considered statistically significant if P < 0.05. All statistical analyses were performed using STATISTICA software.\n\n3 RESULTS\nIn our group, the clinical characteristics and risk factor distribution were representative of DLBCL and comparable to those described in the literature (Table 1).17, 18 At the end of first‐line treatment, 150 (67.26%) patients achieved complete remission (CR), 62 (27.8%) partial remission (PR), 3 (1.3%) stable disease, and 7 (3.1%) progressive disease (PD). As anticipated, a high IPI (4 or 5) was associated with an increased risk of lymphoma progression and earlier death (median PFS and median OS 1.6 and 4.5 years, respectively), and patients with a low IPI (0‐1) had the best prognosis and had not reached the median PFS and OS at the median follow‐up of 6 years (Figures 1, 2). In our cohort, IPI risk factors that were most important for the prediction of progression were as follows: age over 60 years (HR = 1.73), elevated lactate dehydrogenase (LDH) activity (HR = 1.70), and extranodal location (HR = 2.14).\n\nFigure 1 \nPFS according to the IPI (Kaplan‐Meier analysis, P < 0.00001) IPI\tHigh\tIntermediate\tLow\t\nMedian PFS\t1.6 years\tNot reached\tNot reached\t\n\n\n\nFigure 2 \nOS according to IPI (Kaplan‐Meier analysis, P < 0.00001) IPI\tHigh\tIntermediate\tLow\t\nMedian OS\t4.5 years\tNot reached\tNot reached\t\n\n\n\nFurther analysis revealed that both PFS and OS depended on the ARDI of the R‐CHOP regimen. The median PFS was significantly different: 1.9 years, 4.1 years and not reached in patients with ARDI <80% (n = 29, 13%), 80%‐90% (n = 33, 14.8%), and >90% (n = 161, 72.2%), respectively (Figure 3). Surprisingly, Kaplan‐Meier curve analysis showed no significant difference in OS between patients with ARDI <80% and 80%‐90% (Figure 4), while the longest OS was observed in patients with ARDI>90%. In multivariate Cox proportional risk analysis, both a low IPI (0 or 1) and a high ARDI (>90%) during R‐CHOP immunochemotherapy were independent and favorable prognostic factors that were significant for predicting PFS and OS (Table 2).\n\nFigure 3 \nPFS according to the ARDI (Kaplan‐Meier analysis, P < 0.00001)ARDI\t<80%\t80%‐90%\t>90%\t\nMedian PFS\t1.9 years\t4.1 years\tNot reached\t\n\n\n\nFigure 4 \nOS according to the ARDI (Kaplan‐Meier analysis, P < 0.00001) ARDI\t<80%\t80%‐90%\t>90%\t\nMedian OS\t4.0 years\t4.6 years\tNot reached\t\n\n\n\nTable 2 Cox proportional risk model: ARDI >90% or low baseline IPI was correlated with favorable PFS and OS in a study cohort\n\nSurvival\tARDI >90%\tLow IPI (0 or 1)\t\nUnivariate analysis\t\nPFS\tHR = 0.28\tHR = 0.39\t\n95%CI: 0.18‐0.44\t95%CI: 0.22‐0.69\t\n\nP < 0.000001\t\nP = 0.001\t\nOS\tHR = 0.30\tHR = 0.43\t\n95%CI: 0.20‐0.46\t95%CI: 0.24‐0.77\t\n\nP < 0.000001\t\nP = 0.004\t\nMultivariate analysis\t\nPFS\tHR = 0.31\tHR = 0.43\t\n95%CI: 0.20‐0.47\t95%CI: 0.24‐0.76\t\n\nP < 0.000001\t\nP = 0.004\t\nOS\tHR = 0.32\tHR = 0.48\t\n95%CI: 0.21‐0.48\t95%CI: 0.27‐0.85\t\n\nP < 0.000001\t\nP = 0.01\t\nHR, Hazard Ratio; CI, Confidence Interval.\n\nJohn Wiley & Sons, LtdThe most frequent cause of a decreased ARDI is an extended time interval between R‐CHOP therapy cycles (110 of 223 patients, 49.3%), due to neutropenia and infections. Although an extended time between cycles did not exceed 7 days in the majority of cases (59 of 223, 26.5%), it was responsible for an over 10% decrease in the ARDI in 43 of 223 patients (19.28%).\n\nIn a cohort with an ARDI<80%, an even greater prolongation of the time intervals between cycles was observed: < 1 week in two patients (0.89%), 1‐3 weeks in five patients (2.2%), and above 3 weeks in 17 patients (7.6%). In an intermediate subgroup with an ARDI in the range of 80%‐90%, the interval time was extended to 1 week in 11 patients (4.9%), by almost 1‐3 weeks in nine patients (4%), and above 3 weeks in six patients (2.7%) patients.\n\nThe doses of anticancer drugs were reduced in 44 of 223 patients (19.7%); seven patients (3.1%) had reduced doses of ≥ 2 cytostatics (Table 3). The reduction in rituximab doses (18 patients, 8.1%) was mostly related to ampule dispensing and economic issues and not connected to adverse events; for this reason we did not consider this factor in the analysis of the causes of drug reduction. The most commonly reduced drug was doxorubicin (27 patients, 12.1%), mainly as a consequence of cardiotoxicity (23 patients, 10.3%). The doses of vincristine (in four patients; 1.8%) or cyclophosphamide (in two patients; 0.9%) were reduced due to neutropenia. For the same reason, all components of R‐CHOP were reduced in four patients (1.8%).\n\nTable 3 Cytostatic dose reductions in a study cohort\n\n\tTotal number of patients n (%)\tARDI <80 n (%)\tARDI 80‐90 n (%)\tARDI >90 n (%)\t\nADM\t27 (12.11)\t20 (8.97)\t6 (2.70)\t1 (0.45)\t\nCTX\t2 (0.89)\t2 (0.89)\t0 (0.00)\t0 (0.00)\t\nVCR\t4 (1.79)\t2 (0.89)\t1 (0.45)\t1 (0.45)\t\nRituximab\t18 (8.07)\t15 (6.73)\t2 (0.9)\t1 (0.45)\t\nJohn Wiley & Sons, LtdThe causes of death in subgroups depending on the ARDI and IPI are presented in Table 4. The analysis identified 85 deaths (38.1%), 58 cases related to lymphoma progression, 20 cases of cardiovascular complications, and seven cases of death from other causes: multiorgan failure, secondary cancers, or infections.\n\nTable 4 Cause of death in subgroups of the study cohort stratified by the ARDI or baseline IPI\n\n\tDeaths (all) n = 85\tLymphoma‐related n = 58\tCardiovascular n = 20\tOther causes n = 7\t\nIPI\t\nHigh\t37 pts\t26\t22\t2\t2\t\nIntermediate\t120 pts\t45\t28\t14\t3\t\nLow\t66 pts\t14\t8\t4\t2\t\nARDI\t\n>90%\t161 pts\t43\t29\t12\t2\t\n80%‐90%\t33 pts\t21\t14\t5\t2\t\n<80%\t29 pts\t21\t15\t3\t3\t\nJohn Wiley & Sons, Ltd4 DISCUSSION\nIn lymphoma patients, the IPI (Table 1) remains clinically important19; however there have been many attempts to establish the potential prognostic role of chemotherapy DI and efficacy (8,9 10, 11). In DLBCL patients treated with R‐CHOP therapy, decreasing anthracycline RDI to <0.8 (80%) resulted in a significant decrease in complete responses (CR ‐ 52% vs 23%) and 5‐year OS (81% vs 54%).8 The 80% RDI threshold was also used in the study assessing DI in patients with breast cancer.5, 6 Several retrospective studies have shown that maintenance of the RDI of R‐CHOP can improve outcomes of patients with DLBCL, recognizing the RDI as an independent predictor of response and survival.20, 21 In another study, 157 DLBCL patients were prospectively evaluated, and R‐CHOP21 and R‐CHOP14 were shown to be equivalent regimens in terms of response and survival, but only if RDI reductions are avoided using clinical and support measures.22 Despite clear data, the dosage of cytostatics is often reduced, especially in older patients, to avoid treatment‐related side effects that would interrupt further therapy. However, the results of the retrospective study showed that older patients aged 70‐80 years who were treated with full treatment doses had better prognoses than patients with treatment attenuation; not all elderly patients are sufficiently healthy to tolerate the full‐dose treatment.23 The analysis of 479 de novo DLBCL patients aged 70‐79 years who were treated with R‐CHOP demonstrated that maintenance of the RDI was associated with improved outcome of elderly patients with DLBCL, suggesting that maintaining an RDI with adequate dose reduction is more important than uniformly administering a full dose of R‐CHOP to elderly patients.24\n\n\nThe role of G‐CSF in preventing neutropenia and infections was investigated in non‐Hodgkin's lymphoma patients (with the WHO classification, most of the participating patients would be currently classified as DLBCL).25 Neutropenia occurred in 37% of the G‐CSF‐treated patients and 85% of the controls, which indicates that the relative risk for control patients was 2.31 (P = 0.00001). A significantly greater DI was achieved in patients receiving G‐CSF without any additional drug toxicities. However, none of those observations led to the determination of the optimal ARDI level.\n\nThe aim of the current study was to determine whether the treatment intensity could be a prognostic factor independent from the IPI. In the multivariate analysis, we demonstrated that both a low IPI and an ARDI >90% may have independent positive predictive value for PFS and, consequently, OS. It has been shown that the probability of lymphoma relapse increases significantly with the decrease in the intensity of chemotherapy: the risk was highest when the ARDI was decreased to <80%, and the ARDI range of 80%‐90% was also unsatisfactory, especially for the prognosis of overall mortality. Previously, studies assessed the ARDI after treatment. In the Jagiellonian University Department of Haematology, the OWID® computer program specially designed for dosage intensity assessment was introduced in 2007. This program allows us to check the average DI of the treatment during therapy, therefore helping us make optimal clinical decisions in real time.\n\nAs the extension of time intervals between R‐CHOP therapy cycles was the most common cause of a decreased ARDI (observed in 49% of patients). Improvement in the ARDI can be achieved by using G‐CSF in primary prophylaxis of neutropenia, in the prevention of infections and to better organize the ward routine to eliminate admission delays. The second most important problem is cardiotoxicity, which is the main reason for doxorubicin dose reduction and cardiac mortality. Our data (Table 4) confirmed the observations of a Polish Lymphoma Research Group (PLRG), showing that cardiac mortality is the second most common cause of death in lymphoma patients treated with R‐CHOP after the disease progression26 and that ensuring a good prognosis for patients with cardiovascular disorders is a special clinical challenge.27 Therapeutic strategies incorporating primary cardioprotection and close monitoring of cardiopulmonary capacity seem to be necessary. A number of potential cardioprotective therapies have been explored, and the most promising results were observed with the use of modified liposomal anthracycline,28 renin‐angiotensin system antagonists, and beta‐blockers 29, 30, 31; however, several combined cardioprotective measures may be more effective.32, 33\n\n\nIn most cases, a reduction in the rituximab dose results from rounding the amount administered to a full 100 mg, due to the size of the vials available and the relatively high cost of monoclonal antibodies. At present, due to the introduction of a central cytostatic dissolution laboratory in a hospital pharmacy, all doses are individually tailored. The need for dose reductions due to adverse reactions to rituximab was very rare, as prolonging infusion time and premedication with antihistamine drugs were adequate in most cases.\n\nIn conclusion, keeping the ARDI above 90% significantly increases OS in DLBCL patients receiving R‐CHOP therapy. It is therefore advisable to monitor the ARDI in all patients during therapy to allow the early introduction of primary neutropenia prophylaxis. The use of G‐CSF is widely accepted, but primary neutropenia prophylaxis should be further encouraged. Primary cardioprotection methods are not yet regarded as a standard of care. Implementing optimal cardioprotective strategies is particularly necessary in patients at increased risk of anthracycline cardiotoxicity, as the efficacy of R‐CHOP may be improved (by allowing a high ARDI) and the risk of cardiac mortality may be decreased.\n==== Refs\nREFERENCES\n1 \n\nChaganti \nS \n, \nIllidge \nT \n, \nBarrington \nS \n, et al. British Committee for Standards in Haematology. Guidelines for the management of diffuse large B‐cell lymphoma . Br J Haematol . 2016 ;174 (1 ):43 ‐56 .27196701 \n2 \n\nCoiffier \nB \n, \nLepage \nE \n, \nBriere \nJ \n, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large‐B‐cell lymphoma . N Engl J Med . 2002 ;346 (4 ):235 ‐242 .11807147 \n3 \n\nEpelbaum \nR \n, \nFaraggi \nD \n, \nBen‐Arie \nY \n, et al. Survival of diffuse large cell lymphoma. A multivariate analysis including dose intensity variables . Cancer . 1990 ;66 (6 ):1124 ‐1129 .2205353 \n4 \n\nHryniuk \nWM \n. Average relative dose intensity and the impact on design of clinical trials . Semin Oncol . 1987 ;14 (1 ):65 ‐74 .3823917 \n5 \n\nTattersall \nMH \n, \nTobias \nJS \n. How strong is the case for intensive cancer chemotherapy? \nLancet . 1976 ;2 (7994 ):1071 ‐1072 .62911 \n6 \n\nFrei \nE \n3rd\n, \nCanellos \nGP \n. Dose: a critical factor in cancer chemotherapy . Am J Med . 1980 ;69 (4 ):585 ‐594 .6999898 \n7 \n\nColdman \nAJ \n, \nGoldie \nJH \n. Impact of dose‐intense chemotherapy on the development of permanent drug resistance . Semin Oncol . 1987 ;14 (4 Suppl 4 ):29 ‐33 .\n8 \n\nEpelbaum \nR \n, \nHaim \nN \n, \nBen‐Shahar \nM \n, \nRon \nY \n, \nCohen \nY \n. Dose‐intensity analysis for CHOP chemotherapy in diffuse aggressive large cell lymphoma . Isr J Med Sci . 1988 ;24 (9–10 ):533 ‐538 .3060443 \n9 \n\nKwak \nLW \n, \nHalpern \nJ \n, \nOlshen \nRA \n, \nHorning \nSJ \n. Prognostic significance of actual dose intensity in diffuse large‐cell lymphoma: results of a tree‐structured survival analysis . J Clin Oncol . 1990 ;8 (6 ):963 ‐977 .2348230 \n10 \n\nMeyer \nRM \n, \nHryniuk \nWM \n, \nGoodyear \nMD \n. The role of dose intensity in determining outcome in intermediate‐grade non‐Hodgkin's lymphoma . J Clin Oncol . 1991 ;9 (2 ):339 ‐347 .1824863 \n11 \n\nFisher \nRI \n, \nGaynor \nER \n, \nDahlberg \nS \n, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non‐Hodgkin's lymphoma . N Engl J Med . 1993 ;328 (14 ):1002 ‐1006 .7680764 \n12 \n\nZiepert \nM \n, \nHasenclever \nD \n, \nKuhnt \nE \n, et al. Standard International prognostic index remains a valid predictor of outcome for patients with aggressive CD20 + B‐cell lymphoma in the rituximab era . J Clin Oncol . 2010 ;28 (14 ):2373 ‐2380 .20385988 \n13 \n\nCarbone \nPP \n, \nKaplan \nHS \n, \nMusshoff \nK \n, \nSmithers \nDW \n, \nTubiana \nM \n. Report of the Committee on Hodgkin's Disease Staging Classification . Cancer Res . 1971 ;31 (11 ):1860 ‐1861 .5121694 \n14 \n\nOlweny \nCL \n. Cotswolds modification of the Ann Arbor staging system for Hodgkin's disease . J Clin Oncol . 1990 ;8 (9 ):1598 .\n15 \n\nCheson \nBD \n, \nPfistner \nB \n, \nJuweid \nME \n, et al. Revised response criteria for malignant lymphoma . J Clin Oncol . 2007 ;25 (5 ):579 ‐586 .17242396 \n16 \n\nJuweid \nME \n, \nStroobants \nS \n, \nHoekstra \nOS \n, et al. Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma . J Clin Oncol . 2007 ;25 (5 ):571 ‐578 .17242397 \n17 \n\nPfreundschuh \nM \n, \nKuhnt \nE \n, \nTrumper \nL \n, et al. CHOP‐like chemotherapy with or without rituximab in young patients with good‐prognosis diffuse large‐B‐cell lymphoma: 6‐year results of an open‐label randomised study of the MabThera International Trial (MInT) Group . Lancet Oncol . 2011 ;12 (11 ):1013 ‐1022 .21940214 \n18 \n\nJurczak \nW \n, \nOchrem \nB \n, \nGiza \nA \n, et al. Role of rituximab in the first‐line therapy of high‐risk diffuse large B‐cell lymphoma: a retrospective analysis by the Polish Lymphoma Research Group . Pol Arch Med Wewn . 2015 ;125 (10 ):741 ‐748 .26334344 \n19 \nInternational Non‐Hodgkin's Lymphoma Prognostic Factors Project \n. A predictive model for aggressive non‐Hodgkin's lymphoma . N Engl J Med . 1993 ;329 (14 ):987 ‐994 .8141877 \n20 \n\nTerada \nY \n, \nNakamae \nH \n, \nAimoto \nR \n, et al. Impact of relative dose intensity (RDI) in CHOP combined with rituximab (R‐CHOP) on survival in diffuse large B‐cell lymphoma . J Exp Clin Cancer Res . 2009 ;28 :116 .19689822 \n21 \n\nHirakawa \nT \n, \nYamaguchi \nH \n, \nYokose \nN \n, \nGomi \nS \n, \nInokuchi \nK \n, \nDan \nK \n. Importance of maintaining the relative dose intensity of CHOP‐like regimens combined with rituximab in patients with diffuse large B‐cell lymphoma . Ann Hematol . 2010 ;89 (9 ):897 ‐904 .20414658 \n22 \n\nGutierrez \nA \n, \nBento \nL \n, \nBautista‐Gili \nAM \n, et al. Differential impact of relative dose‐intensity reductions in diffuse large B‐Cell lymphoma treated with R‐CHOP21 or R‐CHOP14 . PLoS ONE . 2015 ;10 (4 ):e0123978 .25909361 \n23 \n\nEyre \nTA \n, \nSalisbury \nR \n, \nEyre \nDW \n, \nWatson \nC \n, \nCollins \nGP \n, \nHatton \nCS \n. Results of a large retrospective analysis of the effect of intended dose intensity of R‐CHOP on outcome in a cohort of consecutive, unselected elderly patients with de novo diffuse large B cell lymphoma . Br J Haematol . 2016 ;173 (3 ):487 ‐491 .26223361 \n24 \n\nKanemasa \nY \n, \nShimoyama \nT \n, \nSasaki \nY \n, et al. The impacts of initial and relative dose intensity of R‐CHOP on outcomes of elderly patients with diffuse large B‐cell lymphoma . Leuk Lymphoma . 2017 ;58 (3 ):736 ‐739 .27686739 \n25 \n\nPettengell \nR \n, \nGurney \nH \n, \nRadford \nJA \n, et al. Granulocyte colony‐stimulating factor to prevent dose‐limiting neutropenia in non‐Hodgkin's lymphoma: a randomized controlled trial . Blood . 1992 ;80 (6 ):1430 ‐1436 .1381626 \n26 \n\nJurczak \nW \n, \nSzmit \nS \n, \nSobocinski \nM \n, et al. Premature cardiovascular mortality in lymphoma patients treated with (R)‐CHOP regimen ‐ a national multicenter study . Int J Cardiol . 2013 ;168 (6 ):5212 ‐5217 .23998543 \n27 \n\nSzmit \nS \n, \nJurczak \nW \n, \nZaucha \nJM \n, et al. Acute decompensated heart failure as a reason of premature chemotherapy discontinuation may be independent of a lifetime doxorubicin dose in lymphoma patients with cardiovascular disorders . Int J Cardiol . 2017 ;235 :147 ‐153 .28268088 \n28 \n\nSmith \nLA \n, \nCornelius \nVR \n, \nPlummer \nCJ \n, et al. Cardiotoxicity of anthracycline agents for the treatment of cancer: systematic review and meta‐analysis of randomised controlled trials . BMC Cancer . 2010 ;10 :337 .20587042 \n29 \n\nBosch \nX \n, \nRovira \nM \n, \nSitges \nM \n, et al. Enalapril and carvedilol for preventing chemotherapy‐induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmopathies) . J Am Coll Cardiol . 2013 ;61 (23 ):2355 ‐2362 .23583763 \n30 \n\nCardinale \nD \n, \nColombo \nA \n, \nLamantia \nG \n, et al. Anthracycline‐induced cardiomyopathy: clinical relevance and response to pharmacologic therapy . J Am Coll Cardiol . 2010 ;55 (3 ):213 ‐220 .20117401 \n31 \n\nCardinale \nD \n, \nColombo \nA \n, \nBacchiani \nG \n, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy . Circulation . 2015 ;131 (22 ):1981 ‐1988 .25948538 \n32 \n\nZamorano \nJL \n, \nLancellotti \nP \n, \nMunoz \nDR \n, et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines . Eur Hear J . 2016 ;37 (36 ):2768 ‐2801 .\n33 \n\nArmenian \nSH \n, \nLacchetti \nC \n, \nBarac \nA \n, et al. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline . J Clin Oncol . 2017 ;35 (8 ):893 ‐911 .27918725\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "8(3)",
"journal": "Cancer medicine",
"keywords": "average relative dose intensity; cardiotoxicity; chemotherapy; diffuse large B-cell lymphoma; neutropenia",
"medline_ta": "Cancer Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011241:Prednisone; D011379:Prognosis; D016016:Proportional Hazards Models; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "1103-1109",
"pmc": null,
"pmid": "30740919",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": "25948538;1824863;23583763;23998543;27567406;26223361;2264856;2205353;3823917;19689822;62911;3686044;30740919;20117401;1381626;26334344;27918725;3060443;11807147;6999898;17242396;27686739;25909361;21940214;27196701;7680764;28268088;2348230;20587042;5121694;17242397;8141877;20385988;20414658",
"title": "The average relative dose intensity of R-CHOP is an independent factor determining favorable overall survival in diffuse large B-cell lymphoma patients.",
"title_normalized": "the average relative dose intensity of r chop is an independent factor determining favorable overall survival in diffuse large b cell lymphoma patients"
} | [
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"companynumb": "PL-PFIZER INC-2019168023",
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"abstract": "BACKGROUND\nAspirin overdose causes acid-base disturbances and organ dysfunction. Management is guided by research reported over 50 years ago when chronic aspirin toxicity was common and accounted for significant morbidity. We investigate our experience of aspirin overdose and the effectiveness of charcoal and bicarbonate administration over 20 years.\n\n\nMETHODS\nThis is a retrospective series of acute aspirin overdose from two toxicology units from January 2000 to September 2019. Acute aspirin ingestions > 3000 mg were identified in each unit's database. Excluded were cases of chronic exposure, hospital presentation > 24 hours after ingestion, and cases without a salicylate concentration. Included in our analysis was demographic data, clinical effects, investigations, complications, and treatment.\n\n\nRESULTS\nThere were 132 presentations in 108 patients (79 females (73%)). The median age was 28 years (range: 13-93 years). The median dose ingested was 7750 mg (IQR: 6000-14,400 mg). There were 44 aspirin-only ingestions. Mild toxicity (nausea, vomiting, tinnitus or hyperventilation) occurred in 22 with a median dose of 160 mg/kg. Moderate toxicity (acid-base disturbance, confusion) occurred in 16 with a median ingested dose of 297 mg/kg. There were no cases of severe toxicity (coma or seizures) due to aspirin alone. The median peak salicylate concentration was 276 mg/L (IQR: 175-400 mg/L, range: 14-814 mg/L). There was a moderate association between dose ingested and peak concentration (Pearson r = 0.58; 95% CI 0.45-0.68). Activated charcoal was administered in 36 (27%) cases, which decreased the median peak salicylate concentration (34.2 to 24.8 mg/L/g (difference: 9.4, 95% CI: 1.0-13.1)). Bicarbonate was administered in 34 (26%) presentations, decreasing the median apparent elimination half-life from 13.4 to 9.3 h (difference: 4.2 h, 95% CI: 1.0-6.5 h).\n\n\nCONCLUSIONS\nAcute aspirin overdose caused only mild to moderate effects in this series. Early administration of activated charcoal decreased absorption and use of bicarbonate enhanced elimination.",
"affiliations": "Clinical Toxicology Unit, Princess Alexandra Hospital, Brisbane, QLD, Australia. katherine.isoardi@health.qld.gov.au.;Faculty of Medicine, University of Queensland, Brisbane, QLD, Australia.;Clinical Toxicology Unit, Princess Alexandra Hospital, Brisbane, QLD, Australia.;Clinical Toxicology Research Group, University of Newcastle, Newcastle, NSW, Australia.",
"authors": "Isoardi|K Z|KZ|;Henry|C|C|;Harris|K|K|;Isbister|G K|GK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-021-00865-0",
"fulltext": null,
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"issn_linking": "1556-9039",
"issue": null,
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "Activated charcoal; Aspirin; Bicarbonate; Overdose; Poisoning; Salicylate",
"medline_ta": "J Med Toxicol",
"mesh_terms": null,
"nlm_unique_id": "101284598",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34845647",
"pubdate": "2021-11-29",
"publication_types": "D016428:Journal Article",
"references": "7834163",
"title": "Activated Charcoal and Bicarbonate for Aspirin Toxicity: a Retrospective Series.",
"title_normalized": "activated charcoal and bicarbonate for aspirin toxicity a retrospective series"
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"companynumb": "AU-MYLANLABS-2022M1015510",
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"actiondrug": "6",
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"activesubstancename": "ASPIRIN"
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{
"abstract": "A 44-year-oldwoman was diagnosedwith right breast cancer andund erwent mastectomy andaxillary lymph node dissection in February 2006. She was pathologically diagnosed with invasive ductal carcinoma without lymph node metastasis. Immunohistochemical examination showedthat the tumor was estrogen receptor positive, progesterone receptor negative, andhada HER2 status score of 0. She received 4 cycles of AC, followedby leuprorelin andtamoxifen. Several metastases were identified in the right supraclavicular lymph nodes in August 2008 during the endocrine therapy. Then, she received S-1 as the first-line chemotherapy. Although metastases showed complete response, she developed an eye disorder caused by S-1 and thus the treatment agent was changedto leuprorelin andanastrozole. She complainedof headache andright homonymous hemianopsia in November 2013. MRI showeda 42mm diameter tumor in the left occipital lobe, suspectedto be brain metastasis from breast cancer. Craniotomy was performedto remove the brain tumor, which was pathologically diagnosedas metastasis from breast cancer. In the brain tumor, the estrogen receptor status hadchangedto negative, but the HER2 status remained unchanged, showing a score of 0. Vinorelbine was administered after the brain surgery. Unfortunately, brain metastasis was foundin the dura mater near the surgical cavity, andgamma knife radiosurgery was performedin January 2014. Thereafter, brain metastases were repeatedly found, and gamma knife radiosurgery was again performed in January 2015, September 2016, and February 2017. In addition, a large tumor appearedin the left occipital lobe andwas surgically removed in June 2016. No other distant metastases were found, andvinorelbine was continueduntil February 2018. Because the patient developed dyslexia caused by gamma knife-induced radiation necrosis, bevacizumab was administered between November 2018 and April 2019. MRI showed that the edema due to radiation necrosis reduced and dyslexia symptoms improved. As of now, she has survivedfor 5 years and 6 months after the diagnosis of brain metastases.",
"affiliations": "Dept. of Surgery, Kansai Rosai Hospital.",
"authors": "Egawa|Chiyomi|C|;Yanai|Ayako|A|;Yanagawa|Takehiro|T|;Takatsuka|Yuichi|Y|;Takeno|Atsushi|A|;Masuzawa|Toru|T|;Hata|Taishi|T|;Kagawa|Yoshinori|Y|;Ohmura|Yoshiaki|Y|;Katsura|Yoshiteru|Y|;Murakami|Kohei|K|;Sakamoto|Takuya|T|;Kawai|Kenji|K|;Takeda|Yutaka|Y|;Murata|Kohei|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D001932:Brain Neoplasms; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008207:Lymphatic Metastasis; D008408:Mastectomy; D016634:Radiosurgery",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2063-2065",
"pmc": null,
"pmid": "32157060",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Long-Term Survival in a Case of Breast Cancer with Brain Metastases and No Other Distant Metastases Treated by Surgical Removal and Gamma Knife Radiosurgery.",
"title_normalized": "long term survival in a case of breast cancer with brain metastases and no other distant metastases treated by surgical removal and gamma knife radiosurgery"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-249117",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ANASTROZOLE"
},
"dru... |
{
"abstract": "Cerebral venous sinus thrombosis may present with transient aphasia and focal seizure-likeactivity mimicking a TIA or stroke. In this case, the patient's presentation was further complicated by non-diagnostic CT findings, which can be common in up to 27% of cases [1]. An 86-year-old right-handed male with a history of colon adenocarcinoma status post resection and recent surgery for right sphenoid wing meningioma presented to the ED with transient episodes of fluent aphasia lasting approximately 10 minutes and one episode of involuntary right-hand clenching, both of which resolved spontaneously and were concerning for possible TIA. Non-contrast head CT, CTA head and neck, and CT perfusion studies showed non-opacification of the left transverse and sigmoid sinuses, but no perfusion defects. Subsequent MRI brain with gadolinium revealed a new left transverse sinus thrombus. EEG was without epileptiform features. For the 13-day remainder of his hospitalization the patient received low molecular weight heparin for anticoagulation, and he experienced no recurrence of his symptoms. He was discharged on apixiban and levetiracetam to follow-up for possible tumor recurrence. Cerebral venous sinus thrombosis can present with stroke-like symptoms, and CT perfusion studies can be normal. CT venography, MRI with gadolinium, and MR venography are sensitive imaging modalities for diagnosing dural sinus thrombosis and should be considered, especially for patients with hypercoagulable risk factors, MR venography being the most sensitive, preferred modality [2]. Additionally, it is important to recall the laterality of focal symptoms, as a history of cerebrovascular disease can be a confounding factor in diagnosis.",
"affiliations": "Department of Internal Medicine, Reading Hospital and Medical Center, Reading, PA, USA.;Department of Internal Medicine, Reading Hospital and Medical Center, Reading, PA, USA.;Department of Internal Medicine, Reading Hospital and Medical Center, Reading, PA, USA.",
"authors": "Engelmann|Alexander|A|;DiPastina|Katherine|K|;Liu|Tianyu|T|https://orcid.org/0000-0002-2590-6082",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/20009666.2020.1852704",
"fulltext": "\n==== Front\nJ Community Hosp Intern Med Perspect\nJ Community Hosp Intern Med Perspect\nJournal of Community Hospital Internal Medicine Perspectives\n2000-9666\nTaylor & Francis\n\n10.1080/20009666.2020.1852704\n1852704\nVersion of Record\nCase Report\nCase Report\nThe ugly duckling of aphasia: cerebral venous sinus thrombosis as a mimic of TIA and stroke\nA. ENGELMANN ET AL.\nJOURNAL OF COMMUNITY HOSPITAL INTERNAL MEDICINE PERSPECTIVES\nEngelmann Alexander\nDiPastina Katherine\nhttps://orcid.org/0000-0002-2590-6082\nLiu Tianyu\nDepartment of Internal Medicine, Reading Hospital and Medical Center , Reading, PA, USA\nCONTACT Alexander Engelmann alex.engelmann30@gmail.comReading Hospital and Medical Center , Reading, PA\n26 1 2021\n2021\n11 1 156157\n© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group on behalf of Greater Baltimore Medical Center.\n2020\nThe Author(s)\nhttp://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nABSTRACT\n\nCerebral venous sinus thrombosis may present with transient aphasia and focal seizure-likeactivity mimicking a TIA or stroke. In this case, the patient's presentation was further complicated by non-diagnostic CT findings, which can be common in up to 27% of cases [1].\n\nAn 86-year-old right-handed male with a history of colon adenocarcinoma status post resection and recent surgery for right sphenoid wing meningioma presented to the ED with transient episodes of fluent aphasia lasting approximately 10 minutes and one episode of involuntary right-hand clenching, both of which resolved spontaneously and were concerning for possible TIA. Non-contrast head CT, CTA head and neck, and CT perfusion studies showed non-opacification of the left transverse and sigmoid sinuses, but no perfusion defects. Subsequent MRI brain with gadolinium revealed a new left transverse sinus thrombus. EEG was without epileptiform features. For the 13-day remainder of his hospitalization the patient received low molecular weight heparin for anticoagulation, and he experienced no recurrence of his symptoms. He was discharged on apixiban and levetiracetam to follow-up for possible tumor recurrence.\n\nCerebral venous sinus thrombosis can present with stroke-like symptoms, and CT perfusion studies can be normal. CT venography, MRI with gadolinium, and MR venography are sensitive imaging modalities for diagnosing dural sinus thrombosis and should be considered, especially for patients with hypercoagulable risk factors, MR venography being the most sensitive, preferred modality [2]. Additionally, it is important to recall the laterality of focal symptoms, as a history of cerebrovascular disease can be a confounding factor in diagnosis.\n\nKEYWORDS\n\nCerebral venous sinus thrombosis\ndural venous sinus thrombosis\nstroke\nTIA\nstroke-mimic\nTIA-mimic\nseizure\n==== Body\nCerebral venous sinus thrombosis may present with transient aphasia and focal seizure-like activity mimicking a TIA or stroke. In this case, the patient’s presentation was further complicated by non-diagnostic CT findings, which can be common in up to 27% of cases [1].\n\nAn 86-year-old right-handed male with a history of colon adenocarcinoma status post resection and recent surgery for right sphenoid wing meningioma presented to the ED with transient episodes of fluent aphasia lasting approximately 10 minutes and one episode of involuntary right-hand clenching, both of which resolved spontaneously and were concerning for possible TIA. Non-contrast head CT, CTA head and neck, and CT perfusion studies showed non-opacification of the left transverse and sigmoid sinuses, but no perfusion defects. Subsequent MRI brain with gadolinium revealed a new left transverse sinus thrombus. EEG was without epileptiform features. For the 13-day remainder of his hospitalization the patient received low molecular weight heparin for anticoagulation, and he experienced no recurrence of his symptoms. He was discharged on apixiban and levetiracetam to follow-up for possible tumor recurrence.\n\nCerebral venous sinus thrombosis can present with stroke-like symptoms, and CT perfusion studies can be normal. CT venography, MRI with gadolinium, and MR venography are sensitive imaging modalities for diagnosing dural sinus thrombosis and should be considered, especially for patients with hypercoagulable risk factors, MR venography being the most sensitive, preferred modality [2]. Additionally, it is important to recall the laterality of focal symptoms, as a history of cerebrovascular disease can be a confounding factor in diagnosis.\n\nDisclosure statement\n\nNo authors involved in the production of this manuscript have any commercial associations that might create or pose a conflict of interest with information presented herein. Such associations include consultancies, stock ownership, or other equity interests, patent licensing arrangements, and payments for conducting or publicizing a study described in the manuscript.\n==== Refs\nReferences\n\n[1] Dmytriw AA, Song JSA, Yu E, et al Cerebral venous thrombosis: state of the art diagnosis and management. Neuroradiology. 2018;60 (7 ):669–685.29752489\n[2] Saposnik G, Barinagarrementeria F, Brown RD, et al On behalf of the American heart association stroke council and the council on epidemiology and prevention diagnosis and management of cerebral venous thrombosis: a statement for healthcare professionals from the American heart association/American stroke association. Stroke. 2011;42 :1158–1192.21293023\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2000-9666",
"issue": "11(1)",
"journal": "Journal of community hospital internal medicine perspectives",
"keywords": "Cerebral venous sinus thrombosis; TIA; TIA-mimic; dural venous sinus thrombosis; seizure; stroke; stroke-mimic",
"medline_ta": "J Community Hosp Intern Med Perspect",
"mesh_terms": null,
"nlm_unique_id": "101601396",
"other_id": null,
"pages": "156-157",
"pmc": null,
"pmid": "33552442",
"pubdate": "2021-01-26",
"publication_types": "D002363:Case Reports",
"references": "21293023;29752489",
"title": "The ugly duckling of aphasia: cerebral venous sinus thrombosis as a mimic of TIA and stroke.",
"title_normalized": "the ugly duckling of aphasia cerebral venous sinus thrombosis as a mimic of tia and stroke"
} | [
{
"companynumb": "US-UCBSA-2021009847",
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"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
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"drugadditional": "4",
... |
{
"abstract": "A neonate born at 25 + 1/7 weeks developed ventilator-associated pneumonia at 29 + 3/7 weeks post-menstrual age with Escherichia coli that was originally sensitive to gentamicin. After 3 days of treatment with gentamicin, the minimum inhibitory concentration (MIC) changed from less than 1 mg/L to more than 16 mg/L. It appears that suboptimal gentamicin dosing led to the development of gentamicin resistance. As the patient was not improving clinically, the antibiotics were changed once the gentamicin resistance was identified. To minimize resistance and treatment failure, clinicians should consider the patient-specific pharmacokinetic parameters, achieved peak level, and the amount of time the gentamicin level will remain below the MIC of the organism being treated.",
"affiliations": "Neonatal and Pediatric Pharmacy, Surrey Memorial Hospital, Surrey, British Columbia, Canada.",
"authors": "Newby|Brandi D|BD|https://orcid.org/0000-0002-5123-5841",
"chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190020940124",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "34(6)",
"journal": "Journal of pharmacy practice",
"keywords": "drug resistance; gentamicin; infant; newborn",
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000900:Anti-Bacterial Agents; D004926:Escherichia coli; D005839:Gentamicins; D006801:Humans; D007231:Infant, Newborn; D008826:Microbial Sensitivity Tests; D053717:Pneumonia, Ventilator-Associated",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "975-979",
"pmc": null,
"pmid": "32648511",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Development of Gentamicin Resistance During Treatment of Escherichia coli Ventilator-Associated Pneumonia in a Neonate.",
"title_normalized": "development of gentamicin resistance during treatment of escherichia coli ventilator associated pneumonia in a neonate"
} | [
{
"companynumb": "CA-LUPIN PHARMACEUTICALS INC.-2022-00919",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
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"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BETAMETHASONE"
},
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{
"abstract": "Warfarin is an oral anticoagulant used extensively in clinical practice; However, its side-effect of causing renal damage has been recently detected. The mechanism leading to renal damage is glomerular hemorrhage and red blood cell tubular casts prothrombin time. Recently, it was found that warfarin causes renal damage in patients with chronic kidney disease and is also associated with progression of renal disease. Warfarin causing acute kidney injury in patients with normal renal function is a rare manifestation. It is important to be aware of this condition as its innocuous presence can lead to chronic kidney disease if not corrected in time. Further studies have also found that novel oral anticoagulants such as dabigatran also cause a similar syndrome and hence a new term called anticoagulant-related nephropathy is now in vogue.",
"affiliations": "Department of Medicine, Armed Forces Medical College and Command Hospital, Pune, Maharashtra, India.;Department of Pathology and Laboratory Science and Armed Forces Medical College and Command Hospital, Pune, Maharashtra, India.;Department of Medicine, Armed Forces Medical College and Command Hospital, Pune, Maharashtra, India.;Department of Medicine, Armed Forces Medical College and Command Hospital, Pune, Maharashtra, India.",
"authors": "Mendonca|S|S|;Gupta|D|D|;Valsan|A|A|;Tewari|R|R|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0971-4065.177142",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-27-7810.4103/0971-4065.177142Case ReportWarfarin related acute kidney injury: A case report Mendonca S. Gupta D. 1Valsan A. Tewari R. Department of Medicine, Armed Forces Medical College and Command Hospital, Pune, Maharashtra, India1 Department of Pathology and Laboratory Science and Armed Forces Medical College and Command Hospital, Pune, Maharashtra, IndiaAddress for correspondence: Dr. S. Mendonca, Armed Forces Medical College and Command Hospital, Pune - 411 040, Maharashtra, India. E-mail: drsatishmendonca@gmail.comJan-Feb 2017 27 1 78 80 Copyright: © 2017 Indian Journal of Nephrology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Warfarin is an oral anticoagulant used extensively in clinical practice; However, its side-effect of causing renal damage has been recently detected. The mechanism leading to renal damage is glomerular hemorrhage and red blood cell tubular casts prothrombin time. Recently, it was found that warfarin causes renal damage in patients with chronic kidney disease and is also associated with progression of renal disease. Warfarin causing acute kidney injury in patients with normal renal function is a rare manifestation. It is important to be aware of this condition as its innocuous presence can lead to chronic kidney disease if not corrected in time. Further studies have also found that novel oral anticoagulants such as dabigatran also cause a similar syndrome and hence a new term called anticoagulant-related nephropathy is now in vogue.\n\nAcute kidney injuryanticoagulant-related nephropathywarfarinwarfarin-related nephropathy\n==== Body\nIntroduction\nWarfarin is an oral vitamin K antagonist, which inhibits γ-carboxylation of clotting factors II, VII, IX, and X. It is one of the most widely used drugs for treating and preventing thromboembolism. Although very cheap and effective, warfarin use is potentially complicated by bleeding manifestations and over-anticoagulation. Warfarin is mainly metabolized by CYP-2CP microsomal liver enzymes, which is affected by a multitude of different environmental factors, diet, drug interactions, and genetics, especially CYP2 complex mutations which can alter the pharmacokinetics and pharmacodynamics of warfarin metabolism leading to toxicity and prolonged international normalized ratio (INR).[1] The prothrombin time, standardized as the INR, is used to monitor warfarin anticoagulation. Warfarin-related nephropathy (WRN) is a recently reported clinical entity, secondary to a prolonged INR.[2] It can occur in patients with or without chronic kidney disease (CKD) and is associated with progression of CKD leading to a poor outcome.[3] Further studies also found that novel oral anticoagulants such as dabigatran also caused a similar syndrome and hence the term anticoagulant-related nephropathy is now used.[4]\n\nCase Report\nA 33-year-old male, recently de-inducted from a high altitude area with no known prior comorbidities, was admitted to our center with breathlessness, dry cough, hemoptysis, and left-sided pleuritic chest pain of sudden onset. Physical examination revealed tachypnea, tachycardia, and normal blood pressure. On systemic examination, the chest was clear and there were no cardiovascular localizing signs. His initial evaluation revealed normal hematological and biochemical parameters. The serum creatinine at admission was 0.9 mg/dl (normal range - 0.8–1.1 mg/dl), blood urea was 20 mg/dl (normal range - 20–40 mg/dl), and urine examination was normal. Chest X-ray, 2D echocardiography, and Doppler scan of lower limbs and pelvic vessels were normal. Electrocardiogram showed sinus tachycardia. Renal ultrasound demonstrated normal-sized kidneys with preserved cortical thickness and no obstruction. A computed tomography pulmonary angiogram revealed acute pulmonary thromboembolism in the descending branch of the left pulmonary artery and the 2nd order branch medial basal and superior segment of the right descending pulmonary artery (modified Well's score - 4). A serological workup including antineutrophil antibody, ds DNA, complement C3/C4 levels, antineutrophil cytoplasmic antibody, and procoagulant studies was essentially normal. He was thrombolyzed with recombinant tissue plasminogen activator and thereafter started on low molecular weight heparin and bridged onto warfarin. On day 22 of the warfarin therapy, he again developed increasing left-sided chest pain and hematuria. Repeat imaging revealed no fresh embolism. His INR was 5.3 and his serum creatinine had also progressively risen to 2.6 mg/dl. His urine routine examination revealed albumin of 2+, with numerous red blood cells (RBCs) and a 24 h urinary protein of 2292 mg/day. He however was nonoliguric. A pre- and post-renal cause for acute kidney injury (AKI) was excluded, and a thorough drug history was also not contributory toward a cause for suspicion of acute interstitial nephritis. A provisional diagnosis of WRN was made. His warfarin was withheld and the coagulation parameters corrected with adequate blood component support. Over the next few days, his azotemia showed a settling trend. As the INR normalized, a renal biopsy was done which showed the modest matrix expansion associated with vascular hyalinosis, glomerular congestion with RBCs [Figure 1], and diffuse tubular damage with large and occlusive RBC casts in the tubules associated with interstitial hemosiderin laden macrophages suggestive of interstitial hemorrhage [Figure 2]. Immunofluorescence studies were negative.\n\nFigure 1 A congested glomerulus with red blood cells in the capillary vessels. The glomerular architecture is maintained other than mild vascular hyalinosis (H and E, ×40)\n\nFigure 2 Extensive and diffuse tubular damage. Also seen are large occlusive red blood cell casts in the tubular lumina. The interstitium shows focal areas of hemosiderin-laden macrophages suggestive of interstitial hemorrhage (arrow) PAS stain (×40)\n\nThe patient was restarted on warfarin in escalating doses till a therapeutic INR was attained. At present, his renal functions have settled back to normal.\n\nDiscussion\nWarfarin can cause nephropathy by several mechanisms, namely acute interstitial nephritis, atheroembolism, direct mesangial damage, and the recently described WRN. WRN is defined as an acute increase in serum creatinine of >0.3 mg/dl within 1 week of an INR >3.0.[5] The cause of renal damage is glomerular hemorrhage and tubular RBC casts causing obstruction and inflammatory and oxidative damage to the tubular epithelial cells. Warfarin is mainly metabolized by CYP-2CP microsomal liver enzymes, which is affected by a multitude of different environmental factors, diet, drug interactions, and genetics, especially CYP2 complex mutations which can alter the pharmacokinetics and pharmacodynamics of warfarin metabolism leading to toxicity and increase in the INR. In the pioneering study by Brodsky et al., WRN developed in 37.0% of patients with CKD, who had an INR >3 and 20.5% of patients without CKD.[6] There was no correlation between the INR increase and the rise in serum creatinine and the mean INR at which it occurred was around 4.[6] The major mechanisms for WRN are glomerular hemorrhage and tubular dysfunction by obstruction due to RBC casts. Hematuria is not a consistent feature but can occur in 50% of patients.[7] Subnephrotic proteinuria is common, but its extent has not been studied. Awareness of WRN is important because the subtle renal impairment can lead to long-term kidney damage and reduced GFR as seen in the study by Brodsky SV et al., where an episode of WRN-accelerated progression of CKD studied. Studies revealed that this entity is also caused by other oral anticoagulants; hence, the new term anticoagulant-related nephropathy.[8] We suggest that WRN should always be considered a possible cause of AKI occurring during episodes of over-anticoagulation and hence monitor the INR meticulously.[9] It is usually a clinical diagnosis as biopsy is difficult due to the risk of bleeding; however, a transvenous renal biopsy can be attempted in cases where it is felt obligatory by the treating nephrologist to rule out or confirm a diagnosis.\n\nConclusion\nWRN in patients with normal renal functions is very rare. Early detection and timely intervention can go a long way in preventing renal damage leading to chronic kidney disease.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Timson DJ Dicoumarol: A drug which hits at least two very different targets in Vitamin K metabolism Curr Drug Targets 2015 [Epub ahead of print] \n2 Rizk DV Warnock DG Warfarin-related nephropathy: Another newly recognized complication of an old drug Kidney Int 2011 80 131 3 21720303 \n3 Brodsky SV Collins M Park E Rovin BH Satoskar AA Nadasdy G Warfarin therapy that results in an International Normalization Ratio above the therapeutic range is associated with accelerated progression of chronic kidney disease Nephron Clin Pract 2010 115 c142 6 20413993 \n4 Ryan M Ware K Qamri Z Satoskar A Wu H Nadasdy G Warfarin-related nephropathy is the tip of the iceberg: Direct thrombin inhibitor dabigatran induces glomerular hemorrhage with acute kidney injury in rats Nephrol Dial Transplant 2014 29 2228 34 24009280 \n5 Brodsky SV Nadasdy T Rovin BH Satoskar AA Nadasdy GM Wu HM Warfarin-related nephropathy occurs in patients with and without chronic kidney disease and is associated with an increased mortality rate Kidney Int 2011 80 181 9 21389969 \n6 Brodsky SV Satoskar A Chen J Nadasdy G Eagen JW Hamirani M Acute kidney injury during warfarin therapy associated with obstructive tubular red blood cell casts: A report of 9 cases Am J Kidney Dis 2009 54 1121 6 19577348 \n7 Ware K Brodsky P Satoskar AA Nadasdy T Nadasdy G Wu H Warfarin-related nephropathy modeled by nephron reduction and excessive anticoagulation J Am Soc Nephrol 2011 22 1856 62 21885669 \n8 Wheeler DS Giugliano RP Rangaswami JR Anticoagulation-related nephropathy J Thromb Haemost 2015 [Epub ahead of print] \n9 Hughes S Szeki I Nash MJ Thachil J Anticoagulation in chronic kidney disease patients-the practical aspects Clin Kidney J 2014 7 442 9 25878775\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "27(1)",
"journal": "Indian journal of nephrology",
"keywords": "Acute kidney injury; anticoagulant-related nephropathy; warfarin; warfarin-related nephropathy",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "78-80",
"pmc": null,
"pmid": "28182051",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "21389969;26670286;21885669;19577348;20413993;24009280;26201483;21720303;25878775",
"title": "Warfarin related acute kidney injury: A case report.",
"title_normalized": "warfarin related acute kidney injury a case report"
} | [
{
"companynumb": "IN-IPCA LABORATORIES LIMITED-IPC201702-000088",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
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"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
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{
"abstract": "Systemic lupus erythematosus (SLE) is a systemic non-organ specific autoimmune disease associated with multiple autoantibodies targeting autoantigens from the nucleus. Given the complex pathophysiology of SLE and the role of TNF alpha in that disease, modulation of TNF alpha (in SLE or non-SLE patients) using TNF blockers could either be detrimental or beneficial in some patients. In this review we will focus on lupus autoantibodies and clinical manifestations after TNF blockade in SLE patients and conversely on drug-induced-SLE in non-SLE patients. Some hypotheses regarding the mechanism of induction of autoantibodies in RA patients treated with TNF blockers are proposed.",
"affiliations": "Rheumatology Department, Hôpital Robert Ballanger, Aulnay sous Bois, France. m.debandt@ch-aulnay.fr",
"authors": "De Bandt|M|M|",
"chemical_list": "D001323:Autoantibodies; D014409:Tumor Necrosis Factor-alpha",
"country": "England",
"delete": false,
"doi": "10.1177/0961203306071703",
"fulltext": null,
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"issn_linking": "0961-2033",
"issue": "15(11)",
"journal": "Lupus",
"keywords": null,
"medline_ta": "Lupus",
"mesh_terms": "D017209:Apoptosis; D001323:Autoantibodies; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "762-7",
"pmc": null,
"pmid": "17153848",
"pubdate": "2006",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Lessons for lupus from tumour necrosis factor blockade.",
"title_normalized": "lessons for lupus from tumour necrosis factor blockade"
} | [
{
"companynumb": "PL-CELLTRION INC.-2019PL017625",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
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... |
{
"abstract": "OBJECTIVE\nTo evaluate the role of thrombin-based haemostatic agent Surgiflo® (Ethicon) in improving the outcome of cricotracheal resection anastomosis.\n\n\nMETHODS\nRandomised controlled clinical trial.\n\n\nMETHODS\nOtorhinolaryngology Department, Mansoura University Hospitals, Egypt.\n\n\nMETHODS\nThis study included 55 patients with grade III and IV subglottic and/or cervical tracheal stenosis, who underwent cricotracheal resection anastomosis. Patients were randomly assigned into two groups: Surgiflo group (n = 20) and control group (n = 35). In Surgiflo patients, Surgiflo® was applied at the end of surgery over the whole operative field including the line of airway anastomosis with the purpose of adequate haemostasis and enhancing healing of the anastomosis.\n\n\nMETHODS\nThe success rate and the incidence of complications in both groups were compared.\n\n\nRESULTS\nAt the end of treatment, decannulation rate was 95% (19/20) in the Surgiflo groups and 82.8% (29/35) in the control group. The overall incidence of complications was significantly lower in the Surgiflo group (P = .021). Need for further surgical airway interventions in the form of repeated dilatation, granulation tissue removal or performing a tracheotomy was reported in 22.9% (8/35) of control group patients, in comparison with 5% (1/20) in Surgiflo group.\n\n\nCONCLUSIONS\nDirect Surgiflo® application in the operative field enhances the anastomotic healing, decreases the incidence of anastomotic complications and subsequently improves the outcome. It can be recommended as an adjuvant to surgery in patients undergoing cricotracheal resection anastomosis.",
"affiliations": "Faculty of Medicine, Mansoura University, Mansoura, Egypt.;Faculty of Medicine, Mansoura University, Mansoura, Egypt.;Faculty of Medicine, Mansoura University, Mansoura, Egypt.",
"authors": "El-Fattah|Ahmed Musaad Abd|AMA|https://orcid.org/0000-0002-7004-8697;Ebada|Hisham Atef|HA|https://orcid.org/0000-0003-4848-9223;Tawfik|Ali|A|",
"chemical_list": "D006490:Hemostatics; C000629581:Surgiflo; D005780:Gelatin; D013917:Thrombin",
"country": "England",
"delete": false,
"doi": "10.1111/coa.13614",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1749-4478",
"issue": "45(6)",
"journal": "Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery",
"keywords": "Surgiflo; anastomosis; complications; cricotracheal; healing; outcome; resection; tracheal",
"medline_ta": "Clin Otolaryngol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000714:Anastomosis, Surgical; D004534:Egypt; D005260:Female; D005780:Gelatin; D006490:Hemostatics; D006801:Humans; D015994:Incidence; D007829:Laryngostenosis; D008297:Male; D011183:Postoperative Complications; D013917:Thrombin; D014135:Tracheal Stenosis; D014945:Wound Healing",
"nlm_unique_id": "101247023",
"other_id": null,
"pages": "870-876",
"pmc": null,
"pmid": "32734638",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Surgiflo® may have a potential impact on the healing process in cricotracheal resection anastomosis.",
"title_normalized": "surgiflo may have a potential impact on the healing process in cricotracheal resection anastomosis"
} | [
{
"companynumb": "EG-JNJFOC-20200813266",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "THROMBIN HUMAN"
},
"drugadditional": null,
... |
{
"abstract": "Preapproval clinical trials examining the safety and efficacy of rosuvastatin demonstrated an increased incidence of proteinuria, hematuria, rhabdomyolysis, and other acute kidney injury of unknown cause at high doses. The latter cases manifested with urine sediment findings and in some cases, renal histology, indicating renal tubular injury in the absence of rhabdomyolysis. Despite these provocative findings, there have been very few reports in the literature regarding non-rhabdomyolysis-mediated acute kidney injury associated with high-dose rosuvastatin since its widespread introduction more than a decade ago, suggesting that it is either a rare entity or systematically underdiagnosed and under-reported. We present a case of renal tubular toxicity attributable to the initiation of rosuvastatin treatment at a dose of 40mg in a patient with no prior evidence of kidney disease. Tubular toxicity should be considered in cases of unexplained kidney injury in the setting of exposure to a potent statin such as rosuvastatin, particularly at high dose. The limited evidence suggests a good kidney prognosis following withdrawal of the agent in these cases.",
"affiliations": "Division of Nephrology, Department of Medicine, University Health Network, Toronto, Canada. Electronic address: francis.ward@uhn.ca.;Department of Pathology, University Health Network, Toronto, Canada.;Division of Nephrology, Department of Medicine, University Health Network, Toronto, Canada.;Division of Nephrology, Department of Medicine, University Health Network, Toronto, Canada.",
"authors": "Ward|Frank L|FL|;John|Rohan|R|;Bargman|Joanne M|JM|;McQuillan|Rory F|RF|",
"chemical_list": "D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D000068718:Rosuvastatin Calcium",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2016.08.037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "69(3)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Acute kidney injury (AKI); acute tubular necrosis; rosuvastatin; statin; tubular toxicity",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007683:Kidney Tubular Necrosis, Acute; D008875:Middle Aged; D000068718:Rosuvastatin Calcium",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "473-476",
"pmc": null,
"pmid": "27856086",
"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal Tubular Toxicity Associated With Rosuvastatin Therapy.",
"title_normalized": "renal tubular toxicity associated with rosuvastatin therapy"
} | [
{
"companynumb": "CA-MYLANLABS-2017M1018975",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ROSUVASTATIN"
},
"drugadditional": "1",
... |
{
"abstract": "Monoclonal antibody (mAb) therapies for relapsing-remitting multiple sclerosis (MS) target immune cells or other molecules involved in pathogenic pathways with extraordinary specificity. Natalizumab and alemtuzumab are the only two currently approved mAbs for the treatment of MS, having demonstrated significant reduction in clinical and magnetic resonance imaging disease activity and disability in clinical studies. Ocrelizumab and daclizumab are in the late stages of phase III trials, and several other mAbs are in the early stages of clinical evaluation. mAbs have distinct structural characteristics (e.g. chimeric, humanized, fully human) and unique targets (e.g. blocking interactions, induction of signal transduction by receptor binding, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity) conferring different mechanisms of action in MS. Because of these differences, mAbs for MS do not constitute a single treatment class; each must be considered individually when selecting appropriate therapy. Furthermore, in reviewing the data from clinical studies of mAbs, attention should be drawn to use of different comparators (e.g. placebo or interferon β-1a) and study designs. Each mAb treatment has a unique administration schedule. In the decision to select the appropriate treatment for each individual MS patient, careful review of the benefits relative to risks of mAbs is balanced against the risk of development of MS-associated disability.",
"affiliations": "Sahlgrenska Academy at University of Gothenburg, Sahlgrenska University Hospital, 41345 Gothenburg, Sweden.",
"authors": "Lycke|Jan|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1756285615605429",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-2856",
"issue": "8(6)",
"journal": "Therapeutic advances in neurological disorders",
"keywords": "antibodies; autoimmunity; monoclonal; multiple sclerosis; therapy",
"medline_ta": "Ther Adv Neurol Disord",
"mesh_terms": null,
"nlm_unique_id": "101480242",
"other_id": null,
"pages": "274-93",
"pmc": null,
"pmid": "26600872",
"pubdate": "2015-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "20682002;24453078;18946064;23994464;23740801;18256405;24849515;22084440;19847908;21673034;19364933;21613333;23122650;16510745;15161974;22442431;16758413;21487835;23562009;21960587;23728144;11950476;23568998;22076546;24680560;21777829;23122652;21647730;20223720;24656609;24732657;22048950;24682966;19763798;24463630;1538783;22503411;25273271;17761550;21228027;17018129;18272891;23175722;22183929;15319372;22591293;20163990;21975205;22162056;22025301;26150206;19740383;16510744;24498318;23287362;23765090;18703004;20483748;22047971;19255407;21543733;19546505;22739991;24170099;24977406;23634189;22171583;22056965;24377479;17709711;21832229;10568572;16634029;25391494;23088447;8960740;17452584;24409199;20530322;24566807;25159275;23200102;10449105;11807632;23459571;16231285;12510038;25340070",
"title": "Monoclonal antibody therapies for the treatment of relapsing-remitting multiple sclerosis: differentiating mechanisms and clinical outcomes.",
"title_normalized": "monoclonal antibody therapies for the treatment of relapsing remitting multiple sclerosis differentiating mechanisms and clinical outcomes"
} | [
{
"companynumb": "US-BIOGENIDEC-2010BI041496",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Cisplatin-containing salvage regimens followed by autologous hematopoietic stem cell (HSC) transplantation are the current standard of care for relapsed or refractory (R/R) lymphomas. We retrospectively analyzed efficacy and stem cell mobilizing activity of oxaliplatin, cytarabine, dexamethasone and rituximab (R-DHAOx) in 53 R/R diffuse large B cell lymphomas (DLBCL) treated in our center (median lines 2, range 2-5; median age 59, range 22-79). Hematological toxicity was manageable and no patients experienced renal impairment. After 2 courses the overall response rate was 60% (CR 49%, PR 11%). Median overall survival (OS) was 30.53 months (95% CI 11.5-49.55), 3-year OS 40.5%. Twenty-two eligible patients collected HSC and transplantation was performed in 21/22 patients (95%), after a median of 52 days from last cycle. Our results suggest that in DLBCL R-DHAOx has an excellent stem cell mobilizing capability, response rate comparable to cisplatin-containing regimens and good toxicity profile.",
"affiliations": "Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.;Clinic of Hematology, Department of Internal Medicine (DiMI), University of Genoa, Genoa, Italy.",
"authors": "Manconi|Lorenzo|L|0000-0002-8705-7784;Coviello|Elisa|E|;Canale|Filippo|F|;Giannoni|Livia|L|;Minetto|Paola|P|;Guolo|Fabio|F|;Clavio|Marino|M|;Marcolin|Riccardo|R|;Cea|Michele|M|;Cagnetta|Antonia|A|;Gobbi|Marco|M|;Miglino|Maurizio|M|;Ballerini|Filippo|F|;Lemoli|Roberto Massimo|RM|",
"chemical_list": "D003561:Cytarabine; D000077150:Oxaliplatin; D000069283:Rituximab; D003907:Dexamethasone",
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"keywords": "Oxaliplatin; refractory/relapsed diffuse large B cell lymphoma; salvage; stem cell mobilization",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D003907:Dexamethasone; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D000077150:Oxaliplatin; D012189:Retrospective Studies; D000069283:Rituximab; D016879:Salvage Therapy; D013234:Stem Cells; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Dexamethasone, oxaliplatin and cytarabine (R-DHAOx) as salvage and stem cells mobilizing therapy in relapsed/refractory diffuse large B cell lymphomas.",
"title_normalized": "dexamethasone oxaliplatin and cytarabine r dhaox as salvage and stem cells mobilizing therapy in relapsed refractory diffuse large b cell lymphomas"
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"abstract": "With the use of nitrous oxide increasing, overuse and excessive exposure to this gas are also more prevalent. Neuropathy, expressed as amnesia, aphasia or weakness, numbness, and incoordination affecting all extremities, is the common result of frequent overexposure. For optimal dental treatment, it is recommended that both patient and dentist be aware that nitrous oxide can be an exogenous toxin, damaging to neuronal structures, if used in excess.",
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"title": "\"Recreational\" misuse of nitrous oxide.",
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"abstract": "Pneumatosis intestinalis is defined as the presence of gas in the bowel wall. The combination of the two risks, pre-existing connective tissue diseases and barium contrast examination, may trigger pneumatosis intestinalis, albeit at a low incidence. Clinicians should be aware of the condition for proper differential diagnosis.",
"affiliations": "Department of Rheumatology Kawasaki Medical School Kurashiki Japan.;Department of Rheumatology Kawasaki Medical School Kurashiki Japan.;Department of Rheumatology Kawasaki Medical School Kurashiki Japan.;Department of Rheumatology Kawasaki Medical School Kurashiki Japan.",
"authors": "Yamamoto|Shintaro|S|;Mukai|Tomoyuki|T|https://orcid.org/0000-0002-0103-1621;Fujita|Shunichi|S|;Morita|Yoshitaka|Y|",
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"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4775\nCCR34775\nClinical Image\nClinical Images\nBarium‐induced pneumatosis intestinalis in a patient with anti‐synthetase syndrome\nYAMAMOTO et al.\nYamamoto Shintaro 1\nMukai Tomoyuki https://orcid.org/0000-0002-0103-1621\n1 2 mukait@med.kawasaki-m.ac.jp\n\nFujita Shunichi 1\nMorita Yoshitaka 1\n1 Department of Rheumatology Kawasaki Medical School Kurashiki Japan\n2 Department of Immunology and Molecular Genetics Kawasaki Medical School Kurashiki Japan\n* Correspondence\nTomoyuki Mukai, Department of Rheumatology, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama 701‐0192, Japan.\nEmail: mukait@med.kawasaki-m.ac.jp\n\n05 9 2021\n9 2021\n9 9 10.1002/ccr3.v9.9 e0477505 8 2021\n01 7 2021\n19 8 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nPneumatosis intestinalis is defined as the presence of gas in the bowel wall. The combination of the two risks, pre‐existing connective tissue diseases and barium contrast examination, may trigger pneumatosis intestinalis, albeit at a low incidence. Clinicians should be aware of the condition for proper differential diagnosis.\n\nPneumatosis intestinalis is defined as the presence of gas in the bowel wall. The combination of the two risks, pre‐existing connective tissue diseases and barium contrast examination, may trigger pneumatosis intestinalis, albeit at a low incidence. Clinicians should be aware of the condition for proper differential diagnosis.\n\nanti‐synthetase syndrome\nbarium\nconnective tissue disease\npneumatosis intestinalis\nUCB Japan source-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:05.09.2021\nYamamotoS, MukaiT, FujitaS, MoritaY. Barium‐induced pneumatosis intestinalis in a patient with anti‐synthetase syndrome. Clin Case Rep. 2021;9 :e04775. 10.1002/ccr3.4775\n\nFunding information\n\nThe publication of this article was partly supported by a research grant from UCB Japan\n==== Body\npmc1 INTRODUCTION\n\nA 43‐year‐old man underwent follow‐up chest computed tomography for pre‐existing anti‐synthetase syndrome‐associated interstitial pneumonia, which had been stable with prednisolone, tacrolimus, and azathioprine therapy. He had mild chronic constipation but no comorbidities, including diabetes mellitus. He had no chest and abdominal symptoms. Computed tomography revealed intramucosal gas in the colon and free air around the liver (Figure 1A). The anal side of the colon was filled with high‐density contents (Figure 1B). He had undergone an upper gastrointestinal series with barium contrast for his comprehensive medical check‐up 3 days prior. Abdominal physical examination and laboratory tests revealed normal findings. He was diagnosed with pneumatosis intestinalis (PI). The intramucosal gas and free air resolved spontaneously with laxative treatment.\n\nFIGURE 1 Computed tomography images of the upper abdomen. (A) Intramucosal gas in the colon (arrowheads) and free air around the liver (arrows) in a lung window setting. (B) High‐density contents, indicating barium contrast medium in a mediastinal window setting.\n\nPI is diagnosed based on the presence of intramucosal gas, which can develop as a rare complication of connective tissue diseases.1, 2 Microangiopathy and steroid treatment have been proposed as its pathogenesis in patients with connective tissue diseases.1, 2 Also, increased intestinal pressure by intestinal obstruction is assumed to trigger the PI.3 In our case, intestinal obstruction due to impaction of barium contrast medium may have triggered PI in association with mucosal fragility due to anti‐synthetase syndrome and steroid treatment. Accumulation of similar cases is needed to clarify the potential links in this rare condition. Clinicians should be aware of PI as a possible adverse event of barium contrast examination in patients with connective tissue diseases.\n\nCONFLICT OF INTEREST\n\nNot declared.\n\nAUTHOR CONTRIBUTIONS\n\nSY and SF gave original idea. SY, TM, SF, and YM wrote the manuscript.\n\nETHICAL APPROVAL\n\nThe publication of present study was in accordance with the ethical standards of our institution.\n\nACKNOWLEDGEMENTS\n\nWritten informed consent for this case report was obtained from the patient.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 SagaraA, KitagawaK, FuruichiK, et al. Three cases of pneumatosis intestinalis presenting in autoimmune diseases. Mod Rheumatol. 2012;22 :610‐615.22068684\n2 ZarbalianY, von RosenvingeEC, TwadellW, MikdashiJ. Recurrent pneumatosis intestinalis in a patient with dermatomyositis. BMJ Case Rep. 2013;2013 :bcr2013200308.\n3 PhothongN, SwangsriJ, AkaraviputhT, ChinswangwatanakulV, TrakarnsangaA. Colonic stenting for malignant colonic obstruction with pneumatosis intestinalis. Int J Surg Case Rep. 2016;26 :38‐41.27448227\n\n",
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"keywords": "anti‐synthetase syndrome; barium; connective tissue disease; pneumatosis intestinalis",
"medline_ta": "Clin Case Rep",
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"pubdate": "2021-09",
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"title": "Barium-induced pneumatosis intestinalis in a patient with anti-synthetase syndrome.",
"title_normalized": "barium induced pneumatosis intestinalis in a patient with anti synthetase syndrome"
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"abstract": "BACKGROUND\nProgression of inflammation in acute appendicitis can lead to appendiceal perforation, which is associated with higher morbidity and mortality. Bacteremia due to a perforated appendicitis can lead to distal bacterial seeding, resulting in further complications.\n\n\nMETHODS\nWe present here a case of appendiceal perforation in a 32-year-old previously healthy male. Patient was conservatively managed with intravenous (IV) antibiotics and was discharged on hospitalization day-6. Prior to scheduled interval appendectomy, he developed right sided hip pain with decreased range of motion. Computed tomography (CT) scan with contrast showed right hip abscess and enlarged pelvic lymph nodes. Arthrocentesis yielded purulent fluid with leukocytosis (84.8 k/CMM) and neutrophilia (89%). Patient underwent emergent incision and drainage of the hip abscess followed with 42-days of IV antibiotics for septic arthritis.\n\n\nCONCLUSIONS\nThis case presents a unique occurrence of a complication from appendiceal perforation in patients who are initially managed non-operatively. Clinicians should be mindful of rare complications associated with non-operative management of appendicitis.",
"affiliations": "Texas A&M College of Medicine, 3050 Health Professions Education Building, 8447 Riverside Pkwy, Bryan, TX 77807, United States; Houston Methodist Hospital, TAMHSC Partnership, Houston, TX 77030, United States. Electronic address: mzia2@houstonmethodist.org.;Texas A&M College of Medicine, 3050 Health Professions Education Building, 8447 Riverside Pkwy, Bryan, TX 77807, United States; Houston Methodist Hospital, Department of Surgery, Houston, TX 77030, United States.",
"authors": "Zia|Mahnoor|M|;Maghami|Nima|N|",
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"doi": "10.1016/j.ijscr.2020.05.093",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612 Elsevier \n\nS2210-2612(20)30410-7\n10.1016/j.ijscr.2020.05.093\nArticle\nSeptic arthritis of the hip, an unreported complication of perforated appendicitis: A case report\nZia Mahnoor mzia2@houstonmethodist.orgab⁎ Maghami Nima ac a Texas A&M College of Medicine, 3050 Health Professions Education Building, 8447 Riverside Pkwy, Bryan, TX 77807, United States\nb Houston Methodist Hospital, TAMHSC Partnership, Houston, TX 77030, United States\nc Houston Methodist Hospital, Department of Surgery, Houston, TX 77030, United States\n⁎ Corresponding author at: Houston Methodist Hospital, 6565 Fannin, TAMHSC Partnership- West Pavilion 5th floor, Houston, TX 77030, United States. mzia2@houstonmethodist.org\n11 6 2020 \n2020 \n11 6 2020 \n72 281 284\n13 4 2020 27 5 2020 27 5 2020 © 2020 The Authors2020This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Highlights\n• Septic arthritis can result from recent bacteremia.\n\n• Septic arthritis of hip joint secondary to perforated appendicitis has not been previously reported.\n\n• Limited literature exists on complications in patients who are non-surgically managed for perforated appendicitis.\n\n\n\nIntroduction\nProgression of inflammation in acute appendicitis can lead to appendiceal perforation, which is associated with higher morbidity and mortality. Bacteremia due to a perforated appendicitis can lead to distal bacterial seeding, resulting in further complications.\n\nPresentation of case\nWe present here a case of appendiceal perforation in a 32-year-old previously healthy male. Patient was conservatively managed with intravenous (IV) antibiotics and was discharged on hospitalization day-6. Prior to scheduled interval appendectomy, he developed right sided hip pain with decreased range of motion. Computed tomography (CT) scan with contrast showed right hip abscess and enlarged pelvic lymph nodes. Arthrocentesis yielded purulent fluid with leukocytosis (84.8 k/CMM) and neutrophilia (89%). Patient underwent emergent incision and drainage of the hip abscess followed with 42-days of IV antibiotics for septic arthritis.\n\nConclusion\nThis case presents a unique occurrence of a complication from appendiceal perforation in patients who are initially managed non-operatively. Clinicians should be mindful of rare complications associated with non-operative management of appendicitis.\n\nKeywords\nAppendicitisInterval appendectomyArthropathySeptic arthritisArthrocentesisCase report\n==== Body\n1 Introduction\nComplicated appendicitis (defined as perforation of the appendix, empyema or abscess formation, and finally fecal peritonitis) is a feared complication of acute appendicitis, associated with higher morbidity and mortality. Progression of inflammation can lead to appendiceal perforations and gangrenous appendicitis which may subsequently progress to peri-appendiceal abscess [1]. Average rate of perforations at presentation are between 16%–30% [2]. A 9% increased risk of appendiceal perforation is reported for each day delay in management [3]. Other risk factors include extremes of age, male sex, febrile on admission, presence of fecalith, immunosuppression, comorbid medical conditions and previous abdominal surgery [3,4]. Postoperative morbidity, reported as high as 20%, is associated with development of abdominal abscess, prolonged ileus, pneumonia, and congestive heart failure [3,5,6].\n\nTimely management of acute perforated appendicitis is necessary, otherwise bacterial seeding can occur. Previously reported rare complications from perforated appendicitis include mesenteric vein thrombosis and necrotizing fasciitis of the thigh [7,8]. We present a unique case of septic arthritis of the hip as a complication of perforated appendicitis. This case illustrates additional complications that can occur due to perforated appendicitis which may need prompt surgical management.\n\nThis case report has been reported in accordance with the SCARE Criteria [9].\n\n2 Presentation of case\nA 32-year-old male with a medical history of perforated appendicitis 18-days prior to presentation, was admitted to the hospital with a 4-day history of worsening right hip pain. Physical examination was remarkable for moderate tenderness to palpation on the right lateral hip and restricted range of motion. Laboratory evaluation was notable for elevated inflammatory markers including sedimentation rate (35 mm/hr) and C-reactive protein (7.52 mg/L). Patient was afebrile (98.3 °F) without leukocytosis (7.92 k/μL). Monoarticular joint pain was concerning for septic arthritis or crystal arthropathy. Patient was started on IV vancomycin and cefepime. Per Infectious Diseases recommendations, cefepime was later changed to ertapenem for broader gram negative and anaerobic coverage. Computed tomography (CT) of lower extremities with contrast was remarkable for right hip joint effusion with multiple enlarged right pelvic wall lymph nodes (Fig. 1). CT of abdomen and pelvis showed appendix and previous periappendiceal inflammatory changes had improved to near complete resolution (Fig. 2). Arthrocentesis of the right hip was performed by interventional radiology (IR) and yielded cloudy serous fluid. Synovial fluid analysis revealed leukocytosis (84.8 k/CMM) with neutrophilia (89%) without any evidence of crystals. Bacterial and fungal cultures were negative.Fig. 1 Representative axial and coronal computed tomography (CT) images of the right lower extremity with contrast depicting moderate right hip joint effusion.\n\nFig. 1Fig. 2 Computed tomography (CT) of abdomen and pelvis showing interval improvement in peri-appendiceal inflammation. Appendicolith is visible at tip of appendix in the right lower quadrant.\n\nFig. 2\n\nOn review of past medical history, patient was admitted to our facility 2-weeks earlier with acute onset abdominal pain localized to right lower quadrant, associated with anorexia and a fever (102.3 °F). Serum studies were positive for leukocytosis (14.3 k/uL) with neutrophilia (77%). CT abdomen and pelvis was remarkable for fat stranding and a loculated 4.5-cm fluid collection consistent with peri-appendiceal abscess (Fig. 3). The abscess was too small for IR drainage. Patient was medically managed and started on IV Piperacillin/Tazobactam. Patient stabilized clinically; leukocytosis improved on hospitalization day-2 (7.85 k/μL). Repeat CT abdomen and pelvis on hospitalization day-4 displayed diffusely inflamed appendix with prominent appendicolith at the tip, and the peri-appendiceal abscess had decreased in size to 3-cm and no drainable fluid collection was noted (Fig. 4). Patient was discharged on hospitalization day-6 with oral amoxicillin/clavulanic acid for 14-days. An interval appendectomy was scheduled for 4-weeks post-discharge.Fig. 3 Perforated appendicitis with associated 4.5 cm abscess and surrounding fat stranding and inflammation.\n\nFig. 3Fig. 4 Sequela of perforated appendicitis with interval decrease in size of the previously identified periappendiceal abscess. No drainable fluid collections noted.\n\nFig. 4\n\nRecovery post hospital admission for perforated appendicitis was complicated with inflammatory arthropathy in the right hip. He underwent an open arthrotomy with incision and drainage of the right hip abscess. Intra-operatively, patient was noted to have copious amount of purulence in the right hip joint, in addition to grade 1 cartilage changes in his right hip, and necrotic right hip capsule. Magnetic resonance imaging of hip without contrast on postoperative day-3 noted post-operative changes, resolution of periarticular abscess, and continued enlarged lymph nodes likely to be reactive. He was discharged with home health and a 42-day course of IV ertapenem.\n\nUpon completion of IV antibiotics, patient returned for an interval appendectomy. Laparoscopic appendectomy was performed. Appendix appeared normal with thin adhesions to the pelvis. Pathology was benign with evidence of acute on chronic inflammatory changes. Patient was seen two weeks post-appendectomy, and he was free of pain, tolerating a diet, and having regular bowel movements. He continued to improve with his ambulation and hip range of motion through a structured physical therapy regimen.\n\n3 Discussion\nPathogenesis of septic arthritis involves bacterial invasion of the synovial membrane which leads to inflammatory process producing the characteristic purulent synovial fluid observed with arthrocentesis [10]. Septic arthritis most commonly occurs due to hematogenous seeding secondary to a bacteremia, other causes include penetrating trauma and corticosteroids joint injections [11]. The diagnosis of septic arthritis is established with arthrocentesis of the effected joint. Leukocytosis (WBC of >50k/μL) and polymorphonuclear cells of greater than 90% increase the likelihood of septic arthrits. Diagnosis and etiology are confirmed with gram stain and culture of the joint fluid [11]. Risk factors for septic arthritis includes age older than 60 years, recent bacteremia, degenerative arthritis, rheumatoid arthritis, metabolic syndrome, immune compromised state, joint prosthetics, skin infection and history of sexually transmitted diseases [10,11].\n\nOur patient had presented with monoarticular arthritis, synovial fluid was inflammatory, on open arthrotomy of right hip, extensive purulence was noted. This increased likelihood for septic arthritis. The patient had received IV antibiotics prior to arthrocentesis which can lead to negative bacterial cultures. The only identifiable risk factor for developing septic arthritis in our patient was history of perforated appendicitis. Previously published literature has reported severe complications from complicated appendicitis. For example, hematogenous spread of gut bacteria secondary to appendiceal perforation can lead to mesenteric vein thrombosis and pyogenic liver abscesses [7]. Furthermore, direct propagation of infection through the Petit and Grynfeltt-Lesshaft (inferior and superior lumbar) triangles have led to necrotizing fasciitis of lower limbs [8]. Therefore, several different mechanisms can be responsible for the complication observed in our patient.\n\n4 Conclusion\nThere is a trend to conservatively manage acute appendicitis, this case report highlights a potential complication associated with conservative management of acute appendicitis that clinicians should be vigilant about. The literature is sparse regarding discussion of complications prior to interval appendectomy in patients who undergo conservative management. Septic arthritis due to perforated appendicitis in an immune-competent patient has not been previously reported. This case presentation serves as a unique example of a severe life-threatening complication from a perforated appendicitis, necessitating close follow up with patients who initially present with complicated appendicitis.\n\nDeclaration of Competing Interest\nNo conflicts of interest regarding this publication.\n\nFunding\nNo funds were received for any part of this case report.\n\nEthical approval\nThis case report is exempt from ethical approval at our institution as this is not a research study.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nMahnoor Zia: Preparation, creation and presentation of the submission, writing-original draft.\n\nNima Maghami, MD, FACS: Patient management. Writing, reviewing and editing this submission.\n\nRegistration of research studies\n1. Name of the registry: Not required.\n\n2. Unique identifying number or registration ID: not required.\n\n3. Hyperlink to your specific registration (must be publicly accessible and will be checked):\n\n\n\nGuarantor\nNima Maghami.\n\nProvenance and peer review\nNot commissioned, externally peer-reviewed.\n==== Refs\nReferences\n1 Humes D.J. Simpson J. Acute appendicitis BMJ 333 7567 2006 530 534 16960208 \n2 Bickell N.A. Aufses J.A.H. Rojas M. Bodian C. How time affects the risk of rupture in appendicitis J. Am. Coll. Surg. 202 2006 401 406 16500243 \n3 Westfall K.M. Charles A.G. Risk of perforation in the era of nonemergent management for acute appendicitis Am. Surg. 85 11 2019 1209 1212 31775960 \n4 Drake F.T. Mottey N.E. Farrokhi E.T. Florence M.G. Johnson M.G. Mock C. Steele S.R. Thirlby R.C. Flum D.R. Time to appendectomy and risk of perforation in acute appendicitis NIH Public Access 149 8 2014 837 844 \n5 Frazee R. Abernathy S. Davis M. Isbell T. Regner J. Smith R. Fast track pathway for perforated appendicitis Am. J. Surg. 213 4 2017 739 741 27816201 \n6 Kulvatunyou N. Zimmerman S.A. Joseph B. Friese R.S. Gries L. O’Keeffe T. Stroster J.A. Tang A.L. Risk factors for perforated appendicitis in the acute care surgery era—minimizing the patient’s delayed presentation factor J. Surg. Res. 238 2019 113 118 30769247 \n7 Yoon S.H. Lee M.-J. Jung S.Y. Ho I.G. Kim M.K. Mesenteric venous thrombosis as a complication of appendicitis in an adolescent Medicine 98 48 2019 e18002 \n8 Hua J. Yao L. He Z.G. Xu B. Song Z.S. Necrotizing fasciitis caused by perforated appendicitis: a case report Int. J. Clin. Exp. Pathol. 8 3 2015 3334 3338 26045863 \n9 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A. Orgill D.P. For the SCARE Group The SCARE 2018 statement: updating consensus surgical case report (SCARE) guidelines Int. J. Surg. 60 2018 132 136 30342279 \n10 Shirtliff M.E. Mader J.T. Acute septic arthritis Clin. Microbiol. Rev. 15 4 2002 527 544 12364368 \n11 Margaretten M.E. Kohlwes J. Moore D. Bent S. Clinician’s corner does this adult patient have septic arthritis? Clinical scenario of septic arthritis J. Am. Med. Assoc. 297 13 2007 1478 1488\n\n",
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"keywords": "Appendicitis; Arthrocentesis; Arthropathy; Case report; Interval appendectomy; Septic arthritis",
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"title": "Septic arthritis of the hip, an unreported complication of perforated appendicitis: A case report.",
"title_normalized": "septic arthritis of the hip an unreported complication of perforated appendicitis a case report"
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "Neuroblastoma is the most common extracranial malignancy of childhood. Patients with high-risk disease receive multimodal treatment including chemotherapy combinations containing alkylating agents and topoisomerase inhibitors with potential for inducing therapy-related malignancy later in life. Most commonly, cytogenetic changes of pediatric therapy-related myelodysplastic syndrome/acute myeloid leukemia involve chromosome 5 or 7. Here we report a novel case of therapy-related myelodysplastic syndrome/acute myeloid leukemia 30 months after treatment for high-risk neuroblastoma with biphenotypic cell surface markers and a not yet described translocation t(1;6)(q25;p23).",
"affiliations": "*Department of Pediatrics, Section of Hematology-Oncology, Baylor College of Medicine/Texas Children's Hospital †Department of Pathology and Immunology ‡Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX.",
"authors": "Whittle|Sarah B|SB|;Punia|Jyotinder N|JN|;López-Terrada|Dolores|D|;Gaikwad|Amos|A|;Hampton|Oliver A|OA|;Heczey|Andras|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000956",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "39(8)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D001853:Bone Marrow; D002675:Child, Preschool; D002871:Chromosome Banding; D002878:Chromosomes, Human, Pair 1; D002896:Chromosomes, Human, Pair 6; D017809:Fatal Outcome; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016130:Immunophenotyping; D015470:Leukemia, Myeloid, Acute; D009190:Myelodysplastic Syndromes; D016609:Neoplasms, Second Primary; D009447:Neuroblastoma; D010641:Phenotype; D014178:Translocation, Genetic; D019172:Transplantation Conditioning",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e486-e488",
"pmc": null,
"pmid": "28902076",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Therapy-related Acute Leukemia With Mixed Phenotype and Novel t(1: 6)(q25;p23) After Treatment for High-risk Neuroblastoma.",
"title_normalized": "therapy related acute leukemia with mixed phenotype and novel t 1 6 q25 p23 after treatment for high risk neuroblastoma"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201710671",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
... |
{
"abstract": "The aim of the study was to analyze the characteristics of posterior reversible encephalopathy syndrome (PRES) cases treated at 10 different institutions in our country. Fifty-eight patients diagnosed with PRES were included in this study. The data of PRES cases from 10 departments of pediatric hematology/oncology were analyzed. The mean age of the patients at the time of diagnosis of PRES was 8.95±3.66 years. Most patients (80.4%) had a primary diagnosis of acute leukemia. Patients received chemotherapy (71.4%) and/or used steroids within 14 days before the diagnosis of PRES (85.7%). Hypertension was found in 83.9% of the patients. Twenty-six patients had infections and 22 of them had febrile neutropenia. The most common electrolyte disorders were hypocalcemia, hypomagnesemia, and hypopotassemia. Six patients had tumor lysis syndrome and 4 had inappropriate antidiuretic hormone syndrome. Magnetic resonance imaging was used for diagnosis in all patients. The most commonly involved regions by magnetic resonance imaging were occipital (58%), parietal (51%), and frontal lobes (45%), respectively. Twenty-five patients required intensive care and 7 patients were intubated. In conclusion, PRES may develop during the follow-up and treatment of hematological diseases. In addition to steroid and intense combined chemotherapies, immunosuppressive agents and hypertension are also factors that may be responsible for PRES.",
"affiliations": "Department of Pediatric Hematology and Oncology, Ministry of Health Ankara City Hospital.;Department of Pediatric Hematology-Oncology Cerrahpasa Faculty of Medicine Istanbul University.;Department of Pediatric Hematology, Başkent University Faculty of Medicine.;Pediatric Hematology and Oncology, Uludag University Medical Faculty, Bursa.;Department of Pediatric Hematology and Oncology, Tepecik Education and Training Hospital.;Department of Pediatric Hematology, Dokuz Eylul University Medical Faculty, Izmir.;Department of Pediatric Haematology, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.;Istanbul University Medical Faculty.;Pediatric Hematology and Oncology, University of Health Sciences, İstanbul Hamidiye Şişli Etfal Training and Research Hospital, İstanbul.;Pediatric Hematology and Oncology, Dr Abdurrahman Yurtaslan Ankara Oncology Training and Research Hospital, Ankara.;Department of Pediatric Hematology and Oncology, Ministry of Health Ankara City Hospital.;Department of Pediatric Hematology-Oncology Cerrahpasa Faculty of Medicine Istanbul University.;Department of Pediatric Hematology and Oncology, Ministry of Health Ankara City Hospital.",
"authors": "Bilir|Özlem A|ÖA|;Dikme|Gürcan|G|;Malbora|Bariş|B|;Evim|Melike S|MS|;Siviş|Zühal Ö|ZÖ|;Tüfekçi|Özlem|Ö|;Bahadir|Ayşenur|A|;Karaman|Serap|S|;Vural|Sema|S|;Bayhan|Turan|T|;Yarali|Hüsniye N|HN|;Celkan|Tiraje|T|;Özbek|Namik Y|NY|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000001965",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "43(4)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D002648:Child; D005260:Female; D006402:Hematologic Diseases; D006801:Humans; D006973:Hypertension; D007938:Leukemia; D008279:Magnetic Resonance Imaging; D008297:Male; D054038:Posterior Leukoencephalopathy Syndrome; D014883:Water-Electrolyte Imbalance",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e462-e465",
"pmc": null,
"pmid": "33060391",
"pubdate": "2021-05-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Posterior Reversible Encephalopathy Syndrome in Childhood Hematological/Oncological Diseases: Multicenter Results.",
"title_normalized": "posterior reversible encephalopathy syndrome in childhood hematological oncological diseases multicenter results"
} | [
{
"companynumb": "TR-STRIDES ARCOLAB LIMITED-2021SP030599",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drug... |
{
"abstract": "Cryptococcus meningitis is a potentially lethal disease, and cerebrospinal fluid cytology is crucial in establishing diagnosis. We report a novel and interesting morphological sign of Cryptococcus neoformansin CSF cytology resembling the logo of Mercedes-Benz. The sign is highly suggestive of Cryptococcus infection and is a strong indicator for more specific tests and timely treatment.",
"affiliations": "Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.;Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.;Department of Neurology, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China, guanhz@263.net.",
"authors": "Xu|Xiaolu|X|;Ren|Haitao|H|;Guan|Hongzhi|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000499971",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0014-3022",
"issue": "81(1-2)",
"journal": "European neurology",
"keywords": "Cerebrospinal fluid; Cryptococcus meningitis; Cytology",
"medline_ta": "Eur Neurol",
"mesh_terms": "D000328:Adult; D002555:Cerebrospinal Fluid; D003455:Cryptococcus neoformans; D003581:Cytodiagnosis; D006801:Humans; D016867:Immunocompromised Host; D008181:Lupus Nephritis; D008297:Male; D016919:Meningitis, Cryptococcal",
"nlm_unique_id": "0150760",
"other_id": null,
"pages": "79-80",
"pmc": null,
"pmid": "31112978",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "\"Mercedes-Benz Sign\" on CSF Cytology.",
"title_normalized": "mercedes benz sign on csf cytology"
} | [
{
"companynumb": "CN-PFIZER INC-2019294919",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nBortezomib demonstrates synergism with gemcitabine via a fixed-dose rate (FDR). The aim of this phase I trial in solid tumors was to establish the maximum tolerated dose (MTD) and safety data for this combination.\n\n\nMETHODS\nTwenty-nine patients with a median age of 63 (range 36-84) years and median Karnofsky Performance Status of 90 (range 60-100) were enrolled and treated with bortezomib (1.0 or 1.3 mg/m(2)) on days 1, 4, 8 and 11 and FDR gemcitabine (750, 1,000, or 1,250 mg/m(2)) on days 1 and 8 of each 21-day cycle. Response was evaluated every two cycles.\n\n\nRESULTS\nDose-limiting toxicities were grade 4 thrombocytopenia and neutropenia and grade 3 liver function test abnormalities. The MTD was bortezomib 1 mg/m2 and FDR gemcitabine 1,250 mg/m(2). The median number of cycles delivered was 3 (range 1-28). There was one partial response and six cases of stable disease. The median duration of response was 8.5 (range 3-20) months.\n\n\nCONCLUSIONS\nFDR gemcitabine and bortezomib combination can be delivered effectively with acceptable toxicity.",
"affiliations": "Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA 91010, USA. tluu@coh.org",
"authors": "Luu|Thehang|T|;Chow|Warren|W|;Lim|Dean|D|;Koczywas|Marianna|M|;Frankel|Paul|P|;Cristea|Mihaela|M|;Margolin|Kim|K|;Doroshow|James H|JH|;Somlo|George|G|;Gaur|Shikha|S|;Yen|Yun|Y|;Morgan|Robert J|RJ|",
"chemical_list": "D001897:Boronic Acids; D011719:Pyrazines; D003841:Deoxycytidine; D000069286:Bortezomib; C056507:gemcitabine",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "30(1)",
"journal": "Anticancer research",
"keywords": null,
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001897:Boronic Acids; D000069286:Bortezomib; D001943:Breast Neoplasms; D048708:Cell Growth Processes; D045744:Cell Line, Tumor; D003841:Deoxycytidine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004357:Drug Synergism; D006801:Humans; D008875:Middle Aged; D009369:Neoplasms; D011719:Pyrazines",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "167-74",
"pmc": null,
"pmid": "20150632",
"pubdate": "2010-01",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Phase I trial of fixed-dose rate gemcitabine in combination with bortezomib in advanced solid tumors.",
"title_normalized": "phase i trial of fixed dose rate gemcitabine in combination with bortezomib in advanced solid tumors"
} | [
{
"companynumb": "US-TAKEDA-2018MPI006731",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"dru... |
{
"abstract": "OBJECTIVE\nColorectal cancer is one of the most common malignancies in the world, and irinotecan (CPT-11) is useful in its treatment. However, the safety and pharmacokinetics of irinotecan in dialysis patients with metastatic colorectal cancer are unclear.\n\n\nMETHODS\nWe report the case of a 74-year-old man receiving chronic hemodialysis who had metastatic colorectal cancer. Palliative chemotherapy with irinotecan (80 mg/m2 weekly) was administered after hemodialysis. Blood samples were collected before and 1.5, 3, 6, 9, and 15 hours after administration of irinotecan. The peak serum concentrations (Cmax) of irinotecan and SN-38 in this patient were 1,480 and 17.8 ng/mL, respectively, which were similar to the reported values in patients with normal renal function after a similar dose of irinotecan (75 mg/m2). The area under the serum concentration-time curve (AUC0-∞) was 8,240 ng×h/mL for irinotecan and 619 ng×h/mL for SN-38. The AUC0-∞ for SN-38 was markedly higher than that for patients with normal renal function. Sequencing analysis of the UGT1A genes found that the patient had variant alleles of UGT1A1*28, UGT1A1*60 and UGT1A9*22, which may lead to decreased glucuronidation and excretion of SN-38, and may account for increased irinotecan-related toxicity. The patient developed febrile grade 4 neutropenia on day 7 after chemotherapy and died of septic shock on day 14.\n\n\nCONCLUSIONS\nUGT1A polymorphisms and renal failure may lead to accumulation of SN-38, which may have played a role in the death of this patient. Irinotecan should be used cautiously in dialysis patients with metastatic colorectal cancer and screening for UGT1A polymorphisms may help in identifying patients with lower SN-38 glucuronidation rates and greater susceptibility to irinotecan-induced toxicity.",
"affiliations": "Department of Medicine, National Yang-Ming University Hospital, Taiwan.",
"authors": "Huang|Sung-Hao|SH|;Chao|Yee|Y|;Wu|Ying-Ying|YY|;Luo|Jiing-Chyuan|JC|;Kao|Chien-Hui|CH|;Yen|Sang-Hue|SH|;Li|Chung-Pin|CP|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; C000715591:UGT1A9 protein, human; D000077146:Irinotecan; C418331:UGT1A1 enzyme; D014453:Glucuronosyltransferase; D000090264:UDP-Glucuronosyltransferase 1A9; C524630:UGT1A7 protein, human; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1700/667.7793",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "97(2)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D000368:Aged; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D003110:Colonic Neoplasms; D004334:Drug Administration Schedule; D017809:Fatal Outcome; D005838:Genotype; D014453:Glucuronosyltransferase; D006801:Humans; D007262:Infusions, Intravenous; D000077146:Irinotecan; D007676:Kidney Failure, Chronic; D008297:Male; D009367:Neoplasm Staging; D009503:Neutropenia; D011110:Polymorphism, Genetic; D006435:Renal Dialysis; D012772:Shock, Septic; D000090264:UDP-Glucuronosyltransferase 1A9",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": "243-7",
"pmc": null,
"pmid": "21617725",
"pubdate": "2011",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Concurrence of UGT1A polymorphism and end-stage renal disease leads to severe toxicities of irinotecan in a patient with metastatic colon cancer.",
"title_normalized": "concurrence of ugt1a polymorphism and end stage renal disease leads to severe toxicities of irinotecan in a patient with metastatic colon cancer"
} | [
{
"companynumb": "TW-PFIZER INC-2014307971",
"fulfillexpeditecriteria": "1",
"occurcountry": "TW",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Complete remission from recurrent EBV-positive lymphoma is not mandatory before HSCT to achieve long-term cure in a patient suffering from a recently described immunodeficiency affecting the T-cell coactivation molecule 4-1BB.",
"affiliations": "Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany. Electronic address: christine.wildermann@uniklinik-ulm.de.;Department of Pediatrics, King Saudi University, Riyadh, Saudi Arabia; Division of Immunology, Boston Children's Hospital and Department of Pediatrics Harvard Medical School, Boston, MA, USA.;Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.;Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.;Department of Pathology, University Medical Center Ulm, Germany.;Department of Pathology, University Medical Center Ulm, Germany.;Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.;Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.;Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.;Department of Oncology, King Faisal Specialist Hospital and Research Center, Jeddah, Saudi Arabia.;Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.;Division of Immunology, Boston Children's Hospital and Department of Pediatrics Harvard Medical School, Boston, MA, USA.;Department of Pediatrics and Adolescent Medicine, University Medical Center Ulm, Germany.",
"authors": "Wildermann|Christine|C|;Alosaimi|Mohammed|M|;Liebenehm|Sophie|S|;Jacobsen|Eva-Maria|EM|;Barth|Thomas F E|TFE|;Möller|Peter|P|;Debatin|Klaus-Michael|KM|;Schulz|Ansgar|A|;Sirin|Mehtap|M|;Abosoudah|Ibraheem F|IF|;Alkuraya|Fowzan S|FS|;Geha|Raif S|RS|;Hönig|Manfred|M|",
"chemical_list": "D053330:4-1BB Ligand; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clim.2020.108639",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1521-6616",
"issue": "222()",
"journal": "Clinical immunology (Orlando, Fla.)",
"keywords": "4-1BB; Epstein Barr virus; HSCT; Recurrent lymphoproliferation",
"medline_ta": "Clin Immunol",
"mesh_terms": "D053330:4-1BB Ligand; D002648:Child; D020031:Epstein-Barr Virus Infections; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human; D006801:Humans; D016393:Lymphoma, B-Cell; D008297:Male; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9",
"nlm_unique_id": "100883537",
"other_id": null,
"pages": "108639",
"pmc": null,
"pmid": "33259966",
"pubdate": "2021-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Successful hematopoietic stem cell transplantation in a 4-1BB deficient patient with EBV-induced lymphoproliferation.",
"title_normalized": "successful hematopoietic stem cell transplantation in a 4 1bb deficient patient with ebv induced lymphoproliferation"
} | [
{
"companynumb": "DE-ASPEN-GLO2021DE005428",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "THIOTEPA"
},
"drugadditional": null,
... |
{
"abstract": "A 76-year-old man with epigastric pain developed 1 month earlier was referred to our department for additional screening and treatment after abdominal ultrasound revealed a mass shadow in the pancreatic head and liver. Blood biochemistry revealed signs of mild jaundice and hepatic dysfunction. Abdominal contrast-computed tomography revealed an irregular hypodense mass with poor enhancement in the pancreatic head and several hypodense nodules in the liver. Endoscopic examination revealed duodenal infiltration signs. The biopsied duodenal mucosa contained atypical cells with high nuclear-to-cytoplasmic ratios; the cells stained positive for CD56, chromogranin, and synaptophysin, and the Ki-67 index was 90%. Accordingly, pancreatic neuroendocrine carcinoma (PanNEC) was diagnosed. Platinum-based chemotherapy (6 courses) and streptozotocin (10 courses) were adopted as the first- and second-line regimens, respectively. However, the patient showed progressive disease (PD). Pembrolizumab was added as a third-line regimen (13 courses) after confirming PanNEC with high microsatellite instability (MSI-high). Despite a temporary partial response (PR), the patient showed PD by the end of the 13 courses and died 1 year and 7 months after diagnosis. Although there is no established PanNEC therapy, those with MSI-high may respond favorably to pembrolizumab. Therefore, we should ascertain the MSI status of any PanNEC in routine practice.",
"affiliations": "Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan. t-iwai@kitasato-u.ac.jp.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.;Department of Gastroenterology, Internal Medicine, Kitasato University School of Medicine, 1-15-1 Kitasato, Minami-ku, Sagamihara, Kanagawa, 252-0375, Japan.",
"authors": "Kogami|Taro|T|;Iwai|Tomohisa|T|http://orcid.org/0000-0001-6656-4499;Kida|Mitsuhiro|M|;Okuwaki|Kosuke|K|;Hasegawa|Rikiya|R|;Kurosu|Takahiro|T|;Watanabe|Masafumi|M|;Matsushita|Masahiro|M|;Imawari|Kana|K|;Adachi|Kai|K|;Tadehara|Masayoshi|M|;Tamaki|Akihiro|A|;Imaizumi|Hiroshi|H|;Koizumi|Wasaburo|W|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C582435:pembrolizumab",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-021-01505-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "14(6)",
"journal": "Clinical journal of gastroenterology",
"keywords": "MSI-high; Neuron-specific enolase; PanNEC; Pembrolizumab",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D018278:Carcinoma, Neuroendocrine; D006801:Humans; D008297:Male; D053842:Microsatellite Instability; D010179:Pancreas",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1804-1810",
"pmc": null,
"pmid": "34495482",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of pancreatic neuroendocrine carcinoma with a favorable clinical response to pembrolizumab.",
"title_normalized": "a case of pancreatic neuroendocrine carcinoma with a favorable clinical response to pembrolizumab"
} | [
{
"companynumb": "JP-MYLANLABS-2022M1045524",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Programmed cell death-1 (PD-1) inhibitors stimulate immune recognition of tumour cells in cancer patients, but have significant autoimmune side effects including pneumonitis. We report the case of a patient with asthma and mild eosinophilia who developed unusual pulmonary side effect of bronchiectasis, severe eosinophilia (absolute eosinophil count: 3200 c/mm3) and elevated IgE levels (7050 IU/mL; normal: <164 IU/mL) 4 months into therapy with the PD-1 inhibitor pembrolizumab. Aspergillus fumigatus IgG was elevated at 15.60 U/mL (normal: <12.01 U/mL). He responded to therapy with corticosteroids and voriconazole and was able to resume pembrolizumab thereafter with good clinical response.",
"affiliations": "Internal Medicine, Reading Health System, West Reading, Pennsylvania, USA.;Pulmonary and Critical Care, Tower Health System, West Reading, Pennsylvania, USA.",
"authors": "Donato|Anthony A|AA|http://orcid.org/0000-0002-8294-6769;Krol|Ronald|R|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000908:Antibodies, Fungal; D061067:Antibodies, Monoclonal, Humanized; C582435:pembrolizumab; D065819:Voriconazole",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-227814",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(2)",
"journal": "BMJ case reports",
"keywords": "lung cancer (oncology); unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000908:Antibodies, Fungal; D061067:Antibodies, Monoclonal, Humanized; D001229:Aspergillosis, Allergic Bronchopulmonary; D001232:Aspergillus fumigatus; D004804:Eosinophils; D006801:Humans; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed; D065819:Voriconazole",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30765445",
"pubdate": "2019-02-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28797493;27472273;29376934;20722638;27646942;28945858",
"title": "Allergic bronchopulmonary aspergillosis presumably unmasked by PD-1 inhibition.",
"title_normalized": "allergic bronchopulmonary aspergillosis presumably unmasked by pd 1 inhibition"
} | [
{
"companynumb": "US-009507513-1902USA011445",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nAnaemia in low-risk myelodysplastic syndromes (MDS) is associated with reduced quality of life (QoL). Response to treatment with erythropoietin ± granulocyte colony-stimulating factor (G-CSF) is associated with improved QoL, but whether transfusion therapy with higher haemoglobin (Hb) target levels has similar effects is unknown. The objective for this prospective phase II Nordic multicentre trial was to assess QoL, response rate and physical function in elderly anaemic MDS patients treated to a target Hb level of >120 g/L.\n\n\nMETHODS\nThirty-six elderly patients with low- and intermediate-1 risk MDS received darbepoetin (DA) 300 μg/wk, with the addition of G-CSF if no response. If the Hb target was reached at 16 wk, treatment was maintained until week 26. Remaining patients were transfused to reach the target level for at least 8 wk.\n\n\nRESULTS\nTwenty-seven patients completed the study. Response rate to DA ± G-CSF was 67% in evaluable patients and 56% according to intention to treat. Eighteen patients reached the target Hb level according to protocol. QoL scores for fatigue, dyspnoea, constipation, and physical, role and social functioning improved significantly during study, with similar results for transfused and untransfused patients. Maintaining Hb >120 g/L did not confer a higher transfusion rate, once the target was reached. In two of fourteen patients, magnetic resonance imaging T2* indicated cardiac iron overload, however, without association with ferritin levels.\n\n\nCONCLUSIONS\nIn elderly anaemic MDS patients, an increment in haemoglobin is associated with improved QoL, whether induced by growth factor treatment or transfusion therapy.",
"affiliations": "Section of Hematology and Coagulation, Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden. herman.n-ehle@vgregion.se",
"authors": "Nilsson-Ehle|Herman|H|;Birgegård|Gunnar|G|;Samuelsson|Jan|J|;Antunovic|Petar|P|;Astermark|Jan|J|;Garelius|Hege|H|;Engström|Lena M|LM|;Kjeldsen|Lars|L|;Nilsson|Lars|L|;Olsson|Anna|A|;Skov-Holm|Mette|M|;Wallvik|Jonas|J|;Gulbrandsen|Nina|N|;Hellström-Lindberg|Eva|E|",
"chemical_list": "D006454:Hemoglobins; D011994:Recombinant Proteins; D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D000068256:Darbepoetin alfa; D005293:Ferritins; D000069585:Filgrastim",
"country": "England",
"delete": false,
"doi": "10.1111/j.1600-0609.2011.01654.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "87(3)",
"journal": "European journal of haematology",
"keywords": null,
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000068256:Darbepoetin alfa; D017707:Erythrocyte Transfusion; D004921:Erythropoietin; D005260:Female; D005293:Ferritins; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006454:Hemoglobins; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D009190:Myelodysplastic Syndromes; D011788:Quality of Life; D011994:Recombinant Proteins; D016896:Treatment Outcome",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "244-52",
"pmc": null,
"pmid": "21623919",
"pubdate": "2011-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Quality of life, physical function and MRI T2* in elderly low-risk MDS patients treated to a haemoglobin level of ≥120 g/L with darbepoetin alfa ± filgrastim or erythrocyte transfusions.",
"title_normalized": "quality of life physical function and mri t2 in elderly low risk mds patients treated to a haemoglobin level of 120 g l with darbepoetin alfa filgrastim or erythrocyte transfusions"
} | [
{
"companynumb": "SE-AMGEN-SWESP2016141748",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DARBEPOETIN ALFA"
},
"drugadditional": null,
... |
{
"abstract": "Perampanel (PER) is a new-generation antiepileptic drug that has an occasional but significant shortcoming, psychiatric adverse effects (PAEs). Recently, antiepileptic drug-related adverse reactions, such as skin rash and even PAEs, have been discovered to be correlated with certain human leukocyte antigen (HLA) types. Thus, we aimed to analyze specific HLA alleles as risk factors for PER-PAEs. We prospectively enrolled 17 patients with epilepsy who were prescribed PER between May 2016 and Jul 2018 at Seoul National University Hospital and developed PAEs while taking PER. Their HLA types were analyzed compared to those of 19 patients in the PAE-tolerant group and the general Korean population. In silico docking was performed with two different computational programs, AutoDock Vina and SwissDock, to theoretically evaluate the binding affinity of PER in the grooves of the specific HLA alleles. The HLA-DQB1*06:01, DRB1*08:03, and B*54:01 alleles were significantly associated with the patients who developed PER-PAEs compared with the general Korean population (odds ratio [OR] 3.94, p = 0.008, OR 9.24, p = 0.037, and OR 3.25, p = 0.041, respectively). As a haplotype, the combination of the three alleles was significantly more frequent in the PER-PAE group than in both the PER-tolerant group and the general Korean population. DQB1*06:01 and B*54:01 also demonstrated higher docking scores with PER than other alleles. This is the first study to analyze the association of PER-PAEs with specific HLA genotypes. Our results suggest that an HLA-associated genetic predisposition and a possible immunological mechanism are involved in the occurrence of PER-PAEs.",
"affiliations": "Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Department of Neurology, Ajou University School of Medicine, Suwon, South Korea.;Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Department of Neurology, Gyeongsang National University Changwon Hospital, Gyeongsang National University School of Medicine, Changwon, South Korea.;Department of Neurology, Keimyung University Dongsan Medical Center, Daegu, South Korea.;Department of Neurology, Ulsan University Hospital, Ulsan, South Korea.;Department of Neurology, Chamjoeun Hospital, Gwangju, South Korea.;Department of Neurology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea.;Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea.;Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea. stemcell.snu@gmail.com.;Laboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744, South Korea. sangkun2923@gmail.com.",
"authors": "Jang|Yoonhyuk|Y|http://orcid.org/0000-0002-3346-3357;Kim|Tae-Joon|TJ|http://orcid.org/0000-0001-8451-6634;Moon|Jangsup|J|http://orcid.org/0000-0003-1282-4528;Yang|Tae-Won|TW|;Kim|Keun Tae|KT|;Park|Byeong-Su|BS|;Lim|Jung-Ah|JA|;Jun|Jin-Sun|JS|;Lee|Soon-Tae|ST|;Jung|Keun-Hwa|KH|;Park|Kyung-Il|KI|;Jung|Ki-Young|KY|;Chu|Kon|K|http://orcid.org/0000-0001-5863-0302;Lee|Sang Kun|SK|http://orcid.org/0000-0003-1908-0699",
"chemical_list": "D000927:Anticonvulsants; D059866:HLA-DQ beta-Chains; D009570:Nitriles; D011728:Pyridones; C551441:perampanel",
"country": "England",
"delete": false,
"doi": "10.1038/s41598-020-70601-1",
"fulltext": "\n==== Front\nSci Rep\nSci Rep\nScientific Reports\n2045-2322 Nature Publishing Group UK London \n\n70601\n10.1038/s41598-020-70601-1\nArticle\nHLAs associated with perampanel-induced psychiatric adverse effects in a Korean population\nhttp://orcid.org/0000-0002-3346-3357Jang Yoonhyuk 1 http://orcid.org/0000-0001-8451-6634Kim Tae-Joon 2 http://orcid.org/0000-0003-1282-4528Moon Jangsup 13 Yang Tae-Won 4 Kim Keun Tae 5 Park Byeong-Su 6 Lim Jung-Ah 7 Jun Jin-Sun 8 Lee Soon-Tae 1 Jung Keun-Hwa 1 Park Kyung-Il 19 Jung Ki-Young 1 http://orcid.org/0000-0001-5863-0302Chu Kon stemcell.snu@gmail.com 1 http://orcid.org/0000-0003-1908-0699Lee Sang Kun sangkun2923@gmail.com 1 1 grid.412484.f0000 0001 0302 820XLaboratory for Neurotherapeutics, Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 110-744 South Korea \n2 grid.251916.80000 0004 0532 3933Department of Neurology, Ajou University School of Medicine, Suwon, South Korea \n3 grid.412484.f0000 0001 0302 820XRare Disease Center, Seoul National University Hospital, Seoul, South Korea \n4 grid.256681.e0000 0001 0661 1492Department of Neurology, Gyeongsang National University Changwon Hospital, Gyeongsang National University School of Medicine, Changwon, South Korea \n5 grid.414067.00000 0004 0647 8419Department of Neurology, Keimyung University Dongsan Medical Center, Daegu, South Korea \n6 grid.412830.c0000 0004 0647 7248Department of Neurology, Ulsan University Hospital, Ulsan, South Korea \n7 Department of Neurology, Chamjoeun Hospital, Gwangju, South Korea \n8 grid.464606.60000 0004 0647 432XDepartment of Neurology, Kangnam Sacred Heart Hospital, Hallym University College of Medicine, Seoul, South Korea \n9 grid.412484.f0000 0001 0302 820XDepartment of Neurology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, South Korea \n12 8 2020 \n12 8 2020 \n2020 \n10 136676 5 2020 29 7 2020 © The Author(s) 2020Open 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/.Perampanel (PER) is a new-generation antiepileptic drug that has an occasional but significant shortcoming, psychiatric adverse effects (PAEs). Recently, antiepileptic drug-related adverse reactions, such as skin rash and even PAEs, have been discovered to be correlated with certain human leukocyte antigen (HLA) types. Thus, we aimed to analyze specific HLA alleles as risk factors for PER-PAEs. We prospectively enrolled 17 patients with epilepsy who were prescribed PER between May 2016 and Jul 2018 at Seoul National University Hospital and developed PAEs while taking PER. Their HLA types were analyzed compared to those of 19 patients in the PAE-tolerant group and the general Korean population. In silico docking was performed with two different computational programs, AutoDock Vina and SwissDock, to theoretically evaluate the binding affinity of PER in the grooves of the specific HLA alleles. The HLA-DQB1*06:01, DRB1*08:03, and B*54:01 alleles were significantly associated with the patients who developed PER-PAEs compared with the general Korean population (odds ratio [OR] 3.94, p = 0.008, OR 9.24, p = 0.037, and OR 3.25, p = 0.041, respectively). As a haplotype, the combination of the three alleles was significantly more frequent in the PER-PAE group than in both the PER-tolerant group and the general Korean population. DQB1*06:01 and B*54:01 also demonstrated higher docking scores with PER than other alleles. This is the first study to analyze the association of PER-PAEs with specific HLA genotypes. Our results suggest that an HLA-associated genetic predisposition and a possible immunological mechanism are involved in the occurrence of PER-PAEs.\n\nSubject terms\nHaplotypesEpilepsyImmunologyRisk factorsthe Seoul National University Hospital Research Fund0620172900Lee Sang Kun issue-copyright-statement© The Author(s) 2020\n==== Body\nIntroduction\nPerampanel (PER) is a new-generation antiepileptic drug (AED) that blocks α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors1–3. PER has many advantages as a new-generation AED: it has efficacy in drug-resistant focal seizures, a fast loading capacity, few drug-drug interactions, a long half-life, and no critical cutaneous adverse effect as seen with aromatic AEDs4,5. Therefore, PER has prevalently been prescribed as a good option in clinical settings.\n\nHowever, PER has a significant side effect, psychiatric adverse effects (PAEs)6,7. In 5–10% of the patients prescribed PER, aggression and irritability have been reported to occur5,8. The onset of the symptoms is obscure, but if the symptoms develop, they are hazardous to both the patients and their caregivers; therefore, PER should be discontinued in these patients. However, the pathomechanism of PAEs is largely unknown, making it difficult to prevent symptoms. Given that levetiracetam (LEV)-associated PAEs are associated with specific human leukocyte antigen (HLAs)9, we hypothesized that PER-PAEs might have a similar HLA-associated mechanism.\n\nHere, we investigated HLA associations in patients with PER-PAEs. The HLA genotypes of the PER-PAE group were compared to those of the general population as well as the PER-tolerant group. In addition, through in silico analysis, possible immunological reactions were investigated as a pathomechanism of PER-PAEs.\n\nMethod\nPatient enrollment\nThis study was approved by the Institutional Review Board of the Seoul National University (IRB No 1604-067-754). Written informed consent was obtained from all patients. All methods were carried out in accordance with relevant guidelines and regulations.\n\nAdult patients (age 18–85) who were diagnosed with epilepsy at Seoul National University Hospital were prospectively recruited between May 2016 and Jul 2018 for enrolment in the PER-PAE group. The psychiatric manifestations were evaluated by epilepsy specialists according to the modified version of the Psychiatric Symptoms and Behavior Checklist of the Vanderbilt-Kennedy Center10. Psychiatric symptoms included agitation, irritability, aggression, self-injurious behavior, labile mood, impulsivity, and psychosis (delusion, depersonalization, etc.). If psychiatric manifestations were detected, PER was immediately discontinued. PER-PAEs were defined if the patients developed psychiatric symptoms after the last dose titration of PER within 6 weeks, if PER was the only offending drug the patients were exposed to, or if the symptoms disappeared after the discontinuation of PER. Patients with the following conditions were excluded from the study: (1) previous mental illness history, (2) severe mental retardation, (3) severe illness resulting in an inability to evaluate psychiatric symptoms, (4) incomplete clinical data, and (5) an uncertainty of PER as the causative drug. As a control group, the PER-tolerant group and a general Korean population group were compared to the PER-PAE group. The PER-tolerant group was composed of 19 patients who did not show any psychiatric symptoms with a 10 mg dose of PER for 6 months. We used the data of 485 individuals for the general Korean population group11.\n\nHLA genotyping\nFor DNA extraction, peripheral blood was collected from every patient in both the PER-PAE and PER-tolerant groups. Then, the genotyping of HLA class I and class II genes, including HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1, was performed at the four-digit allele level by direct sequence analysis with established protocols (Biowithus, Seoul, Korea). The previously documented allele frequencies in the Korean population were used as the control group values of the general Korean population.\n\nIn silico docking\nIn silico docking was performed as previously described12. We obtained the three-dimensional structures of PER from the Human Metabolome Database (https://www.hmdb.ca). All HLA subtypes observed in the present study were analyzed in association with PER molecules. The crystallographic structures of HLA-A*02:07, A*11:01, DRB1*11:01, A*24:02, and B*15:01 have been previously determined (Protein Data Bank [PDB] code 3OXS, 4MJ5, 6CPN, 3WL9, 5TXS, respectively). The heterodimeric structures including HLA-DRB1*08:03, DQB1*06:01, B*54:01, C*14:02, C*15:02, DQB1*05:03, DQB1*04:01, and DRB1*04:05 were created using homology modeling with Swiss-Model and UCSF Chimera from the template structures (PDB code 4IS6 for HLA-DRB1, 6DIG for HLA-DQB1, 5TXS for HLA-B, 5VGD for HLA-C) because their crystallographic structures have not been determined experimentally. We used a computational program, AutoDock Vina, and a web-based docking software program, SwissDock (https://www.swissdock.ch/), to calculate the docking score (ΔG) of PER13,14.\n\nStatistics\nThe difference in the HLA genotype frequencies between the PER-PAE group and the control groups was analyzed with Fisher’s exact test or the Mann–Whitney U test. Haplotypes of the control groups were estimated using Arlequin software (version 3.5.2.2) as previously described15,16. Statistical analysis was conducted in R version 3.5.3 (R Foundation for Statistical Computing, Vienna, Austria), and a p-value < 0.05 was considered statistically significant.\n\nEthical publication statement\nWe confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.\n\nResult\nCharacteristics and psychiatric manifestations of patients with PER-PAEs\nA total of seventeen patients developed PER-PAEs (Table 1). Of the patients with PER-PAEs, seven (41%) were male, and the median age was 33 years [interquartile range 28–43 years]. Temporal lobe epilepsy was the most common indication for the administration of PER (13, 76%). The patients had suffered epilepsy for 17.6 ± 8.2 years, and until the onset of PAEs, PER was administered for 2.6 ± 2.3 months with a median dose of 4 mg [interquartile range 4–6 mg].Table 1 Demographics and clinical characteristics of the patients with perampanel-induced psychiatric adverse events.\n\nNoa\tSex\tAge\tSeizure type\tClinical diagnosis\tBaseline seizure frequency\tEpilepsy duration (yr)\tConcomitant AEDs (mg/d)\tLatency (months)\tPER dose (mg/day)\tManifestations of PER-PAEs\t\n1\tF\t28\tFocal aware\tPLE\t1/m\t21\tCBZ 1,100 dVPA 2,000 ZNS 300 PGB 300 CZP 1.5\t1\t6\tSelf-injurious behavior, aggression, impulsivity, psychosis (paranoid delusion)\t\n2\tF\t32\tFocal impaired awareness\tTLE\t1/m\t12\tLEV 1,500 ZNS 300 CLB 30\t7\t8\tSelf-injurious behavior, impulsivity\t\n3\tM\t27\tFocal impaired awareness\tTLE\t2/d\t27\tOXC 1,500 PGB 600 CZP 1.5\t3\t6\tSelf-injurious behavior, labile mood, impulsivity\t\n4\tF\t33\tFocal impaired awareness or focal to bilateral tonic–clonic\tTLE\t8/m\t20\tCBZ 1,200 LTG 300 ZNS 400\t3\t4\tPsychosis (undescribed delusion)\t\n5\tF\t36\tFocal impaired awareness or focal to bilateral tonic–clonic\tTLE\t4/m\t17\tLTG 200 OXC 750 LEV 1,000 VPA 600 PB 90 CLB 10\t2\t6\tPsychosis (depersonalization)\t\n6\tF\t58\tFocal to bilateral tonic–clonic\tTLE\t3/m\t17\tOXC 1,800 ZNS 200 PRM 1,000 CLB 20\t8\t2\tPsychosis (persecutory delusion), irritability\t\n7\tM\t28\tGeneralized\tIGE\t1/yr\t22\tCBZ 800\t1\t4\tImpulsivity\t\n8\tF\t44\tFocal impaired awareness\tTLE\t2/m\t12\tZNS 600\t2\t6\tAggression, irritability\t\n9\tF\t34\tFocal impaired awareness or focal to bilateral tonic–clonic\tTLE\t12/m\t12\tLTG 300 OXC 900 dVPA 1,600 TPM 250 PGB 150 CLB 12.5\t4\t8\tAggression, irritability\t\n10\tF\t19\tFocal impaired awareness\tTLE\t3/m\t2\tLEV 500\t3\t4\tAggression\t\n11\tF\t40\tFocal impaired awareness\tTLE\t4/m\t16\tCBZ 1,000 dVPA 250\t1\t4\tAggression, irritability\t\n12\tM\t25\tFocal impaired awareness\tTLE\t3/m\t24\tOXC 1,200 LEV 1,000 CLB 20\t< 1\t2\tAggression, agitation, labile mood\t\n13\tM\t47\tFocal impaired awareness\tTLE\t4/m\t22\tOXC 1,800 LEV 2,000 PB 180 CLB 10\t1\t6\tAggression, agitation, loss of interest\t\n14\tM\t65\tFocal to bilateral tonic–clonic\tTLE\t6/yr\t3\tRFM 200\t< 1\t4\tAggression, labile mood\t\n15\tM\t29\tFocal impaired awareness or focal to bilateral tonic–clonic\tFLE\t10/m\t18\tVPA 1,500 LEV 1,000\t5\t8\tAggression\t\n16\tF\t25\tFocal impaired awareness\tTLE\t3/d\t18\tPHT 200 LEV 2,000 TPM 400 CLB 10\t3\t4\tAggression\t\n17\tM\t43\tFocal to bilateral tonic–clonic\tFLE\t4/yr\t36\tOXC 1,200 dVPA 1,750\t1\t4\tAggression\t\nNo number, AED antiepileptic drug, PER perampanel, PER-PAE perampanel-induced psychiatric adverse event, F female, M male, PLE parietal lobe epilepsy, TLE temporal lobe epilepsy, FLE frontal lobe epilepsy, IGE idiopathic generalized epilepsy, m month, d day, yr year, CBZ carbamazepine, dVPA divalproex, ZNS zonisamide, PGB pregabalin, CZP clonazepam, LEV levetiracetam, CLB clobazam, OXC oxcarbazepine, LTG lamotrigine, VPA valproic acid, PB phenobarbital, PRM primidone, TPM topiramate, RFM rufinamide, PHT phenytoin.\n\naPatients were listed according to representative types of PER-PAEs and significant alleles.\n\n\n\nThe most common manifestation of PER-PAEs was aggression (11, 65%) (Table 1). For the second most common manifestation of PAEs, irritability, impulsivity, and psychosis were similarly common (4, 24%, respectively). Specific psychoses were as follows: paranoid delusion (Patient 1), depersonalization (Patient 5), persecutory delusion (Patient 6), and undescribed delusion in the medical record (Patient 4). Three patients (18%, Patient 1, 2, 3) attempted self-injurious behavior, and for one patient (Patient 3), it was serious enough to be admitted to the intensive care unit. Additionally, three patients (18%, Patient 3, 12, 14) showed labile mood. Otherwise, two patients (Patient 12, 13) had agitation, and one patient (Patient 13) suffered a loss of interest.\n\nHLA genotypes and their association with the phenotype of PER-PAE\nHLA genotypes were analyzed in seventeen patients with PER-PAEs and in nineteen patients with PER tolerance. Detailed four-digit HLA alleles of the patients with PER-PAEs are described in Table 2 and Supplementary Table S1.Table 2 Human leukocyte antigen genotypes of patients with perampanel-induced psychiatric adverse events.\n\nNoa\tRepresentative PER-PAE\tHLA-A\tHLA-B\tHLA-C\tHLA-DQB1\tHLA-DRB1\t\n1\tSelf-injurious behavior\t30:01/30:01\t13:02/54:01\t01:02/06:02\t06:01/06:03\t08:03/13:01\t\n2\t02:07/24:02\t40:02/46:01\t01:02/03:04\t03:01/06:01\t08:03/11:01\t\n3\t11:01/33:03\t15:01/58:01\t03:02/04:01\t03:01/03:02\t04:01/04:06\t\n4\tPsychosis\t24:02/26:01\t54:01/55:02\t01:02/01:02\t03:02/06:01\t08:02/08:03\t\n5\t02:07/24:02\t39:01/46:01\t01:02/07:02\t06:01/06:01\t08:03/08:03\t\n6\t32:01/33:03\t44:02/58:01\t03:02/05:01\t02:01/03:01\t03:01/12:01\t\n7\tImpulsivity\t11:01/24:02\t51:01/52:01\t12:02/14:02\t03:03/06:01\t09:01/15:02\t\n8\tAggression\t02:01/33:03\t15:18/54:01\t07:04/14:03\t04:01/06:01\t04:05/08:03\t\n9\t02:06/11:01\t51:01/52:01\t12:02/14:02\t04:02/06:01\t04:10/15:02\t\n10\t24:02/24:02\t07:02/54:01\t01:02/07:02\t05:01/06:01\t01:01/08:03\t\n11\t02:03/02:06\t07:02/38:02\t07:02/07:02\t05:01/05:01\t01:01/15:02\t\n12\t11:01/11:02\t54:01/55:02\t01:02/12:03\t03:01/05:03\t11:01/14:05\t\n13\t31:01/33:03\t40:06/58:01\t03:02/08:01\t03:01/06:09\t12:02/13:02\t\n14\t02:01/26:01\t15:11/51:01\t03:03/03:04\t03:01/05:02\t11:01/14:54\t\n15\t02:01/02:06\t15:38/40:01\t03:03/03:04\t03:02/06:02\t04:06/15:01\t\n16\t02:07/11:01\t51:01/51:01\t14:02/14:02\t03:01/06:02\t11:01/15:01\t\n17\t30:04/31:01\t14:01/51:01\t08:02/14:02\t04:02/06:02\t04:04/15:01\t\nNo number, PER-PAE perampanel-induced psychiatric adverse event, HLA human leukocyte antigen.\n\nBold typefaces indicate alleles that increased significantly in this PER-PAE group. See Table 3.\n\naPatients were listed according to representative types of PER-PAEs and significant alleles.\n\n\n\nAmong the alleles, the frequencies of DQB1*06:01 and B*54:01 were significantly higher in the PER-PAE group than in the general Korean population (p = 0.008, odds ratio [OR] 3.94, 95% confidence interval [CI] 1.47–11.60, p = 0.041, OR 3.25, 95% CI 1.06–9.52, respectively) but not in the PER-tolerant group (Table 3). In addition, the HLA-DRB1*08:03 allele also showed a significantly higher genotype frequency in the PER-PAE group than in both the PER-tolerant group (p = 0.037, OR 9.24, 95% CI 1.14–234.18) and the general Korean population (p = 0.041, OR 2.97, 95% CI 1.06–8.34).Table 3 Association between four-digit HLA alleles and perampanel-induced psychiatric adverse events.\n\nHLA allele or haplotype\tPhenotype frequency\tPER-PAE versus PER-tolerant\tPER-PAE versus general population\tPER-tolerant versus general population\tDocking scores in –ΔG\t\nPER-PAE (% of 17)\tPER-tolerant (% of 19)\tGeneral population (% of 485)\tOR (95% CI)\tP value\tOR (95% CI)\tP value\tOR (95% CI)\tP value\tAutoDock Vina\tSwissDock\t\nPrevalent alleles or haplotypes in the PER-PAE group\t\nDQB1*06:01\t8 (47%)\t3 (16%)\t89 (18%)\t4.53 (0.90–24.61)\t0.070\t3.94 (1.47–11.60)\t0.008a\t0.83 (0.20–2.88)\t> 0.999\t10.7\t8.0\t\nDRB1*08:03\t6 (35%)\t1 (5%)\t75 (15%)\t9.24 (1.14–234.18)\t0.037a\t2.97 (1.06–8.34)\t0.041a\t0.30 (0.01–2.01)\t0.333\t8.2\t7.6\t\nB*54:01\t5 (29%)\t3 (16%)\t55 (11%)\t2.17 (0.42–12.39)\t0.434\t3.25 (1.06–9.52)\t0.041a\t1.46 (0.35–4.91)\t0.471\t9.6\t7.8\t\nA*02:07\t3 (18%)\t1 (5%)\t29 (6%)\t3.72 (0.37–104.92)\t0.326\t3.36 (0.78–12.62)\t0.087\t0.87 (0.04–5.43)\t> 0.999\t8.0\t7.6\t\nA*11:01\t5 (29%)\t1 (5%)\t100 (21%)\t7.11 (0.75–183.93)\t0.081\t1.60 (0.53–4.55)\t0.369\t0.21 (0.01–1.40)\t0.143\t9.0\t7.9\t\nDRB1*11:01\t4 (24%)\t2 (11%)\t43 (9%)\t2.55 (0.41–21.63)\t0.391\t3.15 (0.91–10.05)\t0.065\t1.21 (0.19–5.16)\t0.683\t8.1\t7.6\t\nHaplotype #1b\t6 (35%)\t1 (5%)\t66 (14%)\t9.24 (1.14–234.18)\t0.037a\t3.45 (1.22–9.74)\t0.024a\t0.35 (0.02–2.35)\t0.492\t\t\t\nHaplotype #2b\t4 (24%)\t0\t10 (2%)\tInf (1.11–Inf)\t0.040a\t14.37 (3.73–56.51)\t0.001a\t0 (0–11.96)\t> 0.999\t\t\t\nPrevalent alleles in the PER-tolerant group\t\nC*14:02\t4 (24%)\t6 (32%)\t61 (13%)\t0.67 (0.15–3.12)\t0.717\t2.13 (0.62–6.62)\t0.257\t3.20 (1.16–9.35)\t0.029a\t8.8\t7.2\t\nC*15:02\t0\t3 (16%)\t25 (5%)\t0 (0–1.84)\t0.231\t0 (0–4.30)\t> 0.999\t3.44 (0.80–12.60)\t0.082\t7.3\t7.0\t\nA*24:02\t5 (29%)\t11 (58%)\t188 (39%)\t0.31 (0.07–1.27)\t0.106\t0.66 (0.22–1.87)\t0.613\t2.17 (0.84–5.59)\t0.101\t9.2\t7.0\t\nDQB1*05:03\t1 (6%)\t4 (21%)\t46 (9%)\t0.24 (0.01–2.12)\t0.342\t0.60 (0.03–3.65)\t> 0.999\t2.54 (0.75–7.93)\t0.109\t7.9\t7.8\t\nDQB1*04:01\t1 (6%)\t5 (26%)\t80 (16%)\t0.18 (0.01–1.74)\t0.182\t0.32 (0.02–1.95)\t0.332\t1.81 (0.61–5.40)\t0.343\t9.5\t7.8\t\nDRB1*04:05\t1 (6%)\t5 (26%)\t83 (17%)\t0.18 (0.01–1.74)\t0.182\t0.30 (0.01–1.87)\t0.329\t1.73 (0.58–5.15)\t0.350\t8.1\t7.6\t\nB*15:01\t1 (6%)\t4 (21%)\t93 (19%)\t0.24 (0.01–2.12)\t0.342\t0.26 (0.01–1.79)\t0.218\t1.12 (0.34–3.59)\t0.771\t9.2\t7.1\t\nHLA human leukocyte antigen, PER-PAE perampanel-induced psychiatric adverse event, PER perampanel, OR odds ratio, CI confidence interval.\n\naP value < 0.05.\n\nbHaplotype #1, HLA-DQB1*06:01-DRB1*08:03, Haplotype #2: HLA-B*54:01-DQB1*06:01-DRB1*08:03 or HLA-B*54:01-DRB1*08:03.\n\n\n\nAs a haplotype, concomitant DQB1*06:01 and DRB1*08:03 alleles showed significantly higher frequency in the PER-PAE group than in both the PER-tolerant group (p = 0.037, OR 9.24, 95% CI 1.14–234.18) and the general Korean population (p = 0.024, OR 3.45, 95% CI 1.22–9.74) (Table 3). The combination of the alleles DQB1*06:01, DRB1*08:03, and B*54:01 was also significantly more frequent both in the PER-tolerant group (p = 0.040, OR Inf, 95% CI 1.11–Inf) and in the general Korean population (p = 0.014, OR 14.37, 95% CI 3.73–56.51). Remarkably, haplotype HLA-DQB1*06:01-DRB1*08:03 had a tendency to be more frequent in the patients with more severe PER-PAEs; four of 6 patients (66.7%) who showed self-injurious behavior or psychosis concomitantly had the DQB1*06:01 and DRB1*08:03 alleles (Table 2).\n\nIn silico docking\nThe binding affinity of the PER molecule to HLA alleles calculated by two different software programs is displayed in Table 3. HLA alleles causing PER-PAEs tended to have higher docking scores than alleles prevalent in the PER-tolerant group. In detail, PER was predicted to be docked into the groove of DQB1*06:01 (Fig. 1) with a docking score of 10.7, which was higher than the docking scores of DQB1*05:03 and DQB1*04:01 (docking scores (− kcal/mol) 7.9 and 9.5, respectively, in AutoDock Vina). B*54:01 had a higher binding affinity than B*15:01 (docking scores (− kcal/mol) 9.6 vs. 9.2 in AutoDock Vina and 7.8 vs. 7.1 in SwissDock).Figure 1 In silico modeling of the molecular interaction between HLA-DQB1*06:01 and PER. (A,B) The PER molecule was predicted to be docked into the middle of the groove of HLA-DQB1*06:01 with higher affinity (− 10.7 kcal/mol). (C) Specific plot of the interaction between ligand (PER) and receptor (HLA-DQB1*06:01) using LigPlot + v2.1. HLA human leukocyte antigen, PER perampanel.\n\n\n\nHowever, DRB1*08:03, the allele significantly more frequent in the PER-PAE group than in both the PER-tolerant group and the general Korean population, did not show stronger binding than DRB1*04:05 (docking scores (kcal/mol) 8.2 vs. 8.1 in AutoDock Vina and 7.6 vs. 7.6 in SwissDock).\n\nDiscussion\nThis is the first study to analyze the association of PER-PAEs with specific HLA genotypes. We demonstrated that the HLA-DQB1*06:01, DRB1*08:03, and B*54:01 alleles were associated with PER-PAEs. As a haplotype, the combination of the three alleles was significantly more frequent in the PER-PAE group than in both the PER-tolerant group and the general Korean population. Among them, DQB1*06:01 might be the allele most susceptible to PER-PAEs, since it was more frequent in the patients with more severe PAEs and had a higher docking score with PER than other alleles. Our research implies that HLA-associated genetic susceptibility could be involved in the occurrence of PER-PAEs.\n\nIn our study, the PER-PAEs were categorized according to the modified version of the Psychiatric Symptoms and Behavior Checklist of the Vanderbilt-Kennedy Center. Aggression was the most common PAE observed in our patients taking PER. This is consistent with previous reports6,7, and aggression dramatically increases the burden of epilepsy on patients and caregivers. Impulsivity, one of the second most common symptoms, becomes extremely dangerous when it is accompanied by self-injurious behavior17,18. Indeed, all three patients who attempted self-injurious behavior simultaneously showed impulsivity, and one male patient even attempted suicide, which resulted in his admittance to an intensive care unit. Therefore, in regard to the patients’ safety and caregivers’ burden, the importance of researching the risk factors for PER-PAEs cannot be emphasized enough.\n\nSpecific HLA genotypes are known to be risk factors for several AED adverse reactions. For instance, we have demonstrated the association between the cutaneous adverse reaction induced by lamotrigine and oxcarbazepine with certain HLA types12,19. By showing in silico docking of the AED in the HLA groove, we have suggested the possibility of oxcarbazepine acting as a hapten in the allergic reaction. In the same regard, it is remarkable that PER-PAEs had significant associations with the HLA-DQB1*06:01, DRB1*08:03, and B*54:01 alleles, as LEV-PAEs were correlated with the specific HLA genotype A*11:019. This implies that PAEs that develop in the brain could also be idiosyncratic adverse reactions induced by an immunological response. In patients with autoimmune encephalitis such as N-methyl-d-aspartate receptor-encephalitis and leucine-rich glioma-inactivated protein1-antibody encephalitis, it has been demonstrated that psychiatric manifestations can be induced by an autoimmune mechanism in the brain10,20,21. It might not be a coincidence that an association of house-dust-mite-sensitive allergic rhinitis and the same HLA genotypes, DQB1*06:01 and DRB1*08:03, was demonstrated in Chinese subjects22. Moreover, in the Korean population, B*54:01 was associated with Kawasaki disease, an acute systemic vasculitis causing heart disease in children23.\n\nThe in silico docking analysis supports this hypothesis. Remarkably, the docking scores of DRB1*06:01 and B*54:01 were higher than those of the other alleles that were prevalent in the PER-tolerant group. Since the docking score indirectly indicates a binding affinity of an antigen to HLA grooves, the higher scores imply stronger binding of PER to the particular HLA as the antigen or hapten causing the immunological reaction. It is notable that two different programs, AutoDock Vina and SwissDock, showed similar results for the docking scores. Thus, our analysis would reflect more objective and realistic results. On the other hand, the score of DRB1*08:03 was not much higher than those of the other alleles. DRB1*08:03 might be just a bystander of DQB1*06:01 or B*54:01, not the main cause of the immunological reaction that induces PER-PAEs. Indeed, both alleles, DQB1*06:01 and B*54:01, have high phenotypic frequencies (14% for HLA-DQB1*06:01-DRB1*08:03 and 2% for HLA-B*54:01-DQB1*06:01-DRB1*08:03, respectively) when composing the haplotype with DRB1*08:03 in the Korean population11. In our study, the haplotype analysis further demonstrated that HLA-DQB1*06:01-DRB1*08:03 and HLA-B*54:01-DQB1*06:01-DRB1*08:03 were concomitantly associated with PER-PAEs.\n\nAccording to the high docking scores, the alleles DQB1*06:01 or B*54:01 could be the main risk factors involved in the PAE pathomechanism. However, it is remarkable that the two alleles have different antigen processing; DQB1*06:01 is a major histocompatibility complex (MHC) class II allele, interacting with CD4+ T cells through extracellular antigen processing, and B*54:01 is an MHC class I allele, interacting with CD8+ T cells through intracellular processing. In the clinic, CD4+ T cell involvement might be more plausible, in that PER-PAEs are fully reversible if the AED is discontinued, than a cytotoxic CD8+ T cell response, which results in irreversible damage to the target. Actually, for AED-related cutaneous adverse drug reactions, MHC class II molecules are associated with relatively mild maculopapular eruption, but MHC class I molecules are significantly correlated with an irreversible skin rash such as Stevens–Johnson syndrome and toxic epidermal necrolysis12,24. Although DQB1*06:01 was associated with more severe clinical manifestations, it would be noteworthy that the patients with PER-PAEs fully recovered without any sequelae after the discontinuation of PER.\n\nTaken together, among the three alleles, we cautiously suggest that DQB1*06:01 could be the allele most susceptible to PER-PAEs. In addition to its high docking score and high frequency in the patients with PER-PAEs, DQB1*06:01 was more common in the patients with more severe psychiatric manifestations, such as self-injurious behavior or psychosis, and the pathomechanism of MHC class II molecules might be more plausible than that of MHC class I molecules in that the clinical manifestation was fully reversible. Nevertheless, we should not completely exclude the possibility that HLA-B*54:01 and DRB1*08:03 are involved in the pathomechanism of PER-PAEs; DRB1*08:03 had a higher odds ratio in the PER-PAE group than in the PAE-tolerant group. Moreover, as previous results have shown, LEV-PAEs were associated with MHC class I molecules9, and it is not yet known exactly how AED-related cerebral adverse effects occur at the cellular level. The immune reaction in the central nervous system would be much more complex than in the skin. Beside the antigen presentation and CD8+ T cell activation, MHC class I molecules are known to perform nonclassical functions in association with multiple cytokines and may be engaged in controlling neuronal plasticity25–29. We hypothesize that the nonclassical function of MHC class I molecule could also be associated with a reversible phenotype, but this should be investigated in further studies. Future analysis with genome-wide association studies might also play a critical role in the identification of which HLA alleles would be important for PER-PAEs.\n\nThe study is limited by the small number of patients who were included in the PER-PAE group and the PAE-tolerant group. In addition, the analysis was not controlled for co-medications. However, to overcome this limitation, patients with PER-PAEs were strictly selected according to certain criteria, and the PER-tolerant group was qualified to be an extreme phenotype with a daily dose of 10 mg per day for 6 months. Moreover, the PER-PAEs were analyzed using an objective tool, the modified version of the Psychiatric Symptoms and Behavior Checklist of the Vanderbilt-Kennedy Center. The results will need to be validated in an independent large cohort. Lastly, the HLA allele frequency differs according to ethnicity so that further investigation is required in multiple ethnic groups.\n\nIn summary, our study shows that PER-PAEs were associated with HLA-DQB1*06:01, DRB1*08:03, and B*54:01 and their combinations as haplotypes in the Korean population. Among the alleles, DQB1*06:01 could be the most likely HLA type correlated with the immunological reaction of PER-PAEs. As HLA-related genetic risk factors for each ethnicity are important in and of themselves, the results of this study would be helpful as a reference to investigate potential screening methods for Korean patients who will be prescribed PER. Moreover, our results of the HLA-related genetic susceptibility of PER-PAEs suggest that psychiatric symptoms induced by adverse drug effects could be induced by an immunological reaction in the brain. Therefore, further research should be performed with a larger number of patients in terms of the pathomechanism of PAEs in the near future.\n\nSupplementary information\nSupplementary Information\n\n Publisher's note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThese authors contributed equally: Yoonhyuk Jang, Tae-Joon Kim and Jangsup Moon.\n\nSupplementary information\nis available for this paper at 10.1038/s41598-020-70601-1.\n\nAcknowledgements\nThis study was supported by the Seoul National University Hospital Research Fund (0420170510 and 0620172900).\n\nAuthor contributions\nY.J., T.-J.K. and J.M. wrote and revised the manuscript. Y.J, T.-J.K. and J.M. analyzed the data. Y.J., T.-J.K., J.M., T.-W.Y., K.T.K., B.-S.P., J.-A.L., J.-S.J., S.-T.L., K.-H.J., K.-I.P., K.-Y.J., K.C., and S.K.L. collected clinical data. T.-J.K., J.M., K.C. and S.K.L. provided study concepts and revised the manuscript. T.-J.K., J.M., S.-T.L., K.-H.J., K.-I.P., K.-Y.J., K.C. and S.K.L. provided materials and funding. K.C. and S.K.L. supervised the study. All authors reviewed the manuscript.\n\nData availability\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n\nCompeting interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Krauss GL Randomized phase III study 306: Adjunctive perampanel for refractory partial-onset seizures Neurology 2012 78 1408 1415 10.1212/wnl.0b013e318254473a 22517103 \n2. French JA Adjunctive perampanel for refractory partial-onset seizures Neurology 2012 79 589 596 10.1212/wnl.0b013e3182635735 22843280 \n3. French JA Evaluation of adjunctive perampanel in patients with refractory partial-onset seizures: Results of randomized global phase III study 305 Epilepsia 2013 54 117 125 10.1111/j.1528-1167.2012.03638.x 22905857 \n4. Faulkner MA Spotlight on perampanel in the management of seizures: Design, development and an update on place in therapy Drug Des. Dev. Ther. 2017 11 2921 2930 10.2147/dddt.s122404 \n5. French JA Perampanel for tonic-clonic seizures in idiopathic generalized epilepsy Neurology 2015 85 950 957 10.1212/wnl.0000000000001930 26296511 \n6. Coyle H Clough P Cooper P Mohanraj R Clinical experience with perampanel: Focus on psychiatric adverse effects Epilepsy Behav. 2014 41 193 196 10.1016/j.yebeh.2014.09.072 25461214 \n7. Ettinger AB Psychiatric and behavioral adverse events in randomized clinical studies of the noncompetitive AMPA receptor antagonist perampanel Epilepsia 2015 56 1252 1263 10.1111/epi.13054 26140524 \n8. Gil-Nagel A A retrospective, multicentre study of perampanel given as monotherapy in routine clinical care in people with epilepsy Seizure 2018 54 61 66 10.1016/j.seizure.2017.10.015 29288911 \n9. Yang T-W HLA-A*11:01 is associated with levetiracetam-induced psychiatric adverse events PLoS ONE 2018 13 e0200812 10.1371/journal.pone.0200812 30020991 \n10. Jang Y Psychiatric symptoms delay the diagnosis of anti-LGI1 encephalitis J. Neuroimmunol. 2018 317 8 14 10.1016/j.jneuroim.2018.02.005 29501086 \n11. Lee KW Oh DH Lee C Yang SY Allelic and haplotypic diversity of HLA-A, -B, -C, -DRB1, and -DQB1 genes in the Korean population Tissue Antigens 2005 65 437 447 10.1111/j.1399-0039.2005.00386.x 15853898 \n12. Moon J HLA-B*40:02 and DRB1*04:03 are risk factors for oxcarbazepine-induced maculopapular eruption Epilepsia 2016 57 1879 1886 10.1111/epi.13566 27666425 \n13. Trott O Olson AJ AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading J. Comput. Chem. 2010 31 455 461 10.1002/jcc.21334 19499576 \n14. Grosdidier A Zoete V Michielin O SwissDock, a protein-small molecule docking web service based on EADock DSS Nucleic Acids Res. 2011 39 W270 W277 10.1093/nar/gkr366 21624888 \n15. Excoffier L Lischer HEL Arlequin suite ver 3.5: A new series of programs to perform population genetics analyses under Linux and Windows Mol. Ecol. Resour. 2010 10 564 567 10.1111/j.1755-0998.2010.02847.x 21565059 \n16. Kim TJ Anti-LGI1 encephalitis is associated with unique HLA subtypes Ann. Neurol. 2017 81 183 192 10.1002/ana.24860 28026029 \n17. Anestis MD Soberay KA Gutierrez PM Hernández TD Joiner TE Reconsidering the link between impulsivity and suicidal behavior Pers. Soc. Psychol. Rev. 2014 18 366 386 10.1177/1088868314535988 24969696 \n18. Brent DA Melhem N Familial transmission of suicidal behavior Psychiatr. Clin. N. Am. 2008 31 157 177 10.1016/j.psc.2008.02.001 \n19. Moon J The HLA-A*2402/Cw*0102 haplotype is associated with lamotrigine-induced maculopapular eruption in the Korean population Epilepsia 2015 56 e161 e167 10.1111/epi.13087 26282450 \n20. Kayser MS Titulaer MJ Gresa-Arribas N Dalmau J Frequency and characteristics of isolated psychiatric episodes in anti-N-methyl-d-aspartate receptor encephalitis Jama Neurol. 2013 70 1133 1139 10.1001/jamaneurol.2013.3216 23877059 \n21. Graus F A clinical approach to diagnosis of autoimmune encephalitis Lancet Neurol. 2016 15 391 404 10.1016/s1474-4422(15)00401-9 26906964 \n22. Zhao Y Zhao Y Li J Zhang Y Zhang L HLA-DRB1*08:03:02 and HLA-DQB1*06:01:01 are associated with house dust mite–sensitive allergic rhinitis in Chinese subjects Int. Forum Allergy Rheum. 2016 6 854 861 10.1002/alr.21747 \n23. Kwon Y-C HLA-B*54:01 is associated with susceptibility to Kawasaki disease Circ. Genom. Precis. Med. 2019 12 e002365 10.1161/CIRCGEN.118.002365 31017802 \n24. Pichler WJ Cellular and molecular pathophysiology of cutaneous drug reactions Am. J. Clin. Dermatol. 2002 3 229 238 10.2165/00128071-200203040-00001 12010068 \n25. Xia S Tao Y Cui L Yu Y Xu S MHC class I molecules exacerbate viral infection by disrupting type I interferon signaling J. Immunol. Res. 2019 2019 5370706 10.1155/2019/5370706 31583257 \n26. Cebrián C Loike JD Sulzer D Neuronal MHC-I expression and its implications in synaptic function, axonal regeneration and Parkinson’s and other brain diseases Front. Neuroanat. 2014 10.3389/fnana.2014.00114 25352786 \n27. Roy ER Type I interferon response drives neuroinflammation and synapse loss in Alzheimer disease J. Clin. Investig. 2020 130 1912 1930 10.1172/JCI133737 31917687 \n28. Shatz CJ MHC class I: An unexpected role in neuronal plasticity Neuron 2009 64 40 45 10.1016/j.neuron.2009.09.044 19840547 \n29. Elmer BM McAllister AK Major histocompatibility complex class I proteins in brain development and plasticity Trends Neurosci. 2012 35 660 670 10.1016/j.tins.2012.08.001 22939644\n\n",
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"issn_linking": "2045-2322",
"issue": "10(1)",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants; D064420:Drug-Related Side Effects and Adverse Reactions; D004827:Epilepsy; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059866:HLA-DQ beta-Chains; D006801:Humans; D015994:Incidence; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D009570:Nitriles; D011728:Pyridones; D056910:Republic of Korea; D055815:Young Adult",
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"pubdate": "2020-08-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "22517103;22843280;22905857;26296511;25461214;26140524;29288911;30020991;29501086;15853898;27666425;19499576;21624888;21565059;28026029;24969696;26282450;23877059;26906964;31017802;12010068;31583257;25352786;31917687;19840547;22939644",
"title": "HLAs associated with perampanel-induced psychiatric adverse effects in a Korean population.",
"title_normalized": "hlas associated with perampanel induced psychiatric adverse effects in a korean population"
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"abstract": "Immune checkpoint inhibitors (ICIs) have improved clinical outcomes with a number of advanced malignancies. However, diverse immune-related adverse events (iRAEs) occurred with the widespread use of ICIs, some of which are rarely and life-threatening. Here we report a 66-year-old patient with lung adenocarcinoma who received two doses of sintilimab, a human monoclonal antibody against programmed cell death-1 (PD-1), experienced a fatal storm of iRAEs. He was admitted to the intensive care unit (ICU) by immune induced-myositis/myocarditis and rhabdomyolysis. Despite immediate immunosuppressive therapy with methylprednisolone (MP) and immunoglobulin intravenously, he developed into myositis-myasthenia gravis (MG) overlap syndrome complicated with myasthenia crisis. We commenced plasma exchange (PLEX), mechanical ventilation, immunosuppressive therapy, as well as other supportive therapies. Three months later, the patient's serum creatine phosphate kinase (CPK) and anti-acetylcholine receptor antibody (anti-AChR-Ab) returned to normal despite tumor progression. Herein we discuss the incidence, operating mechanism and management strategies of the fatal iRAEs. Early admission to the ICU and multidisciplinary collaborative treatment for unstable patients with iRAEs could help to achieve a favorable outcome.",
"affiliations": "Department of Anaesthesia, Critical Care and Pain Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Anaesthesia, Critical Care and Pain Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Anaesthesia, Critical Care and Pain Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Anaesthesia, Critical Care and Pain Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Anaesthesia, Critical Care and Pain Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Anaesthesia, Critical Care and Pain Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China.;Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Anaesthesia, Critical Care and Pain Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China.",
"authors": "Xing|Qian|Q|;Zhang|Zhong-Wei|ZW|;Lin|Qiong-Hua|QH|;Shen|Li-Hua|LH|;Wang|Peng-Mei|PM|;Zhang|Shan|S|;Fan|Ming|M|;Zhu|Biao|B|",
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"doi": "10.21037/atm.2020.01.79",
"fulltext": "\n==== Front\nAnn Transl Med\nAnn Transl Med\nATM\nAnnals of Translational Medicine\n2305-5839\n2305-5847\nAME Publishing Company\n\natm-08-05-250\n10.21037/atm.2020.01.79\nCase Report\nMyositis-myasthenia gravis overlap syndrome complicated with myasthenia crisis and myocarditis associated with anti-programmed cell death-1 (sintilimab) therapy for lung adenocarcinoma\nXing Qian 12\nZhang Zhong-Wei 12\nLin Qiong-Hua 12\nShen Li-Hua 12\nWang Peng-Mei 12\nZhang Shan 12\nFan Ming 23\nZhu Biao 12\n1 Department of Anaesthesia, Critical Care and Pain Medicine, Fudan University Shanghai Cancer Center, Shanghai 200032, China;\n2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China;\n3 Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China\nCorrespondence to: Biao Zhu. Department of ICU, Fudan University Shanghai Cancer Center, No. 270 DongAn Road, Shanghai 200032, China. Email: zhubiaozs@sohu.com.\n3 2020\n3 2020\n8 5 25023 10 2019\n02 1 2020\n2020 Annals of Translational Medicine. All rights reserved.\n2020\nAnnals of Translational Medicine.\nImmune checkpoint inhibitors (ICIs) have improved clinical outcomes with a number of advanced malignancies. However, diverse immune-related adverse events (iRAEs) occurred with the widespread use of ICIs, some of which are rarely and life-threatening. Here we report a 66-year-old patient with lung adenocarcinoma who received two doses of sintilimab, a human monoclonal antibody against programmed cell death-1 (PD-1), experienced a fatal storm of iRAEs. He was admitted to the intensive care unit (ICU) by immune induced-myositis/myocarditis and rhabdomyolysis. Despite immediate immunosuppressive therapy with methylprednisolone (MP) and immunoglobulin intravenously, he developed into myositis-myasthenia gravis (MG) overlap syndrome complicated with myasthenia crisis. We commenced plasma exchange (PLEX), mechanical ventilation, immunosuppressive therapy, as well as other supportive therapies. Three months later, the patient’s serum creatine phosphate kinase (CPK) and anti-acetylcholine receptor antibody (anti-AChR-Ab) returned to normal despite tumor progression. Herein we discuss the incidence, operating mechanism and management strategies of the fatal iRAEs. Early admission to the ICU and multidisciplinary collaborative treatment for unstable patients with iRAEs could help to achieve a favorable outcome.\n\nKeywords:\n\nImmune checkpoint inhibitors (ICIs)\nprogrammed cell death-1 (PD-1)\nimmune-related adverse events (iRAEs)\nimmune induced-myositis/myocarditis\nmyasthenia gravis (MG)\nmyasthenia crisis\nplasma exchange (PLEX)\n==== Body\nIntroduction\n\nThe application of immune checkpoint inhibitors (ICIs) has ushered a new era for cancer therapy and shown the efficacy of improving the survival time for patients with advanced malignancies, such as non-small cell lung cancer and metastatic melanoma (1,2). ICIs potentiate T cells cytotoxicity against cancer cells through targeting cytotoxic T lymphocyte-associated protein-4 (CTLA-4), programmed cell death-1 (PD-1) or programmed cell death-ligand 1 (PD-L1) (3,4). The blockade of PD-1 on T cells or PD-L1 on the surface of the cancer cells with antibodies enhances the anti-tumor immune activity by the T cells (5). However, more and more immune-related adverse events (iRAEs) have been reported with the widespread use of ICIs, some of which are severe and fatal for the patients (6,7). Sintilimab (Tyvyt®), a human immunoglobulin G4 (IgG4) anti-PD-1 monoclonal antibody co-developed by Innovent Biologics and Eli Lilly Company, approved for the treatment for relapsed Hodgkin’s lymphoma after ≥2 lines of systemic chemotherapy in China—since December 2018, is now undergoing phase I, II and III development using in various solid tumors including nonsquamous non-small cell lung cancer (8). Herein we present a case of lung adenocarcinoma, which developed to a fatal storm of iRAEs after two doses of sintilimab.\n\nCase presentation\n\nA 66-year-old man who had a smoking history of 30 years, admitted for myasthenia gravis (MG), accepted radical resection of thymoma and left lung adenocarcinoma in 2006, with postoperative pathology suggesting type AB thymoma. He was found with the right lung adenocarcinoma in 2014, and underwent video-assisted thoracoscopy pulmonary wedge resection followed by three 21-day cycles of chemotherapy, which was consisted of pemetrexed 0.8 g and carboplatin 0.5 g on day 1 (PC chemotherapy).\n\nThree years later, the left lung adenocarcinoma relapsed with the patient. After two cycles of the same PC chemotherapy followed by one course of radiotherapy to 54 Gy in 27 fractions, the tumor continued to progress. As immunohistochemical examination revealed high PD-L1 (test with 22C3 antibody) expression in 50% of the tumor cells from the biopsy of the left lung carcinoma, he was treated with sintilimab at a dose of 200 mg per day intravenously at his demand out of economic reasons. And the second dose was given 21 days later. Four days after two doses of sintilimab, he experienced fatigue, myalgia and tender muscles in both the upper and lower extremities. He was hospitalized to the intensive care unit (ICU) for shortness of breath and progressive muscle weakness 8 days later. Blood results showed increased creatine phosphate kinase (CPK) up to 11,919 (normal 55–170) U/L, serum myoglobin up to over 3,000 (normal 28–72) ng/mL and troponin T (TnT) up to 0.916 (normal 0.013–0.025) ng/mL. Complete right bundle branch block complicated with complete atrioventricular block was seen the electrocardiogram despite normal echocardiogram, resulting in the diagnosis of an immune induced-myositis/myocarditis and rhabdomyolysis. We immediately started an immunosuppressive therapy with methylprednisolone (MP, 2 mg/kg/d) and immunoglobulin (400 mg/kg/d for 5 days) intravenously. And a temporary pace-maker was inserted for 2 days till the normalization of heart rhythm. In the meantime, the patient presented dysphagia, hypercapnic respiratory failure, ptosis, ophthalmoplegia. He had to be put on non-invasive positive pressure ventilation (NIPPV), but eventually intubated. We diagnosed him with myositis-MG overlap syndrome complicated with myasthenia crisis considering the elevated anti-acetylcholine receptor antibody (anti-AChR-Ab) to 8.97 nmol/L (positive >0.50 nmol/L), then adjusted the treatment with MP (500 mg daily for 5 days followed by does-reduction step by step) and pyridostigmine bromide (120 mg, twice a day). In due time the patient was given tracheotomy, antibiotic therapy, nutrition support, ventilator weaning rehabilitation, regular diaphragm mobility assessment by ultrasound, and pulmonary hygiene. A lack of diaphragmatic activity was then confirmed. After all these treatments, symptoms in his peripheral limbs and eye opening improved, the serum level of CPK normalized and anti-AChR-Ab decreased to 2.394 nmol/L a month after admission. However, the weakness in respiratory muscles barely responded to the treatments. Since the half-life of immunoglobulin was 3–4 weeks, plasma exchange (PLEX) was not carried out until the fifth week after immunoglobulin therapy, avoiding to destroy the efficacy of immunoglobulin (9). Owing to two courses of PLEX, the patient could have normal anti-AChR-Ab and breath spontaneously for 8–12 hours per day. Unfortunately, the repeat CT scan revealed the atelectasis of left upper lung from tumor progression (Figure 1), 2 months after sintilimab therapy. Three months since admission to ICU, the patient is now receiving maintenance therapy of pyridostigmine bromide without prednisone, as well as mechanical ventilation (12 hours per day), and continuing rehabilitation in the general ward. Changes in CPK, TnT and anti-AChR-Ab levels after sintilimab therapy are demonstrated in Figure 2.\n\nFigure 1 The comparison of CT images before and after sintilimab therapy. (A) The CT images 3 days before sintilimab therapy; (B) the CT images 2 months after sintilimab therapy. The contrast between the two images suggests the tumor continue to progress, as indicated by the arrows.\n\nFigure 2 The clinical course after sintilimab therapy. MP, methylprednisolone; CPK, creatine phosphate kinase; TnT, troponin T; anti-AChR-Ab, anti-acetylcholine receptor antibody; IVGG, intravenous gamma globulin; NIPPV, non-invasive positive pressure ventilation.\n\nDiscussion\n\nAlthough the incidence of high-grade iRAEs such as myocarditis induced by anti-PD-1 antibody is less than 1%, death occurs from cardiac failure or arrhythmias or complications of a prolonged stay in ICU, leading to a mortality of 46% in the large series. It is reported that the patients, mostly with melanoma or lung cancers, received only one or two doses of anti-PD-1 therapy before the onset of myocarditis, and 25% of them may overlap with myositis or MG (10). Some neuromuscular iRAEs cases, especially in those with preexisting immune disease, seem more likely to suffer from overlap-syndromes indicating myositis, myocarditis and MG present at the same time, and have higher frequencies of myasthenic crisis and fatal deterioration (10-12). The combination of checkpoint blockade is also much easier to have life-threatening adverse effects than mono-therapy (13,14). In a large retrospective study of 9,869 cancer patients in Japan with nivolumab, 12 cases (0.12%) developed MG in 6 weeks after nivolumab and rapidly deteriorated despite immediate management, two of them died from myocarditis and myasthenic crisis. Within the—12 MG patients, 10 cases had positive anti-AChR-Ab, and 4 cases were complicated by myositis while 3 cases were accompanied by myocarditis (7). In a systematic review of 85 patients with neuromuscular disorders following anti-PD-1 therapy, more than 30% of them developed cardiac complications. Among the 23 patients diagnosed with MG from the review, 8 patients (35%) had a history of preexisting MG while 6 of whom showing positive anti-AChR-Ab (15). In addition, the patient in our case did not have anti-AChR-Ab test before sintilimab treatment. It reminded us that it would be reasonable to test for anti-AChR-Ab before the commencement of anti-PD-1 therapy to avoid the high risk of fatal iRAEs, especially in patients with thymoma or MG history. The diagnosis of immune-related MG could be based on the clinical features and the presence of serum anti-AChR-Ab or anti-muscle-specific kinase antibodies (anti-MuSK-Ab), however, the auto-antibodies of some patients with seronegative MG are not detectable. Electromyography could contribute to prompt diagnosis at this time (9,16).\n\nThe operating mechanism of iRAEs is not clear yet. Johnson assumed that there seemed to be cross antigens between tumor tissues and striated muscle (myocardium and skeletal muscle). As a result, the distinct T-cell receptors targeted dissimilar antigens with the mislead of the clonal T-cell receptor sequences across tumor and muscle samples (17). In cases related to ICI-induced myositis/myocarditis, the skeletal muscle and myocardium biopsy demonstrated a greater infiltration of mononuclear cells, especially CD8+ T cells, leading to the development of iRAEs (7,17,18). Besides, muscle biopsy could act as a helpful diagnostic tool to differentiate necrotizing myopathy from MG. So, it is a pity that the patient in our case refused to take muscle biopsy for definite diagnosis. Ji et al., developed a monkey model characterized by anti-PD-1 antibody-induced multiple organ toxicities including myocarditis, indicating increased proliferation in CD4+ and CD8+ T lymphocytes, as well as cardiac troponin-I and NT-pro-BNP in the myocardium (19). The study of animal models supported that either CTLA-4 or PD-1 could prevent from immune-mediated damage, for the block of CTLA4 or PD-1/PD-L1 might result in anti-tumor response and diversification of recognition to myocardium and skeletal muscle by CD8+ T cells (20).\n\nMG has been characterized as the most frequent neuromuscular manifestations among PD-1 inhibitor-associated iRAEs, the clinicians should be aware of how to manage it (21,22). The patients with ICIs-related MG or myasthenic crisis require immediate initiation of intravenous corticosteroid treatment and consideration of treatment escalation with immunoglobulins, PLEX, cyclophosphamide, rituximab, azathioprine or methotrexate (9,11,23). Although immunoglobulins are proved to be equally effective with PLEX for myasthenic crisis, PLEX works more quickly and has better performance in MG patients with positive anti-MuSK-Ab (24,25). Additionally, nearly half of the cases with ICIs-related myasthenic crisis require ventilatory support (7). It is really important to reduce the morbidity by comprehensive assessments of risk factors like history of heart disease, autoimmune disease and diabetes before starting the medication (20). In addition, an early prediction of iRAEs improves the outcome. An American study which enrolled 5160064 anti-PD-1 monotherapy cases from 19 different cancer types, revealed a significant positive correlation between the reporting odds ratios (RORs) of iRAE and the corresponding tumor mutational burden (TMB), which is a biomarker for prediction of therapy response. It strongly suggested cancers with a high TMB, such as melanoma and non-small cell lung cancer, are associated with a higher ROR of iRAE during anti-PD-1 therapy than cancers with a low TMB because of antigen spreading (26). Furthermore, physicians from both oncology and ICU department should have a good knowledge of the salient clinical features and make full use of the examinations to avoid delaying the diagnosis. And cardiac magnetic resonance imaging (MRI) scan is the gold standard noninvasive test for the diagnosis of myocarditis (27). Unfortunately, the patient in this case refused it for economic reasons. Mortality was high in the patients with high-grades iRAEs, despite immediate and adequate treatment strategies including corticosteroid, immunoglobulins, PLEX and immune-adsorption. A PD-1-induced myocarditis case suffered from malignant arrhythmia was reported to get cured by alemtuzumab on the base of fundamental anti-immunotherapy. Alemtuzumab is a monoclonal antibody that binds to CD52 of peripheral immune cells and leads to rapid cytolytic induction of immunosuppression (28). Early admission for unstable patients of iRAEs to ICU is recommended. A collaborative and multidisciplinary approach dominated by the intensivists and physicians from related departments could help to achieve a favorable outcome.\n\nAcknowledgments\n\nFunding: None.\n\nEthical Statement: The authors are 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. Written informed consent was obtained from the patients for publication of this manuscript and any accompanying images.\n\nOpen Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.\n\nConflicts of Interest: The authors have no conflicts of interest to declare.\n==== Refs\nReferences\n\n1 Carbone DP Reck M Paz-Ares L First-line nivolumab in stage IV or recurrent non-small-cell lung cancer. N Engl J Med 2017;376 :2415-26. 10.1056/NEJMoa1613493 28636851\n2 Wolchok JD Chiarion-Sileni V Gonzalez R Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N Engl J Med 2017;377 :1345-56. 10.1056/NEJMoa1709684 28889792\n3 Akella P Loganathan S Jindal V Anti PD-1 immunotherapy related interstitial lung disease presenting as respiratory failure - a review with case series. Respir Med Case Rep 2018;26 :17-22. 10.1016/j.rmcr.2018.11.005 30456167\n4 Canino C Perrone L Bosco E Targeting angiogenesis in metastatic renal cell carcinoma. Expert Rev Anticancer Ther 2019;19 :245-57. 10.1080/14737140.2019.1574574 30678509\n5 Abril-Rodriguez G Ribas A. SnapShot: immune checkpoint inhibitors. 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Lancet 2018;391 :933. 10.1016/S0140-6736(18)30533-6 29536852\n11 Möhn N Beutel G Gutzmer R Neurological immune related adverse events associated with nivolumab, ipilimumab, and pembrolizumab therapy-review of the literature and future outlook. J Clin Med 2019. doi: .10.3390/jcm8111777 31653079\n12 Makarious D Horwood K Coward JIG Myasthenia gravis: an emerging toxicity of immune checkpoint inhibitors. Eur J Cancer 2017;82 :128-36. 10.1016/j.ejca.2017.05.041 28666240\n13 Fazel M Jedlowski PM Severe myositis, myocarditis, and myasthenia gravis with elevated anti-striated muscle antibody following single dose of ipilimumab-nivolumab therapy in a patient with metastatic melanoma. Case Reports Immunol 2019;2019 :2539493. 10.1155/2019/2539493 31183226\n14 Werner JM Schweinsberg V Schroeter M Successful treatment of myasthenia gravis following PD-1/CTLA-4 combination checkpoint blockade in a patient with metastatic melanoma. Front Oncol 2019;9 :84. 10.3389/fonc.2019.00084 30828569\n15 Johansen A Christensen SJ Scheie D Neuromuscular adverse events associated with anti-PD-1 monoclonal antibodies: systematic review. Neurology 2019;92 :663-74. 10.1212/WNL.0000000000007235 30850443\n16 Yuen C Fleming G Meyers M Myasthenia gravis induced by avelumab. Immunotherapy 2019;11 :1181-5. 10.2217/imt-2019-0106 31462152\n17 Johnson DB Balko JM Compton ML Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375 :1749-55. 10.1056/NEJMoa1609214 27806233\n18 Kimura T Fukushima S Miyashita A Myasthenic crisis and polymyositis induced by one dose of nivolumab. Cancer Sci 2016;107 :1055-8. 10.1111/cas.12961 27420474\n19 Ji C Roy MD Golas J Myocarditis in cynomolgus monkeys following treatment with immune checkpoint inhibitors. Clin Cancer Res 2019;25 :4735-48. 10.1158/1078-0432.CCR-18-4083 31085720\n20 Anquetil C Salem JE Lebrun-Vignes B Immune checkpoint inhibitor-associated myositis. Circulation 2018;138 :743-5. 10.1161/CIRCULATIONAHA.118.035898 30359135\n21 Kao JC Brickshawana A Liewluck T Neuromuscular complications of programmed cell death-1 (PD-1) inhibitors. Curr Neurol Neurosci Rep 2018;18 :63. 10.1007/s11910-018-0878-7 30078154\n22 Kolb NA Trevino CR Waheed W Neuromuscular complications of immune checkpoint inhibitor therapy. Muscle Nerve 2018. [Epub ahead of print]. 10.1002/mus.26070 29342325\n23 Thompson JA Schneider BJ Brahmer J Management of immunotherapy-related toxicities, version 1.2019. J Natl Compr Canc Netw 2019;17 :255-89. 10.6004/jnccn.2019.0013 30865922\n24 Schwartz J. Evidence-based guideline update: plasmapheresis in neurologic disorders. Neurology 2011;77:e105-6; author reply e106.\n25 Dhawan PS Goodman BP Harper CM IVIG versus PLEX in the treatment of worsening myasthenia gravis: what is the evidence?: a critically appraised topic. Neurologist 2015;19 :145-8. 10.1097/NRL.0000000000000026 25970838\n26 Bomze D Hasan Ali O Bate A Association between immune-related adverse events during anti-PD-1 therapy and tumor mutational burden. JAMA Oncol 2019. [Epub ahead of print]. 10.1001/jamaoncol.2019.3221 31436791\n27 Mahmood SS Fradley MG Cohen JV Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 2018;71 :1755-64. 10.1016/j.jacc.2018.02.037 29567210\n28 Esfahani K Buhlaiga N Thébault P Alemtuzumab for immune-related myocarditis due to PD-1 therapy. N Engl J Med 2019;380 :2375-6. 10.1056/NEJMc1903064 31189042\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2305-5839",
"issue": "8(5)",
"journal": "Annals of translational medicine",
"keywords": "Immune checkpoint inhibitors (ICIs); immune induced-myositis/myocarditis; immune-related adverse events (iRAEs); myasthenia crisis; myasthenia gravis (MG); plasma exchange (PLEX); programmed cell death-1 (PD-1)",
"medline_ta": "Ann Transl Med",
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"nlm_unique_id": "101617978",
"other_id": null,
"pages": "250",
"pmc": null,
"pmid": "32309397",
"pubdate": "2020-03",
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"references": "27420474;30456167;31183226;31085720;30828569;28666240;22135818;30078154;29745339;29381223;28821685;30678509;31653079;29536852;29567210;27806233;30359135;25970838;30865922;31189042;30850443;31462152;28889792;31436791;29342325;28609660;30742278;28636851",
"title": "Myositis-myasthenia gravis overlap syndrome complicated with myasthenia crisis and myocarditis associated with anti-programmed cell death-1 (sintilimab) therapy for lung adenocarcinoma.",
"title_normalized": "myositis myasthenia gravis overlap syndrome complicated with myasthenia crisis and myocarditis associated with anti programmed cell death 1 sintilimab therapy for lung adenocarcinoma"
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"abstract": "Hydralazine is a common arterial vasodilator used in the management of congestive heart failure and hypertension. It can be associated with drug-induced lupus and less commonly antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV). Drug-induced AAV typically has a favourable long-term prognosis. It is not commonly associated with primary skin involvement, as most cases also have notable kidney and lung disease. Cases with isolated skin findings are rare. We present a rare case of a 60-year-old woman on long-term hydralazine who presented with AAV with primary skin and mucosal involvement, in the form of diffuse bullous and ulcerative lesions, which posed a diagnostic challenge. Her hospital course was marked by several complications including disseminated intravascular coagulation. She required intensive therapy with high-dose steroids, plasmapheresis and rituximab. She tolerated immunosuppression well and with multidisciplinary supportive care, she recovered well and was able to be discharged from the hospital.",
"affiliations": "Internal Medicine, Albany Medical Center, Albany, New York, USA huom@amc.edu.;Internal Medicine, Albany Medical Center, Albany, New York, USA.;Internal Medicine, Albany Medical Center, Albany, New York, USA.",
"authors": "Huo|Mae Xintong|MX|;Avelino|Alzira Rocheteau M|ARM|;Singh|Gurpreet|G|",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D006830:Hydralazine; D003606:Dacarbazine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238609",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "cardiovascular system; dermatology; unwanted effects / adverse reactions; vasculitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D003606:Dacarbazine; D005260:Female; D006801:Humans; D006830:Hydralazine; D007668:Kidney; D008875:Middle Aged",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33975832",
"pubdate": "2021-05-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe cutaneous presentation of hydralazine-induced ANCA vasculitis without renal or pulmonary involvement, complicated by DIC.",
"title_normalized": "severe cutaneous presentation of hydralazine induced anca vasculitis without renal or pulmonary involvement complicated by dic"
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"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-03031",
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"activesubstance": {
"activesubstancename": "POTASSIUM CHLORIDE"
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... |
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"abstract": "The development of pustular cutaneous T-cell lymphoma (CTCL) on the palms and soles is rare. Without confirmatory biopsy and molecular studies, CTCL can be misdiagnosed as many benign inflammatory skin diseases. We present a case of cutaneous T-cell lymphoma (CTCL) that mimicked palmoplantar pustular psoriasis, a rarely reported manifestation of the disease. We stress the importance of biopsy to confirm diagnoses, especially when preliminary diagnoses do not respond to empiric treatment.",
"affiliations": "University of Central Florida College of Medicine, Orlando, FL, USA.;H. Lee Moffitt Cancer and Research Center, Cutaneous Oncology Program, Tampa, FL, USA.;H. Lee Moffitt Cancer and Research Center, Cutaneous Oncology Program, Tampa, FL, USA.;Department of Dermatology, University of Central Florida College of Medicine, Orlando, FL, USA.",
"authors": "Hignett|Emma|E|;Seminario-Vidal|Lucia|L|;Shulman|Kenneth|K|;Sami|Naveed|N|https://orcid.org/0000-0003-4141-9468",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.13544",
"fulltext": null,
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"issn_linking": "0004-8380",
"issue": "62(2)",
"journal": "The Australasian journal of dermatology",
"keywords": "CTCL; cutaneous T-cell lymphoma; mycosis fungoides; mycosis fungoides palmaris et plantaris",
"medline_ta": "Australas J Dermatol",
"mesh_terms": null,
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "e280-e282",
"pmc": null,
"pmid": "33386610",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cutaneous T-cell lymphoma mimicking palmoplantar pustular psoriasis: A rare variant.",
"title_normalized": "cutaneous t cell lymphoma mimicking palmoplantar pustular psoriasis a rare variant"
} | [
{
"companynumb": "US-AMGEN-USASP2021089027",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
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... |
{
"abstract": "BACKGROUND\nSmoking during pregnancy is a modifiable risk factor associated with adverse pregnancy outcomes. Smoking during pregnancy has been shown to increase the risk of spontaneous abortion, prematurity, low birthweight, congenital malformations, and sudden infant death syndrome. Despite the fact that it is well known that smoking can lead to adverse pregnancy outcomes, 13-25% of pregnant women overall continue to smoke during this critical period.\n\n\nOBJECTIVE\nThe objective of the study was to evaluate the effect of gestational use of bupropion and nicotine patch replacement therapy on the risk of the following: (1) smoking cessation, (2) prematurity, and (3) small for gestational age.\n\n\nMETHODS\nWomen included in the Quebec Pregnancy Cohort who filled the annual autoadministered questionnaire between Jan. 1, 1998, and June 30, 2009, were studied. Smokers before gestation with a pregnancy resulting in a live birth comprised the study population. Three mutually exclusive study groups were formed among those who smoked at the beginning of pregnancy: gestational users of nicotine patch replacement therapy, bupropion, and smokers who did not use nicotine patch replacement therapy or bupropion. Rate of smoking cessation during pregnancy as well as the risk of prematurity and small for gestational age were studied.\n\n\nRESULTS\nOf the 1288 women who met inclusion criteria, 900 were smokers, 72 were bupropion users, and 316 were nicotine patch replacement therapy users. Bupropion and nicotine patch replacement therapy use during pregnancy were associated with higher rates of smoking cessation: 81% in the bupropion group; 79% for nicotine patch replacement therapy; and 0% in those not using buproprion or nicotine patch replacement therapy. After discontinuing smoking cessation medications, 60% of bupropion users and 68% of nicotine patch replacement therapy users did not smoke again during and after pregnancy. Adjusting for potential confounders, nicotine patch replacement therapy use was associated with a lower risk of prematurity (adjusted odds ratio, 0.21, 95% confidence interval, 0.13-0.34), and small-for-gestational-age (adjusted odds ratio, 0.61, 95% confidence interval, 0.41-0.90) compared to smoking. Bupropion was associated with a lower risk of prematurity only (adjusted odds ratio, 0.12, 95% confidence interval, 0.03-0.50).\n\n\nCONCLUSIONS\nBupropion and nicotine patch replacement therapy have an impact on smoking cessation during and after pregnancy. Nicotine patch replacement therapy also decreased the risk of prematurity and small for gestational age.",
"affiliations": "Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada; Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada. Electronic address: anick.berard@umontreal.ca.;Faculty of Pharmacy, University of Montreal, Montreal, QC, Canada; Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.;Research Centre, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.",
"authors": "Bérard|Anick|A|;Zhao|Jin-Ping|JP|;Sheehy|Odile|O|",
"chemical_list": "D018765:Dopamine Uptake Inhibitors; D016642:Bupropion; D009538:Nicotine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajog.2016.06.059",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9378",
"issue": "215(5)",
"journal": "American journal of obstetrics and gynecology",
"keywords": "bupropion; nicotine patch replacement; prematurity; small for gestational age; smoking cessation during pregnancy",
"medline_ta": "Am J Obstet Gynecol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D016642:Bupropion; D018765:Dopamine Uptake Inhibitors; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007236:Infant, Small for Gestational Age; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009538:Nicotine; D011247:Pregnancy; D011256:Pregnancy Outcome; D047928:Premature Birth; D011295:Prenatal Care; D012189:Retrospective Studies; D012307:Risk Factors; D016540:Smoking Cessation; D061485:Tobacco Use Cessation Devices; D055815:Young Adult",
"nlm_unique_id": "0370476",
"other_id": null,
"pages": "611.e1-611.e8",
"pmc": null,
"pmid": "27402053",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Success of smoking cessation interventions during pregnancy.",
"title_normalized": "success of smoking cessation interventions during pregnancy"
} | [
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"companynumb": "CA-CIPLA LTD.-2016CA21119",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPROPION"
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"drugadditional": null,
... |
{
"abstract": "We describe a fatal case of diffuse alveolar hemorrhage (DAH) complicated by rheumatoid arthritis (RA). A female patient was diagnosed with RA two months earlier and was treated with prednisolone and tacrolimus due to abnormalities in chest images. The patient was admitted to Hamanomachi Hospital for exertional dyspnea and was treated for exacerbation of chronic heart failure. Even after treatment for heart failure, exertional dyspnea remained. Chest CT imaging revealed contractile, patchy consolidations and ground-glass opacities (GGO) with a peribronchial distribution, suggesting an organizing pneumonia (OP) pattern. She was then treated with an additional 25 mg/day of prednisolone following a clinical diagnosis of OP. When the prednisolone dose was tapered, chest imaging showed worsening infiltration. A bronchoscopy was conducted, and bronchoalveolar lavage fluid was sanguineous, indicating DAH. Given that additional workup for the other etiology of DAH was negative, DAH was thought to be related to RA. Intensive treatment, including pulse dose methylprednisolone, failed to halt progression of respiratory failure, leading to a fatal outcome. The clinical presentation proved challenging due to its rarity. DAH might be a differential diagnosis in RA patients with consolidations and GGO in chest CT images. We review past cases of RA-associated DAH and assess potential treatment choices for future cases.",
"affiliations": "Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Rheumatology, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Rheumatology, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.;Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan.",
"authors": "Nakashima|Kazuki|K|;Nishimura|Naoya|N|;Yanagihara|Toyoshi|T|;Egashira|Ayaka|A|;Ogo|Naruhiko|N|;Asoh|Tatsuma|T|;Yoshizawa|Seiji|S|;Maeyama|Takashige|T|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2021.101363",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00025-3\n10.1016/j.rmcr.2021.101363\n101363\nCase Report\nA fatal case of diffuse alveolar hemorrhage complicated by rheumatoid arthritis\nNakashima Kazuki a\nNishimura Naoya b\nYanagihara Toyoshi yanagiha@kokyu.med.kyushu-u.ac.jp\na∗\nEgashira Ayaka a\nOgo Naruhiko a\nAsoh Tatsuma a\nYoshizawa Seiji b\nMaeyama Takashige a\na Department of Respiratory Medicine, Hamanomachi Hospital, Fukuoka, 810-8539, Japan\nb Department of Rheumatology, Hamanomachi Hospital, Fukuoka, 810-8539, Japan\n∗ Corresponding author. yanagiha@kokyu.med.kyushu-u.ac.jp\n17 2 2021\n2021\n17 2 2021\n32 10136324 12 2020\n15 1 2021\n13 2 2021\n© 2021 The Author(s)\n2021\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nWe describe a fatal case of diffuse alveolar hemorrhage (DAH) complicated by rheumatoid arthritis (RA). A female patient was diagnosed with RA two months earlier and was treated with prednisolone and tacrolimus due to abnormalities in chest images. The patient was admitted to Hamanomachi Hospital for exertional dyspnea and was treated for exacerbation of chronic heart failure. Even after treatment for heart failure, exertional dyspnea remained. Chest CT imaging revealed contractile, patchy consolidations and ground-glass opacities (GGO) with a peribronchial distribution, suggesting an organizing pneumonia (OP) pattern. She was then treated with an additional 25 mg/day of prednisolone following a clinical diagnosis of OP. When the prednisolone dose was tapered, chest imaging showed worsening infiltration. A bronchoscopy was conducted, and bronchoalveolar lavage fluid was sanguineous, indicating DAH. Given that additional workup for the other etiology of DAH was negative, DAH was thought to be related to RA. Intensive treatment, including pulse dose methylprednisolone, failed to halt progression of respiratory failure, leading to a fatal outcome. The clinical presentation proved challenging due to its rarity. DAH might be a differential diagnosis in RA patients with consolidations and GGO in chest CT images. We review past cases of RA-associated DAH and assess potential treatment choices for future cases.\n\nKeywords\n\nDiffuse alveolar hemorrhage\nRheumatoid arthritis\nRheumatoid vasculitis\nAnti-citrullinated protein antibodies\n==== Body\n1 Introduction\n\nRheumatoid arthritis (RA) is a common, systemic, autoimmune disease that primarily affects the joints, often leading to significant morbidity and mortality [1]. Extra-articular manifestations can occur in the skin, eyes, kidneys, heart, gastrointestinal tract, and lungs. Clinically, lung involvement can present several patterns of interstitial lung diseases, rheumatoid nodules, pleural disease, and upper/lower airway diseases (bronchiectasis, follicular bronchiolitis, etc.) [2]. Rarely, diffuse alveolar hemorrhage (DAH) may occur as a pulmonary vascular involvement of RA, which has been described in a few case reports.\n\nDAH is a disease state characterized by pulmonary hemorrhage due to disruption of the alveolar-capillary basement membrane [3,4]. Hemoptysis and progressive exertional dyspnea are the usual presenting symptoms, although these are not always manifest.\n\nIn this report, we describe a case of a patient with DAH, complicated by RA, but without any signs of systemic vasculitis. The clinical presentation proved challenging, resulting in a fatal outcome. We review past cases of RA-associated DAH and assess potential treatment choices for future cases.\n\n2 Case report\n\nAn 89-year-old Japanese woman was referred to the Department of Respiratory Medicine for mild exertional dyspnea with abnormal chest imaging.\n\nShe had been diagnosed with seropositive RA two months earlier for multiple arthralgias involving knees, shoulders, elbows, wrists, and hands, along with significant morning stiffness over five months. She was a housewife and a life-long non-smoker, with no family history of autoimmune diseases. A blood test at the time of her RA diagnosis revealed elevated C-reactive protein (CRP) (5.61 mg/dL) and anti-citrullinated protein antibodies (ACPA) (211 U/mL). Anti-neutrophil cytoplasmic antibody (ANCA), antinuclear antibody (ANA), and rheumatoid factor (RF) were negative. Ultrasonography of the wrist joints showed the presence of synovitis. Based on these findings, she was diagnosed with RA. Chest CT imaging showed slight subpleural reticular shadows in both lower lobes and subpleural consolidations (Fig. 2A). Treatment was initiated with 10 mg/day of prednisolone and tacrolimus due to abnormalities in her chest images, but tacrolimus was discontinued later because of concerns about drug-induced interstitial pneumonia.\n\nShe was admitted to Hamanomachi Hospital due to progressive exertional dyspnea that had continued more than one month. She was diagnosed with exacerbation of chronic heart failure, based on findings of pitting edema in her legs, cardiac enlargement with right pleural effusion in chest images, and an elevated NT-proBNP level in a blood test. Additionally, chest CT showed patchy consolidations and ground-glass opacities (GGO) with a peribronchial distribution, predominantly in the right lobes, suggesting a radiologic pattern of organizing pneumonia (OP) (Fig. 2B). These CT findings suggested that pulmonary edema was aggravating the interstitial pneumonia.\n\nFirst, she was treated with furosemide and spironolactone for the heart failure from admission day 1. She responded well to these diuretics, and symptoms of heart failure improved, but exertional dyspnea remained. She underwent coronary angiography on day 3, which confirmed the absence of significant stenotic lesions. Since her exertional dyspnea did not improve much even after treatment for heart failure, pulmonary disease was suspected.\n\nThe patient was then referred to the Department of Respiratory Medicine on day 8. She had a temperature of 36.5 °C, blood pressure of 108/68 mmHg, a heart rate of 76 beats per minute, oxygen saturation of 98% under room air. Her RA-associated joint symptoms were well controlled. Physical examination revealed slight late inspiratory crackles in her right chest with no peripheral edema. Sputum cultures showed no evidence of bacterial or fungal infections. Given her advanced age, a bronchoscopy examination was not performed at that time. She was treated with additional PSL doses (25 mg/day) for clinical diagnosis of OP from day 9 (Fig. 4).\n\nThe PSL dose was tapered to 20 mg/day on day 23. Chest imaging showed worsening of infiltration (Fig. 1D, Fig. 2C) on day 26. Her oxygen saturation (SpO2) dropped to <90%, and oxygen therapy was initiated with nasal canula at 1 L/min on day 27. Repeated physical examination revealed no peripheral edema. Her level of NT-proBNP was decreased compared to that on admission. Echocardiography showed preserved left ventricular function with no dilation of the inferior vena cava. These findings indicated little contribution of chronic heart failure to the worsening lung infiltration. To enable a diagnosis, bronchoscopy was performed on day 28. Bronchoscopy showed hemoptysis from the right main bronchus to the trachea. (Fig. 3B). Bronchoalveolar lavage fluid from the right B3 bronchus was sanguineous, indicating DAH. Cytology of the lavage showed neutrophil predominance (neutrophils 85%, lymphocytes 2%, macrophages 13%). Infectious workup was negative, including Aspergillus antigen and Pneumocystis jirovecii DNA PCR. We ordered additional serological examinations to evaluate the etiology of DAH: repeated ANCA and ANA, anti-double-stranded DNA, anti-glomerular basement membrane (GBM), anti-Ro, anti-La, anti-RNP, and anti-phospholipid antibodies were all negative. Urinary analysis revealed no hematuria, proteinuria, or erythrocyte casts through the course. A thorough review of patient medications was performed, and edoxaban for chronic atrial fibrillation was discontinued.Fig. 1 Chest X-ray images of the patient.\n\nChest X-ray images (A) upon diagnosis of rheumatoid arthritis, (B) on admission, (C) on day 15, (D) on day 26, and (E) on day 37.\n\nFig. 1\n\nFig. 2 Chest CT images of the patient.\n\n(A) Chest CT images at the initial diagnosis of rheumatoid arthritis. Slight subpleural reticular shadows in both lower lobes and subpleural consolidations are manifest. (B) On admission to Hamanomachi Hospital (day 1). Chest CT images showed patchy consolidations and ground-glass opacities (GGO) with peribronchial distribution predominantly in the right lobes, suggesting a radiologic pattern of organizing pneumonia (OP). Right pleural effusion was also noted. (C) On day 26, chest CT images showed worsening GGO and consolidations. Pleural effusion was reduced compared to that on admission.\n\nFig. 2\n\nFig. 3 Bronchoscopic findings showing diffuse alveolar hemorrhage.\n\n(A) Bronchoscopy shows hemoptysis from the right main bronchus to the trachea. (B) Bronchoalveolar lavage fluid from the right B3 bronchus shows significant alveolar hemorrhage.\n\nFig. 3\n\nFig. 4 A clinical course of the case.\n\nThe patient was referred to the Department of Respiratory Medicine on admission day 8. Diffuse alveolar hemorrhage was diagnosed by bronchoscopy on day 28. Despite treatment, including pulsed-dose methylprednisolone, respiratory failure progressed, leading to a fatal outcome on day 39.mPSL: methylprednisolone, PSL: prednisolone, IVIG: intravenous immunoglobulin, RBC: red blood cell transfusion, LVFX: levofloxacin, ST: sulfamethoxazole-trimethoprim, CRP: C-reactive protein, LDH: lactate dehydrogenase, BF: bronchoscopy, NHF: nasal high flow, FiO2: fraction of inspiratory oxygen, NPPV: non-invasive positive pressure ventilation. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 4\n\nDespite treatment with pulsed-dose methylprednisolone and levofloxacin, respiratory failure and anemia continued to progress. Hemoptysis appeared from day 32. The patient received additional treatment with red blood cell transfusions, intravenous immunoglobulin (IVIG), and sivelestat, which were unable to halt the progression of DAH. The patient died on day 39.\n\n3 Discussion\n\nDAH is one of the rarer presentations of RA and it is a diagnostic challenge for the physician. DAH can occur in a large variety of clinical conditions: granulomatosis with polyangiitis, microscopic polyangiitis, anti-GBM disease, systemic lupus erythematosus, Sjogren syndrome, bland hemorrhages in patients with mitral valve disease, excessive anticoagulation, and drug-related [3,4]. DAH associated with RA is considered to be pulmonary capillaritis, and most reported cases complicate the systemic vasculitis, especially those with serum ANCA activity [5] or a high RF titer [6,7], called rheumatoid vasculitis [8]. This patient had a low RF titer and normal complement titers, atypical for rheumatoid vasculitis.\n\nWe excluded other etiologies of DAH. ANA, anti-ds-DNA antibodies, anti-Ro, anti-La, anti-GBM antibodies, anti-phospholipid antibodies, and anti-RNP antibodies were all negative, with no evidence of hematuria, proteinuria, or erythrocyte casts in the urine. These findings excluded SLE, anti-GBM disease, and ANCA-related vasculitis. There was no evidence of mitral abnormalities in the echocardiogram. Anticoagulation therapy with edoxaban could have contributed to worsening DAH, but it could not have been the main cause, since it continued to progress, even after discontinuation of edoxaban. Therefore, we concluded that DAH was related to RA without other etiologies.\n\nTo date, only five cases of RA-associated DAH without systemic vasculitis have been reported (Table 1) [[9], [10], [11]]. Four cases had DAH with a known diagnosis of RA [9,11]. In the fifth case, DAH was the initial presentation of RA [10]. The patient in this report is the sixth case of RA-associated DAH without systemic vasculitis. There could be unknown, autoimmune pathogenesis underlying RA-associated DAH without systemic vasculitis in these cases.Table 1 Clinical characteristics of patients with rheumatoid arthritis-associated diffuse alveolar hemorrhage in the absence of systemic vasculitis.\n\nTable 1Age\tSex\tACPA\tRF\tTreatment\tOutcome\tReference\t\n56\tM\tn.a.\t1:1280\tGlucocorticoid, cyclophosphamide\tImproved\t[9]\t\n64\tM\tn.a.\t1:1280\tGlucocorticoid\tFatal (cardiac)\t[9]\t\n25\tF\tn.a.\t1:2560\tGlucocorticoid, cyclophosphamide\tImproved\t[9]\t\n45\tF\tn.a.\t70 IU/mL\tGlucocorticoid\tImproved\t[10]\t\n36\tF\tn.a.\tn.a.\tGlucocorticoid, rituximab, AZA\tImproved\t[11]\t\n89\tF\t211 U/mL\t3.0 IU/mL\tGlucocorticoids, IVIG, sivelestat\tFatal\tThis case\t\nn.a.: not available, ACPA: anticitrullinated peptide antibodies, RF: rheumatoid factor, AZA: azathioprine, IVIG: intravenous immunoglobulin.\n\nThe clinical presentation of the patient in this report was challenging since radiologic features presented an OP pattern without hemoptysis or desaturation. In general, DAH shows similar CT findings, regardless of its cause [12]. Chest CT findings include GGO or consolidation in the presence of acute hemorrhage [12]. Ill-defined centrilobular nodules may predominate in some DAH cases [12]. Within days of an acute episode of hemorrhage, the presence of interlobular septal thickening may be seen in association with GGO [12]. In later stages, an interstitial abnormality and fibrosis may sometimes occur [12]. In this case, there were two possibilities: DAH might have occurred coincidentally with OP, or DAH might just have resembled an OP pattern in chest CT images.\n\nAlthough evidence of treatment for DAH is limited, corticosteroids and immunosuppressive agents remain the standard treatment [13]. High-dose glucocorticoids are usually initiated while waiting for test results to confirm a specific cause of capillaritis, which then guides the selection of additional immunosuppressive therapies. As reported, cyclophosphamide, rituximab, azathioprine, and IVIG, in addition to glucocorticoids, are generally the options to treat DAH associated with RA [[9], [10], [11]]. This patient's advanced age made us hesitant to administer an aggressive therapy, such as cyclophosphamide or rituximab. We chose IVIG in combination with pulsed glucocorticoids for safer medication; however, the possible efficacy of IVIG in patients with DAH is unknown. We also used sivelestat, a neutrophil elastase inhibitor that is approved for acute respiratory distress syndrome (ARDS) in Japan [14] on the assumption of neutrophil inflammation in conjunction with DAH. Again, the therapeutic potential of sivelestat on DAH is unknown.\n\nThe limitation of this case is the lack of tissue biopsy, but we were concerned about biopsy-related complications at the patient's very advanced age. From the clinical course and laboratory values, such as LDH, it was assumed that the patient had pulmonary vasculitis, but this could not be verified directly.\n\nIn summary, we witnessed a fatal case of DAH complicated with RA in an elderly patient. Despite its rarity, this case emphasizes consideration of DAH in RA patients who present a radiographic appearance of GGO and consolidation.\n\nPatient consent for publication\n\nWritten, informed consent was obtained from the patient and her family.\n\nDeclaration of competing interest\n\nAll authors of the manuscript declare that there are no conflicts of interest.\n==== Refs\nReferences\n\n1 Aletaha D. Smolen J.S. Diagnosis and management of rheumatoid arthritis: a review JAMA, J. Am. Med. Assoc. 320 2018 1360 1372 10.1001/jama.2018.13103\n2 Wang D. Zhang J. Lau J. Wang S. Taneja V. Matteson E.L. Vassallo R. Mechanisms of lung disease development in rheumatoid arthritis Nat. Rev. Rheumatol. 15 2019 581 596 10.1038/s41584-019-0275-x 31455869\n3 Krause M.L. Cartin-Ceba R. Specks U. Peikert T. Update on diffuse alveolar hemorrhage and pulmonary vasculitis Immunol. Allergy Clin. 32 2012 587 600 10.1016/j.iac.2012.08.001\n4 Lara A.R. Schwarz M.I. Diffuse alveolar hemorrhage Chest 137 2010 1164 1171 10.1378/chest.08-2084 20442117\n5 Travis W.D. V Colby T. Lombard C. Carpenter H.A. A clinicopathologic study of 34 cases of diffuse pulmonary hemorrhage with lung biopsy confirmation Am. J. Surg. Pathol. 14 1990 1112 1125 http://www.ncbi.nlm.nih.gov/pubmed/2252102 2252102\n6 Voskuyl A.E. Zwinderman A.H. Westedt M.L. Vandenbroucke J.P. Breedveld F.C. Hazes J.M.W. Factors associated with the development of vasculitis in rheumatoid arthritis: results of a case-control study Ann. Rheum. Dis. 55 1996 190 192 10.1136/ard.55.3.190 8712883\n7 Myasoedova E. Crowson C.S. Turesson C. Gabriel S.E. Matteson E.L. Incidence of extraarticular rheumatoid arthritis in olmsted county, Minnesota, in 1995-2007 versus 1985-1994: a population-based study J. Rheumatol. 38 2011 983 989 10.3899/jrheum.101133 21459933\n8 Kishore S. Maher L. Majithia V. Rheumatoid vasculitis: a diminishing yet devastating menace Curr. Rheumatol. Rep. 19 2017 39 10.1007/s11926-017-0667-3 28631066\n9 Schwarz M.I. Zamora M.R. Hodges T.N. Chan E.D. Bowler R.P. Tuder R.M. Isolated pulmonary capillaritis and diffuse alveolar hemorrhage in rheumatoid arthritis and mixed connective tissue disease Chest 113 1998 1609 1615 10.1378/chest.113.6.1609 9631801\n10 Dua R. Rawat J. Diffuse alveolar hemorrhage in a patient of rheumatoid arthritis Lung India 31 2014 194 10.4103/0970-2113.129899 24778495\n11 Osman A. Galiatsatos P. Bose S. Danoff S. Rheumatoid arthritis causing diffuse alveolar haemorrhage: a novel therapeutic approach BMJ Case Rep. 2017 2017 2 6 10.1136/bcr-2017-220509\n12 Webb Wayne Richard Muller Nestor L. Naidich David P. High-Resolution CT of the Lung fifth ed. 2014 Lippincott Williams & Wilkins\n13 Ioachimescu O.C. Stoller J.K. Diffuse alveolar hemorrhage: diagnosing it and finding the cause Cleve. Clin. J. Med. 75 2008 258 280 10.3949/ccjm.75.4.258 18491433\n14 Kido T. Muramatsu K. Yatera K. Asakawa T. Otsubo H. Kubo T. Fujino Y. Matsuda S. Mayumi T. Mukae H. Efficacy of early sivelestat administration on acute lung injury and acute respiratory distress syndrome Respirology 22 2017 708 713 10.1111/resp.12969 27990710\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0071",
"issue": "32()",
"journal": "Respiratory medicine case reports",
"keywords": "Anti-citrullinated protein antibodies; Diffuse alveolar hemorrhage; Rheumatoid arthritis; Rheumatoid vasculitis",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101363",
"pmc": null,
"pmid": "33747760",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "2252102;8712883;21459933;9631801;28631066;24778495;28619978;30285183;23102067;20442117;27990710;31455869;18491433",
"title": "A fatal case of diffuse alveolar hemorrhage complicated by rheumatoid arthritis.",
"title_normalized": "a fatal case of diffuse alveolar hemorrhage complicated by rheumatoid arthritis"
} | [
{
"companynumb": "JP-PBT-000482",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"druga... |
{
"abstract": "In the era of highly potent illicit opioids, such as fentanyl and carfentanil, injectable opioid agonist treatment (iOAT) is an effective treatment for those with severe and treatment-refractory opioid use disorder. Untreated opioid use disorder in pregnancy can lead to maternal and neonatal morbidity and mortality. There are currently limited reports on the use of iOAT in pregnant women. The in-patient setting may provide an opportunity to pregnant women for stabilization with iOAT where first line therapies have been ineffective.\n\n\n\nWe report a case of a pregnant individual who engaged in daily intravenous fentanyl who was admitted to the hospital at 29 weeks gestation for stabilization with iOAT, methadone, and slow-release oral morphine. Before admission, she endured 6 opioid overdoses in her pregnancy and continued to use illicit intravenous opioids in the community despite high dose methadone combined with slow-release oral morphine. Her withdrawal symptoms and cravings were ameliorated with hydromorphone 90 mg IM/IV BID, methadone 135 mg daily, and morphine sulfate sustained release 600 mg daily. With this regimen, she was able to reduce her intravenous fentanyl use to a single episode during her hospitalization. She completed her pregnancy in hospital, delivering a full-term live infant after receiving comprehensive prenatal care.\n\n\n\nThis case report highlights iOAT as an option during pregnancy and describes the in-patient setting as appropriate to retain high-risk patients in care. This approach may benefit those who are refractory to standard opioid agonist treatment, the numbers of whom may be rising as tolerance to the illicit supply increases.",
"affiliations": "Post-graduate Medical Education, University of Toronto, Toronto, ON, Canada (SG), St. Michael's Hospital, Department of Pediatrics, Toronto, ON, Canada (DMC, MS), Department of Pediatrics, University of Toronto, Toronto, ON, Canada (DMC, MS), Department of Mental Health and Addictions, St. Michael's Hospital, Toronto, ON, Canada (SG, AC, TG, WL, ST), Department of Psychiatry, University of Toronto, Toronto, ON, Canada (AC, TG, WL), Department of Family and Community Medicine, St Michael's Hospital, Toronto, ON, Canada (SG, EL, MN, ST), Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada (EL, MN, ST), Department of Family Medicine, McMaster University, Hamilton, ON, Canada (ST).",
"authors": "Griffiths|Sarah|S|;Campbell|Douglas M|DM|;Caudarella|Alexander|A|;Guimond|Tim|T|;Lamba|Wiplove|W|;Lurie|Erin|E|;Nader|Maya|M|;Sgro|Michael|M|;Turner|Suzanne|S|",
"chemical_list": "D000701:Analgesics, Opioid; D004091:Hydromorphone; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000776",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "15(5)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000701:Analgesics, Opioid; D005260:Female; D006801:Humans; D004091:Hydromorphone; D007231:Infant, Newborn; D008691:Methadone; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011247:Pregnancy",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "435-438",
"pmc": null,
"pmid": "33234803",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Use of Injectable Opioid Agonist Therapy in a In-Patient Setting for a Pregnant Patient With Opioid Use Disorder: A Case Report.",
"title_normalized": "use of injectable opioid agonist therapy in a in patient setting for a pregnant patient with opioid use disorder a case report"
} | [
{
"companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2020-08784",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
... |
{
"abstract": "A 76-year-old woman with spontaneous reactivation of hepatitis B virus (HBV) without any immunosuppressants who had been successfully treated with tenofovir alafenamide fumarate (TAF) was reported. The patient was admitted to our hospital because of acute exacerbation of the liver function and jaundice. She had been found to have chronic HBV infection with a normal liver function and had been treated for lifestyle-related diseases, such as diabetes mellitus, dyslipidemia and hypertension, for over 10 years at a local clinic. At admission, her serum HBV DNA was high (7.3 log IU/mL), and anti-hepatitis B core protein immunoglobulin M was slightly elevated (1.47 S/CO). Due to the absence of known risk factors for HBV reactivation, the reactivation was regarded as \"spontaneous\". After the initiation of the nucleotide analog TAF, her liver function gradually improved with a decrease in the HBV DNA load. Her HBV genome was typed as subgenotype B1 and possessed a frameshift mutation due to an insertion of T after nucleotide (nt) 1817 and G to A mutations at nt 1896 and nt 1899 (G1896A/G1899A) in the precore region as well as serine to glutamine substitution of amino acid 21 in the core protein. In addition to these viral mutations, aging and complications of lifestyle-related diseases in the present case may have been responsible for the spontaneous HBV reactivation. Careful observation and management of aged HBV carriers with underlying diseases are needed even when persistent HBV infection is free from symptoms and liver dysfunction and no immunosuppressive conditions are involved.",
"affiliations": "Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22, Fujioka, Gunma, 375-0024, Japan. htakagi@kusunoki-hp.com.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22, Fujioka, Gunma, 375-0024, Japan.;Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22, Fujioka, Gunma, 375-0024, Japan.;Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.;Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan.",
"authors": "Takakusagi|Satoshi|S|;Takagi|Hitoshi|H|http://orcid.org/0000-0002-5924-1170;Yokoyama|Yozo|Y|;Kizawa|Kazuko|K|;Marubashi|Kyoko|K|;Kosone|Takashi|T|;Nagashima|Shigeo|S|;Takahashi|Masaharu|M|;Murata|Kazumoto|K|http://orcid.org/0000-0002-3419-6297;Okamoto|Hiroaki|H|http://orcid.org/0000-0003-0827-0964",
"chemical_list": "D004279:DNA, Viral; D006513:Hepatitis B e Antigens",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-021-01423-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "14(4)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Hepatitis B virus; Precore mutation; Spontaneous reactivation; Tenofovir alafenamide fumarate",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D000368:Aged; D004279:DNA, Viral; D005260:Female; D016368:Frameshift Mutation; D006509:Hepatitis B; D006513:Hepatitis B e Antigens; D006515:Hepatitis B virus; D006801:Humans; D008019:Life Style; D009154:Mutation",
"nlm_unique_id": "101477246",
"other_id": null,
"pages": "1202-1210",
"pmc": null,
"pmid": "33959934",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32104912",
"title": "Spontaneous reactivation of hepatitis B virus with a frameshift mutation in the precore region in an elderly hepatitis B virus carrier with lifestyle-related diseases.",
"title_normalized": "spontaneous reactivation of hepatitis b virus with a frameshift mutation in the precore region in an elderly hepatitis b virus carrier with lifestyle related diseases"
} | [
{
"companynumb": "JP-DSJP-DSJ-2021-127616",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OLMESARTAN MEDOXOMIL"
},
"drugadditional": "1",... |
{
"abstract": "Protamine is widely used in medicine as a rapidly-acting antidote to heparin, particularly for reversing heparin anticoagulation after cardiac surgery. Protamine is also used as a stabilizing additive to certain preparations of insulin. Recent reports demonstrate that protamine and heparin form multimolecular complexes that result in high rates of immunization in post-cardiac surgery patients, particularly of immunoglobulin G (IgG) class antibodies; a subset of these anti-protamine/heparin IgG antibodies activates platelets through their FcγIIA (IgG) receptors. Although the clinical consequences of anti-protamine/heparin antibodies that are newly generated after cardiac surgery are unknown, there is evidence that platelet-activating anti-protamine/heparin antibodies already present at the time of cardiac surgery might occasionally explain more severe thrombocytopenia with delayed platelet count recovery, as well as thromboembolic complications, in the post-cardiac surgery setting. Triggers for such antibodies remain poorly-defined, but could include preoperative administration of heparin to diabetic patients receiving protamine-insulin as well as recent previous cardiac surgery. Anti-protamine/heparin antibodies have several features in common with anti-platelet factor 4 (PF4) PF4/heparin antibodies implicated in heparin-induced thrombocytopenia (HIT), including immunization by heparin-containing multimolecular complexes, predominant IgG class, pathological platelet-activating properties, relatively rapid IgG formation without IgM precedence, and antibody transience. Despite these similarities, the risk of anti-protamine/heparin antibody-mediated complications seems to affect the early post-cardiac surgery period, whereas HIT usually occurs at least 5 days following cardiac surgery. Clinicians need to become aware of this recently recognized immunohematological disorder, and research is needed to identify triggers of immunization, improve detection of pathological antibodies and identify patients at risk of this complication.",
"affiliations": "Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, Greifswald, Germany. tamam.bakchoul@uni-greifswald.de, tamam.bakchoul@med.uni-tuebingen.de.;Institute for Immunology and Transfusion Medicine, Universitätsmedizin Greifswald, Greifswald, Germany.;Department of Pathology and Molecular Medicine, McMaster University, Hamilton, ON, Canada.",
"authors": "Bakchoul|T|T|;Jouni|R|R|;Warkentin|T E|TE|",
"chemical_list": "D000906:Antibodies; D000925:Anticoagulants; D000939:Epitopes; D007074:Immunoglobulin G; D011479:Protamines; D010978:Platelet Factor 4; D006493:Heparin",
"country": "England",
"delete": false,
"doi": "10.1111/jth.13405",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-7836",
"issue": "14(9)",
"journal": "Journal of thrombosis and haemostasis : JTH",
"keywords": "IgG; heparin; protamine sulfate; thrombocytopenia; thrombosis",
"medline_ta": "J Thromb Haemost",
"mesh_terms": "D000368:Aged; D000818:Animals; D000906:Antibodies; D000925:Anticoagulants; D001792:Blood Platelets; D006348:Cardiac Surgical Procedures; D015331:Cohort Studies; D000939:Epitopes; D005260:Female; D006493:Heparin; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G; D008297:Male; D051379:Mice; D016513:Mice, SCID; D010343:Patient Admission; D015539:Platelet Activation; D010976:Platelet Count; D010978:Platelet Factor 4; D011479:Protamines; D013921:Thrombocytopenia",
"nlm_unique_id": "101170508",
"other_id": null,
"pages": "1685-95",
"pmc": null,
"pmid": "27378603",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Protamine (heparin)-induced thrombocytopenia: a review of the serological and clinical features associated with anti-protamine/heparin antibodies.",
"title_normalized": "protamine heparin induced thrombocytopenia a review of the serological and clinical features associated with anti protamine heparin antibodies"
} | [
{
"companynumb": "DE-SA-2016SA185478",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "We reviewed the 33727 postmortem toxicology investigations performed in Finland over a period of 5years (2009-2013) and identified those in which the antidepressant bupropion was detected. Cases positive for other antidepressant drugs were reviewed for comparison. The postmortem toxicological examination included, in all cases, the routine screening and quantification of hundreds of drugs and poisons using quality-controlled methods. Bupropion was detected in 65 cases. A large proportion of the bupropion-positive deaths resulted from suicide (55%). In fatal poisoning cases found positive for bupropion, the proportion of suicide was even higher (77%). The measured median bupropion postmortem blood concentration (0.69mg/L) was markedly higher than the normal therapeutic range in plasma in the treatment of depression (up to 0.1mg/L) and even higher in fatal bupropion poisonings (13mg/L). Only 14% of the deceased positive for bupropion were estimated to be drug abusers. However, nearly all of the drug abuse cases were from the last year of the study (2013), indicating a recent increase of the use of bupropion among drug abusers and possibly even abuse of bupropion itself. Suicide victims positive for bupropion were younger than those who died with other antidepressant drugs in their blood. In addition, the percentage of fatal poisonings among bupropion-positive postmortem cases was higher than among the users of other antidepressant drugs. Suicide was significantly more common among the deceased positive for bupropion than among users of other antidepressant drugs. An unknown degree of bupropion degradation before the assay and post-mortem redistribution of bupropion may have impacted the measured levels. Nonetheless, all post-mortem concentrations of bupropion were elevated and especially high concentrations were detected in suicides.",
"affiliations": "Department of Forensic Medicine, University of Helsinki, PO Box 40, FI-00014 Helsinki, Finland. Electronic address: pirkko.kriikku@helsinki.fi.;Department of Forensic Medicine, University of Helsinki, PO Box 40, FI-00014 Helsinki, Finland.",
"authors": "Kriikku|Pirkko|P|;Ojanperä|Ilkka|I|",
"chemical_list": "D000928:Antidepressive Agents; D016642:Bupropion",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2016.06.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "266()",
"journal": "Forensic science international",
"keywords": "Antidepressant; Bupropion; Fatal poisoning; Forensic toxicology; Postmortem; Suicide",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000928:Antidepressive Agents; D001344:Autopsy; D016642:Bupropion; D005387:Finland; D053593:Forensic Toxicology; D006801:Humans; D013405:Suicide",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "343-348",
"pmc": null,
"pmid": "27372438",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The relationship between bupropion and suicide in post-mortem investigations.",
"title_normalized": "the relationship between bupropion and suicide in post mortem investigations"
} | [
{
"companynumb": "DE-IMPAX LABORATORIES, INC-2016-IPXL-00836",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION HYDROCHLORIDE"
},
... |
{
"abstract": "Depression is the main psychiatric symptom in patients living with HIV. Genetic predisposition, stress from disease as well as the antiretroviral therapy itself are discussed as pathogenic factors. We report a 35-year-old HIV-positive man suffering from bipolar disorder who developed major depression shortly after commercing combination antiretroviral therapy (cART) on three occasions. The first two times the patient ceased therapy autonomously, and the depression disappeared completely. The close connection between cART and major depression in the present case supports the depression-inducing potential of cART. Additionally, we present an overview of literature.",
"affiliations": "Department of Psychiatry, University of Muenster, Albert-Schweitzer-Str. 11, D-48129 Muenster, Germany. Florian.Kaestner@ukmuenster.de",
"authors": "Kaestner|F|F|;Anneken|K|K|;Mostert|C|C|;Reichelt|D|D|;Rothermundt|M|M|;Evers|S|S|;Husstedt|I W|IW|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "England",
"delete": false,
"doi": "10.1258/ijsa.2009.009451",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0956-4624",
"issue": "23(6)",
"journal": "International journal of STD & AIDS",
"keywords": null,
"medline_ta": "Int J STD AIDS",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D001714:Bipolar Disorder; D003863:Depression; D015658:HIV Infections; D006801:Humans; D008297:Male; D055118:Medication Adherence",
"nlm_unique_id": "9007917",
"other_id": null,
"pages": "e14-9",
"pmc": null,
"pmid": "22807551",
"pubdate": "2012-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Depression associated with antiretroviral drug therapy in HIV: case report and overview.",
"title_normalized": "depression associated with antiretroviral drug therapy in hiv case report and overview"
} | [
{
"companynumb": "DE-ABBVIE-20K-062-3247180-00",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "Granulomatosis with polyangiitis (GPA) is the most common antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We describe the case of a 38-year-old woman with relapsing GPA who presented with intracranial hypertension, followed by the appearance of cavitated lung nodules despite treatment with azathioprine. Clinical improvement and ANCA titre reduction were observed after rituximab treatment. We report a rare form of GPA relapse and highlight the challenge of following-up patients with GPA, in whom can be hard to distinguish relapse from the consequences of long-term immunosuppression.\nAntineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare inflammatory disease with pauci-immune focal necrotising lesions that affect small and medium vessels. It has a wide clinical presentation, affecting mainly the upper and lower respiratory tract and kidneys.Granulomatosis with polyangiitis (GPA) is frequently associated with PR3-ANCA and is risk factor for relapse.Follow-up of ANCA titres, which may rise before the development of symptoms, is crucial for recurrence diagnosis. Titres can also be used to distinguish recurrence from the consequences of long-term immunosuppression.",
"affiliations": "Internal Medicine Department, Unidade Local de Saúde do Nordeste, Portugal.;Nephrology Department, Centro Hospitalar Universitário do Porto, Portugal.;Pathological Anatomy Department, Centro Hospitalar Universitário do Porto, Portugal.;Nephrology Department, Centro Hospitalar Universitário do Porto, Portugal.;Internal Medicine Department, Unidade Local de Saúde do Nordeste, Portugal.;Nephrology Department, Centro Hospitalar Universitário do Porto, Portugal.;Nephrology Department, Centro Hospitalar Universitário do Porto, Portugal.",
"authors": "Diegues|Andreia|A|;Tavares|Joana|J|;Sá|Diogo|D|;Oliveira|João|J|;Fernandes|Diana|D|;Santos|Josefina|J|;Rocha|Guilherme|G|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2021_002448",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2284-2594",
"issue": "8(4)",
"journal": "European journal of case reports in internal medicine",
"keywords": "ANCA-PR3-associated vasculitis; granulomatosis with polyangiitis; intracranial hypertension; lung nodules",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "002448",
"pmc": null,
"pmid": "33987124",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "26876879;27338776;29446067;31358311",
"title": "Granulomatosis with Polyangiitis: Recurrence or Treatment Consequences?",
"title_normalized": "granulomatosis with polyangiitis recurrence or treatment consequences"
} | [
{
"companynumb": "PT-TEVA-2021-PT-1931255",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
... |
{
"abstract": "The alarming spread of HIV among men who have sex with men (MSM) has become a national concern in China. Estimating men's sexual HIV infectiousness from blood plasma viral load (BPVL) depends on the association between BPVL and seminal plasma viral load (SPVL). However, previous studies were controversial and few concentrated on MSM. Twenty antiretroviral therapy (ART)-naive MSM and 54 MSM under ART were recruited between July and September 2015 in the city of Hangzhou, China. Blood and semen were collected in pairs at the same visit for each individual. BPVL and SPVL were measured by COBAS AmpliPrep/COBAS TaqMan HIV-1 Test ver2.0. The mean viral load in blood plasma was higher than that in semen (4.5 ± 0.9 log10 vs. 3.4 ± 1.3 log10) in 20 ART-untreated MSM, and a positive correlation was found between BPVL and SPVL, as evaluated by linear regression (R2 = 0.565, p < .001). A total of 96.3% (52/54) of ART-treated patients had successful viral suppression (<400 copies/mL) according to the BPVL. Fourteen subjects (25.9%, 14/54) presenting undetectable SPVL showed detectable BPVL, ranging from 20.4 to 7,470 copies/mL. Three subjects (5.6%, 3/54) presented detectable SPVL although BPVL was undetectable. MSM could pose a transmission risk despite undetectable BPVL. Consistent use of condoms and other risk-reduction strategies should be strongly advocated in MSM throughout all stages of HIV infection, regardless of ART.",
"affiliations": "1 Department of HIV/AIDS and STD Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention , Hangzhou, China .;2 National Center for AIDS/STD Control and Prevention, Chinese Center for Disease Control and Prevention , Beijing, China .;1 Department of HIV/AIDS and STD Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention , Hangzhou, China .;1 Department of HIV/AIDS and STD Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention , Hangzhou, China .;1 Department of HIV/AIDS and STD Control and Prevention, Zhejiang Provincial Center for Disease Control and Prevention , Hangzhou, China .",
"authors": "Zhang|Jiafeng|J|;Wang|Ning|N|;He|Lin|L|;Pan|Xiaohong|X|;Ding|Xiaobei|X|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1089/AID.2018.0090",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0889-2229",
"issue": "35(4)",
"journal": "AIDS research and human retroviruses",
"keywords": "HIV; men who have sex with men; semen; viral load",
"medline_ta": "AIDS Res Hum Retroviruses",
"mesh_terms": "D000328:Adult; D000368:Aged; D044466:Asians; D002681:China; D015658:HIV Infections; D018451:Homosexuality, Male; D006801:Humans; D008297:Male; D008875:Middle Aged; D012661:Semen; D019562:Viral Load; D055815:Young Adult",
"nlm_unique_id": "8709376",
"other_id": null,
"pages": "393-395",
"pmc": null,
"pmid": "30411973",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Short Communication: Discordance of HIV-1 Viral Load from Paired Blood and Seminal Plasma Samples in a Chinese Men Who Have Sex with Men Population.",
"title_normalized": "short communication discordance of hiv 1 viral load from paired blood and seminal plasma samples in a chinese men who have sex with men population"
} | [
{
"companynumb": "CN-VIIV HEALTHCARE LIMITED-CN2019075869",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
},
... |
{
"abstract": "BACKGROUND\nRelapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease.\n\n\nMETHODS\nWe infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells.\n\n\nRESULTS\nA total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab.\n\n\nCONCLUSIONS\nChimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).",
"affiliations": "From the Division of Oncology, Children's Hospital of Philadelphia (S.L.M., R.A., D.M.B., N.J.B., S.R.R., D.T.T., S.A.G.), the Departments of Pediatrics (S.L.M., R.A., D.M.B., N.J.B., S.R.R., D.T.T., S.A.G.), Biostatistics and Epidemiology (P.A.S., R.A.), and Pathology and Laboratory Medicine (J.J.M., B.L.L., C.H.J., S.A.G.), the Division of Hematology-Oncology (N.F., D.L.P.), and Abramson Cancer Center (N.F., A.C., V.E.G., Z.Z., S.F.L., Y.D.M., J.J.M., B.L.L., C.H.J., D.L.P., S.A.G.), Perelman School of Medicine, University of Pennsylvania - all in Philadelphia; and Novartis Pharmaceuticals, East Hanover, NJ (A.S.).",
"authors": "Maude|Shannon L|SL|;Frey|Noelle|N|;Shaw|Pamela A|PA|;Aplenc|Richard|R|;Barrett|David M|DM|;Bunin|Nancy J|NJ|;Chew|Anne|A|;Gonzalez|Vanessa E|VE|;Zheng|Zhaohui|Z|;Lacey|Simon F|SF|;Mahnke|Yolanda D|YD|;Melenhorst|Jan J|JJ|;Rheingold|Susan R|SR|;Shen|Angela|A|;Teachey|David T|DT|;Levine|Bruce L|BL|;June|Carl H|CH|;Porter|David L|DL|;Grupp|Stephan A|SA|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1407222",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "371(16)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; D002648:Child; D002675:Child, Preschool; D002678:Chimera; D016207:Cytokines; D005260:Female; D005818:Genetic Engineering; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D007167:Immunotherapy; D016086:Lentivirus; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011948:Receptors, Antigen, T-Cell; D012008:Recurrence; D012074:Remission Induction; D015996:Survival Rate; D013601:T-Lymphocytes; D055815:Young Adult",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "1507-17",
"pmc": null,
"pmid": "25317870",
"pubdate": "2014-10-16",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "24055823;21830940;23233571;21849486;1705867;15908649;23644077;23678006;22189397;23890063;21540550;23527958;23169518;24553386;23243288;18818707;19384291;24667956;21832238;23515080;18509084;23639321;21576633;24727818;8421711;23024237;16648493;20668228;14551141;17062687",
"title": "Chimeric antigen receptor T cells for sustained remissions in leukemia.",
"title_normalized": "chimeric antigen receptor t cells for sustained remissions in leukemia"
} | [
{
"companynumb": "US-AMGEN-USASP2016185080",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLINATUMOMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Following an acute myocardial infarction (MI), patients with persistently elevated biomarkers of inflammation, in particular C-reactive protein (CRP), are at significantly increased risk of further cardiovascular events. Colchicine is a unique anti-inflammatory medication that has shown promise in reducing such events in patients with stable coronary heart disease. The current study tested the ability of low dose colchicine to reduce CRP levels at 30 days after an acute MI, a key marker of future outcome, and its safety and tolerability in this setting.\n\n\n\nWe conducted a randomized, double-blind, trial of low-dose colchicine (0.5 mg daily) or matching placebo in 237 patients admitted with an acute MI. The primary end-point was the proportion of patients with a residual high sensitivity CRP level ≥2 mg/L after 30 days of treatment, a threshold associated with a worse prognosis.\n\n\n\nAt 30-day follow-up, 44% of patients treated with colchicine had a CRP level ≥2 mg/L compared to 50% of those randomized to placebo (P = .35) and the median CRP in patients randomized to colchicine was 1.6 mg/L (interquartile range [IQR] 0.7-3.5) compared to 2.0 mg/L (IQR 0.9-4.0) in patients randomized to placebo (P = .11). The median absolute reduction in CRP levels was -4.3 mg/L (IQR -1.1 to -14.1) among colchicine treated patients and -3.3 mg/L (IQR -0.9 to -14.4, P = .44) in placebo treated patients. The relative reduction was a fall of 78% compared to a fall of 64% (P = .09). Low dose colchicine was well tolerated and did not reduce compliance with other secondary preventative medications at 30-days.\n\n\n\nTreatment with low dose colchicine was safe and well tolerated, but was not associated with a significantly increased likelihood of achieving a CRP level <2 mg/L or lower absolute levels of CRP 30 days after an acute MI.",
"affiliations": "Department of Cardiology, Royal Perth Hospital, Perth and Faculty of Health and Medical Sciences, University of Western Australia; Heart Research Institute, Sydney, Department of Cardiology, Royal Prince Alfred Hospital, Sydney and Faculty of Medicine, University of Sydney.;Department of Cardiology, Royal Perth Hospital, Perth and Faculty of Health and Medical Sciences, University of Western Australia; Heart Research Institute, Sydney, Department of Cardiology, Royal Prince Alfred Hospital, Sydney and Faculty of Medicine, University of Sydney.;Department of Cardiology, Royal Perth Hospital, Perth and Faculty of Health and Medical Sciences, University of Western Australia; Heart Research Institute, Sydney, Department of Cardiology, Royal Prince Alfred Hospital, Sydney and Faculty of Medicine, University of Sydney.;Department of Cardiology, Royal Perth Hospital, Perth and Faculty of Health and Medical Sciences, University of Western Australia; Heart Research Institute, Sydney, Department of Cardiology, Royal Prince Alfred Hospital, Sydney and Faculty of Medicine, University of Sydney.;Department of Cardiology, Royal Perth Hospital, Perth and Faculty of Health and Medical Sciences, University of Western Australia; Heart Research Institute, Sydney, Department of Cardiology, Royal Prince Alfred Hospital, Sydney and Faculty of Medicine, University of Sydney.;Department of Cardiology, Royal Perth Hospital, Perth and Faculty of Health and Medical Sciences, University of Western Australia; Heart Research Institute, Sydney, Department of Cardiology, Royal Prince Alfred Hospital, Sydney and Faculty of Medicine, University of Sydney.;Department of Cardiology, Royal Perth Hospital, Perth and Faculty of Health and Medical Sciences, University of Western Australia; Heart Research Institute, Sydney, Department of Cardiology, Royal Prince Alfred Hospital, Sydney and Faculty of Medicine, University of Sydney. Electronic address: graham.hillis@health.wa.gov.au.",
"authors": "Hennessy|Thomas|T|;Soh|Linda|L|;Bowman|Mitchell|M|;Kurup|Rahul|R|;Schultz|Carl|C|;Patel|Sanjay|S|;Hillis|Graham S|GS|",
"chemical_list": "D015415:Biomarkers; D002097:C-Reactive Protein; D003078:Colchicine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ahj.2019.06.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-8703",
"issue": "215()",
"journal": "American heart journal",
"keywords": null,
"medline_ta": "Am Heart J",
"mesh_terms": "D015415:Biomarkers; D002097:C-Reactive Protein; D003078:Colchicine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007249:Inflammation; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010865:Pilot Projects; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0370465",
"other_id": null,
"pages": "62-69",
"pmc": null,
"pmid": "31284074",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The Low Dose Colchicine after Myocardial Infarction (LoDoCo-MI) study: A pilot randomized placebo controlled trial of colchicine following acute myocardial infarction.",
"title_normalized": "the low dose colchicine after myocardial infarction lodoco mi study a pilot randomized placebo controlled trial of colchicine following acute myocardial infarction"
} | [
{
"companynumb": "AU-TAKEDA-2019TJP018136",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"drugadditional": null,
... |
{
"abstract": "Warfarin have some serious adverse effects, and bleeding is one of the most serious and frequent of them. In this case report, we present the diffuse alveolar hemorrhage case as a rare and life-threatening complication of warfarin.",
"affiliations": "Department of Emergency Medicine, Bagcilar Training and Research Hospital, Bağcılar Eğitim ve Araştırma Hastanesi, Bağcılar, Istanbul, Turkey. Electronic address: eminuysal79@mynet.com.;Department of Emergency Medicine, Van Military Hospital, Van Askeri Hastanesi, Altıntepe, Van, Turkey. Electronic address: cevikerdem@yahoo.com.;Department of Emergency Medicine, Bagcilar Training and Research Hospital, Bağcılar Eğitim ve Araştırma Hastanesi, Bağcılar, Istanbul, Turkey. Electronic address: suleyman.solak@hotmail.com.tr.;Department of Emergency Medicine, Etimesgut Military Hospital, Etimesgut Asker Hastanesi, Etimesgut, Ankara, Turkey. Electronic address: yahya_acar@yahoo.com.;Department of Emergency Medicine, Bagcilar Training and Research Hospital, Bağcılar Eğitim ve Araştırma Hastanesi, Bağcılar, Istanbul, Turkey. Electronic address: mustafayalimol@hotmail.com.",
"authors": "Uysal|Emin|E|;Çevik|Erdem|E|;Solak|Süleyman|S|;Acar|Yahya Ayhan|YA|;Yalimol|Mustafa|M|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "32(6)",
"journal": "The American journal of emergency medicine",
"keywords": null,
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000925:Anticoagulants; D004636:Emergency Service, Hospital; D006469:Hemoptysis; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli; D014057:Tomography, X-Ray Computed; D014859:Warfarin",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "690.e3-4",
"pmc": null,
"pmid": "24412020",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A life-threatening complication of warfarin therapy in ED: diffuse alveolar hemorrhage.",
"title_normalized": "a life threatening complication of warfarin therapy in ed diffuse alveolar hemorrhage"
} | [
{
"companynumb": "PHHY2014TR078709",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "The appropriate sequencing of agents with strong immune system effects has become increasingly important. Transitions require careful balance between safety and protection against relapse. The cases presented herein highlight that rebound events after ceasing fingolimod treatment may happen even with short washout periods (4 weeks) and may perpetuate despite steroid treatment or the immediate use of fast-acting immune therapies, such as rituximab.\n\n\n\nTo describe rebound syndrome in patients with multiple sclerosis (MS) after cessation of fingolimod treatment.\n\n\n\nClinical and demographic data were extracted from electronic medical records from the University of California, San Francisco, Multiple Sclerosis Center from January 2014 to December 2015. Magnetic resonance images were reviewed by MS neurologists (J.S.G., E.W., B.N., and E.C.H.). Rebound syndrome was defined as new severe neurological symptoms after ceasing fingolimod treatment, with the development of multiple new or enhancing lesions exceeding baseline activity. We reviewed the PubMed database from January 2010 to December 2015 for similar cases of severe disease reactivation after ceasing fingolimod treatment using search terms fingolimod and either rebound or reactivation. Participants were included if they stopped receiving fingolimod between January 2014 and December 2015. Five patients were identified who experienced rebound after ceasing fingolimod treatment.\n\n\n\nEach patient received treatment with oral fingolimod for various durations.\n\n\n\nOccurrence of rebound after ceasing fingolimod treatment.\n\n\n\nThe mean (SD) age of the 5 female patients presented in this case series was 35.2 (6.4) years. Of the 46 patients that stopped fingolimod treatment within the 2-year period, 5 (10.9%) experienced severe relapse 4 to 16 weeks after ceasing fingolimod treatment. Despite varying prior severity of relapsing-remitting course, all participants experienced unexpectedly severe clinical relapses accompanied by drastic increases in new or enhancing lesions seen on magnetic resonance imaging evidenced by a median (range) increase of 9 (0->30) new gadolinium-enhancing lesions and a median (range) of 9 (0->30) new T2 lesions. New lesion development persisted for 3 to 6 months despite treatment with corticosteroids (n = 3) and initiation of B-cell depleting therapy (n = 2). In addition, 11 patients were identified through literature review reported as having severe relapses consistent with a rebound syndrome and similar features to our 5 cases.\n\n\n\nThese cases provide evidence for a fingolimod rebound syndrome at a clinically relevant frequency, highlighting the need to determine the best methods for sequencing or discontinuing MS therapies. A large prospective registry or population-based study would be helpful to confirm this rebound phenomenon and to determine contributing factors, including immune biomarkers, that increase risk for this syndrome.",
"affiliations": "Department of Neurology, University of California, San Francisco.;Department of Neurology, University of California, San Francisco.;Department of Neurology, University of California, San Francisco.;Department of Neurology, University of California, San Francisco.;Department of Neurology, University of California, San Francisco.",
"authors": "Hatcher|Stacy Ellen|SE|;Waubant|Emmanuelle|E|;Nourbakhsh|Bardia|B|;Crabtree-Hartman|Elizabeth|E|;Graves|Jennifer S|JS|",
"chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaneurol.2016.0826",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6149",
"issue": "73(7)",
"journal": "JAMA neurology",
"keywords": null,
"medline_ta": "JAMA Neurol",
"mesh_terms": "D000328:Adult; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D008137:Longitudinal Studies; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009103:Multiple Sclerosis; D020529:Multiple Sclerosis, Relapsing-Remitting; D039781:PubMed; D012008:Recurrence",
"nlm_unique_id": "101589536",
"other_id": null,
"pages": "790-4",
"pmc": null,
"pmid": "27135594",
"pubdate": "2016-07-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rebound Syndrome in Patients With Multiple Sclerosis After Cessation of Fingolimod Treatment.",
"title_normalized": "rebound syndrome in patients with multiple sclerosis after cessation of fingolimod treatment"
} | [
{
"companynumb": "PHHY2016US062243",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FINGOLIMOD HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "An immunocompromised patient had positive blood cultures for Mycobacterium intracellulare and no identifiable organ seeding was started on treatment. One month later, the patient was clinically well with negative blood cultures but drug-induced myelotoxicity had developed. Ocular fundus examination at this time revealed bilateral choroidal granulomas which changed patient management.",
"affiliations": "Eye Clinic, Department of Biomedical and Clinical Science \"Luigi Sacco\", Luigi Sacco Hospital, University of Milan, Milan, Italy. alessandro.invernizzi@gmail.com.;Department of Clinical Sciences, Luigi Sacco Hospital, Section of Infectious and Tropical Diseases, University of Milan, Milan, Italy.;Department of Clinical Sciences, Luigi Sacco Hospital, Section of Infectious and Tropical Diseases, University of Milan, Milan, Italy.;Eye Clinic, Department of Biomedical and Clinical Science \"Luigi Sacco\", Luigi Sacco Hospital, University of Milan, Milan, Italy.;Save Sight Institute, Sydney Eye Hospital, University of Sydney, Sydney, Australia.;Department of Clinical Sciences, Luigi Sacco Hospital, Section of Infectious and Tropical Diseases, University of Milan, Milan, Italy.",
"authors": "Invernizzi|Alessandro|A|http://orcid.org/0000-0003-3400-1987;Ricaboni|Davide|D|;Franzetti|Marco|M|;Staurenghi|Giovanni|G|;McCluskey|Peter|P|;Franzetti|Fabio|F|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-017-1109-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "46(3)",
"journal": "Infection",
"keywords": "Atypical mycobacteria; Eye; Fundus; Mycobacterium intracellulare; Screening",
"medline_ta": "Infection",
"mesh_terms": "D000900:Anti-Bacterial Agents; D002833:Choroiditis; D015818:Eye Infections, Bacterial; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D008875:Middle Aged; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D016896:Treatment Outcome",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "423-426",
"pmc": null,
"pmid": "29224191",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25105317;26907735;26361935;26106601;17277290;27347644;27871762;24632814;17314423;14557969;18029267",
"title": "Bilateral choroiditis as the only sign of persistent Mycobacterium intracellulare infection following haematogenous spread in an immunocompromised patient.",
"title_normalized": "bilateral choroiditis as the only sign of persistent mycobacterium intracellulare infection following haematogenous spread in an immunocompromised patient"
} | [
{
"companynumb": "IT-MYLANLABS-2018M1047219",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nSeveral clinical studies have demonstrated the efficacy and safety of adjuvant chemotherapy in patients with completely resected small cell lung cancer for a selected limited stage. However, it is unclear whether adjuvant chemotherapy is feasible in clinical practice. The objective of this study was to analyze the efficacy and safety of adjuvant chemotherapy for small cell lung cancer patients retrospectively in clinical practice.\n\n\nMETHODS\nFrom January 2002 to March 2012, 56 small cell lung cancer patients underwent surgery as initial therapy in our institute. Of these, 26 patients received adjuvant chemotherapy. The clinical data of patients who received adjuvant chemotherapy were retrospectively analyzed.\n\n\nRESULTS\nThe chemotherapy regimens were cisplatin and irinotecan in 16 patients, cisplatin and etoposide in 1 and carboplatin and etoposide in 9. Median follow-up time was 44.8 months. Nineteen (73%) patients received the full course of chemotherapy. Median recurrence-free survival was 21.4 months. Median survival time was not reached. There was no treatment-related death.\n\n\nCONCLUSIONS\nAdjuvant chemotherapy may be generally safe and efficacious in selected small cell lung cancer patients.",
"affiliations": "Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo yutakafu@ncc.go.jp.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.;Department of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo.;Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo.",
"authors": "Mizugaki|Hidenori|H|;Fujiwara|Yutaka|Y|;Yamamoto|Noboru|N|;Yagishita|Shigehiro|S|;Kitazono|Satoru|S|;Tanaka|Ayako|A|;Horinouchi|Hidehito|H|;Kanda|Shintaro|S|;Nokihara|Hiroshi|H|;Tsuta|Koji|K|;Asamura|Hisao|H|;Tamura|Tomohide|T|",
"chemical_list": "D005047:Etoposide; D000077146:Irinotecan; D016190:Carboplatin; D002945:Cisplatin; D002166:Camptothecin",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyu092",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "44(9)",
"journal": "Japanese journal of clinical oncology",
"keywords": "adjuvant chemotherapy; small cell lung cancer; surgery",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D016190:Carboplatin; D002294:Carcinoma, Squamous Cell; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005047:Etoposide; D005260:Female; D006801:Humans; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D012189:Retrospective Studies; D055752:Small Cell Lung Carcinoma; D016896:Treatment Outcome",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "835-40",
"pmc": null,
"pmid": "25097183",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Adjuvant chemotherapy in patients with completely resected small cell lung cancer: a retrospective analysis of 26 consecutive cases.",
"title_normalized": "adjuvant chemotherapy in patients with completely resected small cell lung cancer a retrospective analysis of 26 consecutive cases"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP01216",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Pneumocystis jirovecii pneumonia (PJP) is a known risk in patients with chronic lymphocytic leukemia treated with alemtuzumab (Campath®). However, no recommendation for PJP prophylaxis for alemtuzumab use in multiple sclerosis (Lemtrada®) and no known associated PJP has been reported to date. We report a patient who developed PJP two months after receiving the first course of Lemtrada, and fully recovered after receiving cotrimoxazole treatment. We should remain vigilant of opportunistic infections in patients who develop pneumonitis and evaluate the need for PJP prophylaxis during Lemtrada treatment.",
"affiliations": "Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: alexlau@cuhk.edu.hk.;Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China; Stanley Ho Centre for Emerging Infectious Diseases, The Chinese University of Hong Kong, Hong Kong SAR, China.;Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.;Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.;Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China.;Department of Neurology, Center of Clinical Neuroscience, Carl Gustav Carus University Clinic, University Hospital of Dresden, Dresden, Germany.",
"authors": "Lau|Alexander Y|AY|;Lui|Grace C Y|GCY|;Chan|Ka-Pang|KP|;Au|Cheryl|C|;Mok|Vincent C T|VCT|;Ziemssen|Tjalf|T|",
"chemical_list": "D007155:Immunologic Factors; D000074323:Alemtuzumab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2019.101503",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "38()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "Alemtuzumab; Multiple sclerosis; Pneumocystis jirovecii; Pneumocystis pneumonia; Prophylaxis",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D020529:Multiple Sclerosis, Relapsing-Remitting; D009894:Opportunistic Infections; D011020:Pneumonia, Pneumocystis",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "101503",
"pmc": null,
"pmid": "31743846",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pneumocystis pneumonia in a patient treated with alemtuzumab for relapsing multiple sclerosis.",
"title_normalized": "pneumocystis pneumonia in a patient treated with alemtuzumab for relapsing multiple sclerosis"
} | [
{
"companynumb": "HK-SA-2019SA128211",
"fulfillexpeditecriteria": "1",
"occurcountry": "HK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nLeflunomide is an immunomodulating agent with proven efficacy in rheumatoid arthritis. Although its overall safety profile is good, a few cases of toxic epidermal necrolysis have been reported.\n\n\nMETHODS\nThis 36-year-old woman had rheumatoid arthritis that proved refractory to sulfasalazine and methotrexate, which were used successively in combination with symptomatic drugs. Leflunomide was started. A maculopapular rash and a fever developed 2 weeks later. The skin lesions spread rapidly to most of the body, and ulcers of the ocular and oral mucosa appeared. Leflunomide was stopped. Cholestyramine washout and prednisolone (60 mg/day) were given. The skin lesions healed over the next month. Punctate keratitis with keratinization of the cornea led to complete loss of vision.\n\n\nCONCLUSIONS\nThe main adverse effects of leflunomide consist of diarrhea, nausea, liver enzyme elevation, hypertension, alopecia, and allergic skin reactions. A few cases of severe skin reactions such as toxic epidermal necrolysis have been reported. They require immediate discontinuation of the drug and a washout procedure to hasten drug elimination from the body.\n\n\nCONCLUSIONS\nClose monitoring for severe skin reactions is in order when using leflunomide.",
"affiliations": "Service de Médecine Interne, Hôpital Militaire Moulay Ismail, Meknes, Morocco. hassikouhasna@hotmail.com",
"authors": "Hassikou|Hasna|H|;El Haouri|Mohamed|M|;Tabache|Fatima|F|;Baaj|Mohamed|M|;Safi|Somaya|S|;Hadri|Larbi|L|",
"chemical_list": "D000276:Adjuvants, Immunologic; D005938:Glucocorticoids; D007475:Ion Exchange Resins; D007555:Isoxazoles; D002792:Cholestyramine Resin; D011239:Prednisolone; D000077339:Leflunomide",
"country": "France",
"delete": false,
"doi": "10.1016/j.jbspin.2007.08.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1297-319X",
"issue": "75(5)",
"journal": "Joint bone spine",
"keywords": null,
"medline_ta": "Joint Bone Spine",
"mesh_terms": "D000276:Adjuvants, Immunologic; D000328:Adult; D001172:Arthritis, Rheumatoid; D002792:Cholestyramine Resin; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007475:Ion Exchange Resins; D007555:Isoxazoles; D000077339:Leflunomide; D011239:Prednisolone; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "100938016",
"other_id": null,
"pages": "597-9",
"pmc": null,
"pmid": "18805724",
"pubdate": "2008-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leflunomide-induced toxic epidermal necrolysis in a patient with rheumatoid arthritis.",
"title_normalized": "leflunomide induced toxic epidermal necrolysis in a patient with rheumatoid arthritis"
} | [
{
"companynumb": "KR-SA-2015SA010684",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": null,
"d... |
{
"abstract": "A 54-year-old man was referred to our hospital due to a mass shadow noted on a chest X-ray. Thoracoscopic lobectomy yielded a diagnosis of primary pulmonary synovial sarcoma according to the histology and SYT-SSX1 gene analyses. Five months after the thoracic surgery, he developed brain metastasis; therefore, we performed resection of the brain metastatic focus followed by radiotherapy. As a local recurrence in the thoracic cavity concurrently emerged, systemic chemotherapy was also administered. These observations indicated that a multidisciplinary approach may be useful against primary pulmonary synovial sarcoma, although there is presently no established therapeutic strategy due to its rarity and highly aggressive nature.",
"affiliations": "Department of Respiratory Medicine and Rheumatology, The University of Tokushima Graduate School, Institute of Health Biosciences, Japan.",
"authors": "Ogino|Hirokazu|H|;Hanibuchi|Masaki|M|;Takizawa|Hiromitsu|H|;Sakiyama|Shoji|S|;Sumitomo|Hiroyuki|H|;Iwamoto|Seiji|S|;Ikushima|Hitoshi|H|;Nakajima|Kohei|K|;Nagahiro|Shinji|S|;Yamago|Taito|T|;Toyoda|Yuko|Y|;Bando|Yoshimi|Y|;Nishioka|Yasuhiko|Y|",
"chemical_list": "D004273:DNA, Neoplasm; D015514:Oncogene Proteins, Fusion; C116512:SYT-SSX fusion protein",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.5169",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "55(4)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D001932:Brain Neoplasms; D003131:Combined Modality Therapy; D004273:DNA, Neoplasm; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D015514:Oncogene Proteins, Fusion; D013584:Sarcoma, Synovial; D019616:Thoracic Surgical Procedures; D016896:Treatment Outcome",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "381-7",
"pmc": null,
"pmid": "26875964",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary Pulmonary Synovial Sarcoma Showing a Prolonged Survival with Multimodality Therapy.",
"title_normalized": "primary pulmonary synovial sarcoma showing a prolonged survival with multimodality therapy"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2016032159",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Examine ophthalmologic outcomes and complications of lumbar drain and cerebrospinal fluid shunts in pediatric fulminant intracranial hypertension.\n\n\n\nPatients under 21 years of age with a diagnosis of fulminant intracranial hypertension with temporary lumbar drain only, shunt after lumbar drain, and shunt only were included. Parameters investigated include lumbar drain data, medication freedom, time to resolution of papilledema, improvement in cranial nerve palsy, afferent pupillary defects, visual fields, visual acuity, and complications of each intervention.\n\n\n\nFour patients had temporary lumbar drain, 2 temporary lumbar drain and cerebrospinal fluid shunt, and 3 shunt only. All achieved medication freedom and resolution of papilledema and cranial nerve palsies (if present). Most had resolution of preprocedure afferent pupillary defects. Minor residual visual field deficits occurred in 67%, and all had visual acuity improvement. One patient's lumbar drain dislodged, and one patient had 2 cerebrospinal fluid shunt revisions.\n\n\n\nTemporary lumbar drain with medical therapy may be a viable first approach to fulminant intracranial hypertension.",
"affiliations": "Department of Pediatric Neurosurgery, Nationwide Children's Hospital, Columbus, OH, USA.;Department of Neurology, Nationwide Children's Hospital, Columbus, OH, USA.;The Ohio State University College of Medicine, Columbus, OH, USA.;Department of Pediatric Neurosurgery, Nationwide Children's Hospital, Columbus, OH, USA.",
"authors": "Ploof|Jillian|J|;Aylward|Shawn C|SC|;Jordan|Catherine O|CO|;Drapeau|Annie I|AI|0000-0001-7441-0000",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/08830738211026798",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-0738",
"issue": "36(11)",
"journal": "Journal of child neurology",
"keywords": "CSF shunt; fulminant intracranial hypertension; lumbar drain; papilledema; pediatric",
"medline_ta": "J Child Neurol",
"mesh_terms": null,
"nlm_unique_id": "8606714",
"other_id": null,
"pages": "1047-1053",
"pmc": null,
"pmid": "34259060",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Case Series of Rapid Surgical Interventions in Fulminant Intracranial Hypertension.",
"title_normalized": "case series of rapid surgical interventions in fulminant intracranial hypertension"
} | [
{
"companynumb": "US-MYLANLABS-2022M1018805",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETAZOLAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "We are presenting the case study of the patient diagnosed at the age of 37 with liver cirrhosis due to genotype 1b hepatitis C virus infection. At the age of 46, he was diagnosed with hepatocellular carcinoma with subsequent resection of the tumour in May 2015. In December 2015, the treatment was started with ombitasvir, paritaprevir/ritonavir and dasabuvir (3D) with ribavirin (RBV) 1000 mg per day. After 24 days of this treatment, the patient received a deceased donor liver transplantation, followed by 18-day interruption of 3D therapy. Due to the anaemia, RBV dose was reduced to 600 mg per day for the rest of the treatment. At the 11th week of 3D+RBV treatment, there was another 8-day long discontinuation of therapy due to the postoperative wound infection. In total, the patient received 24 weeks of 3D+RBV treatment, achieving sustained virological response at week 24 post-treatment.",
"affiliations": "Department of Infectious Diseases, Regional Specialistic Hospital, Wroclaw, Poland.;Department of Infectious Diseases, Regional Specialistic Hospital, Wroclaw, Poland.;Department of Infectious Diseases, Regional Specialistic Hospital, Wroclaw, Poland.",
"authors": "Szymanek-Pasternak|Anna|A|;Rostkowska|Karolina|K|;Simon|Krzysztof|K|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; D019438:Ritonavir; C585405:paritaprevir",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-220152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "hepatitis and other GI infections; hepatitis c; infections",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D015081:2-Naphthylamine; D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D006528:Carcinoma, Hepatocellular; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D006526:Hepatitis C; D006801:Humans; D047029:Lactams, Macrocyclic; D008103:Liver Cirrhosis; D008113:Liver Neoplasms; D016031:Liver Transplantation; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D011392:Proline; D012254:Ribavirin; D019438:Ritonavir; D013449:Sulfonamides; D000072230:Sustained Virologic Response; D016896:Treatment Outcome; D014498:Uracil; D014633:Valine",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28918403",
"pubdate": "2017-09-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15761078;17509946;20300384;25911336;26754432;26937151;27667367;28386057",
"title": "Successful twice interrupted therapy of HCV infection in patients with cirrhosis with hepatocellular carcinoma before and after liver transplantation.",
"title_normalized": "successful twice interrupted therapy of hcv infection in patients with cirrhosis with hepatocellular carcinoma before and after liver transplantation"
} | [
{
"companynumb": "PL-BAUSCH-BL-2017-034983",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nNew therapies with diverse mechanisms of action are available for metastatic castration-resistant prostate cancer (mCRPC). This study aims to evaluate the effectiveness, safety and cost of abiraterone acetate (AA) in patients with mCRPC.\n\n\nMETHODS\nObservational retrospective cohort study in which mCRPC patients who initiated AA between January 1, 2012 and December 31, 2017, were included. The patients were followed-up until death or March 31, 2018. Demographic, clinical and economic data were collected from the corporate electronic information systems. Survival distributions were estimated using the Kaplan-Meier method and compared using the log-rank test.\n\n\nRESULTS\nA total of 69 mCRPC patients were started on AA, of whom 18 (26.1%) received prior chemotherapy (post-CT) and 51 (73.9%) did not receive it (CT-naïve). A PSA decline of ≥ 50% was achieved in five (27.8%) post-CT and 32 (62.7%) CT-naïve patients (p = 0.011). Median time to PSA progression, progression-free survival (PFS) and overall survival (OS) were 4.4/7.9 months (p = 0.003), 5.1/7.5 months (p = 0.034) and 12.1/21.3 months (p = 0.119), respectively, for post-CT/CT-naïve patients. Treatment-related adverse events (AEs) occurred in 10 (55.6%) post-CT and 11 (21.6%) CT-naïve patients (p = 0.007). The most common AEs were hypokalaemia (11.6%), hypertension (8.7%) and fatigue (5.8%). The cost per median PFS month and per median OS month was €2818.4/€2784.3 and €1187.9/€980.4 for post-CT/CT-naïve patients, respectively.\n\n\nCONCLUSIONS\nCT-naïve patients treated with AA obtained a better clinical benefit in terms of effectiveness, safety and cost-effectiveness ratio than post-CT patients. The effectiveness outcomes were poorer than those reported previously in the clinical trial setting.",
"affiliations": "Department of Hospital Pharmacy, Francesc de Borja Hospital of Gandia, Valencia, Spain. koninchk_man@gva.es.;Department of Hospital Pharmacy, Francesc de Borja Hospital of Gandia, Valencia, Spain.;Department of Hospital Pharmacy, Francesc de Borja Hospital of Gandia, Valencia, Spain.;Department of Hospital Pharmacy, Francesc de Borja Hospital of Gandia, Valencia, Spain.;Department of Medical Oncology, Francesc de Borja Hospital of Gandia, Valencia, Spain.;Department of Preventive Medicine, Arnau de Vilanova Hospital, Valencia, Spain.",
"authors": "Koninckx|M|M|http://orcid.org/0000-0001-8849-3732;Marco|J L|JL|;Pérez|I|I|;Faus|M T|MT|;Alcolea|V|V|;Gómez|F|F|",
"chemical_list": "D000970:Antineoplastic Agents; D000069501:Abiraterone Acetate",
"country": "Italy",
"delete": false,
"doi": "10.1007/s12094-018-1921-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1699-048X",
"issue": "21(3)",
"journal": "Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico",
"keywords": "Abiraterone acetate; Castration-resistant prostatic cancer; Chemotherapy; Cost-effectiveness analysis; Safety; Survival analysis",
"medline_ta": "Clin Transl Oncol",
"mesh_terms": "D000069501:Abiraterone Acetate; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D015331:Cohort Studies; D018572:Disease-Free Survival; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "101247119",
"other_id": null,
"pages": "314-323",
"pmc": null,
"pmid": "30022386",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "19097774;27591931;28401143;26266103;21859988;27109827;15470213;18309951;29126389;24501545;27031255;28578607;26971191;25601341;28975013;29264205;28529549;16689555;29383035;22995653;25884302;27015255;27001043;24508071",
"title": "Effectiveness, safety and cost of abiraterone acetate in patients with metastatic castration-resistant prostate cancer: a real-world data analysis.",
"title_normalized": "effectiveness safety and cost of abiraterone acetate in patients with metastatic castration resistant prostate cancer a real world data analysis"
} | [
{
"companynumb": "ES-JNJFOC-20190301583",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ABIRATERONE ACETATE"
},
"drugadditional": null,
... |
{
"abstract": "Addison Disease is an uncommon, life-threatening condition affecting people at any age, including women during pregnancy. If left untreated, the disease can be rapidly fatal, but the prognosis is good if promptly recognized and hormones are replaced.",
"affiliations": "Department of Medicine Section of General Medicine and Hypertension University of Verona Verona Italy.;Department of Medicine Section of General Medicine and Hypertension University of Verona Verona Italy.;Department of Medicine Section of Endocrinology, Diabetes and Metabolic Disease University of Verona Verona Italy.;Department of Medicine Section of Endocrinology, Diabetes and Metabolic Disease University of Verona Verona Italy.;Department of Medicine Section of General Medicine and Hypertension University of Verona Verona Italy.;Department of Medicine Section of General Medicine and Hypertension University of Verona Verona Italy.",
"authors": "Tagetti|Angela|A|;Marcon|Denise|D|https://orcid.org/0000-0002-1885-2063;Moghetti|Paolo|P|;Spiazzi|Giovanna|G|;Fava|Cristiano|C|;Minuz|Pietro|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3784",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.3784\nCCR33784\nCase Report\nCase Reports\nOnset of Addison Disease appeared during the first trimester of a twin pregnancy: A case report\nTAGETTI et al.\nTagetti Angela 1 angela.tagetti@libero.it\n\nMarcon Denise https://orcid.org/0000-0002-1885-2063\n1\nMoghetti Paolo 2\nSpiazzi Giovanna 2\nFava Cristiano 1\nMinuz Pietro 1\n1 Department of Medicine Section of General Medicine and Hypertension University of Verona Verona Italy\n2 Department of Medicine Section of Endocrinology, Diabetes and Metabolic Disease University of Verona Verona Italy\n* Correspondence\nAngela Tagetti, Department of Medicine, \"General Medicine and Hypertension\" Unit AOUI ‐ Hospital “Policlinico G.B. Rossi”, University of Verona, P.le LA Scuro 10, Verona 37134, Italy.\nEmail: angela.tagetti@libero.it\n\n05 5 2021\n5 2021\n9 5 10.1002/ccr3.v9.5 e0378404 10 2020\n02 7 2020\n24 12 2020\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nKey Clinical Message\n\nAddison Disease is an uncommon, life‐threatening condition affecting people at any age, including women during pregnancy. If left untreated, the disease can be rapidly fatal, but the prognosis is good if promptly recognized and hormones are replaced.\n\nAddison Disease is an uncommon, life‐threatening condition affecting people at any age, including women during pregnancy. If left untreated, the disease can be rapidly fatal, but the prognosis is good if promptly recognized and hormones are replaced.\n\nAddison disease\npregnancy\ntherapy\ntwins\nsource-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:13.05.2021\nTagetti A , Marcon D , Moghetti P , Spiazzi G , Fava C , Minuz P . Onset of Addison Disease appeared during the first trimester of a twin pregnancy: A case report. Clin Case Rep. 2021;9 :e03784. 10.1002/ccr3.3784\n\nTagetti and Marcon contributed equally to work.\n==== Body\n1 INTRODUCTION\n\nThis case describes the onset of Addison disease in a pregnant woman during the first trimester of a twin pregnancy and gives useful information about the initial and chronic treatment of Addison disease during pregnancy aimed at preserving the mother and fetuses’ health. A 32‐year‐old woman at 16 + 3 gestational weeks, with celiac disease and Hashimoto thyroiditis, was admitted to the Obstetrics division for persistent vomiting with difficulty feeding, weakness, and mild pelvic pain. At admission, the patient's blood pressure was 90/60 mmHg and body temperature 35.4°C. Serum sodium was 117 mmol/L. After the hypothesis of undertreated hypothyroidism was discarded, Addison disease was diagnosed, and intravenous therapy with hydrocortisone was initiated. After five days, hemodynamic stabilization and normalization of laboratory tests were obtained. Intravenous therapy was switched to oral hydrocortisone and fludrocortisone. Fetuses' and mother's conditions were strictly monitored, and the pregnancy ended at 35 + 2 weeks because of premature rupture of membranes. Newborns were in good health status. Fifteen months after delivery, clinical conditions have improved, and hydrocortisone has been gradually reduced to 25 µg/d. Rapid diagnosis, correct adjustment of glucocorticoid, and mineralocorticoid replacement therapy and fetus and mother's close monitoring were the critical point of the successful management. Addison Disease is an uncommon, life‐threatening condition that can affect people at any age, including women during pregnancy. If left untreated, the disease can be rapidly fatal, but the prognosis is good if promptly recognized and hormones are replaced.\n\nPrimary adrenal insufficiency (PAI) is a rare but potentially severe condition. 1 PAI is much more challenging to diagnose and severe if it occurs during gestation. Current guidelines dictate PAI management during pregnancy, but no indications are offered for new‐onset PAI. 1 , 2 Since untreated PAI in pregnant women is associated with high mortality, whereas for adequately treated patients, normal pregnancy course and the outcome are expected, early recognition and diagnosis are crucial. 1\n\n1.1 Case presentation\n\nA 32‐year‐old Caucasian woman at 16 + 3 weeks’ gestation of a dichorionic, diamniotic twin pregnancy, without a history of smoking or drug abuse, was admitted to the Obstetrics division for persistent severe vomiting with difficult feeding, weakness, and mild pelvic pain. The patient had no significant family history. In 2014, the woman was diagnosed with Celiac disease and lactose intolerance treated by gluten and lactose‐free diet. In 2012, she was diagnosed with Hashimoto's thyroiditis and treated with administration of levothyroxine 475 µg/wk. For failure of embryo attachment at 7 + 4 weeks of gestation, she was treated with 200 mg daily of intravaginal progesterone. Treatment was then shifted to 341mg of intramuscular 17‐α hydroxyprogesterone caproate (Lentogest®) every 3 days for topical intolerance from week 9. She appeared healthy at admission, and physical examination was normal except for low blood pressure (90/60 mmHg) and low body temperature (35.4°C). The heart rate was 100 bpm/min.\n\n1.2 Diagnostic assessment\n\nLaboratory tests at admission showed serum sodium 117 mmol/L, potassium 4.68 mmol/L, chloride 64 mmol/L. TSH and thyroid hormones showed a well titrated therapy (TSH 1.19 mUI/L (normal range: 0.35‐3 mUI/L), FT3 4 pg/mL (2.1‐4.9 pg/mL), FT4 11.5 ng/L (8‐19 ng/L). Vomiting ceased a few hours after the admission, and hyperemesis gravidarum was excluded. Further hormonal tests showed increased plasma‐ACTH 648 pg/mL (normal values 8.5‐50), plasma‐cortisol 14.5 μg/dL (4‐25), plasma renin >500 μU/mL (3.3‐41), serum aldosterone 65 pg/mL (35‐300) in orthostatic and 67 pg/mL (7.5‐150) in supine position. Other laboratory tests were normal, except for serum sodium that was persistently low and gradually increased with saline infusion and normalized within six days.\n\n1.3 Treatment\n\nAfter the diagnostic hypothesis of adrenal insufficiency arose, the patient was treated with 100 mg of hydrocortisone intravenously three times a day, then 50 mg tid iv because of hyperglycemia. After five days, oral therapy was started with hydrocortisone 10 mg tid plus fludrocortisone 100 µg, up‐titrated to 200 µg in 6 days.\n\n1.4 Outcome and follow‐up\n\nThe pregnancy proceeded without complications. The patient was clinically stable, with normal plasma electrolytes, glucose, and clinostatic and orthostatic BP. She was admitted to the Hospital for vomiting and diarrhea during the 29th week of pregnancy and was discharged home with the diagnosis of viral gastroenteritis. On that occasion, high dose hydrocortisone was administered (100 mg every 6 hours intravenously) for the first 24 hours; then, the usual oral dosage regiment for corticosteroids was restored and maintained until delivery. Fetal ultrasound examination was normal. Caesarean section for premature rupture of membranes was performed at 35 + 2 weeks without complications, after the iv administration of 12mg of betamethasone for the prevention of respiratory distress syndrome in the new‐born. Two females, 2000 g and 2370 g of weight, presenting normal umbilical cord, plasma pH and Apgar score 10/10, were born. During labor, the mother was treated with iv hydrocortisone (100 mg bolus), followed by infusion of 200 mg for 24 hours along with fluids administration. Thirty‐six hours after delivery, oral therapy was restored at twice the dose taken during pregnancy (hydrocortisone 20 + 20 + 20 mg, fludrocortisone 400 µg). After another day, the dose was reduced to that used in the last weeks of gestation. Five days after delivery, the dosage of fludrocortisone was tapered at 150 µg. One week after the Caesarean section, the patient was discharged home with the following substitutive therapy: hydrocortisone 10 + 5+5 mg + fludrocortisone 150 µg. During the next 5 months, fludrocortisone was gradually reduced to 50 µg/d for edema and low plasma renin. Measurement of serum and urinary cortisol showed that celiac disease did not affect hydrocortisone intestinal absorption. After 16 months, serum sodium, potassium, and glucose levels were normal, urinary cortisol was within the normality (70 nmol/die), and serum‐cortisol peak level was 636 nmol/L, and therapy was therefore confirmed. The patient reported no difficulties in assuming treatment, and no adverse effects were notable.\n\n2 DISCUSSION\n\nA crucial point in this patient's management was the rapidity in recognizing and treating the adrenal insufficiency. The differential diagnosis included at least three other disorders that share the same symptoms and signs: uncontrolled hypothyroidism, hyperemesis gravidarum, and a side effect of progesterone. The first was rapidly ruled‐out based on the patient's clinical features and the normality of thyroid hormones and TSH; additionally, hyponatremia is sometimes associated with hypothyroidism, but this may be mainly in patients with severe primary hypothyroidism and myxedema. 3 , 4 , 5 Hyperemesis gravidarum was also excluded because vomiting ceased with fluid repletion. Progesterone use can be potentially associated with hyponatremia because it may diminish the effects of aldosterone in the renal tubule and decrease sodium reabsorption with the following increase in mineralocorticoid secretion from the adrenal cortex. 6 It is essential to underline that hydrocortisone's dose was slightly modified, while mineralocorticoid dosage had undergone a more critical adjustment. This fact may be due to the anti‐mineralocorticoid action of progesterone, which implies an adaptive response. During pregnancy, there is an activation of renin‐angiotensin‐aldosterone and an increase in progesterone concentration, which competes with aldosterone for binding to the type 1 corticosteroid receptor, resulting in reduced responsiveness to the sodium‐retaining effect of aldosterone. 7 In healthy women, increased plasma renin activity and aldosterone levels compensate for progesterone action. But in Addisonian pregnant patients, a larger dosage of mineralocorticoid replacement may be indicated. 7\n\nThe coexistence of Addison, Hashimoto, and celiac diseases is consistent with the diagnosis of type II polyglandular autoimmune syndrome, an autoimmune disorder of polygenic inheritance, and pleomorphic phenotype. 8 The clinical picture was also challenging because of the twin pregnancy, lack of recommendation for appropriate clinical management and the initial replacement therapy during pregnancy. Current guidelines 1 address the dose adjustment during pregnancy, but initial replacement therapy in new‐onset PAI during pregnancy is not specified. Current guidelines suggest close monitoring for clinical symptoms and signs of glucocorticoid excess or under‐replacement therapy at least once per trimester for pregnant patients with known PAI. During the third trimester, dosage of hydrocortisone should be augmented. Hydrocortisone should be used over cortisone acetate, prednisolone, or prednisone because it is not inactivated in the placenta. During the active phase of labor, a similar dosage to that used in major surgery is recommended. A case report suggests rapid glucocorticoid replacement with iv 100‐200 mg of hydrocortisone as a single bolus and 50‐100 mg boluses every 6‐8 hours during the acute period. 9 In this case, the dose of replacement therapy is modulated, primarily based on serum potassium, serum sodium levels and clinical response as assessed by measuring blood pressure and heart rate. Our clinical case highlights the importance of close collaborations between different medical specialists (internal medicine, endocrinology, obstetrics). It is crucial in detecting and treating such a complex and life‐threatening condition.\n\nCONFLICT OF INTEREST\n\nNo conflict of interest to declare.\n\nAUTHOR CONTRIBUTION\n\nAngela Tagetti and Denise Marcon collected clinical and laboratory data and drafted the manuscript; Cristiano Fava and Pietro Minuz were involved in drafting the manuscript, in the diagnosis and in the initial treatment of the disease; Paolo Moghetti and Giovanna Spiazzi were the patient's physicians. All the authors contributed to the critical review of the paper.\n\nETHICAL APPROVAL\n\nEthical committee Of Verona and Rovigo approved the study in April 27, 2020 (Project number 2666CE; Protocol number n. 23 431).\n\nACKNOWLEDGMENT\n\nAuthors want to express their special thanks to the patients who allowed the publication of this clinical case. Published with written consent of the patient.\n\nDATA AVAILABILITY STATEMENT\n\nNone.\n==== Refs\nREFERENCES\n\n1 Bornstein SR , Allolio B , Arlt W , et al. Diagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2016;101 :364‐389.26760044\n2 Gagliardi L , Ho JT , Torpy DJ . Corticosteroid‐binding globulin: The clinical significance of altered levels and heritable mutations. Mol Cell Endocrinol. 2010;316 :24‐34.19643166\n3 Schrier RW . Body water homeostasis: Clinical disorders of urinary dilution and concentration. J Am Soc Nephrol. 2006;17 :1820‐1832.16738014\n4 Derubertis FR , Michelis MF , Bloom ME , Mintz DH , Field JB , Davis BB . Impaired water excretion in myxedema. Am J Med. 1971;51 :41‐53.5570319\n5 Hanna FW , Scanlon MF . Hyponatraemia, hypothyroidism, and role of arginine‐vasopressin. Lancet. 1997;350 :755‐756.9297992\n6 Randa Hilal‐Dandan and LLB Estrogens and Progestins. Goodman Gilman's Man. Pharmacol. Ther. 2e.\n7 Ambrosi B , Barbetta L , Morricone L . Diagnosis and management of Addison’s disease during pregnancy. J Endocrinol Invest. 2003;26 :698‐702.14594127\n8 Singh G , Jialal I . Polyglandular autoimmune syndrome, Type II (Carpenters, Schmidt). In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK525992/. Accessed January, 2018.\n9 Seaward PG , Guidozzi F , Sonnendecker EW . Addisonian crisis in pregnancy, Case report. Br J Obstet Gynaecol. 1989;96 (11 ):1348‐1350.2558707\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "9(5)",
"journal": "Clinical case reports",
"keywords": "Addison disease; pregnancy; therapy; twins",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
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"pages": "e03784",
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"title": "Onset of Addison Disease appeared during the first trimester of a twin pregnancy: A case report.",
"title_normalized": "onset of addison disease appeared during the first trimester of a twin pregnancy a case report"
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"abstract": "BACKGROUND\nSystemic Lupus Erythematosus (SLE) an autoimmune rheumatic disease with a complex pathogenesis, remains potentially life-threatening. SLE patients have increased morbidity and premature mortality compared to non-SLE patients. The five-year survival rate has improved from <50% in the 1950s to >90% in the 1980s. Lupus patients still have a mortality risk three times that of the general population.\n\n\nOBJECTIVE\nTo provide a detailed analysis of the causes of death, main characteristics and trends in the management of the deceased SLE patients from the lupus clinic at the University College London Hospital (UCLH); during the past four decades.\n\n\nMETHODS\nThis was a non-interventional, retrospective study based on historical real-world data from paper and electronic records of patients followed up at UCLH. The analysis focused on data collected between 1st January 1978 and 31th December 2018. We collected the: causes of death, duration of disease, key laboratory and clinical parameters and the treatment received. We compared the results from the four decades to ascertain trends in the causes of mortality. All statistical analyses were performed using the Statistical Package for Social Sciences (SPSS), version 22.0. The 95% confidence intervals for the means of data were calculated.\n\n\nRESULTS\n111 SLE patients (15%), died during follow-up. Their median age was 51 years (interquartile range (IQR) = 38-63 years) and the median duration of disease, 15 years (IQR = 8.5-24 years). The main causes of death in the past 40 years were infection (31.7%), cancer (26.7%) and cardiovascular disease (CVD) (21.8%). 93.6% of these patients were immunosupressed. During the 40-year period, there were several therapeutic developments notably the introduction of mycophenolate mofetil (MMF) and rituximab; the latter initially only given to patients when more conventional inmunosupressants had failed, but more recently offered to patients at diagnosis. There was a statistically significant increase in the use of hydroxycloroquine (HCQ), MMF and rituximab. In contrast, the use of Azathioprine (AZA) and steroids, hardly changed over time.\n\n\nCONCLUSIONS\nThis retrospective review shows how epidemiological factors, causes of death and treatment of SLE patients have changed during the last 40 years in the UCLH cohort.",
"affiliations": "Department of Internal Medicine, Hospital Universitario De Ourense, Ourense, Spain.;Department of Rheumatology, Division of Medicine, University College London, London, UK.",
"authors": "Lorenzo-Vizcaya|Ana|A|;Isenberg|David|D|https://orcid.org/0000-0001-9514-2455",
"chemical_list": "D018501:Antirheumatic Agents; D004791:Enzyme Inhibitors; D013256:Steroids; D000069283:Rituximab; D006886:Hydroxychloroquine; D009173:Mycophenolic Acid; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1177/0961203320988607",
"fulltext": null,
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"issn_linking": "0961-2033",
"issue": "30(5)",
"journal": "Lupus",
"keywords": "Systemic lupus erythematosus; cause of death; mortality; risk factors; treatment trends",
"medline_ta": "Lupus",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D001379:Azathioprine; D002318:Cardiovascular Diseases; D002423:Cause of Death; D015331:Cohort Studies; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D016867:Immunocompromised Host; D007239:Infections; D008180:Lupus Erythematosus, Systemic; D008297:Male; D008875:Middle Aged; D009017:Morbidity; D061213:Mortality, Premature; D009173:Mycophenolic Acid; D009369:Neoplasms; D012189:Retrospective Studies; D012307:Risk Factors; D000069283:Rituximab; D013256:Steroids; D015996:Survival Rate; D013997:Time Factors; D006113:United Kingdom",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "702-706",
"pmc": null,
"pmid": "33472522",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Analysis of trends and causes of death in SLE patients over a 40-years period in a cohort of patients in the United Kingdom.",
"title_normalized": "analysis of trends and causes of death in sle patients over a 40 years period in a cohort of patients in the united kingdom"
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"companynumb": "GB-CELLTRION INC.-2021GB004842",
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"abstract": "Pediatric patients with high-risk, relapsed, or refractory solid tumors have a poor prognosis. We have previously reported a dose-finding experience of high-dose chemotherapy consisting of thiotepa and melphalan (\"double-conditioning regimen\"). Using doses derived from that study, we have treated patients since 2005. We now report a retrospective review of patients treated by this fixed dose.\n\n\n\nWe reviewed 50 patients (median 4 years; range 0-15 years) with high-risk or relapsed/refractory solid tumors treated by this dose-fixed, double-conditioning regimen from April 2005 to May 2014. Doses were thiotepa 800 mg/m2 and melphalan 280 mg/m2 for children ≥2 years of age, and 32 mg/kg and 6 mg/kg, respectively, for children <2 years of age. Further, doses were reduced according to creatinine clearance with poor renal function.\n\n\n\nNonhematological toxicity was mainly gastrointestinal-grade 3 mucositis (n = 41) and grade 3-4 diarrhea (n = 10). Neurological, renal, and endothelial cell toxicity and sinusoidal obstruction syndrome were not observed. There were two toxic deaths (interstitial viral pneumonia). This regimen demonstrated antitumor activity against several types of tumors. Although the frequency of gastrointestinal toxicity was high, other severe toxicity was not observed.\n\n\n\nOur double-conditioning regimen was very well tolerated and demonstrated antitumor activity. We are moving forward with multi-institutional trials now.",
"affiliations": "Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan.;Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan.",
"authors": "Okada|Keiko|K|0000-0003-0825-2985;Yamasaki|Kai|K|0000-0002-5701-8813;Nitani|Chika|C|;Fujisaki|Hiroyuki|H|;Osugi|Yuko|Y|;Hara|Junichi|J|",
"chemical_list": "D013852:Thiotepa; D003404:Creatinine; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27953",
"fulltext": null,
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"issn_linking": "1545-5009",
"issue": "66(11)",
"journal": "Pediatric blood & cancer",
"keywords": "melphalan; pediatric solid tumor; stem cell transplantation; thiotepa",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D003404:Creatinine; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D005767:Gastrointestinal Diseases; D006402:Hematologic Diseases; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D017563:Lung Diseases, Interstitial; D008297:Male; D008558:Melphalan; D009369:Neoplasms; D036102:Peripheral Blood Stem Cell Transplantation; D011024:Pneumonia, Viral; D012189:Retrospective Studies; D012306:Risk; D016879:Salvage Therapy; D013852:Thiotepa; D019172:Transplantation Conditioning; D014182:Transplantation, Autologous",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27953",
"pmc": null,
"pmid": "31393093",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Double-conditioning regimen consisting of high-dose thiotepa and melphalan with autologous stem cell rescue for high-risk pediatric solid tumors: A second report.",
"title_normalized": "double conditioning regimen consisting of high dose thiotepa and melphalan with autologous stem cell rescue for high risk pediatric solid tumors a second report"
} | [
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"companynumb": "JP-ADIENNEP-2019AD000450",
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"abstract": "BACKGROUND\nThe incidence and prevalence of end-stage renal disease (ESRD) is increasing. The most common cause of ESRD is diabetes mellitus (DM). Kidney transplantation offers better quality of life and survival for patients with ESRD. Because of the use of immunosuppressive therapy and steroids post-kidney transplantation, the patients are at an increased risk for the development of posttransplant DM (PTDM). Management of DM after transplantation (whether pre-existing or transplant related) remains a challenge. Multiple treatment options are currently available to manage PTDM. Those medications have good safety and efficacy record in the general population and in patients with mild degrees of kidney disease.\n\n\nMETHODS\nWe conducted a retrospective single center analysis of safety and efficacy of linagliptin post-kidney transplantation. The study was approved by the institutional review board. We collected data (demographics, laboratory tests, and any symptoms or hospitalizations) for 42 patients for a period of 12 months.\n\n\nRESULTS\nAll 42 patients received linagliptin throughout the study period. Patients' average age was 62 years. Twenty-three were women and all were of Middle Eastern descent and had kidney transplants on average of 25 months when they were included in the study. Nineteen patients had DM before the transplant, and the rest had PTDM. Eighteen patients were on metformin and 15 were on insulin, whereas the rest were not on any other medications at the start of the study. Baseline average creatinine was 1.5 mg/dL (132.9 mmol/L) and glycated hemoglobin (HbA1c) was 8.2 g/dL at the start of the study, whereas creatinine was 1.6 mg/dL (138.5 mmol/L) and HbA1c was 7.4 g/dL at the end. HbA1c dropped 0.8 on average within 3 months of starting linagliptin and remained at the same level for the rest of the study. Urine protein did not change significantly throughout the study. Three patients developed acute myocardial infarction during the study, and a fourth one was hospitalized with an opportunistic infection. Two patients had urinary tract infections. Adverse effects were minimal. No allergic reactions, hypoglycemia, or acute pancreatitis episodes were reported. The average weight and body mass index did not change throughout the study. None of the patients stopped the medication.\n\n\nCONCLUSIONS\nIn this retrospective analysis, linagliptin seems to be safe and efficacious after kidney transplantation. It can be considered as a treatment option to manage DM after transplantation.",
"affiliations": "Department of Nephrology, Medical Subspecialties Institute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates. Electronic address: attalln@clevelandclinicabudhabi.ae.;Imperial College of London Diabetes Center, Abu Dhabi, United Arab Emirates.",
"authors": "Attallah|Nizar|N|;Yassine|Lina|L|",
"chemical_list": "D006442:Glycated Hemoglobin A; D007004:Hypoglycemic Agents; D000069476:Linagliptin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.07.035",
"fulltext": null,
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"issn_linking": "0041-1345",
"issue": "53(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000208:Acute Disease; D003920:Diabetes Mellitus; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006442:Glycated Hemoglobin A; D006801:Humans; D007004:Hypoglycemic Agents; D016030:Kidney Transplantation; D000069476:Linagliptin; D008875:Middle Aged; D010195:Pancreatitis; D011788:Quality of Life; D012189:Retrospective Studies",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2234-2237",
"pmc": null,
"pmid": "34376312",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Linagliptin in the Management of Type 2 Diabetes Mellitus After Kidney Transplant.",
"title_normalized": "linagliptin in the management of type 2 diabetes mellitus after kidney transplant"
} | [
{
"companynumb": "AE-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2021-BI-121657",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "MYCOPHENOLIC ACID"
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... |
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"abstract": "Buprenorphine induction can lead to precipitated opioid withdrawal, even when using novel techniques such as transdermal buprenorphine. Involuntary limb movements are a distressing symptom of precipitated withdrawal that can be difficult to treat. We report a case of a military veteran transitioning from methadone to buprenorphine for the treatment of opioid use disorder (OUD) using small doses of transdermal buprenorphine. Herein, we review the literature associated with opioid withdrawal-related restlessness. Despite the known risk of concurrent benzodiazepine and buprenorphine administration, including decreased respiratory rate and death, we present a clinical presentation in which this medication combination may be necessary while under medical supervision. We suggest a stepwise algorithm for pharmacotherapy in patients experiencing involuntary limb movements associated with precipitated withdrawal. To safeguard the success of medication-assisted treatment (MAT) for opioid addiction, clinicians should be aware of potential clinical challenges when managing precipitated opioid withdrawal in patients with complex psychiatric comorbidities.",
"affiliations": "Department of Psychiatry, University of California San Francisco, 401 Parnassus Ave., RTP- Box 0984, San Francisco, CA 94143, USA.;Department of Psychiatry, University of California San Francisco, 401 Parnassus Ave., RTP- Box 0984, San Francisco, CA 94143, USA.;Department of Psychiatry, University of California San Francisco, 401 Parnassus Ave., RTP- Box 0984, San Francisco, CA 94143, USA.",
"authors": "Kinasz|Kathryn R|KR|;Herbst|Ellen D|ED|;Kalapatapu|Raj K|RK|",
"chemical_list": "D002047:Buprenorphine; D008691:Methadone",
"country": "England",
"delete": false,
"doi": "10.1093/milmed/usaa068",
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"issue": "185(9-10)",
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"mesh_terms": "D002047:Buprenorphine; D006801:Humans; D008691:Methadone; D009293:Opioid-Related Disorders; D011618:Psychotic Disorders; D013375:Substance Withdrawal Syndrome; D014728:Veterans",
"nlm_unique_id": "2984771R",
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"pmid": "32314788",
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"title": "Case Report: Buprenorphine Induction Using Transdermal Buprenorphine in a Veteran With Opioid Use Disorder and Psychosis, Managing Precipitated Withdrawal.",
"title_normalized": "case report buprenorphine induction using transdermal buprenorphine in a veteran with opioid use disorder and psychosis managing precipitated withdrawal"
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"abstract": "•Isolated chloroma should be considered as a systemic disease.•Consolidation radiotherapy has been related with prolonged failure free survival.•Excellent local control of chloroma is achieved with low-dose radiotherapy.",
"affiliations": "Hospital Ramón y Cajal, Madrid, Spain.;Radiation Oncology, Hospital Ramón y Cajal, Spain.;Radiophysics, Hospital Ramón y Cajal, Spain.;Hematology, Hospital Ramón y Cajal, Spain.;Radiation Oncology, Hospital Ramón y Cajal, Spain.",
"authors": "Dominguez Rullán|Jose Antonio|JA|;Fernández Lizarbe|Eva|E|;Capuz|Belén|B|;Piris|Miguel|M|;Sancho García|Sonsoles|S|",
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"fulltext": "\n==== Front\nClin Transl Radiat OncolClin Transl Radiat OncolClinical and Translational Radiation Oncology2405-6308Elsevier S2405-6308(17)30074-510.1016/j.ctro.2017.11.001ArticleRadiotherapy for isolated granulocytic sarcoma: Case report and review of literature Dominguez Rullán Jose Antonio joseantonio.dominguez@salud.madrid.orgab⁎Fernández Lizarbe Eva bCapuz Belén cPiris Miguel dSancho García Sonsoles ba Hospital Ramón y Cajal, Madrid, Spainb Radiation Oncology, Hospital Ramón y Cajal, Spainc Radiophysics, Hospital Ramón y Cajal, Spaind Hematology, Hospital Ramón y Cajal, Spain⁎ Corresponding author. joseantonio.dominguez@salud.madrid.org11 11 2017 1 2018 11 11 2017 8 1 3 24 9 2017 31 10 2017 1 11 2017 © 2017 The Authors2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Isolated chloroma should be considered as a systemic disease.\n\n• Consolidation radiotherapy has been related with prolonged failure free survival.\n\n• Excellent local control of chloroma is achieved with low-dose radiotherapy.\n==== Body\nIntroduction\nGranulocytic sarcoma, also known as myeloid sarcoma or chloroma, is an infrequent extramedullary tumour of immature myeloid cells. Chloromas can appear in the absence of marrow involvement but usually develop in association with acute myeloid leukemia (AML) and other hematological malignancies like myelodysplastic syndrome (MDS) or during the accelerate phase of chronic myeloid leukemia (CML) [1]. The most common sites of presentation include skin, lymph nodes, bone, soft tissue and periostium, although it has been described in other atypical locations (eyes, CNS, testes…). The incidence of 2.5–9.1% in AML is low and can occur concomitantly during initial presentation or at the time of relapse [2].\n\nTreatment strategies include systemic therapy while radiotherapy and surgery have been used to improve local control. Information about the best treatment approach is not clear and due to its poor prognosis, optimization of multimodality management is essential. Low-dose radiation therapy could have a role in cases with inadequate response to chemotherapy, at recurrence or progression, isolated chloromas or in the palliative setting when symptom relief is required. We conducted a review of literature to assess the role of radiotherapy for this rare leukemia manifestation.\n\nCase report\nWe report the case of a 71 year-old male who develops an asymptomatic slow growing 1.5 cm skin nodule in the chest. Extirpation biopsy was conducted and histopathology evaluation showed infiltration of immature large cells. Inmunohistochemical staining identified neoplastic cells positive for CD34, CD117 and myeloperoxidase (MPO) and negative for CD123 suggesting the diagnosis of chloroma. Subsequent bone marrow biopsy revealed low evidence of myeloid blasts (1%) and CT scan was normal. With diagnosis of isolated myeloid sarcoma the patient continued follow-up without further treatment.\n\nThe patient remained disease-free for 9 months, when a small skin nodule appeared in the left forearm and extirpation biopsy showed relapse of chloroma without marrow involvement and negative PET/CT scan. Observation was decided and 3 months later the patient developed local recurrence (without evidence of blasts in BM) and was referred to our clinic for consideration of radiotherapy plus systemic chemotherapy. At this time, the patient refused chemotherapy and radiotherapy to 30–36 Gy was proposed (Fig. 1).Fig. 1 Relapse of chloroma in the left forearm after extirpation and post-radiotherapy image showing complete response.\n\n\n\nRadiotherapy (RT) was provided using 6 MV linear accelerator photons and the RT field included the gross tumour volume and the skin scar with a 20 mm margin. The prescribed dose of 36 Gy (dose-per-fraction of 2 Gy) was decided taking into account that RT was going to be administered as a single modality treatment and the radiation site, but additional 4 Gy where required to achieve a complete response. Treatment was completed between September 14 and October 9, 2015 (40 Gy total dose). RT was well tolerated and the only side effect seen during follow-up was mild dry desquamation within the treatment field.\n\nAt one-month follow-up the patient remained disease-free but in next evaluation the patient developed local relapse (Fig. 2) and physical examination showed left axillary and supraclavicular masses. The liver and spleen were not palpable beneath the ribs. The CT scan revealed pathological cervical/supraclavicular left lymph nodes and a left axillary mass of 45 × 70 mm (Fig. 3). Bone marrow tests and immunophenotyping at this time showed progression to LMA, with evidence of 20% of myeloid blasts with a prominent monocytic component.Fig. 4.Fig. 2 Relapse after radiotherapy initially with isolated skin nodule with rapid progression.\n\nFig. 3 CT scan revealing left supraclavicular and axillary pathological lymph nodes.\n\nFig. 4 Target delineation GTVt (dark blue), CTVt (pink), skar (light blue) and PTV (red). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\n\n\nAn idarubicin and cytarabine regimen (12 mg/m2 idarubicin on days 1–3 and 200 mg/m2 cytarabine on days 1–5) was administered in December 2015 after which complete bone marrow response was obtained and the pathological lymph nodes, left axillary mass and skin nodule decreased in size.\n\nHowever, in January 2016 the tumour progressed in the left forearm nodule and second-line FLAG-IDA regimen (30 mg/m2 fludarabine and 2 g/m2 cytarabine on days 1–4, 10 mg/m2 idarubicin on days 1–3 and 300 μg/m2 G-CSF on days 1–5), was initiated with skin progression with confluent erythematous papules involving the left arm and bone marrow relapse with 9% of myeloid blasts.\n\nThird-line FLUGA regimen (40 mg/m2 oral fludarabine and 75 mg/m2 sc cytarabine on days 1–4) was initiated in April 4, 2016. Two weeks later the patient presented in the emergency room with rectal bleeding. An urgent blood test showed a haemoglobin level of 9.8 g/l, platelet level of 8000/µL, prolongation of the prothrombin time (PT 43.3), fibrinogen level of 75.5 mg/dl, D-Dimer > 35000 µg/L so disseminated intravascular coagulopathy was diagnosed. Treatment included transfusion of platelets, fresh frozen plasma and fibrinogen with clinical and hematological improvement. CT-scan during admission showed cervical-supraclavicular, mediastinal and lung progression. The patient developed rapid neurologic decline and died on April 22, 2016.\n\nDiscussion\nGranulocytic sarcoma in the absence of marrow involvement is a rare entity and timing to systemic and local therapy represents a treatment dilemma. The experience in treatment of chloromas is limited and only few retrospective series and clinical case reports release some information about clinical management.\n\nLocal therapy (surgical resection and radiotherapy) cannot avoid or delay the transformation to AML, and progression usually occurs within 10–12 months after the diagnosis. This suggests that isolated chloroma should be considered as a systemic disease and initial treatment should include chemotherapy with or without transplantation. A retrospective study showed that 25% of patients initially treated without systemic therapy didn’t progress to hematological diseases during follow-up (3.5–16 years) [3]; but most series demonstrate that 88–100% of patients progressed to AML with exclusive local therapy [4].\n\nConsolidation radiotherapy should be considered if not important toxicities are expected due its location. In some series addition of radiotherapy has been related with a prolonged failure free survival and chloroma incomplete response to systemic therapy has been associated with early bone marrow relapse [5], [6]. Benefit of radiation therapy in overall survival has not been demonstrated [7], [8].\n\nExcellent response rate and local control of chloroma is achieved with low-dose radiotherapy. Different fractionation schedules have been used and most studies support prescription dose of 20–40 Gy (2 Gy per fraction) [9], [10]. Chloromas are radiosensity and the complete response rate was 43% (10–19.99 Gy), 86% (20–29.99 Gy) and 89% (>30 Gy) [9]. In Memorial Sloan-Kettering Cancer Center series, with median dose of 20 Gy there was only one local failure in 33 treatments to a sub-site that only received 6 Gy [8]. A recent series including 36 radiation courses for leukemia cutis observed that complete response rate and local control were comparable in low-dose (≤26 Gy) and high-dose regimens although longer median duration of local control was seen in the >26 Gy cohort [11]. Doses of at least 20 Gy are recommended and some authors suggest 24 Gy in 12 fractions as a safe and optimal regimen [8], [12]. AML patients showed better long-term outcomes compared with other types of leukemia [11].\n\nTarget volume should include the visible gross tumour or pre-chemotherapy extent of disease with 15–25 mm margins. Electrons are utilized for superficial myeloid sarcomas; especially after chemotherapy; and photons for deeper lesions.\n\nExtramedullary disease has been related with unfavorable prognosis and allogeneic hematopoietic stem cell transplatation (allo-HSCT) could be used after chemotherapy. A retrospective review analysed a cohort of 99 patients (30 with isolated myeloid sarcoma), 52% of patients underwent allo-HSCT in first remission and at 5 years overall-survival was 48%, with no significant differences in outcomes when comparing isolated and leukemic granulocytic sarcoma. The role of (allo-HSCT) has not been completely established but could be considered as an effective and optimal therapy in firt remission. [13], [14].\n\nConclusions\nGranulocytic sarcoma is frequently associated with worst prognosis and radiotherapy has not shown in the literature a survival benefit. In the presence of bone marrow involvement, radiation is an option for palliation or consolidation when complete response is not achieved after chemotherapy.\n\nIn the recurrence setting, radiation should be considered as consolidation after chemotherapy re-induction, especially in those patients who relapse after allogeneic transplantation.\n\nIn cases of isolated chloromas radiation therapy could improve progression free survival, principally in those with poor or incomplete response to systemic therapy. We suggest adding low-dose radiotherapy has a good toxicity profile and might add benefit in local control.\n\nProspective randomized studies of combined multimodality treatment are needed to better define the role of radiotherapy in chloroma both in the absence or with marrow involvement and at the time of relapse.\n\nDisclosure\nThe following authors have nothing to disclose:\n\nJose Antonio Domínguez Rullán.\n\nEva Fernández Lizarbe.\n\nMiguel Piris.\n\nBelén Capuz.\n\nSonsoles Sancho García.\n==== Refs\nReferences\n1 Paydas S. Zorludemir S. Ergin M. Granulocytic sarcoma: 32 cases and review of the literature Leuk Lymphoma 47 2006 2527 2541 17169797 \n2 Wiernik P.H. Serpick A.A. Granulocytic sarcoma (chloroma) Blood 35 1970 361 369 4908654 \n3 Meis J.M. Butler J.J. Osborne B.M. Manning J.T. Granulocytic sarcoma in nonleukemic patients Cancer 58 1986 2697 2709 3465429 \n4 Avni B. Koren-Michowitz M. Myeloid sarcoma: current approach and therapeutic options Ther Adv Hematol 2 2011 309 316 23556098 \n5 Tsimberidou A.M. Kantarjian H.M. Estey E. Outcome in patients with nonleukemic granulocytic sarcoma treated with chemotherapy with or withour radiotherapy Leukemia 17 2003 1100 1103 12764375 \n6 Byrd J.C. Edenfield W.J. Shields D.J. Extramedullary myeloid cell tumors in acute nonlymphocytic leukemia: a clinical review J Clin Oncol 13 1995 1800 1816 7602369 \n7 Lan T.Y. Lin D.T. Tien H.F. Prognostic factors of treatment outcomes in patients with granulocytic sarcoma Acta Haematol 122 2009 238 246 19887783 \n8 Bakst R. Wolden S. Yahalom J. Radiation therapy for chloroma (granulocytic sarcoma) Int J Radiat Oncol Biol Phys 82 2012 1816 1822 21962486 \n9 Chak L.Y. Sapoz ink M.D. Cox R.S. Extramedullary lesions in non-lymphocytic leukemia: results of radiation therapy Int J Radiat Oncol Biol Phys 9 1983 1173 1176 6575971 \n10 Chen W.Y. Wang C.W. Chang C.H. Liu H.H. Clinicopathologic features and responses to radiotherapy of myeloid sarcoma Radiat Oncol 8 2013 245 24148102 \n11 Elsayad K. Oertel M. Haverkapm U. Eich H. The effectiveness of radiotherapy for leukemia cutis J Cancer Res Clin Oncol 143 2017 851 859 28093639 \n12 Yossi S. de Talhouet S. Ducastelle-Leprete S. Radiothérapie des chloromes ou sarcomes granulocytiques: revue de la littérature Cancer/Radiothérapie 20 2016 60 65 \n13 Chevallier P. Labopin M. Cornelissen J. Allogeneic hematopoietic stem cell transplantation for isolated and leukemic myeloid sarcoma in adults: a report from the Acute Leukemia Working Party of the European group for Blood and Marrow Transplantation Hematologica 96 2011 1391 1394 \n14 Slomowitz Samuel J. Management of extramedullary leukemia as a presentation of myeloid acute leukemia J Natl Compr Canc Netw 10 2012 1165 1169 22956813\n\n",
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"nlm_unique_id": "101713416",
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"pmid": "29594235",
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"title": "Radiotherapy for isolated granulocytic sarcoma: Case report and review of literature.",
"title_normalized": "radiotherapy for isolated granulocytic sarcoma case report and review of literature"
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"abstract": "In non-small cell lung cancer, the EGFR gene mutations identify a patient sub-population with different clinical characteristics and treatment responses to those that do not have these mutations. There are mutations that derive in increased sensitive to EGFR targeted therapy, as well as mutations that result in resistance. The determination of EGFR mutations involves a change in the therapeutic approach to lung cancer patients in current clinical practice. In this article we present a case of a patient suffering from a metastatic lung adenocarcinoma with an activating mutation on diagnosis, initially responding to treatment with erlotinib, who subsequently developed a secondary resistance due to acquiring the T790M mutation in exon 20 of the EGFR gene.",
"affiliations": "Servicio de Oncología Médica, Hospital del Mar, Barcelona, Spain. ATaus@imas.imim.es",
"authors": "Taus|Alvaro|A|;Vollmer|Iván|I|;Arriola|Edurne|E|",
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"issue": "47(2)",
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"mesh_terms": "D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009154:Mutation",
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"title": "Activating and resistance mutations of the epidermal growth factor receptor (EGFR) gene and non-small cell lung cancer: a clinical reality.",
"title_normalized": "activating and resistance mutations of the epidermal growth factor receptor egfr gene and non small cell lung cancer a clinical reality"
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{
"companynumb": "ES-MYLANLABS-2018M1005683",
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"activesubstancename": "ERLOTINIB"
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"abstract": "Milk-alkali syndrome (MAS), characterized by renal failure, metabolic alkalosis and hypercalcemia, is a severe and life-threatening complication of the treatment of hypoparathyroidism. The clinical course is often sudden and is not preceded by any prodromal symptoms. Occurrence does not depend on the duration of hypoparathyroidism treatment, although it is closely related to the applied therapy, especially the dose of calcium carbonate and active vitamin D preparations. Drugs influencing the glomerular filtration rate (angiotensin receptor blockers, sartans, aldosterone receptor antagonists, thiazide diuretics), lack of adequate routine control, changing the calcium carbonate supplementation, dehydration, a diet rich in pH-basic foods (i.e. vegetarian diet), pregnancy and other associated conditions are listed among the factors triggering MAS. A higher calcium carbonate dose is directly associated with an increased risk of milk-alkali syndrome. In case of a high calcium demand it is necessary to control renal function and monitor the level of calcium in the serum more frequently, aiming for the lower end of the reference range. If MAS has been confirmed or if there are alarming neurological symptoms suggestive of hypercalcemia, the patient must be sent to the hospital immediately. Treatment of MAS involves: discontinuation of calcium and vitamin D supplementation, and intravenous infusion of normal saline solution to eliminate volume deficiencies and to achieve forced diuresis while maintaining proper fluid balance. As soon as there is improvement in the patient's clinical condition, it is necessary to begin the treatment of comorbidities increasing the risk of renal failure or alkalosis (i.e. vomiting, diarrhea).",
"affiliations": "Warsaw University of Medicine. agathaskwarek@yahoo.com.",
"authors": "Skwarek|Agata|A|;Pachucki|Janusz|J|;Bednarczuk|Tomasz|T|;Żurecka|Zuzanna|Z|;Popow|Michał|M|;Kondracka|Agnieszka|A|;Bartoszewicz|Zbigniew|Z|",
"chemical_list": "D014807:Vitamin D; D002119:Calcium Carbonate",
"country": "Poland",
"delete": false,
"doi": "10.5603/EP.a2018.0015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0423-104X",
"issue": "69(2)",
"journal": "Endokrynologia Polska",
"keywords": "MAS; active vitamin D; alkalinisation; hypercalcemia; hypercalciuria; hypoparathyroidism; metabolic alkalosis; milk alkali syndrome; renal failure",
"medline_ta": "Endokrynol Pol",
"mesh_terms": "D002119:Calcium Carbonate; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D007011:Hypoparathyroidism; D008875:Middle Aged; D014807:Vitamin D",
"nlm_unique_id": "0370674",
"other_id": null,
"pages": "200-204",
"pmc": null,
"pmid": "29442351",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Milk-alkali syndrome (MAS) as a complication of the treatment of hypoparathyroidism - a case study.",
"title_normalized": "milk alkali syndrome mas as a complication of the treatment of hypoparathyroidism a case study"
} | [
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"companynumb": "PL-MYLANLABS-2018M1074462",
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"activesubstancename": "CALCIUM"
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{
"abstract": "OBJECTIVE\nMalignancy-related thromboembolism, also referred to as Trousseau's syndrome, can present as acute cerebral infarction, nonbacterial thrombotic endocarditis (NBTE), and migratory thrombophlebitis. Therefore, many physical, neurological, and psychological symptoms associated with Trousseau's syndrome may occur in the clinical course.\n\n\nMETHODS\nTo illustrate this, we report a case of a male patient in his 50s with carcinomatous peritonitis caused by gastric cancer, with multiple cerebral infractions that developed during disease progression. The patient was admitted to our hospital for the treatment of side effects of chemotherapy, although he strongly hoped to go home as soon as possible. In addition to making social supports plans, we were required to perform intensive total palliative care, because of his physical pain, general fatigue, anorexia, abdominal and neck pain, and psychological issues (insomnia, delirium, depression, suicidal thoughts, self-mutilation, panic attacks, agoraphobia, fear of death, and feelings of hopelessness).\n\n\nRESULTS\nTo the best of our knowledge, based on the literature search, this is the first reported case of Trousseau's syndrome described in the context of total palliative care, especially psychological care.\n\n\nCONCLUSIONS\nWe propose that neurological symptoms of Trousseau's syndrome cause these extensive mental disorders. Furthermore, because of the prognosis of Trousseau's syndrome, we should utilize our expertise fulfill the patient's wishes.",
"affiliations": "Palliative Care Team, Kamiiida Daiichi General Hospital, Kita-ku, Nagoya, Japan. ukai777@kamiiida-hp.jp",
"authors": "Ukai|Katsuyuki|K|;Okajima|Akiko|A|;Yamauchi|Aya|A|;Sasaki|Eiji|E|;Yamaguchi|Yohsuke|Y|;Kimura|Hiroyuki|H|;Aleksic|Branko|B|;Ozaki|Norio|N|",
"chemical_list": null,
"country": "England",
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"issn_linking": "1478-9515",
"issue": "11(2)",
"journal": "Palliative & supportive care",
"keywords": null,
"medline_ta": "Palliat Support Care",
"mesh_terms": "D002544:Cerebral Infarction; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010166:Palliative Care; D013274:Stomach Neoplasms; D013577:Syndrome; D014057:Tomography, X-Ray Computed",
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"pubdate": "2013-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Total palliative care for a patient with multiple cerebral infarctions that occurred repeatedly in association with gastric cancer (Trousseau's syndrome).",
"title_normalized": "total palliative care for a patient with multiple cerebral infarctions that occurred repeatedly in association with gastric cancer trousseau s syndrome"
} | [
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"companynumb": "JP-RANBAXY-2014RR-86418",
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"activesubstancename": "ZOPICLONE"
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"abstract": "Emergency and critical care physicians commonly evaluate and treat patients poisoned by acetaminophen. While the basics of management were established in the 1970s, over the past 20 years we have recognized subtleties and variations in presentations that alter the approach to evaluation and treatment. In this paper I will present several cases that illustrate some of the most common variations in presentations of acetaminophen poisoning and offer recommendations for modifi cations of testing and treatment based on several recent studies.",
"affiliations": "University of Colorado School of Medicine Section of Medical Pharmacology and Toxicology, Department of Emergency Medicine Aurora, CO USA.",
"authors": "Heard|Kennon|K|",
"chemical_list": null,
"country": "China (Republic : 1949- )",
"delete": false,
"doi": "10.6705/j.jacme.201809_8(3).0001",
"fulltext": null,
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"issue": "8(3)",
"journal": "Journal of acute medicine",
"keywords": "acetaminophen; acetylcysteine; overdose",
"medline_ta": "J Acute Med",
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"nlm_unique_id": "101574304",
"other_id": null,
"pages": "77-85",
"pmc": null,
"pmid": "32995209",
"pubdate": "2018-09-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "18986731;10692190;28644687;22593093;2490426;24708414;10872641;28002875;25133498;29622340;10759684;19280424;1928874;16317692;1954453;21586653;26691690;27108714;24290406;11990202;7469629;3059186;21402629;3710495;27412926;26594846;16040667;20180786;19007345;28404094;15878387;10584587;15459622;16496488",
"title": "Acetaminophen Poisoning: A Case Based Approach.",
"title_normalized": "acetaminophen poisoning a case based approach"
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"companynumb": "US-BAYER-2020-270722",
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"activesubstancename": "UNSPECIFIED INGREDIENT"
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{
"abstract": "Consensus treatment for herpetic meningoencephalitis is intravenous aciclovir but no guidelines are available for alternative treatment in case of renal failure induced by aciclovir. We report to the best of our knowledge, the first case of herpetic meningoencephalitis treated with success by ganciclovir.",
"affiliations": "a Infectious Disease Unit Douai Hospital, Route de Cambrai , Douai , France.;a Infectious Disease Unit Douai Hospital, Route de Cambrai , Douai , France.;a Infectious Disease Unit Douai Hospital, Route de Cambrai , Douai , France.",
"authors": "Blanc|Anne Laure|AL|;El Mansouf|Loubna|L|;Lemaire|Xavier|X|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir; D000212:Acyclovir",
"country": "England",
"delete": false,
"doi": "10.1080/1120009X.2016.1195070",
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"issue": "29(5)",
"journal": "Journal of chemotherapy (Florence, Italy)",
"keywords": "Ganciclovir; Herpes meningoencephalitis",
"medline_ta": "J Chemother",
"mesh_terms": "D000212:Acyclovir; D000998:Antiviral Agents; D020803:Encephalitis, Herpes Simplex; D015774:Ganciclovir; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8907348",
"other_id": null,
"pages": "308-309",
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"pmid": "27268065",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "First case of herpetic meningoencephalitis treated with ganciclovir.",
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"abstract": "BACKGROUND\nSkin metastases from pancreatic neuroendocrine carcinoma (PNEC) are rare and their palliative treatment is challenging. We report our experience in the multimodal management of one of the few reported cases of metastatic PNEC with multiple visceral and subcutaneous secondary lesions, focusing on the effectiveness of palliative radiotherapy for skin metastases.\n\n\nMETHODS\nA 61-years old woman affected by a metastatic PNEC - with subcutaneous growing and bleeding secondary lesions (at the scalp, right scapular region and at the back of the left thoracic wall, respectively) - obtained a successful control of visceral metastases with the use of chemotherapy and an unexpected local response of her skin metastases with palliative radiotherapy. In particular, two subsequent radiation treatments were performed using different fractionation schedules (30 Gy in 10 fractions and 20 Gy in 5 fractions, respectively). Both radiation treatments were well-tolerated and patient's quality of life was improved. Local response was maintained until patient's death - that occurred due to cachexia.\n\n\nCONCLUSIONS\nThe presented case highlights the effectiveness and the good tolerance of radiotherapy in the treatment of subcutaneous metastases; nevertheless, further knowledge of the optimal local palliative approach for PNEC metastatic sites is necessary. The experience gained in this work is the occasion to encourage a routine integrated multidisciplinary team management of metastatic PNECs because of their clinical complexity. The aim is to guarantee the optimization of the care with personalized and more effective systemic and local treatments - also including supportive cares and treatment-related side effects management.",
"affiliations": "Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Policlinico, P.zza Giulio Cesare nr.11, 70124, Bari, Italy.;Interdisciplinary Department of Medicine, Section of Radiology and Radiation Oncology, University of Bari \"Aldo Moro\", P.zza Giulio Cesare nr.11, 70124, Bari, Italy. roberta.carbonara@yahoo.it.;Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Policlinico, P.zza Giulio Cesare nr.11, 70124, Bari, Italy.;Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Policlinico, P.zza Giulio Cesare nr.11, 70124, Bari, Italy.;Department of Oncology, National Institute of Gastroenterology \"Saverio De Bellis\", Research Hospital, Via Turi, 27 Castellana Grotte, Bari, Italy.;Department of Oncology, National Institute of Gastroenterology \"Saverio De Bellis\", Research Hospital, Via Turi, 27 Castellana Grotte, Bari, Italy.;Department of Oncology, National Institute of Gastroenterology \"Saverio De Bellis\", Research Hospital, Via Turi, 27 Castellana Grotte, Bari, Italy.;Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Policlinico, P.zza Giulio Cesare nr.11, 70124, Bari, Italy.;Department of Oncology, National Institute of Gastroenterology \"Saverio De Bellis\", Research Hospital, Via Turi, 27 Castellana Grotte, Bari, Italy.;Interdisciplinary Department of Medicine, Section of Radiology and Radiation Oncology, University of Bari \"Aldo Moro\", P.zza Giulio Cesare nr.11, 70124, Bari, Italy.",
"authors": "Ciliberti|Maria Paola|MP|;Carbonara|Roberta|R|https://orcid.org/0000-0002-4087-3063;Grillo|Antonietta|A|;Leo|Anna Maria|AM|;Lolli|Ivan|I|;Ostuni|Carmela|C|;Troiani|Laura|L|;Turi|Barbara|B|;Vallarelli|Simona|S|;Sardaro|Angela|A|",
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"fulltext": "\n==== Front\nBMC Cancer\nBMC Cancer\nBMC Cancer\n1471-2407 BioMed Central London \n\n32293342\n6845\n10.1186/s12885-020-06845-x\nCase Report\nUnexpected response to palliative radiotherapy for subcutaneous metastases of an advanced small cell pancreatic neuroendocrine carcinoma: a case report of two different radiation schedules\nCiliberti Maria Paola mpciliberti@gmail.com 1 https://orcid.org/0000-0002-4087-3063Carbonara Roberta roberta.carbonara@yahoo.it 2 Grillo Antonietta antoniettagrillo@rocketmail.com 1 Leo Anna Maria anna-m.leo@libero.it 1 Lolli Ivan ivan.lolli@irccsdebellis.it 3 Ostuni Carmela carmela.ostuni@irccsdebellis.it 3 Troiani Laura laura.troiani@irccsdebellis.it 3 Turi Barbara bt78it@yahoo.it 1 Vallarelli Simona simona.vallarelli@irccsdebellis.it 3 Sardaro Angela angela.sardaro@uniba.it 2 1 Radiation Oncology Unit, Azienda Ospedaliero-Universitaria Policlinico, P.zza Giulio Cesare nr.11, 70124 Bari, Italy \n2 grid.7644.10000 0001 0120 3326Interdisciplinary Department of Medicine, Section of Radiology and Radiation Oncology, University of Bari “Aldo Moro”, P.zza Giulio Cesare nr.11, 70124 Bari, Italy \n3 Department of Oncology, National Institute of Gastroenterology “Saverio De Bellis”, Research Hospital, Via Turi, 27 Castellana Grotte, Bari, Italy \n15 4 2020 \n15 4 2020 \n2020 \n20 3111 8 2019 7 4 2020 © The Author(s) 2020Open 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\nSkin metastases from pancreatic neuroendocrine carcinoma (PNEC) are rare and their palliative treatment is challenging. We report our experience in the multimodal management of one of the few reported cases of metastatic PNEC with multiple visceral and subcutaneous secondary lesions, focusing on the effectiveness of palliative radiotherapy for skin metastases.\n\nCase presentation\nA 61-years old woman affected by a metastatic PNEC – with subcutaneous growing and bleeding secondary lesions (at the scalp, right scapular region and at the back of the left thoracic wall, respectively) – obtained a successful control of visceral metastases with the use of chemotherapy and an unexpected local response of her skin metastases with palliative radiotherapy. In particular, two subsequent radiation treatments were performed using different fractionation schedules (30 Gy in 10 fractions and 20 Gy in 5 fractions, respectively). Both radiation treatments were well-tolerated and patient’s quality of life was improved. Local response was maintained until patient’s death – that occurred due to cachexia.\n\nConclusions\nThe presented case highlights the effectiveness and the good tolerance of radiotherapy in the treatment of subcutaneous metastases; nevertheless, further knowledge of the optimal local palliative approach for PNEC metastatic sites is necessary. The experience gained in this work is the occasion to encourage a routine integrated multidisciplinary team management of metastatic PNECs because of their clinical complexity. The aim is to guarantee the optimization of the care with personalized and more effective systemic and local treatments – also including supportive cares and treatment-related side effects management.\n\nKeywords\nPalliative radiotherapySubcutaneous metastasesPancreatic neuroendocrine carcinomaissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nPancreatic neuroendocrine tumors (PNETs) are a rare heterogeneous group of neoplasms [1] that have been classified into two broad categories based on the combination of morphological features and proliferation grading system (G), assessed by the Ki-67 index [1]: well-differentiated PNET G1 (Ki-67 index ≤2%) and G2 (Ki-67 index: 3–20%) and poorly differentiated pancreatic neuroendocrine carcinoma PNEC - G3 (Ki-67 > 20%). Currently, the revised gastroenteropancreatic (GEP)-NET classification acknowledges well differentiated Grade 3 NETs in addition to grade 3 poorly differentiated NEC based on morphology [1]. Patients with poorly differentiated PNEC may be further stratified on the basis of whether their Ki-67 index is between 20 and 55% or is > 55%. Patients with a Ki-67 index > 55% have a worse prognosis and may quickly progress to an unresectable disease with symptoms of mass effects, distant metastases (usually hepatic) or both.\n\nSkin metastases from neuroendocrine tumors are very rare [2–4]. Their presence is sign of poor prognosis and their local management can represent a challenge in the case of rapidly growing lesions which tend to ulcerate and to bleed.\n\nWe describe a singular case of multiple subcutaneous metastases from a pancreatic neuroendocrine carcinoma which gained an unexpected response to palliative radiotherapy.\n\nCase presentation\nA 61-year-old woman presented with upper abdominal pain steady and radiating to the back and a 2 months history of diarrhea, weight loss and fatigue. Physical examination revealed abdominal distension and moderate epigastric pain. Furthermore, the patient presented multiple subcutaneous nodules on the scalp and chest. The nodules were well-circumscribed, skin- or pink-colored, painless to the touch, with a hardened consistency and no adherence to deeper planes, measuring about 1 cm.\n\nFigure 1 represents a timeline of the diagnostic and therapeutic pathway.\nFig. 1 Timeline of the diagnostic-therapeutic pathway\n\n\n\nA full-body computer tomography (CT) showed multiple large heterogeneous enhancing masses at the whole pancreas, sized from 4 to 6 cm, and multiple liver metastases – the largest of about 10 cm at the IV-VIII hepatic segment. The CT also confirmed the presence of multiple enhancing subcutaneous metastases.\n\nAn ultrasound-guided percutaneous biopsy of the largest hepatic metastasis showed a massive infiltration of the hepatic parenchyma by a solid neoplasm of poorly differentiated monomorphic elements with scarce cytoplasm and focal trabecular aspects. Immunohistochemical investigation was positive for Synaptophysin and CD56, negative for Chromogranin A and Neuron Specific Enolase (NSE) and was consistent with the diagnosis of metastasis of NEC/small cell carcinoma with Ki-67 90% as additional poor prognostic factor.\n\nAfter the Medical Oncologist evaluation, the patient started a platinum based chemotherapy with 6 cycles of Cisplatin and Etoposide. Clinically, after an initial partial response (Fig. 2a-b), the subcutaneous nodules had a shocking rapid progression during chemotherapy (Fig. 2c).\nFig. 2 Clinical evaluation of subcutaneous metastases of the scalp\n\n\n\nSome of these nodules reached the size of more than 10 cm, with tendency to skin ulceration and bleeding; others were only purple-colored without ulceration. Furthermore, new peri-centimetric nodules appeared at the skin of both legs, but they were palpable more than visible. All the nodules were painless and not adherent to deeper planes.\n\nUnexpectedly, the control CT performed after three cycles (Fig. 3b) revealed a substantial reduction of the visceral masses while confirming skin metastases progression.\nFig. 3 Changes in visceral and skin metastases detected by CT images\n\n\n\nA combined 18F-FDG CT/PET fusion images showed pathological uptake value in the previously mentioned disease sites. After 6 cycles of chemotherapy, taking into account the different response of visceral masses and skin lesions, a biopsy of a skin nodule was performed: it confirmed that subcutaneous nodules were metastases from the primary small cell neuroendocrine carcinoma with positivity for Synaptophysin and CD56 and negativity for Chromogranin A and CK20. Nuclear staining of ki-67 was positive and the ki-67 index reached 90%. After a multidisciplinary evaluation, the patient was referred to a Radiation Oncologist for a palliative treatment of the largest subcutaneous metastases.\n\nAt the moment of the first physical examination performed by the Radiation Oncologist, the patient presented multiple large scalp metastases. The largest mass (10 cm) appeared at the right fronto-temporal region of the scalp: it was crusted and easily bleeding. Other slightly smaller lesions with the same characteristics were localized at the left pre-auricular region, at the left temporal region and at the nape. A thermoplastic mask for immobilization was made up, and a CT scan of the head and neck was performed for radiotherapy (RT) planning. The largest and bleeding right fronto-temporal metastasis was contoured as Gross Tumor Volume (GTV); the Planning Target Volume (PTV) was obtained through the 5 mm expansion of the GTV. No signs of infiltration of deep subcutaneous tissues or bone were detected at the planning CT. A total dose of 30 Gy in 10 fractions was prescribed. Six 6 MV non-coplanar photon beams tangent to the skin were used for irradiation (Fig. 4). Organ-at-risk (brain, lens, eye) constraints were respected.\nFig. 4 Three-dimensional view of the treatment plan (a) and treatment planning dose distribution in axial view (b) for a subcutaneous metastasis of the scalp. Four tangential beams were used. Planning was performed through a 3D-conformal technique\n\n\n\nDuring RT course, the treated mass stopped bleeding and showed a progressive shrinkage from 10 to 6–7 cm. The skin became increasingly crusted and rough. The patient did not showed acute treatment-related side effects at physical examination. Unfortunately, the other untreated masses continued to grow and some of them began to bleed.\n\nAfter completion of RT, a second line chemotherapy with folinic acid, fluorouracil and irinotecan (FOLFIRI) was started but soon discontinued for thrombocytopenia.\n\nThe patient then was again directed to the radiation oncologist for a re-evaluation. Now the largest lesions, heavily bleeding, appeared at the right scapular region and at the back of the left thoracic wall. Both were approximately 10–12 cm diameter, heavily bleeding, partially necrotic and crusted. The quality of life of the patient was greatly compromised: she could not take lying down, so she couldn’t sleep at night and have a refreshing rest. The previously treated lesion of the scalp now was about 4 cm, dry, crusted and faintly adherent to the underlying skin.\n\nA new planning CT was performed for RT. This time the patient was positioned prone. The two masses of the back were contoured separately as two GTVs, and two distinct PTVs were obtained adding a 5 mm margin. For irradiation, we used the same technique as the previous treatment (two and three tangent 6 MV photon beams). Given the multiplicity of the lesions, the clinical condition of the patient and the ongoing chemotherapy, we decided to administer a total dose of 20 Gy in 5 fractions to each target simultaneously.\n\nThe response to this course of RT was quick and surprising. Already after the first two fractions, both lesions stopped bleeding and appeared reduced in volume. At the end of RT course, they were all crusted and more movable. The necrotic appearance vanished.\n\nAfter a week, the two masses appeared even smaller and drier and less vascularized due to the hemostatic effect of RT. No acute/subacute side effects were reported.\n\nAfter 2 weeks, both lesions had detached from the skin, leaving two small flat crusty areas of a few centimeters (Fig. 5). The patient agreed that she could have started to relax and to rest better, obtaining a beneficial impact on her quality of life.\nFig. 5 Clinical response of the irradiated skin lesion at the right scapular region\n\n\n\nA few days later, the patient restarted chemotherapy with FOLFIRI, interrupted after two cycles because of hematological toxicity. During the chemotherapic treatment, the skin lesions showed an overall diffuse reduction of volume. After discontinuation of chemotherapy, a new progression of the skin metastases, particularly at the level of the left temple and nape, occurred.\n\nThe conditions of the lesions treated with RT, however, remained stationary. At the restaging CT the tumor visceral metastases showed a substantial stability. Unfortunately, the patient gradually developed a cachexia that led her to death about 2 months after completion of RT.\n\nDiscussion and conclusions\nCases of skin (cutaneous/subcutaneous) metastases derived from neuroendocrine tumors of the lung [3–8], gastrointestinal [2, 9–11] and genitourinary tract [12–15] – as well as of other origins or with unknown primary tumor site [16–18] – have been exceptionally reported. In line with observations and revisions by Amorim et Al. [16], we remark that the detection of the primary tumor site in metastatic neuroendocrine tumors is a crucial question to improve the choice of therapeutic strategy. Anyhow, for patients with confirmed metastatic disease, systemic therapies and palliative cares of symptoms are the most common approaches [19]. Our overview of previous published cases with skin metastases from neuroendocrine tumors [3, 4, 6–8, 10–12, 14, 16–18] confirms this finding.\n\nIn published works, (sub) cutaneous metastases from neuroendocrine tumors are reported as single or multiple nodules, with typical location in the scalp/cephalic district and/or trunk, painless in the majority of cases [16]. Zuetenhorst et Al. [20] investigated the pathogenesis of pain which can be eventually associated to these skin metastases and reported that no differences in neuroinvasion, angioinvasion or mitosis between painful and non-painful metastases could be demonstrated. Authors also observed the poor pain-control using analgesics, irradiation or systemic treatments (e.g. interferon or chemotherapy), experiencing that local excision was the only successful treatment option [20].\n\nThe role of RT in the treatment of skin metastases is not well defined and few cases are reported in literature. Data regarding the optimal dose are lacking. Mak et al. [21] reported a significant response to RT of painful and bleeding cutaneous metastases from prostate cancer with a dose of 18 Gy in 3 fractions. A meta-analysis [22] reported response and recurrence rates for skin metastases after local palliative therapies (including radiation therapy, brachytherapy, surgery, electro-chemotherapy, topical, intralesional, or photodynamic therapy). Patients treated with RT (n.120), alone or in combination with other local therapies, showed a complete response rate of more than 60% of cases. However, only two prospective trials were included in the analysis and the primary tumor was breast cancer or melanoma in more than 90% of cases [22].\n\nIn our presented rare case of skin metastases from a small cell PNEC, we performed RT for growing and bleeding lesions using two typical palliative fractionation schedules (30 Gy/10 fractions and 20 Gy/5 fractions). Even if these treatments were performed with a purely palliative intent and dosage, we observed a good and unexpected local response of the treated lesions, which was also maintained with chemotherapy. Both the RT courses were well-tolerated and patient’s quality of life resulted improved.\n\nA recent systematic review on the role of RT in the treatment of gastro-entero-pancreatic neuroendocrine tumors [19] pointed out the lack of high-quality evidences regarding the overall role of RT both in the treatment of primary tumor and metastatic site. Nevertheless, authors confirmed the relationship between RT and reasonably high rates of local control and symptoms palliation. An accurate selection of patients who are candidates for RT, as well as more consistent results from novel fractionation schedules adopted in different clinical scenarios [19] and further knowledge of the synergistic effect of RT and new systemic therapies [19], could support an effective application of RT and improve patients’ outcomes.\n\nPrognosis of NETs with skin metastases remains poor. Our patient and the most reported cases [4–6, 8, 9, 11, 12, 15, 17, 18] died few months after diagnosis. According to our experience, personalized palliative approaches and a multidisciplinary patient’s evaluation (as recommended by international guidelines) lead to improve patient’s outcome and quality of life. Furthermore, our multidisciplinary approach reduced the overall time for the completion of diagnostic path and enabled a better management of iatrogenic toxicity.\n\nIn conclusions, the rarity of cases with skin metastases from PNETs requires efforts to improve the choice of the optimal palliation strategy. In selected patients with bleeding and/or growing lesions, RT could be proposed to reduce local symptoms. Because the most common palliative fractionation schedules are also usually well-tolerated, RT could successfully improve patients’ quality of life. Nevertheless, an integrated multidisciplinary team evaluation aimed at personalized approaches is necessary in the therapeutic management of similar cases with a poor prognosis.\n\nAbbreviations\nPNECPancreatic neuroendocrine carcinoma\n\n(P)NET(s)(Pancreatic) neuroendocrine tumor(s)\n\nCTComputer Tomography\n\nNSENeuron Specific Enolase\n\nRTRadiotherapy\n\nGTVGross Tumor Volume\n\nPTVPlanning Target Volume\n\nFOLFIRIFolinic acid, Fluorouracil and Irinotecan\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable.\n\nAuthors’ contributions\nMCP, AG, AML, IL, CO, LT, BT, SV and AS analyzed and interpreted the patient data regarding the entire diagnostic and therapeutic path. MPC, RC, IL and AS reviewed the literature and were major contributors in writing the manuscript. RC and AS created the timeline of the diagnostic and therapeutic pathway. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analyzed.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nA written informed consent for the publication of personal clinical information in a case report was obtained from the patient before she died. A copy of the signed consent form is available for the journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Rindi G Klimstra DS Abedi-Ardekani B A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal Mod Pathol 2018 31 12 1770 1786 10.1038/s41379-018-0110-y 30140036 \n2. Laschinger ME Naga L Gaspari AA Cutaneous metastases of pancreatic neuroendocrine carcinoma G Ital Dermatol Venereol 2018 153 5 722 724 10.23736/S0392-0488.17.05103-3 30246953 \n3. Linhas R Tente D China N Conde S Barroso A Subcutaneous metastasis of a pulmonary carcinoid tumor: a case report Medicine (Baltimore) 2018 97 2 e9415 10.1097/MD.0000000000009415 29480829 \n4. Falto-Aizpurua L Seyfer S Krishnan B Orengo I Cutaneous metastasis of a pulmonary carcinoid tumor Cutis 2017 99 5 E13 E15 28632813 \n5. Mestre T Rodrigues AM Cardoso J Pulmonary large-cell neuroendocrine carcinoma presenting as multiple cutaneous metastases J Bras Pneumol 2015 41 3 289 291 10.1590/S1806-37132015000004500 26176530 \n6. Pajaziti L Hapçiu SR Dobruna S Hoxha N Kurshumliu F Pajaziti A Skin metastases from lung cancer: a case report BMC Res Notes 2015 8 139 10.1186/s13104-015-1105-0 25889083 \n7. Ishida M Iwai M Kagotani A Iwamoto N Okabe H Cutaneous metastasis from pulmonary large cell neuroendocrine carcinoma in the scalp Int J Clin Exp Pathol 2014 7 5 2701 2706 24966991 \n8. Brinkman D Roche L Ullah K O'Connor TM Multiple cutaneous nodules as the presenting sign of small cell lung cancer BMJ Case Rep 2013 2013 bcr2013009160 10.1136/bcr-2013-009160 23704434 \n9. Białecki M Białecka A Męcińska-Jundziłł K Adamska U Kasperska A Czajkowski R Imaging in a rare case of neuroendocrine tumour with skin metastases Pol J Radiol 2018 83 e63 e67 10.5114/pjr.2018.73307 30038680 \n10. Shin WY Lee KY Ahn SI Park SY Park KM Cutaneous metastasis as an initial presentation of a non-functioning pancreatic neuroendocrine tumor World J Gastroenterol 2015 21 33 9822 9826 10.3748/wjg.v21.i33.9822 26361431 \n11. Wang SM Ye M Ni SM Multiple scalp metastases from colonic neuroendocrine carcinoma: case report and literature review BMC Cancer 2014 14 305 10.1186/1471-2407-14-305 24884973 \n12. Cokmert S Demir L Doganay L Demir N Kocacelebi K Unek IT Gezer E Kilic K Alakavuklar M Large cell neuroendocrine carcinoma of the ovary and its skin metastases: a case report and review of the literature West Indian Med J 2014 63 6 667 672 10.7727/wimj.2014.010 25803388 \n13. Devnani B, Kumar R, Pathy S, Phulware RH, Mathur S, Kumar L. Cutaneous metastases from neuroendocrine carcinoma of the cervix-An unusual metastatic lesion from an uncommon malignancy. Curr Probl Cancer. 2018. 10.1016/j.currproblcancer.2018.04.004.\n14. Lee WJ Kim CH Chang SE Lee MW Choi JH Moon KC Koh JK Cutaneous metastasis from large-cell neuroendocrine carcinoma of the urinary bladder expressing CK20 and TTF-1 Am J Dermatopathol 2009 31 2 166 169 10.1097/DAD.0b013e31818eba4c 19318803 \n15. Kaplan M Atakan IH Bilgi S Inci O Case report: subcutaneous metastasis from small cell carcinoma of the prostate Int Urol Nephrol 2007 39 1 157 160 10.1007/s11255-005-3620-8 17268913 \n16. Amorim GM Quintella D Cuzzi T Rodrigues R Ramos-e-Silva M Cutaneous metastasis of neuroendocrine carcinoma with unknown primary site: case report and review of the literature Case Rep Dermatol 2015 7 263 274 10.1159/000440661 26557073 \n17. Shin MK Choi CM Oh YJ Kim NI CK20 positive large-cell neuroendocrine carcinoma presenting with skin metastases Ann Dermatol 2011 23 Suppl 1 S20 S24 10.5021/ad.2011.23.S1.S20 22028564 \n18. Garcia A, Mays S, Silapunt S. Metastatic neuroendocrine carcinoma in the skin. Dermatol Online J. 2017;23(1):8.\n19. Chan DL Thompson R Lam M External beam radiotherapy in the treatment of gastroenteropancreatic neuroendocrine tumours: a systematic review Clin Oncol 2018 30 400 408 10.1016/j.clon.2018.03.006 \n20. Zuetenhorst JM van Velthuysen ML Rutgers EJ Boot H Taal BC Pathogenesis and treatment of pain caused by skin metastases in neuroendocrine tumours Neth J Med 2002 60 5 207 211 12365476 \n21. Mak G Chin M Nahar N De Souza P Cutaneous metastasis of prostate carcinoma treated with radiotherapy: a case presentation BMC Res Notes 2014 7 505 10.1186/1756-0500-7-505 25103825 \n22. Pratt DE Gordon Spratt EA Wu S DeRosa A Lee NY Lacouture ME Barker CA Efficacy of skin-directed therapy for cutaneous metastases from advanced cancer: a meta-analysis J Clin Oncol 2014 32 28 3144 3155 10.1200/JCO.2014.55.4634 25154827\n\n",
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"issn_linking": "1471-2407",
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"keywords": "Palliative radiotherapy; Pancreatic neuroendocrine carcinoma; Subcutaneous metastases",
"medline_ta": "BMC Cancer",
"mesh_terms": "D002100:Cachexia; D018278:Carcinoma, Neuroendocrine; D018288:Carcinoma, Small Cell; D019583:Dose Fractionation, Radiation; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged; D010166:Palliative Care; D010190:Pancreatic Neoplasms; D012878:Skin Neoplasms",
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"pmid": "32293342",
"pubdate": "2020-04-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Unexpected response to palliative radiotherapy for subcutaneous metastases of an advanced small cell pancreatic neuroendocrine carcinoma: a case report of two different radiation schedules.",
"title_normalized": "unexpected response to palliative radiotherapy for subcutaneous metastases of an advanced small cell pancreatic neuroendocrine carcinoma a case report of two different radiation schedules"
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"abstract": "Terbinafine is an allylamine antifungal agent which is widely used for the treatment of fungal infections. Cutaneous side effects have been reported in 2% of the patients on terbinafine therapy with many morphological patterns. We report a case of terbinafine induced pityriasis rosea, a very rare side effect of terbinafine. This report emphasizes the importance of counseling the patient to report immediately in the event of a cutaneous eruption.",
"affiliations": "Department of Dermatology, Christian Medical College, Ludhiana, Punjab, India.;Department of Dermatology, Christian Medical College, Ludhiana, Punjab, India.;Department of Dermatology, Christian Medical College, Ludhiana, Punjab, India.;Department of Dermatology, Christian Medical College, Ludhiana, Punjab, India.",
"authors": "George|Anisha|A|;Bhatia|Anuradha|A|;Kanish|Bimal|B|;Williams|Abhilasha|A|",
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"fulltext": "\n==== Front\nIndian J PharmacolIndian J PharmacolIJPharmIndian Journal of Pharmacology0253-76131998-3751Medknow Publications & Media Pvt Ltd India IJPharm-47-68010.4103/0253-7613.169574Drug WatchTerbinafine induced pityriasis rosea-like eruption George Anisha Bhatia Anuradha Kanish Bimal Williams Abhilasha Department of Dermatology, Christian Medical College, Ludhiana, Punjab, IndiaCorrespondence to: Dr. Anisha George, E-mail: dranishageorge@gmail.comNov-Dec 2015 47 6 680 681 07 4 2015 08 10 2015 12 10 2015 Copyright: © Indian Journal of Pharmacology2015This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Terbinafine is an allylamine antifungal agent which is widely used for the treatment of fungal infections. Cutaneous side effects have been reported in 2% of the patients on terbinafine therapy with many morphological patterns. We report a case of terbinafine induced pityriasis rosea, a very rare side effect of terbinafine. This report emphasizes the importance of counseling the patient to report immediately in the event of a cutaneous eruption.\n\nKEY WORDS:\nAdverse drug reactiondrug rashpityriasis roseaterbinafine\n==== Body\nIntroduction\nTerbinafine is an allylamine, a lipophilic compound, used for the treatment of onychomycosis and other fungal infections. Adverse effects are reported in 10% and cutaneous reactions in 2% of patients on terbinafine therapy.[1] These include pruritus, rash, urticaria, erythema multiforme, cutaneous lupus, and psoriasis. Terbinafine induced pityriasis rosea-like eruption is not common.\n\nCase Report\nA 25-year-old male with mycologically confirmed fingernail onychomycosis, who was prescribed oral terbinafine 250 mg daily for 18 days, presented with an itchy rash on the body for 4 days. The rash started on the chest and then progressed to involve the rest of the body within 4 days [Figure 1]. There was no history of fever or preceding upper respiratory illness. He was not on any other medication simultaneously and never had a similar rash in the past. There was no history of previous drug allergy. He had taken terbinafine for 1 month for the same indication, which he discontinued 2 weeks before restarting the present course of this antifungal. There was no family history of similar illness.\n\nFigure 1 Erythematous plaques with elevated borders and collarettes of fine scaling on the back. Most of the lesions have their long axis parallel to the lines of cleavage giving a “Christmas tree” distribution\n\nGeneral physical examination was noncontributory. Cutaneous examination revealed scattered erythematous papules and plaques on the trunk, upper limbs, and gluteal region. Few plaques were noted to have peripheral collarettes of scaling. Erythematous tumid plaques were noted on the cheeks. There was a single erythematous papule on the penile shaft. Scalp and oral mucosa were normal. Few fingernails were dystrophic.\n\nHe was clinically diagnosed to have terbinafine induced pityriasis rosea-like eruption and admitted in the dermatology ward. Investigations revealed a total leukocyte count of 5.2 × 109/L with a differential of 67% neutrophils, 30% lymphocytes, and 2% eosinophils. Liver and renal function tests were within normal limits. The Venereal disease research laboratory (VDRL) test was carried out to rule out secondary syphilis, which was negative. However, a skin biopsy was not performed.\n\nThe offending drug, terbinafine, was withdrawn. The patient was given supportive management in the form of antihistamines and topical steroids. The rash began to resolve quickly, and the patient was discharged from the hospital after 4 days.\n\nThe common cutaneous adverse effects associated with terbinafine therapy are urticaria, rash, and pruritus, usually occurring within a month of therapy. The other less common adverse effects are erythema multiforme, toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema annulare-like eruption, fixed drug eruption, alopecia areata, flare up of dermatitis,[1] induction and exacerbation of psoriasis,[23] and subacute cutaneous lupus-like eruption.[4] Pityriasis rosea is a rare adverse effect of terbinafine therapy.[5]\n\nPityriasis rosea is an inflammatory skin disease characterized by erythematous papulosquamous eruptions localized mainly to the trunk. Viral agents, especially human herpes virus 6 and 7, autoimmunity, drugs such as captopril, nonsteroidal anti-inflammatory drugs, barbiturates, metronidazole, isotretinoin, griseofulvin, terbinafine, and psychogenic factors have been proposed as possible etiological factors.[6] The initial lesion is larger than subsequent lesions and is called the herald patch. This herald patch is usually absent in drug induced pityriasis rosea; in our patient too, this feature was conspicuously absent. Itching was a prominent feature in our patient which is consistent with a drug reaction. Gupta et al.[5] have reported pityriasis rosea as an itchy rash beginning on the trunk after 4 weeks of regular treatment with terbinafine. The patient developed lesions after 18 days of regular treatment; however, he had been previously sensitized during the prior treatment with the drug.\n\nSecondary syphilis can a have similar cutaneous presentation but is usually asymptomatic. The patient denied a history of unprotected sexual intercourse and VDRL was negative. Pityriasiform variant of seborrhoeic dermatitis was ruled out because other seborrhoeic sites were spared, and there were no previous episodes of such eruptions. The other supportive evidence in favor of a drug-induced reaction was the improvement noted in the lesions on stopping the offending drug. Pityriasis rosea typically occurs in the spring season with a history of preceding upper respiratory infection. The patient presented in winter without any prodrome. The Naranjo causality assessment score for this case was 6, thereby suggesting probable causal association of the adverse drug reaction with terbinafine.\n\nIt is recommended that all patients who receive terbinafine therapy should be counseled about the possible adverse effects and instructed to discontinue the drug and report to the physician if a cutaneous eruption develops.\n\n\nFinancial Support and Sponsorship\nNil.\n\nConflicts of Interest\nThere are no conflicts of interest.\n==== Refs\n1 Amichai B Grunwald MH Adverse drug reactions of the new oral antifungal agents – Terbinafine, fluconazole, and itraconazole Int J Dermatol 1998 37 410 5 9646122 \n2 Gupta AK Sibbald RG Knowles SR Lynde CW Shear NH Terbinafine therapy may be associated with the development of psoriasis de novo or its exacerbation: Four case reports and a review of drug-induced psoriasis J Am Acad Dermatol 1997 36 5 Pt 2 858 62 9146568 \n3 Verros CD Rallis E The role of terbinafine in induction and/or exacerbation of psoriasis Int J Dermatol 2013 52 1155 6 22998455 \n4 Hill VA Chow J Cowley N Marsden RA Subacute lupus erythematosus-like eruption due to terbinafine: Report of three cases Br J Dermatol 2003 148 1056 12786843 \n5 Gupta AK Lynde CW Lauzon GJ Mehlmauer MA Braddock SW Miller CA Cutaneous adverse effects associated with terbinafine therapy: 10 case reports and a review of the literature Br J Dermatol 1998 138 529 32 9580815 \n6 González LM Allen R Janniger CK Schwartz RA Pityriasis rosea: An important papulosquamous disorder Int J Dermatol 2005 44 757 64 16135147\n\n",
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"title": "Terbinafine induced pityriasis rosea-like eruption.",
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"abstract": "A 49-year-old African American woman was admitted to our hospital with abdominal pain, nausea, vomiting, lethargy, and confusion. She was receiving ciprofloxacin for a urinary-tract infection prior to admission. Laboratory examination revealed anemia, thrombocytopenia, elevated lactate dehydrogenase, and serum creatinine. Peripheral smear showed numerous schistocytes, and the patient was diagnosed with thrombotic thrombocytopenic purpura (TTP). Ciprofloxacin was identified as the offending agent. The patient received treatment with steroids and plasmapheresis, which led to rapid clinical recovery. This is the first case to our knowledge of successfully treated ciprofloxacin-induced TTP; previously reported cases had fulminant outcomes. Quinolones are an important part of the antibiotic armamentarium, and this case can raise awareness of the association between quinolones and TTP. A high index of suspicion for detection and early and aggressive management are vitally important for a successful outcome.",
"affiliations": "Division of Pulmonary and Critical Care Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA.;Division of Pulmonary and Critical Care Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA.;Department of Internal Medicine, Bronx Lebanon Hospital Center, Albert Einstein College of Medicine, Bronx, NY 10457, USA.;Division of Pulmonary and Critical Care Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA.",
"authors": "Hashmi|Hafiz Rizwan Talib|HR|;Diaz-Fuentes|Gilda|G|;Jadhav|Preeti|P|;Khaja|Misbahuddin|M|",
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"fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi Publishing Corporation 10.1155/2015/143832Case ReportCiprofloxacin-Induced Thrombotic Thrombocytopenic Purpura: A Case of Successful Treatment and Review of the Literature Hashmi Hafiz Rizwan Talib \n1\n\n*\nDiaz-Fuentes Gilda \n1\nJadhav Preeti \n2\nKhaja Misbahuddin \n1\n1Division of Pulmonary and Critical Care Medicine, Bronx Lebanon Hospital Center, Bronx, NY 10457, USA2Department of Internal Medicine, Bronx Lebanon Hospital Center, Albert Einstein College of Medicine, Bronx, NY 10457, USA*Hafiz Rizwan Talib Hashmi: rizwan404@hotmail.comAcademic Editor: Caterina Mammina\n\n2015 26 10 2015 2015 1438322 9 2015 12 10 2015 13 10 2015 Copyright © 2015 Hafiz Rizwan Talib Hashmi 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.A 49-year-old African American woman was admitted to our hospital with abdominal pain, nausea, vomiting, lethargy, and confusion. She was receiving ciprofloxacin for a urinary-tract infection prior to admission. Laboratory examination revealed anemia, thrombocytopenia, elevated lactate dehydrogenase, and serum creatinine. Peripheral smear showed numerous schistocytes, and the patient was diagnosed with thrombotic thrombocytopenic purpura (TTP). Ciprofloxacin was identified as the offending agent. The patient received treatment with steroids and plasmapheresis, which led to rapid clinical recovery. This is the first case to our knowledge of successfully treated ciprofloxacin-induced TTP; previously reported cases had fulminant outcomes. Quinolones are an important part of the antibiotic armamentarium, and this case can raise awareness of the association between quinolones and TTP. A high index of suspicion for detection and early and aggressive management are vitally important for a successful outcome.\n==== Body\n1. Introduction\nCiprofloxacin is a DNA gyrase inhibitor that provides excellent coverage of gram-negative bacteria with marginal effectiveness against gram-positive bacteria. It is generally used to treat infections of bones and joints, endocarditis, gastroenteritis, malignant otitis externa, respiratory-tract infections, cellulitis, urinary-tract infections, prostatitis, anthrax, and chancroid. Common side effects include neurological symptoms (dizziness, insomnia, and nervousness), gastrointestinal symptoms (diarrhea, dyspepsia, and nausea), and transaminitis [1].\n\nQuinolones should be prescribed with caution to patients with HIV infection because of the potential for associated hypersensitivity reaction [2]. Uncommon adverse effects of ciprofloxacin include renal failure, agranulocytosis, anemia, bone-marrow suppression, and thrombocytopenia. Although full manifestation of fluoroquinolone-induced thrombotic thrombocytopenic purpura (TTP) requiring plasmapheresis is extremely rare, there are documented cases of life-threatening complications of TTP due to moxifloxacin [3]. There is sparse literature on TTP caused by other fluoroquinolones including ciprofloxacin. Here, we report an unusual case of TTP associated with the use of ciprofloxacin that was successfully treated with steroids and plasmapheresis.\n\n2. Case Presentation\nA 49-year-old African American woman presented to the emergency room with complaints of nausea, vomiting, abdominal pain, and altered sensorium. The abdominal pain was poorly localized, dull, and associated with nonbloody, nonbilious vomiting. The patient reported subjective fever and chills. Her medical history was remarkable for hypertension controlled with diet and lifestyle modifications. She was seen in another hospital 5 days earlier for urinary-tract infection and was prescribed ciprofloxacin and discharged. The patient denied taking any other prescribed or nonprescribed medications. She was a light smoker and denied any history of illicit or recreational drug use. On physical examination, she was in mild distress and confused but had normal vitals, and neurological examination did not reveal sensory or motor deficit. Cardiorespiratory examination was unremarkable. Abdominal examination revealed minimal diffuse tenderness without guarding, rigidity, or other signs of peritonitis. Bowel sounds were present, and no visceromegaly was appreciated. Skin examination did not reveal any petechiae or rash.\n\nLaboratory examination revealed anemia (hemoglobin: 8.1 g/dL, Ref.: 12–16 g/dL) and thrombocytopenia (platelets: 13 k/μL, Ref.: 150–450 k/μL) with 1959 U/L lactate dehydrogenase (Ref.: 100–190 U/L). Serum haptoglobin was 10 mg/dL (Ref.: 30–200 mg/dL), and the patient had reticulocyte count of 14%. Peripheral smear revealed moderate to severe schistocytosis and few platelets (Figure 1). Serum creatinine was 1.3 mg/dL with a baseline of 0.8 mg/dL (Ref.: 0.5–1.5 mg/dL). Serum lipase level was normal. Chest roentgenogram and computed tomography of the brain and abdomen were unremarkable. A clinical diagnosis of TTP was made, and the patient was admitted to the medical intensive care unit.\n\nCoomb's test, HIV antibody test, hepatitis panel, and septic work-up including blood, urine, and stool were negative. The patient's ADAMTS 13 activity was <3 (Ref.: 68–163). During hospitalization, the patient received fresh frozen plasma while awaiting plasmapheresis. Eight sessions of plasmapheresis with one volume exchange in each session were done. In addition, patient received intravenous methylprednisolone 62.5 mg two doses and 40 mg of intravenous methylprednisolone twice a day for two weeks (until a sustained rise in platelet was seen), followed by a gradual taper with oral prednisone. During the course of treatment, the hematological abnormalities, that is, platelets, LDH, and haptoglobin, returned to normal (Figure 2). The patient was discharged and remained asymptomatic with stable hematological profile during follow-up in the ambulatory clinic.\n\n3. Discussion\nTTP, first described by Moschcowitz in 1924 [4], is a form of thrombotic microangiopathy characterized by systemic microvascular platelet aggregation and erythrocyte destruction. It has an estimated annual incidence in the United States of 4 to 11 cases per million people and is more common in women and individuals of African descent [5]. TTP is associated with a pentad of clinical signs and symptoms including thrombocytopenia, microangiopathic hemolytic anemia, neurological abnormalities, renal failure, and fever. Since a randomized control trial demonstrated the efficacy of plasma exchange therapy in the treatment of TTP [6], microangiopathic hemolytic anemia and thrombocytopenia without any alternate etiology have been considered sufficient for diagnosis [7]. The use of those criteria for diagnosis has resulted in a 7-fold increase in the number of patients treated for TTP [8].\n\nTTP has diverse etiologies including infections, medications, and idiopathic and familial causes. Drug-associated TTP represents about 12% of all cases [9]. Before the advent of plasma therapy, most of the patients presenting with acute TTP died: the case-fatality rate reported in clinical series was near 100% until the 1960s [10, 11].\n\nA test for severe deficiency (activity < 5) of von Willebrand factor- (vWF-) cleaving protease called ADAMTS 13 is 100% sensitive and specific for the diagnosis of TTP. ADMATS 13 cleaves vWF multimers, and its absence results in large vWF multimers that react with platelets, resulting in the widespread formation of platelet thrombi, which are responsible for the clinical presentation of TTP [12]. Although it is not always detected, the presence of ADAMTS 13 inhibitor suggests the acquired forms of TTP. Congenital TTP usually presents in early childhood in individuals with a positive family history of similar disorders.\n\nFor adults, plasma exchange is the only treatment supported by well-founded data. The effectiveness of plasma exchange is attributed to the removal of ADAMS 13 autoantibodies and the restoration of ADAMTS 13 activity [4, 13]. Plasma exchange is effective, however, even in patients who do not have severe ADAMTS 13 deficiency [14].\n\nCurrent guidelines recommend daily plasma exchange with replacement of 1.0 to 1.5 times the predicted plasma volume of the patient [15, 16]. Further recommendations include the use of glucocorticoids in all patients with TTP and continued plasma exchange therapy for at least 2 days after the platelet count returns to normal [16, 17].\n\nMany commonly prescribed drugs and pharmacological substances have been associated with the development of TTP. It is difficult to evaluate case reports describing associations between various drugs and the disease entity, however, because there are no standardized criteria to document the drugs as the probable cause of TTP. The incidence of TTP remains poorly defined and is dependent on voluntary reporting. Moreover, the case reports of drug-induced TTP have not been reviewed systemically to determine a formal cause-effect relation, as has been done for drug-induced thrombocytopenia [18].\n\nFluoroquinolones are an emerging but underrecognized cause of drug-induced thrombocytopenia. Cheah et al. described fluoroquinolone-induced thrombocytopenia [19]. Here, we focus on fluoroquinolones as a cause of TTP. Fluoroquinolones have a wide range of immune-hematopathologic effects, and the exact mechanisms for most of those effects remain unclear. It has been hypothesized that similarities in the chemical structures of quinolones and quinine might be contributory [19], because quinines are a well-recognized cause of thrombocytopenia [20].\n\nFluoroquinolones have been associated with TTP and the hemolytic-uremic syndrome. One of the largest published series described “temafloxacin syndrome” in which 95 patients developed hemolytic anemia, thrombocytopenia, and renal failure following treatment with temafloxacin, which was subsequently withdrawn from the market [21]. A comprehensive review of the existing literature on immune thrombocytopenia and TTP secondary to drugs did not indicate fluoroquinolones as a causative agent [7, 22, 23]. The few previous reports of ciprofloxacin-induced TTP described a fulminant course with very high mortality. Mouraux et al. described a case of a 43-year-old female who developed fulminant TTP early in a course of ciprofloxacin therapy. That patient was initially suspected to have meningoencephalitis because of marked thrombocytopenia, however, and spinal tap was delayed. Later on, cerebrospinal fluid analysis was unremarkable, and the patient was diagnosed with TTP; however, the patient died due to systemic complications [24]. Tuccori et al. described a case of TTP in a 30-year-old female receiving ciprofloxacin treatment for a urinary-tract infection, who died within 17 hours of diagnosis [25].\n\n4. Conclusion\nCiprofloxacin is a common and widely used antibiotic with excellent tissue penetration and gastrointestinal absorption. Our patient highlighted a rare but, if unrecognized, potentially fatal complication that clinicians should be aware of. There are no established risk factors to prospectively determine which patients are at increased risk of developing TTP due to ciprofloxacin. Therefore, early recognition and aggressive management are of paramount importance for survival.\n\nConflict of Interests\nNone of the authors has a financial relationship with a commercial entity that has an interest in the subject of the paper. No financial support was used for this case report.\n\nFigure 1 Peripheral smear shows moderate to severe schistocytes (black arrows) and very few platelets (blue arrows).\n\nFigure 2 Platelet count, haptoglobin, and LDH over the course of treatment.\n==== Refs\n1 Deck D. H. Winston L. G. Katzung B. G. Trevor A. J. Sulfonamides, trimethoprim, & quinolones Basic & Clinical Pharmacology 2015 13th New York, NY, USA McGraw-Hill Education \n2 Bertino J. Jr. Fish D. The safety profile of the fluoroquinolones Clinical Therapeutics 2000 22 7 798 817 10.1016/S0149-2918(00)80053-3 2-s2.0-0033872762 10945507 \n3 Surana S. P. Sardinas Z. Multz A. S. Moxifloxacin (Avelox) induced thrombotic thrombocytopenic purpura Case Reports in Medicine 2012 2012 3 459140 10.1155/2012/459140 \n4 Moake J. L. Thrombotic microangiopathies The New England Journal of Medicine 2002 347 8 589 600 10.1056/nejmra020528 2-s2.0-0037158606 12192020 \n5 Terrell D. R. Williams L. A. Vesely S. K. Lämmle B. Hovinga J. A. K. George J. N. The incidence of thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: all patients, idiopathic patients, and patients with severe ADAMTS-13 deficiency Journal of Thrombosis and Haemostasis 2005 3 7 1432 1436 10.1111/j.1538-7836.2005.01436.x 2-s2.0-25144446865 15978100 \n6 Rock G. A. Shumak K. H. Buskard N. A. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura The New England Journal of Medicine 1991 325 6 393 397 10.1056/nejm199108083250604 2062330 \n7 George J. N. Clinical practice. Thrombotic thrombocytopenic purpura The New England Journal of Medicine 2006 354 18 1927 1935 10.1056/nejmcp053024 2-s2.0-33646360865 16672704 \n8 Clark W. F. Garg A. X. Blake P. G. Rock G. A. Heidenheim A. P. Sackett D. L. Effect of awareness of a randomized controlled trial on use of experimental therapy The Journal of the American Medical Association 2003 290 10 1351 1355 10.1001/jama.290.10.1351 2-s2.0-0042413393 12966127 \n9 Bapani S. Epperla N. Kasirye Y. Mercier R. Garcia-Montilla R. ADAMTS13 deficiency and thrombotic thrombocytopenic purpura associated with trimethoprim-sulfamethoxazole Clinical Medicine and Research 2013 11 2 86 90 10.3121/cmr.2012.1105 2-s2.0-84879383000 23262188 \n10 Amorosi E. L. Ultmann J. E. Thrombotic thrombocytopenic purpura: report of 16 cases and review of the literature Medicine 1966 45 2 139 159 10.1097/00005792-196603000-00003 \n11 Torok T. J. Holman R. C. Chorba T. L. Increasing mortality from thrombotic thrombocytopenic purpura in the United States—analysis of national mortality data, 1968–1991 American Journal of Hematology 1995 50 2 84 90 10.1002/ajh.2830500203 2-s2.0-0029129940 7573005 \n12 Tsai H.-M. Physiologic cleavage of von Willebrand factor by a plasma protease is dependent on its conformation and requires calcium ion Blood 1996 87 10 4235 4244 2-s2.0-0029878123 8639782 \n13 Sadler J. E. Moake J. L. Miyata T. George J. N. Recent advances in thrombotic thrombocytopenic purpura Hematology/The Education Program of the American Society of Hematology. American Society of Hematology. Education Program 2004 407 423 2-s2.0-20444446312 15561695 \n14 Vesely S. K. George J. N. Lämmle B. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients Blood 2003 102 1 60 68 10.1182/blood-2003-01-0193 2-s2.0-0037968640 12637323 \n15 Smith J. W. Weinstein R. Hillyer K. L. Therapeutic apheresis: a summary of current indication categories endorsed by the AABB and the American Society for Apheresis Transfusion 2003 43 6 820 822 10.1046/j.1537-2995.2003.00397.x 2-s2.0-0038350660 12757535 \n16 Scully M. Hunt B. J. Benjamin S. Guidelines on the diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic microangiopathies British Journal of Haematology 2012 158 3 323 335 10.1111/j.1365-2141.2012.09167.x 2-s2.0-84863841323 22624596 \n17 Allford S. L. Hunt B. J. Rose P. Machin S. J. Guidelines on the diagnosis and management of the thrombotic microangiopathic haemolytic anaemias British Journal of Haematology 2003 120 4 556 573 10.1046/j.1365-2141.2003.04049.x 2-s2.0-0038323999 12588343 \n18 George J. N. Raskob G. E. Shah S. R. Drug-induced thrombocytopenia: a systematic review of published case reports Annals of Internal Medicine 1998 129 11 886 890 10.7326/0003-4819-129-11_part_1-199812010-00009 2-s2.0-0032403959 9867731 \n19 Cheah C. Y. De Keulenaer B. Leahy M. F. Fluoroquinolone-induced immune thrombocytopenia: a report and review Internal Medicine Journal 2009 39 9 619 623 10.1111/j.1445-5994.2009.01996.x 2-s2.0-70349330402 19769684 \n20 Crum N. F. Gable P. Quinine-induced hemolytic-uremic syndrome Southern Medical Journal 2000 93 7 726 728 10.1097/00007611-200093070-00021 2-s2.0-0034218714 10923967 \n21 Blum M. D. Graham D. J. McCloskey C. A. Temafloxacin syndrome: review of 95 cases Clinical Infectious Diseases 1994 18 6 946 950 10.1093/clinids/18.6.946 2-s2.0-0028217680 8086558 \n22 Cathomas R. Goldhirsch A. von Moos R. Drug-induced immune thrombocytopenia The New England Journal of Medicine 2007 357 18 1870 1871 17985437 \n23 Medina P. J. Sipols J. M. George J. N. Drug-associated thrombotic thrombocytopenic purpura-hemolytic uremic syndrome Current Opinion in Hematology 2001 8 5 286 293 10.1097/00062752-200109000-00004 2-s2.0-0034824687 11604563 \n24 Mouraux A. Gille M. Piéret F. Declercq I. Fulminant thrombotic thrombocytopenic purpura in the course of ciprofloxacin therapy Revue Neurologique 2002 158 11 1115 1117 2-s2.0-0036880168 12451346 \n25 Tuccori M. Guidi B. Carulli G. Blandizzi C. Tacca M. D. Di Paolo M. Severe thrombocytopenia and haemolytic anaemia associated with ciprofloxacin: a case report with fatal outcome Platelets 2008 19 5 384 387 10.1080/09537100801993040 2-s2.0-51849143152 18791946\n\n",
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"references": "19419487;2084989;19721800;6192889;16912017;9027680;7974193;7805405;6802951;15078345",
"title": "The child with spontaneous recurrent bleeding in the eye.",
"title_normalized": "the child with spontaneous recurrent bleeding in the eye"
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"abstract": "We report a case of an 18-yr-old male with high-grade persistent fever, productive cough, malaise, diarrhea and associated abnormal findings on chest radiography. The patient suffered from ulcerative colitis receiving mesalazine and azathioprine. After a further and scrutinized work-up the diagnosis of drug-induced pulmonary toxicity was made. His condition was improved after discontinuing both drugs and the administration of corticosteroids. This is a rarely reported case of eosinophilic pneumonia. Although it has not been reported previously, the possibility of mesalazine and azathioprine synergism cannot be excluded. The clinical, aetiological, diagnostic and therapeutic aspects of the disease are discussed demonstrating the paramount importance of bronchoalveolar lavage in the diagnosis of this disorder. One should be aware of this entity in patients with inflammatory bowel disease.",
"affiliations": "Department of Pneumonology, Army General Hospital of Athens, Athens, Greece. skatsenos@yahoo.gr",
"authors": "Katsenos|Stamatis|S|;Psathakis|Kostas|K|;Kokkonouzis|Ioannis|I|;Panagou|Panagiotis|P|;Tsintiris|Kostas|K|;Bouros|Demosthenes|D|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007166:Immunosuppressive Agents; D019804:Mesalamine; D001379:Azathioprine",
"country": "Belgium",
"delete": false,
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"issn_linking": "1784-3227",
"issue": "70(3)",
"journal": "Acta gastro-enterologica Belgica",
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"medline_ta": "Acta Gastroenterol Belg",
"mesh_terms": "D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal; D001379:Azathioprine; D001992:Bronchoalveolar Lavage Fluid; D003093:Colitis, Ulcerative; D003371:Cough; D003967:Diarrhea; D006801:Humans; D007091:Image Processing, Computer-Assisted; D007166:Immunosuppressive Agents; D008297:Male; D019804:Mesalamine; D011657:Pulmonary Eosinophilia; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0414075",
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"pages": "290-2",
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"pubdate": "2007",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-induced pulmonary toxicity in a patient treated with mesalazine and azathioprine for ulcerative colitis.",
"title_normalized": "drug induced pulmonary toxicity in a patient treated with mesalazine and azathioprine for ulcerative colitis"
} | [
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"abstract": "Hyperkalemia is a commonly encountered clinical problem. Pseudohyperkalemia is believed to be an in vitro phenomenon that does not reflect in vivo serum potassium and therefore should not be treated. Here, we present a case who unfortunately underwent unnecessary treatment because of failure to detect the common lab abnormality of pseudohyperkalemia.\nA 91-year-old female with a history of chronic lymphocytic leukemia presented to the emergency with nausea and vomiting 24 hours after her first chemotherapy with chlorambucil. Physical examination was overall unremarkable. She had a leukocytosis of 210 × 103/µL with 96% lymphocytes along with chronic anemia with hemoglobin of 8.1 g/dL. Her initial sodium and potassium levels were normal. During the clinical course, her potassium progressively worsened and failed to improve despite standard medical treatment. Patient ultimately underwent dialysis.\nDifferentiating true hyperkalemia from pseudohyperkalemia is very important in selected group of patients to avoid unnecessary medications, higher level of care, and unnecessary procedure including dialysis. We want to emphasize the importance of simple yet profound knowledge of technique of blood draws and basic metabolic panel processing for every clinician in day-to-day practice.",
"affiliations": "Internal Medicine, PeaceHealth Southwest Medical Center, 400 NE Mother Joseph Place, Vancouver, WA 98664, USA.;Maimonides Medical Center, 4802 10th Avenue, Brooklyn, NY 11219, USA.;Internal Medicine, PeaceHealth Southwest Medical Center, 400 NE Mother Joseph Place, Vancouver, WA 98664, USA.",
"authors": "Neupane|Sanjay Prakash|SP|0000-0003-2512-5777;Sharma|Pratibha|P|;Dangal|Mahesh Mani|MM|",
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"doi": "10.1155/2018/9060892",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi 10.1155/2018/9060892Case ReportPseudohyperkalemia: Hyperkalemia Cocktail or Alternative Diagnosis http://orcid.org/0000-0003-2512-5777Neupane Sanjay Prakash spn894@gmail.com\n1\nSharma Pratibha \n2\nDangal Mahesh Mani \n1\n\n1Internal Medicine, PeaceHealth Southwest Medical Center, 400 NE Mother Joseph Place, Vancouver, WA 98664, USA\n2Maimonides Medical Center, 4802 10th Avenue, Brooklyn, NY 11219, USAAcademic Editor: Edgar M. Carvalho\n\n2018 24 7 2018 2018 90608922 4 2018 3 7 2018 Copyright © 2018 Sanjay Prakash Neupane et al.2018This 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.Introduction\n Hyperkalemia is a commonly encountered clinical problem. Pseudohyperkalemia is believed to be an in vitro phenomenon that does not reflect in vivo serum potassium and therefore should not be treated. Here, we present a case who unfortunately underwent unnecessary treatment because of failure to detect the common lab abnormality of pseudohyperkalemia. \n\nCase Presentation\n A 91-year-old female with a history of chronic lymphocytic leukemia presented to the emergency with nausea and vomiting 24 hours after her first chemotherapy with chlorambucil. Physical examination was overall unremarkable. She had a leukocytosis of 210 × 103/µL with 96% lymphocytes along with chronic anemia with hemoglobin of 8.1 g/dL. Her initial sodium and potassium levels were normal. During the clinical course, her potassium progressively worsened and failed to improve despite standard medical treatment. Patient ultimately underwent dialysis. \n\nConclusions\n Differentiating true hyperkalemia from pseudohyperkalemia is very important in selected group of patients to avoid unnecessary medications, higher level of care, and unnecessary procedure including dialysis. We want to emphasize the importance of simple yet profound knowledge of technique of blood draws and basic metabolic panel processing for every clinician in day-to-day practice.\n==== Body\n1. Introduction\nHyperkalemia is a commonly encountered clinical problem. It can be fatal if not treated emergently. Common cause of hyperkalemia is due to decreased urinary potassium excretion in the setting of acute and chronic kidney injury. Less common cause includes increased potassium release from cells including pseudohyperkalemia, increased tissue catabolism, and insulin deficiency. We present here a 91-year-old female with a history of chronic lymphocytic leukemia (CLL) presenting with elevated serum potassium level that unfortunately underwent unnecessary treatment because of failure to detect the common lab abnormality of pseudohyperkalemia.\n\n2. Case Presentation\nA 91-year-old Caucasian female with a history of CLL diagnosed 14 years ago, hypothyroidism, glaucoma, and severe osteoarthritis of spine presented to ER, 24 hrs after receiving first chemotherapy for her CLL with chlorambucil in the setting of recent worsening of lymphocytosis, anemia, and exertional dyspnea, with complaints of nausea and vomiting after chemotherapy. There was no diarrhea, abdomen pain, fever, and chills. She had completed a course of Bactrim for UTI a week ago. There were no recent changes in home medications. Vital signs were within normal limits, and systemic physical examination was unremarkable except for dry mucous membrane in ER. She received a liter of normal saline bolus and was started on maintenance normal saline at 75 ml/hr. She started to feel short of breath and wheezy while in ER. Her oxygen saturation dropped to 85% on room air, which was treated with bronchodilators. Upon initial workup, she was found to have leukocytosis of 210 × 103 cells/μL with 96% lymphocytes, along with chronic anemia with hemoglobin of 8.1 and hematocrit of 28. Her electrolytes and renal function were normal with Na of 137 meq/L, K of 4.6 meq/L, BUN of 15 mg/dL, and Cr of 0.8 mg/dL. CXR was unremarkable. Liver function tests were within normal limits. Uric acid was 2.8 mg/dL, and phosphorus was 2.9 mg/dL. The patient got progressively short of breath overnight after admission and was hypoxic. She was, therefore, evaluated for pulmonary embolism based on her risk profile. CTA chest was negative for pulmonary embolism. This revealed diffuse centrilobular emphysematous changes and bibasilar atelectasis. Patient's care was escalated to intensive care, and noninvasive ventilation was initiated. Repeat basic metabolic panel this time revealed K of 6.6 meq/L. Rest of labs including creatinine were essentially within normal limits. The basic metabolic panel was repeated again in 3 hrs, which revealed K of 8.5. EKG did not demonstrate peaked T waves, prolonged QRS interval, or evidence of heart block. She was treated with intravenous calcium gluconate, albuterol nebulization, IV insulin, IV dextrose, IV Lasix, and sodium polystyrene. Her K remained persistently high in 8 meq/dl most of the day despite medical management. When her K rose to 9.1 overnight, a decision was made to proceed to emergent dialysis. Interestingly, her creatinine remained stable throughout, and she was not oliguric. She received 4 hrs of hemodialysis with 2 K bath. Immediately after dialysis, she had a run of supraventricular tachycardia with a heart rate of 130, which did not improve with adenosine. Her potassium by arterial blood gas was 3.0 meq/dL, and K on basic metabolic panel was 3.1 an hour after hemodialysis. Potassium was supplemented intravenously, and she was also loaded with digoxin following which she converted to sinus rhythm. She sustained a demand ischemia with troponins going up to 10 after this event. No cardiac catheterization or ischemic workup was done, as she was asymptomatic after resolution of SVT. Her plasma K was between 3.5 and 4.7 for next six days prior to discharge home from hospital.\n\n3. Discussion\nPseudohyperkalemia is believed to be an in vitro phenomenon that does not reflect in vivo serum potassium and therefore should not be treated. Laboratory finding of pseudohyperkalemia was first described in 1975 in two CLL patients with WBC counts above 600 k/µL [1]. Differentiating true hyperkalemia from pseudohyperkalemia is very important in selected group of patients to avoid unnecessary medications, higher level of care like admitting in ICU, and unnecessary procedures including dialysis. In patients with increased cell counts, RBC, WBC, or platelets, there are several factors that play a role in mechanical disruption of blood cells [1–3]. Before the start of heparinization of the collected blood specimen, this was believed to be due to the clotting process inducing in vitro release of potassium from leukocytes. Potassium is now measured in plasma or in heparinized tubes, clotting is unlikely to be causal, but lysis of cells still can occur [1]. Use of vacuum tubes, pneumatic tube transportation, prolonged incubation, tourniquet use, and processing of specimens through centrifugation have all been implicated as causing lysis of cells and releasing serum potassium [4–6]. In patients with CLL, the leakage of potassium from elevated fragile white blood cells results in falsely elevated serum potassium. Lack of metabolic fuels leading to impaired sodium/potassium adenosine triphosphatase activity may contribute to release of potassium from a large number of white cells [4, 7]. In our case, all the basic metabolic panel testing was done with the standard technique on plasma. After realization of a spurious phenomenon, on subsequent blood draws, mechanical factors were minimized by avoiding tourniquet, decreasing specimen transport delay, and rapidly processing the specimen. ABG was also performed on one occasion. Arterial blood draws might be more accurate than venous blood draws in the similar patients simply due to the fact that arterial samples are less susceptible to stressors because of quick processing and the lack of use of tourniquet. In our case, hemodialysis was felt as the appropriate intervention because of the refractory hyperkalemia. Unfortunately, failure to recognize the possibility of pseudohyperkalemia resulted in intervention that could have led to significant morbidity and mortality in this 91-year-old.\n\n4. Conclusions\nPseudohyperkalemia is not an uncommon entity. However, at many times, we as clinicians tend to go behind numbers rather than seeing the whole picture of the patient. There were several clinical clues pointing towards alternate explanation for the abnormal lab value. The fact that our patient's creatinine being persistently normal, the patient continued to make urine and no EKG changes despite high potassium level should have prompted to think outside of true hyperkalemia. As a clinician, we need to be very attentive and consider several physical and technical factors before interpreting any abnormal lab value. Through this case report, we want to emphasize further on the importance of knowledge of this simple concept related to techniques of blood draws, basic metabolic panel processing, and correlating the lab value with clinical presentation on every clinician in day-to-day practice [8, 9].\n\nAcknowledgments\nThe authors wish to thank the patient for consenting to the publication of this case report.\n\nAbbreviations\nCLL:Chronic lymphocytic leukemia\n\nER:Emergency\n\nUTI:Urinary tract infection\n\nNa:Sodium\n\nK:Potassium\n\nBUN:Blood urea nitrogen\n\nCr:Creatinine\n\nCXR:Chest X-ray\n\nCTA:CT angiogram\n\nEKG:Electrocardiogram\n\nIV:Intravenous\n\nSVT:Supraventricular tachycardia\n\nWBC:White blood cells\n\nRBC:Red blood cells\n\nABG:Arterial blood gas.\n\nData Availability\nAll data generated or analyzed during this study are included in this article.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interests.\n\nAuthors' Contributions\nSanjay Prakash Neupane and Pratibha Sharma were responsible for collecting data and writing of the manuscript. Mahesh Mani Dangal supervised the writing of the manuscript. All authors read and approved the final manuscript.\n==== Refs\n1 Ruddy K. J. Wu D. Brown J. R. Pseudohyperkalemia in chronic lymphocytic leukemia Journal of Clinical Oncology 2008 26 16 2781 2782 10.1200/jco.2008.16.3014 2-s2.0-45749145482 18509189 \n2 Colussi G. Cipriani D. Pseudohyperkalemia in extreme leukocytosis American Journal of Nephrology 1995 15 5 450 452 10.1159/000168883 2-s2.0-0029079767 7503149 \n3 Nijsten M. W. de Smet B. J. Dofferjoff A. S. Pseudohyperkalemia and platelet counts New England Journal of Medicine 1991 325 15 p. 1107 10.1056/nejm199110103251515 2-s2.0-0025934342 \n4 Chawla N. R. Shapiro J. Sham R. L. Pneumatic tube “pseudo tumor lysis syndrome” in chronic lymphocytic leukemia American Journal of Hematology 2009 84 9 613 614 10.1002/ajh.21473 2-s2.0-69549121561 19610017 \n5 Rifkin S. I. Pseudohyperkalemia in patients with chronic lymphocytic leukemia International Journal of Nephrology 2011 2011 3 759749 10.4061/2011/759749 \n6 Kellerman P. S. Thornbery J. M. Pseudohyperkalmia due to pneumatic tube transport in Leukemic patient American Journal of Kidney Diseases 2005 46 4 746 748 10.1053/j.ajkd.2005.06.005 2-s2.0-25644444650 16183430 \n7 Colussi G. Pseudohyperkalemia in leukemias American Journal of Kidney Diseases 2006 47 2 p. 373 10.1053/j.ajkd.2005.10.032 2-s2.0-31044433321 \n8 Don B. R. Sebastian A. Cheitlin M. Christiansen M. Schambelan M. Pseudohyperkalemia caused by fist clinching during phlebotomy New England Journal of Medicine 1990 322 18 1290 1292 10.1056/nejm199005033221806 2-s2.0-0025273039 2325722 \n9 Asirvatham J. R. Moses V. Bjornson L. Errors in potassium measurement: a laboratory perspective for the clinician North American Journal of Medical Sciences 2013 5 4 255 259 10.4103/1947-2714.110426 2-s2.0-84876073156 23724399\n\n",
"fulltext_license": "CC BY",
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"pubdate": "2018",
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"references": "1891016;2325722;23724399;16183430;16431273;19610017;21603111;18509189;7503149",
"title": "Pseudohyperkalemia: Hyperkalemia Cocktail or Alternative Diagnosis.",
"title_normalized": "pseudohyperkalemia hyperkalemia cocktail or alternative diagnosis"
} | [
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"abstract": "The erythrodermic ulcerated form of mycosis fungoides (MF) is exceptional, and treatment of refractory cases is challenging. Brentuximab vedotin (BV) is a monoclonal antibody combined with monomethyl auristatin E, recently approved for the treatment of refractory CD30+ cutaneous T-cell lymphoma. We report a case of refractory MF in a 56-year-old man with a long history of large-plaque parapsoriasis, as revealed by psoriasiform erythroderma, treated initially with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) polychemotherapy, inducing a 2-year complete response. After relapse, interferon and gemcitabine were unsuccessful. Finally, treatment with BV was decided upon, despite the absence of CD30 expression. After three infusions of BV 1·8 mg kg-1 , we achieved a complete and stable response, allowing an allogeneic stem cell transplant. The patient is still in complete remission, 19 months after the graft. This case illustrates the possibility of using BV in refractory CD30- MF as a salvage therapy.",
"affiliations": "Department of Dermatology, AP-HP Hôpital Saint-Louis, Paris, France.;Department of Dermatology, AP-HP Hôpital Saint-Louis, Paris, France.;Department of Pathology, AP-HP Hôpital Saint-Louis, Paris, France.;Department of Pathology, AP-HP Hôpital Saint-Louis, Paris, France.;Department of Pathology, AP-HP Hôpital Saint-Louis, Paris, France.;Sorbonne Paris Cité Université Paris Diderot, Paris, France.;Department of Dermatology, AP-HP Hôpital Saint-Louis, Paris, France.",
"authors": "Mahévas|T|T|0000-0001-5951-1831;Ram-Wolff|C|C|;Battistella|M|M|;Pennamen|M D V|MDV|;Rivet|J|J|;Brice|P|P|;Bagot|M|M|",
"chemical_list": "D000079963:Brentuximab Vedotin",
"country": "England",
"delete": false,
"doi": "10.1111/bjd.17254",
"fulltext": null,
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"issn_linking": "0007-0963",
"issue": "180(6)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D001706:Biopsy; D000079963:Brentuximab Vedotin; D017024:Chemotherapy, Adjuvant; D019008:Drug Resistance, Neoplasm; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009182:Mycosis Fungoides; D020360:Neoadjuvant Therapy; D009364:Neoplasm Recurrence, Local; D012074:Remission Induction; D012867:Skin; D012878:Skin Neoplasms; D013997:Time Factors; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "1517-1520",
"pmc": null,
"pmid": "30269331",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dramatic response to brentuximab vedotin in refractory nontransformed CD30- mycosis fungoides allowing allogeneic stem cell transplant and long-term complete remission.",
"title_normalized": "dramatic response to brentuximab vedotin in refractory nontransformed cd30 mycosis fungoides allowing allogeneic stem cell transplant and long term complete remission"
} | [
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"companynumb": "FR-MYLANLABS-2019M1062068",
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"activesubstancename": "GEMCITABINE"
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... |
{
"abstract": "Anaphylactic reactions to antigens in the perioperative environment are uncommon, but they have a potential to lead to serious morbidity and/or mortality. The incidence of anaphylactic reactions is 1:37 000 pediatric anesthetics, and substantially less than the 1:10 000 to 1:20 000 incidence in the adult population. Neuromuscular blocking agents, latex, and antibiotics are the most frequently cited triggers. To date, there is no comprehensive report on perioperative anaphylactic reactions in children in the United States. Using the Wake-up Safe database, we examined the incidence and consequences of reported perioperative anaphylaxis events.\n\n\n\nWe reviewed the Wake-up Safe database from 2010 to 2017 and identified all reported instances of anaphylaxis. The triggering agent, timing, and location of the registered event, severity of patient harm, and preventability were identified. Narrative review of free-text comments entered by reporting centers was performed to determine presenting symptoms, and interventions required. Type of case was identified from procedure codes provided in mandatory fields.\n\n\n\nAmong 2 261 749 cases reported to the Wake-up Safe database during the study period, perioperative anaphylactic reactions occurred in 1:36 479 (0.003%). Antibiotics, neuromuscular blocking agents, and opioid analgesics were the main triggers. Forty-nine cases (79%) occurred in the operating room, and 13 cases (21%) occurred in off-site locations. Seven (11%) patients required cardiopulmonary resuscitation following the onset of symptoms. Thirty-five (57%) patients were treated with epinephrine or epinephrine plus other medications, whereas 5% were managed only with phenylephrine. Most cases (97%) required escalation of care after the event. Regarding case preventability, 91% of cases were marked as either \"likely could not have been prevented\" or \"almost certainly could not have been prevented.\"\n\n\n\nThe estimated incidence of anaphylaxis and inciting agents among the pediatric population in this study were consistent with the most recent published studies outside of the United States; however, new findings included need for cardiopulmonary resuscitation in 11% of cases, and estimated fatality of 1.6%. The management of perioperative anaphylaxis could be improved for some cases as epinephrine was not administered, or its administration was delayed. Fewer than half of reported cases had additional investigation to formally identify the responsible agent.",
"affiliations": "Department of Anesthesiology & Pain Medicine, Nationwide Children's Hospital, Columbus, OH, USA.;Department of Anesthesiology & Pain Medicine, Nationwide Children's Hospital, Columbus, OH, USA.;Department of Anesthesiology & Pain Medicine, Nationwide Children's Hospital, Columbus, OH, USA.;Department of Anesthesiology & Pain Medicine, Nationwide Children's Hospital, Columbus, OH, USA.;Department of Anesthesiology & Pain Medicine, Nationwide Children's Hospital, Columbus, OH, USA.;Department of Anesthesiology & Pain Medicine, Nationwide Children's Hospital, Columbus, OH, USA.;Department of Anesthesiology & Pain Medicine, Nationwide Children's Hospital, Columbus, OH, USA.",
"authors": "Wakimoto|Mayuko|M|0000-0002-9248-0085;Miller|Rebecca|R|;Kim|Stephani S|SS|;Uffman|Joshua C|JC|0000-0002-6073-5477;NafiuS|Olubukola O|OO|;Tobias|Joseph D|JD|;Beltran|Ralph J|RJ|",
"chemical_list": "D000777:Anesthetics; D009466:Neuromuscular Blocking Agents",
"country": "France",
"delete": false,
"doi": "10.1111/pan.14063",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1155-5645",
"issue": "31(2)",
"journal": "Paediatric anaesthesia",
"keywords": "anaphylaxis; anesthesia; child; complication; hypersensitivity; quality improvement",
"medline_ta": "Paediatr Anaesth",
"mesh_terms": "D000328:Adult; D000707:Anaphylaxis; D000758:Anesthesia; D000777:Anesthetics; D002648:Child; D004342:Drug Hypersensitivity; D006801:Humans; D009466:Neuromuscular Blocking Agents; D014481:United States",
"nlm_unique_id": "9206575",
"other_id": null,
"pages": "205-212",
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"pmid": "33141983",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Perioperative anaphylaxis in children: A report from the Wake-Up Safe collaborative.",
"title_normalized": "perioperative anaphylaxis in children a report from the wake up safe collaborative"
} | [
{
"companynumb": "US-TEVA-2021-US-1938249",
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"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISATRACURIUM"
},
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... |
{
"abstract": "Spontaneous methicillin-resistant Staphylococcus aureus (MRSA) meningitis is extremely rare and has a high mortality rate. We report a case of MRSA meningitis in an otherwise healthy young adult female with no recent trauma or neurosurgical interventions. Despite antibiotics she suffered a vasculitis-induced cerebral vascular ischemic event.",
"affiliations": "Department of Emergency Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA. Electronic address: William.Longhurst@UHhospitals.org.;Department of Emergency Medicine, University Hospitals Cleveland Medical Center, Cleveland, OH 44106, USA. Electronic address: jsheele@gmail.com.",
"authors": "Longhurst|William D|WD|;Sheele|Johnathan M|JM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D014640:Vancomycin; D001241:Aspirin; D011241:Prednisone; D012293:Rifampin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2018.01.098",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": "36(5)",
"journal": "The American journal of emergency medicine",
"keywords": "Bacterial meningitis; Headache; MRSA; Meningitis; Methicillin-resistant Staphylococcus aureus",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D001241:Aspirin; D002531:Cerebellum; D005260:Female; D006801:Humans; D016920:Meningitis, Bacterial; D055624:Methicillin-Resistant Staphylococcus aureus; D011241:Prednisone; D012293:Rifampin; D012307:Risk Factors; D012720:Severity of Illness Index; D013203:Staphylococcal Infections; D014640:Vancomycin; D055815:Young Adult",
"nlm_unique_id": "8309942",
"other_id": null,
"pages": "909.e1-909.e3",
"pmc": null,
"pmid": "29409664",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous methicillin-resistant Staphylococcus aureus (MRSA) meningitis.",
"title_normalized": "spontaneous methicillin resistant staphylococcus aureus mrsa meningitis"
} | [
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"companynumb": "US-BAYER-2018-097435",
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"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
"drugadditional": null,
... |
{
"abstract": "We describe two young immunocompetent women presenting with bilateral retinitis with outer retinal necrosis involving posterior pole with centrifugal spread and multifocal lesions simulating progressive outer retinal necrosis (PORN) like retinitis. Serology was negative for HIV and CD4 counts were normal; however, both women were on oral steroids at presentation for suspected autoimmune chorioretinitis. The retinitis in both eyes responded well to oral valaciclovir therapy. However, the eye with the more fulminant involvement developed retinal detachment with a loss of vision. Retinal atrophy was seen in the less involved eye with preservation of vision. Through these cases, we aim to describe a unique evolution of PORN-like retinitis in immunocompetent women, which was probably aggravated by a short-term immunosuppression secondary to oral steroids.",
"affiliations": "Department of Ophthalmology, All India Institute of Medical Sciences, New Delhi, Delhi, India.;Department of Ophthalmology, All India Institute of Medical Sciences, New Delhi, Delhi, India.;Department of Ophthalmology, All India Institute of Medical Sciences, New Delhi, Delhi, India.;Department of Ophthalmology, All India Institute of Medical Sciences, New Delhi, Delhi, India.",
"authors": "Chawla|Rohan|R|;Tripathy|Koushik|K|http://orcid.org/0000-0002-9756-128X;Gogia|Varun|V|;Venkatesh|Pradeep|P|",
"chemical_list": "D000998:Antiviral Agents; D013256:Steroids; D014633:Valine; D000077483:Valacyclovir; D000212:Acyclovir",
"country": "England",
"delete": false,
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"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
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"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000212:Acyclovir; D000293:Adolescent; D000998:Antiviral Agents; D002825:Chorioretinitis; D005260:Female; D006801:Humans; D007121:Immunocompetence; D015882:Retinal Necrosis Syndrome, Acute; D013256:Steroids; D041623:Tomography, Optical Coherence; D000077483:Valacyclovir; D014633:Valine; D014777:Virus Diseases; D014786:Vision Disorders; D055815:Young Adult",
"nlm_unique_id": "101526291",
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"pmid": "27511757",
"pubdate": "2016-08-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8172275;20089700;24926266;9002130;2220967;708676;23575983;26472486;8116760;1651054;8090452;6303386;9455742;15657772",
"title": "Progressive outer retinal necrosis-like retinitis in immunocompetent hosts.",
"title_normalized": "progressive outer retinal necrosis like retinitis in immunocompetent hosts"
} | [
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"companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-124149",
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"abstract": "Drug-drug interactions (DDIs) are of great concern in the treatment of cancer, especially when target therapies, such as tyrosine kinase inhibitors, are being used. Here, we report a case of probable DDI between erlotinib and amiodarone leading to severe neurotoxicity. Amiodarone inhibits P-glycoprotein (P-gp), for which erlotinib is a substrate. P-gp is an important drug transporter that is involved in limiting the blood-brain barrier penetration of erlotinib. Clinicians should be aware of emerging data characterizing the effect of the P-gp transport system on drug exposure and its potential for DDI.",
"affiliations": "Department of Pharmacy.;Department of Pharmacy.;Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital.;Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital.;Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital.;Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital.;Department of Pharmacy.;Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital.;Department of Medical Oncology, Catalan Institute of Oncology, Doctor Josep Trueta University Hospital.",
"authors": "López Brunsó|Maria|M|;Toro Blanch|Cristina|C|;Sais Girona|Elia|E|;Roa García|Diana|D|;Hernández Martínez|Alejandro|A|;Izquierdo Font|Angel|A|;Guerra Prió|Silvia|S|;Mas Pueyo|Huber Gunter|HG|;Bosch-Barrera|Joaquim|J|",
"chemical_list": "D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000069347:Erlotinib Hydrochloride; D000638:Amiodarone",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000600",
"fulltext": null,
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"issn_linking": "0959-4973",
"issue": "29(4)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000638:Amiodarone; D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D018450:Disease Progression; D004347:Drug Interactions; D000069347:Erlotinib Hydrochloride; D006801:Humans; D060828:Induction Chemotherapy; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010243:Paralysis; D011878:Radiotherapy; D028761:Withholding Treatment",
"nlm_unique_id": "9100823",
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"pages": "380-383",
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"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Probable drug-drug interaction between erlotinib and amiodarone causes severe neurotoxicity in a patient with advanced lung cancer.",
"title_normalized": "probable drug drug interaction between erlotinib and amiodarone causes severe neurotoxicity in a patient with advanced lung cancer"
} | [
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"companynumb": "ES-MYLANLABS-2018M1038240",
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"abstract": "Immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte-associated antigen-4 and anti-programmed death-1, are a type of cancer immunotherapy approved for late-stage malignancy treatment. However, such therapies often induce immune-related adverse events. During anti-programmed death-1 blockade therapy, the most commonly reported adverse effects are skin toxicities, such as psoriasis-a chronic immune-mediated inflammatory disorder affecting the skin. We present the clinical characteristics of flared psoriasis in one patient under anti-programmed death-1 therapy who was diagnosed with T2N2M0/IIIB squamous lung carcinoma with a history of psoriasis for the past 5 years, exacerbated after the first cycle of nivolumab. After the third cycle, the extensive skin plaques necessitated treatment cessation. Following the discontinuation of anti-programmed death-1 treatment, skin lesions were treated locally. Possibly, anti-programmed death-1 immunotherapy can trigger immune-mediated diseases, such as psoriasis. Physicians should be alert to immune-related adverse events. Continuation or permanent cessation of treatment depends on the severity and reversibility of immune-related adverse events.",
"affiliations": "Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.;Department of Obstetrics and Gynecology, Ioannina University Hospital, Ioannina, Greece.;Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.;Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.;Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece.",
"authors": "Politi|Anastasia|A|;Angelos|Dimas|D|;Mauri|Davide|D|;Zarkavelis|George|G|;Pentheroudakis|George|G|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/2050313X19897707",
"fulltext": "\n==== Front\nSAGE Open Med Case RepSAGE Open Med Case RepSCOspscoSAGE Open Medical Case Reports2050-313XSAGE Publications Sage UK: London, England 10.1177/2050313X1989770710.1177_2050313X19897707JCMS Case ReportA case report of psoriasis flare following immunotherapy: Report of an important entity and literature review Politi Anastasia 12Angelos Dimas 3Mauri Davide 12Zarkavelis George 12Pentheroudakis George 121 Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece2 Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece3 Department of Obstetrics and Gynecology, Ioannina University Hospital, Ioannina, GreeceGeorge Pentheroudakis, Department of Medical Oncology, Medical School, University of Ioannina, Stavros Niarchos Avenue, 45110 Ioannina, Greece. Email: oncolsec@cc.uoi.gr13 1 2020 2020 8 2050313X19897707© 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 pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Immune checkpoint inhibitors, such as anti-cytotoxic T-lymphocyte–associated antigen-4 and anti-programmed death-1, are a type of cancer immunotherapy approved for late-stage malignancy treatment. However, such therapies often induce immune-related adverse events. During anti-programmed death-1 blockade therapy, the most commonly reported adverse effects are skin toxicities, such as psoriasis—a chronic immune-mediated inflammatory disorder affecting the skin. We present the clinical characteristics of flared psoriasis in one patient under anti-programmed death-1 therapy who was diagnosed with T2N2M0/IIIB squamous lung carcinoma with a history of psoriasis for the past 5 years, exacerbated after the first cycle of nivolumab. After the third cycle, the extensive skin plaques necessitated treatment cessation. Following the discontinuation of anti-programmed death-1 treatment, skin lesions were treated locally. Possibly, anti-programmed death-1 immunotherapy can trigger immune-mediated diseases, such as psoriasis. Physicians should be alert to immune-related adverse events. Continuation or permanent cessation of treatment depends on the severity and reversibility of immune-related adverse events.\n\nPsoriasisimmune checkpoint inhibitorslung cancernivolumabcover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nPsoriasis is a common, chronic, immune-mediated, inflammatory disorder affecting the skin, nails and joints in both children and adults. The skin disorder is estimated to affect 2.0%–3.5% of the global population.1 It affects both genders and has a bimodal peak of onset. Onset can peak at 20–30 years and 50–60 years of age. The disease is generally thought to be agenetic and triggered by environmental factors—such as trauma, infections, medicines, metabolic/hormonal factors, stress, sun exposure, alcohol use and smoking—and leads to immunological response, psoriasis vulgaris or chronic plaque psoriasis being the most common types.2 Other types include guttatepsoriasis, erythrodermic psoriasis and pustular psoriasis. Depending on the affected body part, psoriasis is further categorized in scalp psoriasis, flexular/inverse psoriasis, nail psoriasis, palmoplantar psoriasis, psoriasis of mucus membranes/genitals and psoriatic arthritis.2 It is also associated with a plethora of extracutaneous comorbidities such as Crohn’s disease, diabetes mellitus type II, obesity, metabolic syndrome, depression and other inflammatory manifestations of the eyes.2 Psoriatic skin lesions are characterized by well-defined erythematousscaly plaques, and tend to have a chronic relapsing and remitting course.1 Severity ranges from a few scattered plaques to involvement of almost the entire body surface.1 Many severity scores have been suggested, to assess the severity of psoriasis, such as the Psoriasis Area and Severity Index (PASI), Dermatology Life Quality Index (DLQI), Body Surface Area (BSA) and Physician Global Assesment (PGA) index (Table 1).2 Treatment of psoriasis is individualized depending on the affected body area, severity of disease and other patient specific features and may be local, systemic treatment or phototherapy.2\n\nTable 1. Management strategies by skin toxicity grade.\n\nSymptom grade\tManagement escalation pathway\t\nGrade 1: Skin rash, with or without symptoms <10% BSA\tAvoid skin irritants, avoid sun exposure, topical emollients recommended.\nTopical steroids (mild strength) cream od ± oral or topical antihistamines for itch.\nProceed with treatment.\t\nGrade 2: Rash covers 10%–30% of BSA\tSupportive management, as mentioned above.\nTopical steroids (moderate strength), cream od or (potent) cream bd ± oral or topical antihistamines for itch.\nProceed with ICPi treatment.\t\nGrade 3: Rash covers >30% of BSA or Grade 2 with substantial symptoms\tWithhold ICPi.\nTopical treatments as mentioned above (potent).\nInitiate steroids: if mild to moderate 0.5–1 mg/kg prednisolone.\nOd for 3 days then wean over 1–2 weeks; or if severe IV (methyl)prednisolone.\n0.5–1 mg/kg and convert to oral steroids on response, wean over 2–4 weeks.\nRecommence ICPi at G1/mild G2 after discussion with patient and consultant.\t\nGrade 4: Skin sloughing >30% of BSA with associated symptoms (e.g. erythema, purpura, epidermal detachment)\tIV (methyl)prednisolone 1–2 mg/kg.\nSeek urgent dermatology review.\nDiscontinue ICPi treatment.\t\nBSA: body surface area.\n\nImmunotherapy is a type of targeted therapy against cancer,3 which boosts the body’s immune response against cancerous cells. There are several types of immunotherapy, including monoclonal antibodies (mAbs), non-specific immunotherapies, oncolytic virus therapy, T-cell therapy and cancer vaccines.4 During the past 20 years, breakthroughs in our understanding of the regulation of T-cell immune response against pathogens or abnormal (cancerous) cells paved the way for development of mAbs that modulate T-cell activity by inhibiting “brake” receptors on the lymphocytic surface. These receptors are now designated as immune checkpoints, such as programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) and cytotoxic T-lymphocyte–associated antigen-4 (CTLA-4).4 Checkpoint inhibitors such as nivolumab or pembrolizumab prevent the binding between T-cell inhibitory receptor PD-1 and its ligands (PD-L1, PD-L2) on the surface of tumor cells, thereby preventing T-cell anergy and unlocking the full activity of the T-cell against the tumor. It has been shown that these immune checkpoint inhibitors (ICOs) can provide durable, long-term survival benefits in patients with a variety of metastatic solid tumors with a manageable toxicity profile, distinct from that of cytotoxic chemotherapy. Generally, adverse effects (AEs) may occur early or late during therapy (within 1 week–3 months after treatment initiation), but the first onset of AEs has been reported as late as 1 year from completion of therapy. These side-effects are generally autoimmune, as a result of excessive T-cell activation and injury of normal tissues. Action should be taken to diagnose early immune-related adverse events (IrAEs), prevent further aggravation and initiate immediate steroid-based therapy. In all but the mildest cases, immunotherapy should be discontinued immediately, and immunosuppressive or immune modulating drugs initiated promptly.5\n\nCase presentation\nA 71-year-old woman with a 40-pack-year smoking history was referred to the emergency department with fever. Her medical history included psoriasis for the past 5 years, psoriatic arthritis for the past 3 years, coronary artery disease and chronic obstructive pulmonary disease. No further symptoms were reported. The patient underwent chest X-ray which detected a mass opacity in the right lung. Further investigations with a chest computed tomography (CT) showed a subpleural mass at the peripheral part of the right middle lobe with lobular margins and irregular enhancement with a maximum diameter of 4.0 cm (Figure 1).\n\nFigure 1. CT initial presentation.\n\nNo additional abnormalities were observed on subsequent detailed metastatic work-up including abdominal and brain CT. A positron emission tomography–computed tomography (PET/CT) revealed high uptake of 18F-fluoro-2-deoxy-d-glucose (FDG) of the subpleural right middle lung lobe mass (standardized uptake value (SUV) = 22.0), of the mediastinal paratracheal lymph nodes (SUV = 3.6), of the subcarinal lymph nodes (SUV = 7.4) and of the right hilar lymph nodes (SUV = 4), suggesting clinical stage T2N2M0/IIIB. Guided biopsy was diagnostic of a high grade squamous lung carcinoma, with positive immune histochemical staining of p40 and lack of expression of TTF-1. The patient subsequently underwent simultaneous chemotherapy with cisplatin 40 mg/m2 i.v. weekly and external beam radiotherapy (RT) to a total dose of 5.600 cGy in 2 months. Two months later, CT staging indicated disease progression in the right middle lobe primary and mediastinum (Figures 2 and 3).\n\nFigure 2. CT after external beam radiotherapy.\n\nFigure 3. CT demonstrating disease progression after chemotherapy.\n\nFollowing a brief exposure to gemcitabine/carboplatin chemotherapy for two cycles and further disease progression, immunotherapy with nivolumab i.v. 3 mg/kg was commenced. Although nivolumab therapy induced psoriatic exanthema with a 2.4 PASI score in the previously asymptomatic patient, treatment was continued for another two cycles (one cycle per 15 days). Hence, the psoriatic exanthema was exacerbated with plaques in the extremities and the trunk with a 41.6 PASI score (Figure 4).\n\nFigure 4. Eruption of psoriasis-skin rashes: (a) trunk, (b) abdomen, (c) thigh, (d) legs and (e) toes.\n\nDue to the exacerbation of psoriatic lesions which coincided with the start of nivolumab treatment, the dermatologist advised an immediate discontinuation of the anti-PD-1 treatment and the local treatment of skin lesions with moisturizing cream (eucerin), mometasone cream, acitretin and psoralen photochemotherapy (PUVA) with p.o. methoxsalen leading to visible clinical improvement of the exanthema (Figure 5) and a 2.7 PASI score.\n\nFigure 5. Recession of proriasis after treatment with steroids: (a) abdomen and (b) trunk.\n\nDiscussion\nImmunotherapy is a new type of targeted therapy aiming at bypassing tumor-induced T-cell anergy/apoptosis, thereby restoring the activity of cytotoxic CD8 + T-lymphocytes against malignant cells that can be recognized as abnormal by the host. Over recent years, it has been licensed for patients with many malignant diseases such as lung, bladder and head and neck cancer. However, immunotherapy may induce a state of immune hyper-reactivity through the relaxation of negative control loops tightly regulating T-helper and T-cytotoxic cells, thereby causing immune-related side-effects (IrAEs), including exacerbation of pre-existing autoimmune diseases. Psoriasis, having an autoimmune aspect, can be triggered during immunotherapy, either as a new case or as worsening of an already known disease. According to the literature, nine similar cases have been reported. In those cases, patients were forced to discontinue immunotherapy because of psoriasis onset (Table 2).\n\nTable 2. Published literature on immunotherapy-induced psoriasis.\n\nAuthor, year of publication\tAge at diagnosis (years) and sex\tPersonal history of psoriasis\tFamily history of psoriasis\tCancer\tImmunotherapy\tTemporal relation of immunotherapy and eruption of psoriasis\tTreatment of psoriasis\t\nSarah Law-Ping-Man Gilles Saffa (2016)6\t80 (M)\t(−)\t(−)\tNSCLC\tNivolumab\tAfter 8 cycles\tTopical steroids, oral MTX (long/week), oral prednisolone—improvement\t\nVoudouri (2017)7\t64 (F)\t(+)\t(−)\tNSCLC\tDurvalumab\tAfter 2 cycles\tUVB-NB—improvement\t\nVoudouri (2017)\t64 (M)\t(−)\t(+)\tNSCLC\tNivolumab\tAfter 6 cycles\tTopical steroids—improvement\t\nVoudouri (2017)\t72 (M)\t(−)\t(+)\tNSCLC\tNivolumab\tAfter 1 cycle\tTopical steroids, oral MTX—improvement\t\nNatsuko Matsomura (2016)8\t87 (M)\t(+)\t(−)\tMetastatic melanoma\tNivolumab\tAfter 2 cycles\tOral prednisolone—improvement\t\nVoudouri (2017)\t60 (M)\t(+)\t(−)\tPapillary urothelial Carcinoma\tDurvalumab\tAfter 1 cycle\tUVB-NB—improvement\t\nVoudouri (2017)\t69 (M)\t(−)\t(−)\tSquamous cell carcinoma of tonsil\tPembrolizumab\tAfter 6 cycles\tUVB-NB—improvement\t\nNaoko Okiyama (2017)9\t80 (M)\t–\t–\tMetastatic melanoma\tNivolumab\tAfter 4 cycles\t–\t\nNaoko Okiyama (2017)\t77 (M)\t–\t–\tMetastatic melanoma\tNivolumab\tAfter 11 cycles\t–\t\nNSCLC: non-small-cell lung carcinoma; MTX: methotrexate; UVB-NB: ultraviolet-B narrow-band; M: male; F: female.\n\nHowever, the possibility to re-institute immunotherapy, especially in those cases where cutaneous IrAEs are controlled using corticosteroids or immunosuppressive agents and in the presence of anti-tumor activity, should be explored with caution.\n\nThe reported skin adverse events include: (1) most common: erythema, maculopapular and pustulopapular rash; (2) rare: toxic epidermal necrolysis, Steven–Johnson syndrome and DRESS (drug rash with eosinophilia and systemic symptoms) and (3) vasculitis may also be present with purpuric rash.\n\nPhysicians who administer ICOs, especially in patients with a positive history of autoimmune disorders including psoriasis, should be aware of, and familiar with timely diagnosis and management of IrAEs. A careful pre-immunotherapy work-up on the extent and activity of psoriasis, particularly to exclude a bone involvement (psoriatic arthritis), should be sought. Moreover, it is obvious that in such cases, more guidance is needed to decide—in collaboration with the dermatologists—the most appropriate course of action on whether the anti-PD-1 treatment should be halted or not with the concurrent treatment of skin lesions, on the type of psoriasis treatment that should be commenced and so on. Depending on the reversibility of the complications, physicians could opt either to permanently discontinue immunotherapy or to reinstate it, provided control of cutaneous IrAEs is achieved and taking into consideration existing options for alternative antineoplastic therapies.10\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient prior to publication.\n==== Refs\nReferences\n1 \nBronckers IMGJ Paller AS van Geel MJ van de Kerkhof PCM , et al\nPsoriasis in children and adolescents: diagnosis, management and comorbidities . Paediatr Drugs \n2015 ; 17 : 373 –384 .26072040 \n2 \nAntoniou C Katsampas A. \nDermatology and venereology . 1st ed \nNicosia, Cyprus : Broken Hill , 2015 .\n3 \nKlener P JrOtáhal P Lateckova L , et al\nImmunotherapy approaches in cancer treatment . Curr Pharm Biotechnol \n2015 ; 16 : 771 –781 , https://www.ncbi.nlm.nih.gov/pubmed/2608799026087990 \n4 \nVentola CL. \nCancer immunotherapy, part 1: current strategies and agents . P T \n2017 ; 42 : 375 –383 , https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5440098/28579724 \n5 \nESMO . Toxicity associated with cancer immunotherapy . ESMO , 7 \n12 \n2017 , www.esmo.org/Conferences/Past-Conferences/ESMO-Immuno-Oncology-Congress-2017/Educational-Articles/Toxicity-Associated-with-Cancer-Immunotherapy\n6 \nLaw-Ping-Man S Martin A Briens E , et al\nPsoriasis and psoriatic arthritis induced by Nivolumab in a patient with advanced lung cancer . Rheumatology (Oxford, England) \n2016 \n11 ; 55 (11 ): 2087 –2089 . 10.1093/rheumatology/kew281 \n7 \nVoudouri D Nikolaou V Laschos K , et al\nAnti-PD1/PDL1 induced psoriasis . Curr Probl Cancer \n2017 \n12 ; 41 (6 ): 407 –412 . 10.1016/j.currproblcancer.2017.10.003 29096940 \n8 \nMatsumura N Ohtsuka M Kikuchi N , et al\nExacerbation of psoriasis during Nivolumab therapy for metastatic melanoma . Acta Dermato-Venereologica \n2016 \n2 ; 96 (2 ): 259 –560 . 10.2340/00015555-2212 26270860 \n9 \nOkiyama N Tanaka R \nVaried immuno-related adverse events induced by immune-check point inhibitors - Nivolumab-associated psoriasiform dermatitis related with increased serum level of interleukin-6 . Nihon Rinsho Men’eki Gakkai Kaishi = Japanese Journal of Clinical Immunology \n2017 ; 40 (2 ): 95 –101 . 10.2177/jsci.40.95 28603207 \n10 \nHaanen JBAG Carbonnel F Robert C , et al\nManagement of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol \n2017 ; 28 (Suppl. 4 ): iv119–iv142.\n\n",
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"issn_linking": "2050-313X",
"issue": "8()",
"journal": "SAGE open medical case reports",
"keywords": "Psoriasis; immune checkpoint inhibitors; lung cancer; nivolumab",
"medline_ta": "SAGE Open Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101638686",
"other_id": null,
"pages": "2050313X19897707",
"pmc": null,
"pmid": "31976071",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26087990;29096940;26270860;28603207;26072040;28579724;27436004;28881921",
"title": "A case report of psoriasis flare following immunotherapy: Report of an important entity and literature review.",
"title_normalized": "a case report of psoriasis flare following immunotherapy report of an important entity and literature review"
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"companynumb": "GR-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-008928",
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"abstract": "Aim: Describe the characteristics of providers ordering, patients receiving, and clinical impact of a psychotropic pharmacogenetic test on veteran care. Patients & methods: Observational cohort study linking veterans' laboratory results to electronic health record data. Changes in psychotropic medication prescribing were measured as a function of test results. Results: A total of 38 providers tested 181 veterans between 10/6/2014 and 2/1/2018. Prescriptions for medications with severe gene-drug interactions decreased; however, 11 such medications were used after testing. For 43 patients, documentation of the results was missing. Conclusion: Most prescribing decisions were congruent with test results, but in a nontrivial number of cases, prescribers appeared not to act on the results. Poor result documentation impeded the potential of results to inform clinical care.",
"affiliations": "VA Boston Healthcare System, Boston, MA 02130, USA.;VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT 84148, USA.;Corporal Michael J Crescenz VA Medical Center, Philadelphia, PA 19104, USA.;Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA 01730, USA.;VA Boston Healthcare System, Boston, MA 02130, USA.;Corporal Michael J Crescenz VA Medical Center, Philadelphia, PA 19104, USA.;Central Arkansas Veterans Healthcare System, Little Rock, AR 72205, USA.;VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System, Salt Lake City, UT 84148, USA.;Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA 01730, USA.",
"authors": "Hull|Leland E|LE|0000-0002-5736-6543;Chanfreau-Coffinier|Catherine|C|;Tuteja|Sony|S|;Berlowitz|Dan|D|;Lehmann|Lisa S|LS|;Oslin|David W|DW|;Pyne|Jeffrey M|JM|;DuVall|Scott L|SL|;Lynch|Julie A|JA|",
"chemical_list": "D011619:Psychotropic Drugs",
"country": "England",
"delete": false,
"doi": "10.2217/pgs-2019-0065",
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"issn_linking": "1462-2416",
"issue": "20(11)",
"journal": "Pharmacogenomics",
"keywords": "pharmacogenetic testing; psychotropic medications; veterans",
"medline_ta": "Pharmacogenomics",
"mesh_terms": "D000328:Adult; D000368:Aged; D015331:Cohort Studies; D004347:Drug Interactions; D011307:Drug Prescriptions; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D000071185:Pharmacogenomic Testing; D011618:Psychotic Disorders; D011619:Psychotropic Drugs; D014728:Veterans",
"nlm_unique_id": "100897350",
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"pages": "781-789",
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"pmid": "31393222",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Early adoption of pharmacogenetic testing for veterans prescribed psychotropic medications.",
"title_normalized": "early adoption of pharmacogenetic testing for veterans prescribed psychotropic medications"
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"abstract": "Advanced squamous cell lung cancer used to have universally dismal long-term outcomes before the use of immune checkpoint inhibitors (ICIs). Due to the expanding role of ICIs, there has been an increasing number of long-term survivors in this relatively large group of patients. ICIs such as anti-cytotoxic T-lymphocyte-associated protein 4 and anti-programmed cell death protein 1/programmed death-ligand 1 monoclonal antibodies increase the T-cell activation and limit the tumor capacity to escape the adaptive immune response. However, efficacy comes along with unique immune-related adverse events. We present an unusual case of cutaneous sarcoidosis in a 63-year-old white female who was diagnosed with stage IV squamous cell lung cancer developed skin manifestations 3 months after started chemo/pembrolizumab. Sarcoidosis was confirmed by skin punch biopsy and resolved after a short course of systemic glucocorticoid while maintained on pembrolizumab with lower frequency. These sarcoid-like lesions associated with the blockage of programmed death receptor-1 have been increasingly described in many different malignancies especially in melanoma. There is a need for further investigation to the characterization of the population prone to this immune-related adverse events.",
"affiliations": "University of Miami Miller School of Medicine/Holy Cross Hospital.;Department of Dermatology, Dermatology Consultants of South Florida, Coral Springs, FL.;Department of Hematology Oncology, Holy Cross Medical Group, Fort Lauderdale.",
"authors": "Trilleras-Gomez|Angelica P|AP|;Hull|Kimberly J|KJ|;Drew|David Z|DZ|",
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"issue": "44(2)",
"journal": "Journal of immunotherapy (Hagerstown, Md. : 1997)",
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"medline_ta": "J Immunother",
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"pages": "90-94",
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"pmid": "33298795",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
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"title": "Case Report and Review of 7 Similar Cases in the Literature: Cutaneous Sarcoidosis as Side Effect of Pembrolizumab Plus Chemotherapy in Stage IV Squamous Cell Carcinoma of Lung.",
"title_normalized": "case report and review of 7 similar cases in the literature cutaneous sarcoidosis as side effect of pembrolizumab plus chemotherapy in stage iv squamous cell carcinoma of lung"
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"abstract": "Drug-induced lupus erythematosus has features distinct from primary systemic lupus erythematosus. It can occur with a wide variety of agents that result in the generation of anti-histone or other types of antibodies. Systemic manifestations of drug-induced systemic lupus erythematosus may include renal dysfunction due to circulating immune complexes or due to other immune reactions to the culprit medication(s). Acute interstitial nephritis occurs due to DNA-drug or protein-drug complexes that trigger an allergic immune response. We report a patient who developed acute kidney injury, rash, and drug-induced systemic lupus diagnosed by serologies after starting chlorthalidone and amiodarone. A renal biopsy showed acute interstitial nephritis and not lupus-induced glomerulonephritis. It is important to note that systemic lupus erythematosus and acute interstitial nephritis can occur together, and this report highlights the role of the kidney biopsy in ascertaining the pathological diagnosis and outlining therapy in drug-induced lupus erythematosus.",
"affiliations": "Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Renal Pathology Division, Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.;Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.;Division of Nephrology, Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.",
"authors": "Selamet|Umut|U|;Hanna|Ramy M|RM|https://orcid.org/0000-0003-1807-8909;Sisk|Anthony|A|;Abdelnour|Lama|L|;Ghobry|Lena|L|;Kurtz|Ira|I|",
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"doi": "10.1177/2050313X20910029",
"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\n10.1177/2050313X20910029\n10.1177_2050313X20910029\nCase Report\nAcute interstitial nephritis and drug-induced systemic lupus\nerythematosus due to chlorthalidone and amiodarone: A case\nreport\nSelamet Umut 1 https://orcid.org/0000-0003-1807-8909Hanna Ramy M 12 Sisk Anthony 3 Abdelnour Lama 1 Ghobry Lena 4 Kurtz Ira 15 1 Division of Nephrology, Department of\nMedicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA\n2 Division of Nephrology, Department of\nMedicine, UCI Medical Center, Orange, CA, USA\n3 Renal Pathology Division, Department of\nPathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los\nAngeles, CA, USA\n4 Graduate School of Public Health,\nUniversity of Pittsburgh, Pittsburgh, PA, USA\n5 Brain Research Institute, University of\nCalifornia, Los Angeles, CA, USA\nRamy M Hanna, Division of Nephrology,\nDepartment of Medicine, David Geffen School of Medicine at UCLA, Room 7-155,\nFactor Bldg. 700 Tiverton Ave., Los Angeles, CA 90095, USA. Emails:\nrhannamd81@yahoo.com; ramyh1@uci.edu\n1 3 2020 \n2020 \n8 2050313X2091002915 5 2019 30 1 2020 © The Author(s) 20202020SAGE PublicationsThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Drug-induced lupus erythematosus has features distinct from primary systemic\nlupus erythematosus. It can occur with a wide variety of agents that result in\nthe generation of anti-histone or other types of antibodies. Systemic\nmanifestations of drug-induced systemic lupus erythematosus may include renal\ndysfunction due to circulating immune complexes or due to other immune reactions\nto the culprit medication(s). Acute interstitial nephritis occurs due to\nDNA–drug or protein–drug complexes that trigger an allergic immune response. We\nreport a patient who developed acute kidney injury, rash, and drug-induced\nsystemic lupus diagnosed by serologies after starting chlorthalidone and\namiodarone. A renal biopsy showed acute interstitial nephritis and not\nlupus-induced glomerulonephritis. It is important to note that systemic lupus\nerythematosus and acute interstitial nephritis can occur together, and this\nreport highlights the role of the kidney biopsy in ascertaining the pathological\ndiagnosis and outlining therapy in drug-induced lupus erythematosus.\n\nDrug-induced lupus erythematosussystemic lupus erythematosusamiodaronechlorthalidoneacute interstitial nephritisproteinuriaglomerular diseaseFoundation for the National Institutes of\nHealthhttps://doi.org/10.13039/100000009R01-DK077162cover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nDrug-induced lupus erythematosus (DILE) is marked by the development of immunological\nand dermatological manifestations after the initiation of one or more medications’\nWhile hydralazine and anti-histone antibodies are the best-known examples, other\ndrugs have been known to cause a lupus-like reaction.1,2 Anti-histone antibodies are\nclassically associated with DILE, but can also be seen in systemic lupus\nerythematosus (SLE).3 DILE usually involves skin and joint manifestations. Renal manifestations due\nto the presence of drug–protein immune complexes circulating in the blood are possible.4 While medications can cause acute interstitial nephritis (AIN) as an adverse\nreaction, it is not the expected renal lesion in DILE. Ascertaining the causality of\nthe renal injury can be challenging using mere serology and urinary sediment.\n\nSome common agents that more commonly cause DILE are hydralazine, procainamide, and\nquinidine, and they do so by inducing anti-nuclear antibodies (ANAs) as well as\nanti-histone antibodies.1 A more extensive list of agents, including diuretics and drugs with sulfa\nmoieties, is associated with positive ANAs but generally do not cause SLE.2 Amiodarone has been reported to cause a lupus-like syndrome and, in other\ncases, has demonstrated features typical of DILE.5,6\n\nWe report a case of a 69-year-old woman who was started on amiodarone for atrial\nfibrillation and chlorthalidone for hypertension. The patient developed acute kidney\ninjury (AKI) and a simultaneous drug rash. Workup revealed positive ANAs and\nanti-histone antibodies. The patient had improvement in renal function with the\nwithdrawal of both chlorthalidone and amiodarone and remission of the drug-related\nexanthem.\n\nCase report\nA 69-year-old Caucasian woman with a past medical history of type 2 diabetes\nmellitus, resistant hypertension, diastolic congestive heart failure with preserved\nejection fraction. She had pulmonary nodules incidentally noted on chest\nradiography, and workup of these ruled out malignancy, granulomatous disease,\ntuberculosis, and fungal infection as possible etiologies. The patient was diagnosed\nwith sick sinus syndrome, and underwent pacemaker placement 5 years prior to her\npresentation to our center. She was diagnosed with recurrent atrial fibrillation\nwith rapid ventricular response 3 months prior to presenting to nephrology. She was\nstarted on amiodarone therapy for atrial fibrillation as well as chlorthalidone for\nhypertension.\n\nShe presented to nephrology clinic with AKI, and her serum creatinine was 3.88 mg/dL,\nwhich was elevated from her baseline level of 1.2–1.7 mg/dL. Her medication history\nincluded apixaban, atorvastatin, cholecalciferol, clonidine, fexofenadine, glargine\ninsulin, labetalol, latanoprost eye drops, and nifedipine. She was also on topical\ntriamcinolone for a new skin rash that developed 3 months after the initiation of\nchlorthalidone and amiodarone.\n\nThree months after starting the aforementioned medications, the patient reported the\ndevelopment of a rash on her chest, arms, and legs. The patient had a prior rash\nwith hydrochlorothiazide, and she reacted similarly to chlorthalidone. Her\ncreatinine rose to a peak of 3.88 mg/dL 11 weeks after the initiation of amiodarone\nand chlorthalidone. She had moderate proteinuria of 0.4–0.6 g protein/g creatinine\nat baseline, and the level of proteinuria did not change from baseline after\ninitiation of chlorthalidone and amiodarone.\n\nLiver function tests were checked on presentation to nephrology: alanine transaminase\n(ALT) 22 units/L, aspartate transaminase (AST) levels 25 units/L, total bilirubin\nlevels (Tbilli) 0.4 mg/dL, and alkaline phosphatase (ALP) at 67 units/L. Thyroid\nfunction tests were also checked and showed a mild elevation in thyroid-stimulating\nhormone (TSH) to 8.1 mcIU (microinternational unit)/L, with free T3 at 283 pg/dL and\nfree T4 at 1.6 ng/dL. Free T3 and free T4 were within normal limits, and this\npattern suggests subclinical hypothyroidism. Blood pressures had improved from\n159/66 mmHg at the time of drug initiation to 120–140/80 mmHg 3 months after\namiodarone and chlorthalidone initiation.\n\nA serological workup was sent given the rise in serum creatinine and demonstrated a\n1:160 homogeneous ANA (reference range <1:40 titer). Anti-double-stranded DNA\nantibody (anti dsDNA) was measured at 874 IU (international unit)/mL (reference\nrange <1:200 IU/L). Anti-histone antibody was confirmed to be positive at 2 units\n(reference range = 0–0.9 units). An anti-smooth muscle antibody was also positive at\n1:160 titer (reference range titer 0). The rest of the workup was negative,\nincluding anti-ribonucleic protein (RNP), anti-smith, anti-Sjogren’s serologies (SSA\nand SB), rheumatoid factor, scleroderma antibodies, Jo1 antibody, anti-citrullinated\nprotein antibody (anti-CCP), thyroid peroxidase, and anti-neutrophil cytoplasmic\nantibodies (ANCAs). Cardiolipin IgG was noted to be positive at borderline level,\n16 GPL (reference range <15 GPL).\n\nThe patient’s known proteinuria and albuminuria attributed to diabetic nephropathy\nremained less than 1 g of protein/g of creatinine (0.6–0.8 g/g). Besides\nproteinuria, urinary sediment showed a slight increase in hematuria (1→9 red blood\ncells) and pyuria (4→13 white blood cells) over the time period of 11 weeks between\ndrug initiation and the patient’s presentation to nephrology clinic. Urinary\neosinophils were negative, and there was no evidence of peripheral eosinophilia.\nGiven worsening AKI and persistent skin rash, a skin biopsy and a kidney biopsy were\nordered.\n\nThe skin biopsy showed interface/lichenoid dermatitis and a lymphocyte-predominant\ninfiltrate with eosinophils. There were no infectious organisms, and the colloidal\niron and alcian special blue stains showed only minimal mucin accumulation. The\ninterpretation was a lichenoid, lichen planus-like or lupus-like drug-related\neruption and DILE being in the histologic differential diagnosis.\n\nThe patient had a kidney biopsy 13 weeks after drug initiation and 1 week after\npresentation to nephrology clinic with AKI. The biopsy yielded two cores of renal\nparenchyma with at least 17 glomeruli; six of which were obsolescent. The remaining\nglomeruli were enlarged with normal cellularity. Glomeruli had smooth single\ncontoured basement membranes. One glomerulus showed a segment of sclerosis. The\ntubulointerstitium had patchy scarring involving about 20% of the cortex with\ninterstitial fibrosis and tubular atrophy. There was a mild infiltrate of\nmononuclear cells in the areas of scar formation. There was focal mild interstitial\ninflammation in areas of early scar formation with some edema and associated\ntubulitis. Eosinophils were seen in these areas as well as scattered throughout the\ninterstitium.\n\nImmunofluorescence staining was reported as negative. The specimen for electron\nmicroscopy showed one glomerulus with segmental sclerosis but no deposits. Podocytes\nhad mild to moderate patchy foot processes effacement involving about 50% of the\nsurface areas. Basement membranes were mildly thickened and segmentally wrinkled.\nOverall, the renal biopsy disclosed acute interstitial nephritis with eosinophils,\nsuggestive of a hypersensitivity reaction, secondary focal and segmental\nglomerulosclerosis (FSGS), thickened glomerular basement membrane suggestive of\nearly diabetic nephropathy, and acute tubular necrosis (ATN) with mild interstitial\nfibrosis. See Figure 1 for\nrenal biopsy findings.\n\nFigure 1. Renal biopsy findings showing acute interstitial nephritis: (a) Proximal\ntubules are irregularly attenuated with loss of brush border staining.\nPeriodic acid-Schiff stain, 100× magnification. Black arrow: acute tubular\nnecrosis; (b) low-power magnification slide showing lymphocyte-predominant\ninterstitial infiltrate. Hematoxylin and eosin stain, 10×. Black arrow:\ngroup of lymphocytes; and (c) tubules are spaced apart by interstitial\ninflammation with clusters of eosinophils and edema. Hematoxylin and eosin,\n400× magnification. Red arrow: group of eosinophils.\n\nThe patient was advised to stop amiodarone and chlorthalidone, the two new drugs\nintroduced proximal to the event of AKI. Her serum creatinine dropped from a peak of\n3.88–2.91 mg/dL, and it continued to trend down until it returned to 2.24 mg/dL\n6 weeks after the renal biopsy. The estimated glomerular filtration rate (eGFR) had\noverall improved from 13 to 25 mL/min (from stage V to stage IIIb-IV by Kidney\nDisease Improving Global Outcomes (KDIGO) chronic kidney disease (CKD) staging). The\nproteinuria remained <1 g/g as before (0.8 g protein/g creatinine), similar to\nbaseline levels of proteinuria thought to be due to coexisting diabetic nephropathy.\nThere were no changes noted in the urinary sediment findings of mild pyuria and\nhematuria. The drug rash also resolved after cessation of amiodarone and\nchlorthalidone. There was no renal replacement therapy used during the AKI episode,\neven though plans were made for the use of corticosteroids. The resolution of renal\ninjury with the cessation of nephrotoxic drugs made the use of corticosteroids\nunnecessary. The patient’s renal function returned closer to baseline at 1.98 mg/dL\n26 weeks after drug initiation.\n\nPlease see Figure 2 for the\ntrend of serum creatinine and timing of introduction of chlorthalidone and\namiodarone, the renal biopsy, and the discontinuation of the suspect culprit\nagents.\n\nFigure 2. Trend of serum creatinine (mg/dL), versus week after initiation of drugs. Red\narrow: start of amiodarone and chlorthalidone, black arrow: kidney biopsy,\ngreen arrow: cessation of amiodarone and chlorthalidone.\n\nDiscussion\nWe present a case showing AKI due to a drug-related reaction along with serological\nfindings suggestive of DILE. The patient had uncontrolled diabetes, hypertension,\ndiastolic congestive heart failure (CHF), and atrial fibrillation, so the initial\nsuspicion for worsening kidney functions was attributed to diabetic nephropathy and\ncardiorenal syndrome before nephrology evaluation. The presence of a skin rash\nfollowing the introduction of two new drugs prompted a more thorough workup for AKI,\nincluding serology and a kidney biopsy. It is also important to note that neither of\nthe culprit drugs were agents commonly associated with DILE. It is a reminder that\nDILE can occur secondary to the use of amiodarone and sulfa moiety containing\ndiuretics.\n\nThe results of serology could not completely exclude SLE, but the clinical course and\nrapid improvement in rash and renal parameters with withholding both offending\nagents supported the diagnosis of DILE well. The appearance of anti-histone\nantibodies supports the diagnosis of DILE over SLE as well but is not definitive.\nRenal biopsy results did not reveal immune complex disease expected with both DILE\nand SLE. The finding of AIN provided a cogent clinical clue that the patient was\nsuffering from a drug-induced process. Epidemiologically, de novo SLE in an older\npatient is less likely, and the observed remission by withholding medications alone\nwithout immunosuppressive therapy is also more typical of DILE than SLE. The\npatient’s renal function and proteinuria patterns need to be monitored, though, and\nrebiopsy is indicated in SLE or DILE patients who appear to have a flare up.7\n\nThis case suggests the importance of remaining vigilant for unusual causes of AKI and\nglomerular disease in diabetic patients. The risk of misattribution of kidney injury\ndue to reversible etiologies in diabetic patients to worsening diabetic nephropathy\nis high. In this case, the clinical suspicion combined with a thorough serologic\nworkup suggested a need for a kidney biopsy. This biopsy yielded a reversible cause\nand significantly improved the patient’s renal function. It is a further reminder of\nthe possibility of DILE in patients taking agents that are not typically associated\nwith lupus. As such, we recommend a thorough workup for any dermatologic–renal\npresentation, and we must also consider the need for a kidney biopsy.8,9 It is important to mention that\nsome cases of DILE can present without overt renal dysfunction but with interstitial\nfindings on kidney biopsy.10 A growing list of over 1000 agents have been compiled that have been reported\nto cause DILE, and it is important for practitioners to remain up to date on all\nagents where this idiopathic reaction may be observed.11\n\nConclusion\nWe report a rare case of a syndrome typical of drug-induced lupus without the\nusual triggers.\n\nThe renal biopsy was important as it pointed to AIN as the primary\nnephrological pathology, rather than lupus nephritis.\n\nAIN is an unexpected finding in DILE but pointed to a drug-induced process\nrather than classical SLE.\n\nA large number of agents have been reported to cause DILE.\n\nDeclaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nEthics approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nFunding: The author(s) disclosed receipt of the following financial support for the\nresearch, authorship, and/or publication of this article: I.K. is supported in\npart by funds from the National Institutes of Health (NIH) (R01-DK077162), the\nAllan Smidt Charitable Fund, the Factor Family Foundation, and the Ralph Block\nFamily Foundation.\n\nInformed consent: Written informed consent was obtained from the patient documented in the medical\nrecord to publish patient information and biopsy images, but no identifiable\nimages. No identifiable patient information is used in this case report.\n\nORCID iD: Ramy M Hanna \nhttps://orcid.org/0000-0003-1807-8909\n==== Refs\nReferences\n1 \nVedeove CD Simon JC Girolomoni G , et al\nDrug-induced lupus\nerythematosus with emphasis on skin manifestations and the role of anti-TNFα\nagents\n. J Dtsch Dermatol Ges \n2012 ; 10 (12 ):\n889 –897\n.22937775 \n2 \nWilson JD. \nAnti nuclear antibodies and cardiovascular drugs\n.\nDrugs \n1980 ; 19 :\n292 –305\n.6103797 \n3 \nEpstein A Barland P. \nThe diagnostic value of antihistone antibodies in drug-induced\nlupus erythematosus\n. Arthritis Rheum \n1985 ; 28 (2 ):\n158 –162\n.3882094 \n4 \nSheikh TK Charron RC Katz A. \nRenal manifestations of drug-induced systemic lupus\nerythematosus\n. Am J Clin Pathol \n1981 ; 75 (5 ):\n755 –762\n.7015825 \n5 \nYachoui R Saad W. \nAmiodarone-induced lupus-like syndrome\n.\nAm J Ther \n2015 ; 22 (1 ):\ne20 –e21\n.23846521 \n6 \nSusano R Caminal L Ramos D , et al\nAmiodarone-induced\nlupus\n. Ann Rheum Dis \n1999 ; 58 :\n655 –656\n.10577372 \n7 \nAnders H. \nRe-biopsy in lupus nephritis\n. Ann Transl\nMed \n2018 ; 6 (Suppl. 1 ):\nS41 .30613616 \n8 \nKatz U Zandman-Goddard G. \nDrug-induced lupus: an update\n. Autoimmun\nRev \n2010 ; 10 (1 ):\n46 –50\n.20656071 \n9 \nHogan JJ Markowitz GS Radhakrishnan J. \nDrug-induced glomerular disease: immune-mediated\ninjury\n. Clin J Am Soc Nephrol \n2015 ; 10 (7 ):\n1300 –1310\n.26092827 \n10 \nMclaughlin K Gholoum B Guiraudon C , et al\nDrug-induced lupus: an\nupdate\n. Am J Kidney Dis \n1998 ; 32 (4 ):\n698 –702\n.9774137 \n11 \nArnaud L Mertz P Gavand PE , et al\nDrug-induced systemic lupus:\nrevisiting the ever-changing spectrum of the disease using the WHO\npharmacovigilance database\n. Ann Rheum Dis \n2019 ; 78 (4 ):\n504 –508\n.30793701\n\n",
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"keywords": "Drug-induced lupus erythematosus; acute interstitial nephritis; amiodarone; chlorthalidone; glomerular disease; proteinuria; systemic lupus erythematosus",
"medline_ta": "SAGE Open Med Case Rep",
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"title": "Acute interstitial nephritis and drug-induced systemic lupus erythematosus due to chlorthalidone and amiodarone: A case report.",
"title_normalized": "acute interstitial nephritis and drug induced systemic lupus erythematosus due to chlorthalidone and amiodarone a case report"
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"abstract": "Lichen planus pemphigoides (LPP) is a rare clinical variant of bullous pemphigoid (BP). A 35-year-old female patient presented to our hospital complaining of pruritic violaceous-colored plaques or papules on the extremities. Tense vesicles were also seen on the soles. Skin biopsies from the papules and vesicles demonstrated lichen planus and BP, respectively. Direct immunofluorescence demonstrated linear IgG and C3 deposition on the basement membrane zone. Indirect immunofluorescence on 1 M NaCl split skin detected IgG reactivity with the epidermal side. Enzyme-linked immunosorbent assay also detected anti-BP180 antibodies. After treatment with oral prednisolone alone had failed, low-dose cyclosporine A (CyA) was added. The clinical symptoms immediately improved and the titer of the anti-BP180 antibodies decreased. Although there is little information about the treatment of recalcitrant LPP, additional CyA appeared to be beneficial.",
"affiliations": "Department of Dermatology, Nishi-Kobe Medical Center, Kobe, Kurume University School of Medicine and Kurume University Institute of Cutaneous Cell Biology, Kurume, Japan.",
"authors": "Washio|Ken|K|;Nakamura|Atsuko|A|;Fukuda|Shunpei|S|;Hashimoto|Takashi|T|;Horikawa|Tatsuya|T|",
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"fulltext": "\n==== Front\nCase Rep DermatolCase Rep DermatolCDECase Reports in Dermatology1662-6567S. 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 10.1159/000350285cde-0005-0084Published online: March, 2013A Case of Lichen Planus Pemphigoides Successfully Treated with a Combination of Cyclosporine A and Prednisolone Washio Ken aNakamura Atsuko aFukuda Shunpei bHashimoto Takashi bHorikawa Tatsuya a*aDepartment of Dermatology, Nishi-Kobe Medical Center, Kobe, Kurume University School of Medicine and Kurume University Institute of Cutaneous Cell Biology, Kurume, JapanbDepartment of Dermatology, Kurume University School of Medicine and Kurume University Institute of Cutaneous Cell Biology, Kurume, Japan*Tatsuya Horikawa, MD, Department of Dermatology, Nishi-Kobe Medical Center, 5-7-1 Kojidai, Nishiku, Kobe 651-2273 (Japan), E-Mail: thorikaw@med.kobe-u.ac.jpJan-Apr 2013 20 3 2013 20 3 2013 5 1 84 87 Copyright © 2013 by S. Karger AG, Basel2013This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No-Derivative-Works License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Lichen planus pemphigoides (LPP) is a rare clinical variant of bullous pemphigoid (BP). A 35-year-old female patient presented to our hospital complaining of pruritic violaceous-colored plaques or papules on the extremities. Tense vesicles were also seen on the soles. Skin biopsies from the papules and vesicles demonstrated lichen planus and BP, respectively. Direct immunofluorescence demonstrated linear IgG and C3 deposition on the basement membrane zone. Indirect immunofluorescence on 1 M NaCl split skin detected IgG reactivity with the epidermal side. Enzyme-linked immunosorbent assay also detected anti-BP180 antibodies. After treatment with oral prednisolone alone had failed, low-dose cyclosporine A (CyA) was added. The clinical symptoms immediately improved and the titer of the anti-BP180 antibodies decreased. Although there is little information about the treatment of recalcitrant LPP, additional CyA appeared to be beneficial.\n\nKey words\nLichen planus pemphigoidesBullous pemphigoidLichen planusCyclosporine A\n==== Body\nIntroduction\nLichen planus pemphigoides (LPP) is a rare clinical variant of bullous pemphigoid (BP), which is characterized by clinical and histological findings of both lichen planus (LP) and BP. Although several reports of LPP suggest an efficacy of corticosteroid therapy with or without dapsone [1], there is limited information about the treatment of severe corticosteroid-resistant cases of LPP. Hence, we report a case of refractory LPP, which was successfully treated with a combination of low-dose cyclosporine A (CyA) and prednisolone (PSL).\n\nCase Presentation\nA 35-year-old Japanese female was referred to our hospital for itchy skin lesions on the legs. She first noticed pruritic papules in April 2009, and 2 months later many vesicles emerged. On physical examination, flat-topped, polygonal, violaceous-colored plaques or papules were seen on the extremities, and some papules were accompanied by small vesicles or erosions on top of them (fig. 1a). Tense vesicles were also seen on the soles (fig. 1b). Lace-like, reticulated, whitish lesions were seen on the buccal mucosa (fig. 1c). Histopathological examination of the skin biopsy from the papular lesion on the right leg revealed hyperkeratosis, hypergranulosis, acanthosis and liquefaction degeneration in the epidermis and band-like infiltration of lymphocytes in the upper dermis, which was compatible with LP (fig. 2a). A further biopsy specimen from the right sole showed subepidermal blister formation with moderate inflammatory infiltrates (fig. 2b). Direct immunofluorescence demonstrated linear IgG (fig. 2c) and C3 (fig. 2d) deposition on the basement membrane zone. Indirect immunofluorescence on 1 M NaCl split skin detected IgG reactivity with the epidermal side (fig. 2e). Reactivity against the recombinant protein of the BP180-NC16a domain, but not the BP180-C-terminal domain, was detected by immunoblotting assays (data not shown). Enzyme-linked immunosorbent assay also detected anti-BP180 antibodies (index: 39; normal <9). Based on concurrent clinical and pathological features of BP and LP, we diagnosed our case as LPP.\n\nPSL (20 mg/day: 0.4 mg/kg/day) failed to inhibit disease activity, resulting in exacerbation of vesicle formation, increase of itchiness and elevation of the anti-BP180 antibody titer index to 72. As the patient complained of insomnia caused by low-dose corticosteroid therapy, CyA administration was considered, although an increase in the dose of PSL would have been the standardized therapeutic strategy. Soon after the addition of low-dose CyA (100 mg/day: 2 mg/kg/day), the vesicles flattened and the itchiness improved. Three months later, the anti-BP180 antibody titer index dropped to 14, and both the skin lesions (fig. 1d, e) and oral enanthemata (fig. 1f) markedly improved. We tapered down the dose of PSL and CyA. The dose of CyA was decreased to 25 mg/day in November 2011, and in January 2013, the dose of PSL was decreased to 2 mg/day. The titer of anti-BP180 antibody has been undetectable since April 2010. The patient maintained remission of bullous formation, although mild itching due to LP persisted. During the follow-up period, the side effect of corticosteroid resulted in a double bone fracture despite bisphosphonate administration. The presumable side effect of combination therapy was influenza, which was successfully treated with oseltamivir. Other serious side effects of CyA, such as sepsis and renal dysfunction, were not observed.\n\nDiscussion\nIn most cases of LPP, therapy with low to middle doses of oral corticosteroid seems to be effective [1]. In some cases, only topical corticosteroid administration was effective [2]. Combination therapy with corticosteroid and dapsone was also successfully used [1, 3]. There is little information about combination therapy with immunosuppressant drugs and corticosteroid for LPP. Only one atypical case of LPP with Castleman's disease was treated with CyA and mycophenolate mofetil [4]. Despite the absence of previous evidence, CyA therapy appears to have some advantages. First, it does not need hospitalization, which is inevitable for steroid pulsed therapy, intravenous immunoglobulin or plasmapheresis. Second, it is applicable to patients with anemia (as in our case), who cannot be treated with dapsone therapy. Third, CyA inhibits the itching by modulating the function of CD4-positive T cells. In LPP cases, long-standing LP lesions with basal keratinocyte damage by liquefaction may increase the antigen exposure of the BP180 protein, followed by autoantibody production and induction of bullous lesions [5]. Therefore, it is reasonable to use CyA for the treatment of LPP to suppress the dermal infiltration of lymphocytes in LP lesions. The effectiveness of CyA in our case supports this hypothesis of LPP etiology. Furthermore, another case of severe LP could also be well controlled with a very low dose of CyA [6].\n\nIn conclusion, we demonstrated that combination therapy with low-dose CyA and PSL was effective and without any side effects in a case of LPP. Although we reported only one case, this therapy could also be useful in other severe LPP cases.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFig. 1 LP-like lesions on the extremities (a). Vesicles with erythema on the right sole (b). Lace-like lesion on the buccal mucosa (c). After combination therapy with CyA and PSL, these skin and mucosal lesions remarkably improved (d–f).\n\nFig. 2 Histopathological findings of the LP-like (a; ×40) and blistering (b; ×100) skin lesions. The result of direct immunofluorescence for IgG (c; ×100) and C3 (d; ×100). The result of indirect immunofluorescence on 1 M NaCl split skin for IgG antibodies (e; ×200).\n==== Refs\nReferences\n1 Demirçay Z Baykal C Demirkesen C Lichen planus pemphigoides: report of two cases Int J Dermatol 2001 40 757 759 11903670 \n2 Harting MS Hsu S Lichen planus pemphigoides: a case report and review of the literature Dermatol Online J 2006 12 10 17083865 \n3 Barnadas MA Roé E Dalmau J Alomar A Martínez L Gelpí C Lichen planus pemphigoides: detection of anti-BP 180 antibodies by ELISA and immunoblotting tests J Eur Acad Dermatol Venereol 2010 24 1360 1361 20337815 \n4 Hsiao CJ Hsu MM Lee JY Chen WC Hsieh WC Paraneoplastic pemphigus in association with a retroperitoneal Castleman's disease presenting with a lichen planus pemphigoides-like eruption. A case report and review of literature Br J Dermatol 2001 144 372 376 11251576 \n5 Stingl G Holubar K Coexistence of lichen planus and bullous pemphigoid. A immunopathological study Br J Dermatol 1975 93 313 320 1103935 \n6 Levell NJ Munro CS Marks JM Severe lichen planus clears with very low-dose cyclosporin Br J Dermatol 1992 127 66 67 1637703\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1662-6567",
"issue": "5(1)",
"journal": "Case reports in dermatology",
"keywords": "Bullous pemphigoid; Cyclosporine A; Lichen planus; Lichen planus pemphigoides",
"medline_ta": "Case Rep Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101517685",
"other_id": null,
"pages": "84-7",
"pmc": null,
"pmid": "23626545",
"pubdate": "2013-01",
"publication_types": "D002363:Case Reports",
"references": "11903670;1103935;1637703;17083865;11251576;20337815",
"title": "A case of lichen planus pemphigoides successfully treated with a combination of cyclosporine a and prednisolone.",
"title_normalized": "a case of lichen planus pemphigoides successfully treated with a combination of cyclosporine a and prednisolone"
} | [
{
"companynumb": "JP-BAUSCH-BL-2019-022822",
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"occurcountry": "JP",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "Infant-onset bilateral sensorineural hearing loss is a key presenting symptom of the autoinflammatory cryopyrin-associated periodic syndrome. Other symptoms include periodic fever, cold-induced urticaria-like rash, chronic aseptic meningitis, polyarticular arthralgias, and renal AA amyloidosis. Early recognition and treatment with interleukin-1 blockade are critical for preventing disabling or fatal complications. We describe a patient with severe cryopyrin-associated periodic syndrome who presented at age 18 months with macrocephaly and moderate sensorineural hearing loss, later developing systemic sequelae. The pathogenic nature of the de novo NLRP3 gene variant identified was supported by a markedly elevated serum amyloid A level and sustained clinical response to anti-IL-1 therapy.",
"affiliations": "Division of Pediatric Otolaryngology, Department of Surgery, IWK Health Centre, 5850/5980 University Avenue, PO Box 9700, Halifax, NS, B3K 6R8, Canada. Electronic address: amaris.hui@dal.ca.;Division of Pediatric Otolaryngology, Department of Surgery, IWK Health Centre, 5850/5980 University Avenue, PO Box 9700, Halifax, NS, B3K 6R8, Canada. Electronic address: liane.johnson@iwk.nshealth.ca.;Allergy and Clinical Immunology, Department of Pediatrics, Chaleur Regional Hospital, 1750 Sunset Ave, Bathurst, NB, E2A 4L7, Canada. Electronic address: Rony.Greemberg@cornwallhospital.ca.;Division of Medical Genetics, Department of Pediatrics, IWK Health Centre, 5850/5980 University Ave, PO Box 9700, Halifax, NS, B3K 6R8, Canada. Electronic address: lynette.penney@iwk.nshealth.ca.;Division of Pediatric Rheumatology, Department of Pediatrics, IWK Health Centre, 5850/5980 University Ave, PO Box 9700, Halifax, NS, B3K 6R8, Canada. Electronic address: suzanne.ramsey@iwk.nshealth.ca.",
"authors": "Hui|Amaris|A|;Johnson|Liane B|LB|;Greemberg|Rony|R|;Penney|Lynette|L|;Ramsey|Suzanne E|SE|",
"chemical_list": "D053590:Interleukin 1 Receptor Antagonist Protein; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.ijporl.2019.01.037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5876",
"issue": "120()",
"journal": "International journal of pediatric otorhinolaryngology",
"keywords": "Anakinra; Canakinumab; Cryopyrin-associated periodic syndrome; Neonatal-Onset Multisystem Inflammatory Disease; Sensorineural hearing loss",
"medline_ta": "Int J Pediatr Otorhinolaryngol",
"mesh_terms": "D001299:Audiometry; D002648:Child; D056587:Cryopyrin-Associated Periodic Syndromes; D006319:Hearing Loss, Sensorineural; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D008297:Male; D009154:Mutation; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein",
"nlm_unique_id": "8003603",
"other_id": null,
"pages": "68-72",
"pmc": null,
"pmid": "30772614",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Severe cryopyrin-associated periodic syndrome first characterized by early childhood-onset sensorineural hearing loss - Case report and literature review.",
"title_normalized": "severe cryopyrin associated periodic syndrome first characterized by early childhood onset sensorineural hearing loss case report and literature review"
} | [
{
"companynumb": "CA-BIOVITRUM-2019CA0392",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "ANAKINRA"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThis study aimed to determine the clinical efficacy and safety of nonoperative management (NOM) for patients with rectal cancer with a clinical complete response (cCR) after short-course radiation therapy and consolidation chemotherapy.\n\n\nMETHODS\nPatients with stage I-III rectal adenocarcinoma underwent short-course radiation therapy followed by consolidation chemotherapy between January 2018 and May 2019 (n = 90). Clinical response was assessed by digital rectal examination, pelvic magnetic resonance imaging, and endoscopy. Of the patients with an evaluable initial response, those with a cCR (n = 43) underwent NOM, and those with a non-cCR (n = 43) underwent surgery. The clinical endpoints included local regrowth-free survival, regional control, distant metastasis-free survival, disease-free survival, and overall survival.\n\n\nRESULTS\nCompared with patients with an initial cCR, patients with initial non-cCR had more advanced T and N stage (P = .05), larger primary tumors (P = .002), and more circumferential resection margin involvement on diagnostic magnetic resonance imaging (P < .001). With a median follow-up of 30.1 months, the persistent cCR rate was 79% (30 of 38 patients) in the NOM cohort. The 2-year local regrowth-free survival was 81% (95% confidence interval [CI], 70%-94%) in the initial cCR group, and all patients with local regrowth were successfully salvaged. Compared with those with a non-cCR, patients with a cCR had improved 2-year regional control (98% [95% CI, 93%-100%] vs 85% [95% CI, 74%-97%], P = .02), distant metastasis-free survival (100% [95% CI, 100%-100%] vs 80% [95% CI, 69%-94%], P < .01), disease-free survival (98% [95% CI, 93%-100%] vs 71% [95% CI, 59%-87%], P < .01), and overall survival (100% [95% CI, 100%-100%] vs 88% [95% CI, 79%-98%], P = .02). No late grade 3+ gastrointestinal or genitourinary toxicities were observed in the patients who underwent continued NOM.\n\n\nCONCLUSIONS\nShort-course radiation therapy followed by consolidation chemotherapy may be a feasible organ preservation strategy in rectal cancer. Additional prospective studies are necessary to evaluate the safety and efficacy of this approach.",
"affiliations": "Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri.;Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri.;Division of Hematology and Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.;Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri.;Section of Colon and Rectal Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri.;Section of Colon and Rectal Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri.;Division of Hematology and Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.;Section of Colon and Rectal Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri.;Section of Colon and Rectal Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri.;Section of Colon and Rectal Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri.;Division of Hematology and Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.;Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri.;Section of Abdominal Imaging, Mallinckrodt Institute of Radiology, Washington University School of Medicine, Saint Louis, Missouri.;Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri.;Section of Colon and Rectal Surgery, Department of Surgery, Washington University School of Medicine, Saint Louis, Missouri.;Department of Radiation Oncology, Washington University School of Medicine, Saint Louis, Missouri. Electronic address: kim.hyun@wustl.edu.",
"authors": "Chin|Re-I|RI|;Roy|Amit|A|;Pedersen|Katrina S|KS|;Huang|Yi|Y|;Hunt|Steven R|SR|;Glasgow|Sean C|SC|;Tan|Benjamin R|BR|;Wise|Paul E|PE|;Silviera|Matthew L|ML|;Smith|Radhika K|RK|;Suresh|Rama|R|;Badiyan|Shahed N|SN|;Shetty|Anup S|AS|;Henke|Lauren E|LE|;Mutch|Matthew G|MG|;Kim|Hyun|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijrobp.2021.10.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": null,
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": null,
"nlm_unique_id": "7603616",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34653579",
"pubdate": "2021-10-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Complete Response in Patients With Rectal Adenocarcinoma Treated With Short-Course Radiation Therapy and Nonoperative Management.",
"title_normalized": "clinical complete response in patients with rectal adenocarcinoma treated with short course radiation therapy and nonoperative management"
} | [
{
"companynumb": "US-ROCHE-3070848",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nWhile often idiopathic, anterior ischemic optic neuropathy occasionally may occur from an identifiable cause.\n\n\nMETHODS\nObservational case report.\n\n\nRESULTS\nA 19-year-old woman with unremarkable medical and ophthalmic histories developed visual loss from nonarteritic anterior ischemic optic neuropathy in her right eye after otherwise uneventful dental extraction of the inferior third molars.\n\n\nCONCLUSIONS\nAnterior ischemic optic neuropathy may rarely occur after dental extraction. Potential pathophysiologic mechanisms of this rare occurrence are discussed.",
"affiliations": null,
"authors": "Kravitz|Elizabeth|E|;Foroozan|Rod|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/WNO.0000000000000711",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1070-8022",
"issue": "39(1)",
"journal": "Journal of neuro-ophthalmology : the official journal of the North American Neuro-Ophthalmology Society",
"keywords": null,
"medline_ta": "J Neuroophthalmol",
"mesh_terms": "D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D005654:Fundus Oculi; D006801:Humans; D008964:Molar, Third; D009900:Optic Nerve; D018917:Optic Neuropathy, Ischemic; D011183:Postoperative Complications; D041623:Tomography, Optical Coherence; D014081:Tooth Extraction; D014792:Visual Acuity; D014794:Visual Fields; D055815:Young Adult",
"nlm_unique_id": "9431308",
"other_id": null,
"pages": "14-17",
"pmc": null,
"pmid": "30179990",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Anterior Ischemic Optic Neuropathy After Dental Extraction.",
"title_normalized": "anterior ischemic optic neuropathy after dental extraction"
} | [
{
"companynumb": "US-SEPTODONT-201905246",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": null,
"... |
{
"abstract": "Fanconi anemia (FA) is an autosomal recessive inherited syndrome characterized by congenital abnormalities, aplastic anemia, and a high likelihood of developing cancer. We describe a child who presented with 2 synchronous solid tumors (Wilms tumor and neuroblastoma), later found to have FA, who developed severe toxicity and died after a first cycle of chemotherapy. Our experience emphasizes that a predisposing genetic condition should be sought in cases of multiple tumors and that managing FA patients with cancer can be particularly difficult.",
"affiliations": "Hematology/Oncology Division, Department of Pediatrics, University Hospital of Padova, 35128 Padova, Italy.",
"authors": "Compostella|Alessia|A|;Toffolutti|Tiziana|T|;Soloni|Pietro|P|;Dall'Igna|Patrizia|P|;Carli|Modesto|M|;Bisogno|Gianni|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpedsurg.2009.11.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3468",
"issue": "45(2)",
"journal": "Journal of pediatric surgery",
"keywords": null,
"medline_ta": "J Pediatr Surg",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000741:Anemia, Aplastic; D001855:Bone Marrow Diseases; D015897:Comorbidity; D019468:Disease Management; D005199:Fanconi Anemia; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007223:Infant; D007680:Kidney Neoplasms; D009378:Neoplasms, Multiple Primary; D009447:Neuroblastoma; D013577:Syndrome; D009396:Wilms Tumor",
"nlm_unique_id": "0052631",
"other_id": null,
"pages": "e5-8",
"pmc": null,
"pmid": "20152336",
"pubdate": "2010-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multiple synchronous tumors in a child with Fanconi anemia.",
"title_normalized": "multiple synchronous tumors in a child with fanconi anemia"
} | [
{
"companynumb": "IT-PFIZER INC-2010036570",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "The authors report a significant increase in dyscontrol in patients with borderline personality disorder who were taking alprazolam during a double-blind, placebo-controlled crossover study. They suggest that caution be used in prescribing alprazolam to patients with similar histories.",
"affiliations": null,
"authors": "Gardner|D L|DL|;Cowdry|R W|RW|",
"chemical_list": "D014151:Anti-Anxiety Agents; D010919:Placebos; D001569:Benzodiazepines; D000525:Alprazolam",
"country": "United States",
"delete": false,
"doi": "10.1176/ajp.142.1.98",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-953X",
"issue": "142(1)",
"journal": "The American journal of psychiatry",
"keywords": null,
"medline_ta": "Am J Psychiatry",
"mesh_terms": "D000328:Adult; D000525:Alprazolam; D000553:Ambulatory Care; D014151:Anti-Anxiety Agents; D001569:Benzodiazepines; D001883:Borderline Personality Disorder; D002986:Clinical Trials as Topic; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007175:Impulsive Behavior; D010554:Personality Disorders; D010919:Placebos; D012652:Self Mutilation; D013406:Suicide, Attempted; D014754:Violence",
"nlm_unique_id": "0370512",
"other_id": null,
"pages": "98-100",
"pmc": null,
"pmid": "2857071",
"pubdate": "1985-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Alprazolam-induced dyscontrol in borderline personality disorder.",
"title_normalized": "alprazolam induced dyscontrol in borderline personality disorder"
} | [
{
"companynumb": "US-PFIZER INC-2020383477",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALPRAZOLAM"
},
"drugadditional": "3",
... |
{
"abstract": "1 patient with SSPE at 4 y. He had had measles and measles encephalitis at 7.5 months. In China, the first and the second measles immunizations are recommended at 8 months and at 18-24 months, respectively. We recommend above immunizations should be given separately at 6 months and at 12-15 months.",
"affiliations": "a Department of Pediatrics , Affiliated Hospital of Guizhou Medical University , Guiyang , China.;a Department of Pediatrics , Affiliated Hospital of Guizhou Medical University , Guiyang , China.;b Department of Ophthalmology , Affiliated Hospital of Guizhou Medical University , Guiyang , China.;c Department of Neurology , Affiliated Hospital of Guizhou Medical University , Guiyang , China.;a Department of Pediatrics , Affiliated Hospital of Guizhou Medical University , Guiyang , China.",
"authors": "Liu|Wei-Liang|WL|;He|Zhi-Xu|ZX|;Li|Fang|F|;He|Dian|D|;Ai|Rong|R|",
"chemical_list": "D022542:Measles-Mumps-Rubella Vaccine",
"country": "United States",
"delete": false,
"doi": "10.1080/21645515.2017.1358582",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2164-5515",
"issue": "13(9)",
"journal": "Human vaccines & immunotherapeutics",
"keywords": "fatal disease; infancy; measles; measles immunizations; subacute sclerosing panencephalitis",
"medline_ta": "Hum Vaccin Immunother",
"mesh_terms": "D002675:Child, Preschool; D060740:Disease Eradication; D006801:Humans; D008297:Male; D008457:Measles; D022542:Measles-Mumps-Rubella Vaccine; D013344:Subacute Sclerosing Panencephalitis; D014611:Vaccination",
"nlm_unique_id": "101572652",
"other_id": null,
"pages": "2038-2040",
"pmc": null,
"pmid": "28750182",
"pubdate": "2017-09-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23047165;3221414;15837229;11528592;15195246",
"title": "Subacute sclerosing panencephalitis should be eliminated by measles vaccination.",
"title_normalized": "subacute sclerosing panencephalitis should be eliminated by measles vaccination"
} | [
{
"companynumb": "CN-PFIZER INC-2017449616",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IMMUNE GLOBULIN NOS"
},
"drugadditional": nul... |
{
"abstract": "A 54-year-old woman presented with a 1-month history of pain and numbness in both feet. She had taken metronidazole for over 4 years previously to treat vaginitis. On nerve conduction studies (NCS), neither the sural nor right superficial peroneal nerve (SPN) was evoked, nor did the left SPN have small amplitude, suggesting axonal peripheral polyneuropathy with sensory fiber involvement. When she restarted metronidazole, she immediately complained of recurrent paresthesia of the feet. We performed three electromyography (EMG) studies and followed the patient for 6 months.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Kyung-Hee Medical Center, 23, Kyungheedae-ro, Dongdaemun-gu, Seoul, Korea.",
"authors": "Soh|Yunsoo|Y|",
"chemical_list": "D008795:Metronidazole",
"country": "India",
"delete": false,
"doi": "10.4103/0028-3886.310097",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3886",
"issue": "69(1)",
"journal": "Neurology India",
"keywords": "Electromyography; metronidazole; nerve conduction studies; peripheral neuropathy",
"medline_ta": "Neurol India",
"mesh_terms": "D004576:Electromyography; D005260:Female; D006801:Humans; D008795:Metronidazole; D008875:Middle Aged; D009431:Neural Conduction; D010292:Paresthesia; D010543:Peroneal Nerve",
"nlm_unique_id": "0042005",
"other_id": null,
"pages": "174-176",
"pmc": null,
"pmid": "33642295",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Metronidazole-Induced Recurrent Paresthesia: A Case Report.",
"title_normalized": "metronidazole induced recurrent paresthesia a case report"
} | [
{
"companynumb": "KR-LUPIN PHARMACEUTICALS INC.-2021-12093",
"fulfillexpeditecriteria": "2",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditio... |
{
"abstract": "BACKGROUND\nDense deposit disease (DDD) is a rare glomerular disease caused by an uncontrolled activation of the alternative complement pathway leading to end-stage renal disease in 50 % of patients. As such, DDD has been classified within the spectrum of complement component 3 (C3) glomerulopathies due to its pathogenesis from alternative pathway dysregulation. Conventional immunosuppressive therapies have no proven effectiveness. Eculizumab, a terminal complement inhibitor, has been reported to mitigate disease in some cases.\n\n\nMETHODS\nWe report on the efficacy of eculizumab in a pediatric patient who failed to respond to cyclophosphamide, corticosteroids, and plasma exchange. Complement biomarker profiling was remarkable for low serum C3, low properdin, and elevated soluble C5b-9. Consistent with these findings, the alternative pathway functional assay was abnormally low, indicative of alternative pathway activity, although neither C3-nephritic factors nor Factor H autoantibodies were detected. Eculizumab therapy was associated with significant improvement in proteinuria and renal function allowing discontinuation of hemodialysis (HD). Repeat C3 and soluble C5b-9 levels normalized, showing that terminal complement pathway activity was successfully blocked while the patient was receiving eculizumab therapy. Repeat testing for alternative pathway activation allowed for a successful decrease in eculizumab dosing.\n\n\nCONCLUSIONS\nThe case reported here demonstrates the successful recovery of renal function in a pediatric patient on HD following the use of eculizumab.",
"affiliations": "Department of Pediatrics, Division of Pediatric Nephrology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA. tran.cheryl2@mayo.edu.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.;Department of Pediatrics, Division of Pediatric Nephrology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Pediatrics, Division of Pediatric Nephrology, Mayo Clinic, 200 First Street SW, Rochester, MN, 55905, USA.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.;Department of Internal Medicine and Pediatrics, University of Iowa, Iowa City, IA, USA.;Department of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA.",
"authors": "Tran|Cheryl L|CL|;Sethi|Sanjeev|S|;Murray|David|D|;Cramer|Carl H|CH|;Sas|David J|DJ|;Willrich|Maria|M|;Smith|Richard J|RJ|;Fervenza|Fernando C|FC|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; C038245:C3 protein, human; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D007166:Immunosuppressive Agents; C481642:eculizumab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-015-3306-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "31(4)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": "Alternative complement pathway; Dense deposit disease; Eculizumab; Hemodialysis; Soluble C5b-9",
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D000293:Adolescent; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D001706:Biopsy; D003167:Complement Activation; D003176:Complement C3; D015938:Complement Membrane Attack Complex; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D006435:Renal Dialysis; D016896:Treatment Outcome",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "683-7",
"pmc": null,
"pmid": "26759144",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24464478;24908321;22435382;22233157;25530108;22403278;22435383;26316621;17675665;26185203;24408225;19177158;22456601;24672732;26251714",
"title": "Discontinuation of dialysis with eculizumab therapy in a pediatric patient with dense deposit disease.",
"title_normalized": "discontinuation of dialysis with eculizumab therapy in a pediatric patient with dense deposit disease"
} | [
{
"companynumb": "US-BAXTER-2016BAX019528",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALBUMIN HUMAN"
},
"drugadditional": null,
... |
{
"abstract": "Kearns-Sayre syndrome (KSS) is characterized by external ophthalmoplegia, retinal pigmentation and cardiac conduction defects due to mitochondrial DNA (mtDNA) deletions. Short stature and growth hormone (GH) deficiency have been reported in KSS, but data on GH treatment is limited. We describe the clinical presentation, phenotype evolution, and response to GH in a patient with KSS and report data on eight additional KSS patients from the KIGS database. Our patient with KSS and GH deficiency achieved a final adult height at -0.8 SDS. In the KIGS database GH treatment resulted in mean improvement in height from -3.9 to -2.9 SDS in patients with KSS. Two patients did not show growth improvement. Our data shows improvement in height SDS in our patient and mixed results in eight additional patients from the KIGS database after treatment with GH. Heterogeneity in responsiveness may relate to presence of GH deficiency or severity of underlying mitochondrial dysfunction.",
"affiliations": null,
"authors": "Quintos|Jose Bernardo|JB|;Hodax|Juanita K|JK|;Gonzales-Ellis|Bryn A|BA|;Phornphutkul|Chanika|C|;Wajnrajch|Michael P|MP|;Boney|Charlotte M|CM|",
"chemical_list": "D019382:Human Growth Hormone",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0334-018X",
"issue": "29(11)",
"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": null,
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": "D001827:Body Height; D002648:Child; D057286:Electronic Health Records; D005260:Female; D006130:Growth Disorders; D020249:Hormone Replacement Therapy; D019382:Human Growth Hormone; D006801:Humans; D007625:Kearns-Sayre Syndrome; D057285:Precision Medicine; D016896:Treatment Outcome",
"nlm_unique_id": "9508900",
"other_id": null,
"pages": "1319-1324",
"pmc": null,
"pmid": "27718492",
"pubdate": "2016-11-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Efficacy of growth hormone therapy in Kearns-Sayre syndrome: the KIGS experience.",
"title_normalized": "efficacy of growth hormone therapy in kearns sayre syndrome the kigs experience"
} | [
{
"companynumb": "US-ROCHE-2351196",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SOMATROPIN"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Epstein-Barr virus (EBV) load monitoring after allogeneic hematopoietic stem cell transplantation (HSCT) enables earlier detection of EBV replication and often serves as a trigger for preemptive therapies aimed at reducing EBV-related diseases. Our institutional strategy is to treat patients with clinical signs of EBV-related disease accompanied by a rising viral load, rather than to intervene based solely on viral load. This affords an opportunity to study the natural history of EBV replication and to assess whether our strategy reduces overtreatment without compromising outcomes. The objectives of the present study were to assess the natural history of untreated EBV replication in patients who underwent an alemtuzumab-based allogeneic HSCT and to examine whether our clinical strategy reduced overtreatment without compromising patient outcomes. In this retrospective single-center observational study of 515 consecutive patients (age ≥18 years) undergoing T cell-depleted allogeneic HSCT incorporating alemtuzumab, patients underwent surveillance monitoring for EBV by quantitative PCR in the peripheral blood at least weekly up to 100 days post-transplantation and longer if they remained on immunosuppressive therapy. The cumulative incidence of EBV detection and EBV-related disease were assessed. Among the 515 patients, 192 had EBV DNA detectable on ≥1 occasion, with a cumulative incidence of 35.8% (31.8% to 40.4%), although this remained below the limit of quantification in 93 patients. The median time to first detection was 89.5 days (range, 0 to 2254 days). The incidence was higher in recipients of sibling donor transplants (45.4% versus 30%; P = .00021) compared with recipients of unrelated donor transplants. Twenty patients developed EBV-related disease (cumulative incidence, 3.9%). Two patients had immunosuppression reduction alone, 18 received rituximab, and 5 required additional therapies. Five patients died from post-transplantation lymphoproliferative disorder, all of whom had received rituximab. The positive predictive value of EBV load for disease was higher in the unrelated donor cohort but remained <75% regardless of EBV threshold (57.1% to 72.7%). The cumulative incidence of EBV-related disease in our study (3.9%) is comparable to that reported in other studies incorporating alemtuzumab, and our clinical strategy reduced overtreatment in this patient population. PCR-based surveillance strategies have limitations, as reflected in the relatively low sensitivity of the assay coupled with the low positive predictive value, which may influence the potential choice of a threshold for preemptive intervention. We conclude that it remains unclear whether treatment based on a rising EBV viral load alone provides superior overall results to treatment based on the development of clinical signs of EBV-related disease in the context of a rising viral load.",
"affiliations": "Department of Haematology, UCL Cancer Institute, University College London, London, Uinted Kingdom; Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom. Electronic address: m.marzolini@ucl.ac.uk.;Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Virology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.;Department of Haematology, UCL Cancer Institute, University College London, London, Uinted Kingdom; Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom.",
"authors": "Marzolini|Maria A V|MAV|;Wilson|Andrew J|AJ|;Sanchez|Emilie|E|;Carpenter|Ben|B|;Chakraverty|Ronjon|R|;Hough|Rachael|R|;Kottaridis|Panos|P|;Morris|Emma C|EC|;Thomson|Kirsty J|KJ|;Peggs|Karl S|KS|",
"chemical_list": "D004279:DNA, Viral; D000074323:Alemtuzumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jtct.2021.04.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2666-6367",
"issue": "27(8)",
"journal": "Transplantation and cellular therapy",
"keywords": "Alemtuzumab; Allogeneic HSCT; Epstein-Barr virus; Post-transplantation lymphoproliferative disorder",
"medline_ta": "Transplant Cell Ther",
"mesh_terms": "D000293:Adolescent; D000074323:Alemtuzumab; D004279:DNA, Viral; D020031:Epstein-Barr Virus Infections; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human; D006801:Humans; D012189:Retrospective Studies; D014184:Transplantation, Homologous; D019562:Viral Load",
"nlm_unique_id": "101774629",
"other_id": null,
"pages": "682.e1-682.e12",
"pmc": null,
"pmid": "33962069",
"pubdate": "2021-08",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Natural History of Epstein-Barr Virus Replication and Viral Load Dynamics after Alemtuzumab-Based Allogeneic Stem Cell Transplantation.",
"title_normalized": "natural history of epstein barr virus replication and viral load dynamics after alemtuzumab based allogeneic stem cell transplantation"
} | [
{
"companynumb": "GB-SA-2021SA392712",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "4",
... |
{
"abstract": "We report a unique case of herpes zoster that developed shortly after Varicella Zoster vaccination.",
"affiliations": null,
"authors": "Gustafson|Cheryl Janene|CJ|;Woodard|Meredith|M|;Hanke|C William|CW|",
"chemical_list": "D019433:Chickenpox Vaccine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "15(2)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000368:Aged; D019433:Chickenpox Vaccine; D006562:Herpes Zoster; D006801:Humans; D008297:Male; D013997:Time Factors; D014611:Vaccination",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "241-3",
"pmc": null,
"pmid": "26885795",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Unique Case of Herpes Zoster Within One Week of Varicella Zoster Vaccination.",
"title_normalized": "a unique case of herpes zoster within one week of varicella zoster vaccination"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/17/0094095",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALACYCLOVIR HYDROCHLORIDE"
},
"drugaddi... |
{
"abstract": "The information about the outcome of primary CNS lymphoma (PCNSL) in India is scarce, because there is no population-based or large hospital-based data.\n\n\n\nThis is a retrospective study that spanned 17 years (2001 to 2017) to study the outcome of PCNSL at the All India Institute of Medical Sciences (AIIMS), which is a tertiary care center in Northern India.\n\n\n\nOnly one of 99 patients was positive for HIV serology. Diffuse large B-cell lymphoma was the most common histology (97.7%). The median patient age was 50 years (range, 13 to 70 years), and the ratio of men to women was 1.9. The median duration of symptoms before diagnosis was 3.5 months (range, 0.5 to 48 months), and 58.5% had a performance status (PS) of 3 or more. Multiple intracranial lesions were present in 81.8% of patients. Surgical resection was performed in 45%, and approximately 22% of patients were ineligible for treatment. Most patients (n = 73) were treated with high-dose methotrexate (HDMTX)-based regimens (ie, methotrexate, vincristine, and procarbazine with or without rituximab). Pharmacokinetic monitoring of methotrexate was not available at our center. HDMTX-related mortality was 3.9%. The median follow-up duration, event-free survival (EFS), and overall survival (OS) were 34 months, 20.4 months, and 31.7 months, respectively. Addition of rituximab (n = 27) to MVP resulted in a higher objective response rate (88.9% v 73.9% without rituximab; P = .12), complete remission (81.5% v 56.5%; P = .03), 2-year EFS (57.3% v 40.4%; P = .02), and 2-year OS (61.6% v 53.4%; P = .056).\n\n\n\nThis is the largest study of PCNSL from India. The patients were immunocompetent and young but presented with a high-burden disease that precluded treatment in approximately 22%. The treatment with HDMTX appears safe without pharmacokinetic monitoring. The outcome is comparable to those observed in the West, and rituximab use showed additional benefit. There are notable barriers with respect to management of PCNSL in the real world, and efforts are required to improve the outcome more.",
"affiliations": "1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.;1 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India.",
"authors": "Patekar|Mukesh|M|;Adhikari|Narayan|N|;Biswas|Ahitagni|A|;Raina|Vinod|V|;Kumar|Lalit|L|;Mohanti|Bidhu Kalyan|BK|;Gogia|Ajay|A|;Sharma|Atul|A|;Batra|Atul|A|;Bakhshi|Sameer|S|;Garg|Ajay|A|;Thulkar|Sanjay|S|;Sharma|Meher Chand|MC|;Vishnubhatla|Sreenivas|S|;Baghmar|Saphalta|S|;Sahoo|Ranjit Kumar|RK|",
"chemical_list": "D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1200/JGO.18.00124",
"fulltext": "\n==== Front\nJ Glob OncolJ Glob OncoljgojgoJGOJournal of Global Oncology2378-9506American Society of Clinical Oncology 180012410.1200/JGO.18.00124Hematologic Malignancies: LymphomasNeurooncologyOriginal ReportPrimary CNS Lymphoma in India: A 17-Year Experience From the All India Institute of Medical Sciences PCNSL in India: AIIMS ExperiencePatekar Mukesh MD12Adhikari Narayan MD12Biswas Ahitagni MD, DNB, ECMO, FRCR12Raina Vinod MD12Kumar Lalit MD, DM12Mohanti Bidhu Kalyan MD12Gogia Ajay MD, DM12Sharma Atul MD12Batra Atul MD, DM12Bakhshi Sameer MD12Garg Ajay MD12Thulkar Sanjay MD12Sharma Meher Chand MD12Vishnubhatla Sreenivas PhD12Baghmar Saphalta MD, DM12Sahoo Ranjit Kumar MD, DM121 Dr B.R.A. Institute Rotary Cancer Hospital, New Delhi, India 2 All India Institute of Medical Sciences, New Delhi, IndiaRanjit Kumar Sahoo, MD, DM, Room 218, Department of Medical Oncology, Dr B.R.A. Institute Rotary Cancer Hospital and All India Institute of Medical Sciences, New Delhi-110 029, India; e-mail: drranjitmd@gmail.com.2019 27 2 2019 5 JGO.18.0012403 1 2019 © 2019 by American Society of Clinical Oncology2019American Society of Clinical OncologyLicensed under the Creative Commons Attribution 4.0 License: https://creativecommons.org/licenses/by/4.0/PURPOSE\nThe information about the outcome of primary CNS lymphoma (PCNSL) in India is scarce, because there is no population-based or large hospital-based data.\n\nMATERIALS AND METHODS\nThis is a retrospective study that spanned 17 years (2001 to 2017) to study the outcome of PCNSL at the All India Institute of Medical Sciences (AIIMS), which is a tertiary care center in Northern India.\n\nRESULTS\nOnly one of 99 patients was positive for HIV serology. Diffuse large B-cell lymphoma was the most common histology (97.7%). The median patient age was 50 years (range, 13 to 70 years), and the ratio of men to women was 1.9. The median duration of symptoms before diagnosis was 3.5 months (range, 0.5 to 48 months), and 58.5% had a performance status (PS) of 3 or more. Multiple intracranial lesions were present in 81.8% of patients. Surgical resection was performed in 45%, and approximately 22% of patients were ineligible for treatment. Most patients (n = 73) were treated with high-dose methotrexate (HDMTX)–based regimens (ie, methotrexate, vincristine, and procarbazine with or without rituximab). Pharmacokinetic monitoring of methotrexate was not available at our center. HDMTX-related mortality was 3.9%. The median follow-up duration, event-free survival (EFS), and overall survival (OS) were 34 months, 20.4 months, and 31.7 months, respectively. Addition of rituximab (n = 27) to MVP resulted in a higher objective response rate (88.9% v 73.9% without rituximab; P = .12), complete remission (81.5% v 56.5%; P = .03), 2-year EFS (57.3% v 40.4%; P = .02), and 2-year OS (61.6% v 53.4%; P = .056).\n\nCONCLUSION\nThis is the largest study of PCNSL from India. The patients were immunocompetent and young but presented with a high-burden disease that precluded treatment in approximately 22%. The treatment with HDMTX appears safe without pharmacokinetic monitoring. The outcome is comparable to those observed in the West, and rituximab use showed additional benefit. There are notable barriers with respect to management of PCNSL in the real world, and efforts are required to improve the outcome more.\n\n SJS Export v1\n==== Body\nINTRODUCTION\nPrimary CNS lymphoma (PCNSL) is a form of extranodal non-Hodgkin lymphoma (NHL) that is confined to brain, eyes, and—rarely—spinal cord or leptomeninges. More than 90% of these cases are classified as diffuse large B-cell lymphoma (DLBCL). It is a rare neoplasm that accounts for a fraction of NHL (approximately 1%) and all primary brain tumors (approximately 4%) in the United States and occurs predominantly in men of ages 60s or 70s, but it occurs one or two decades earlier in immunocompromised patients (eg, those with HIV).1 The prognosis in untreated patients is extremely poor (3 to 4 months) and modestly improved with whole-brain radiation therapy (WBRT; approximately 12 months); it is substantially improved (32 to 37 months) with high-dose methotrexate (HDMTX)–based chemotherapy and is improved even more by the addition of rituximab.2-6 However, this improvement in survival is not mirrored in patients treated outside of a clinical trial or in the population-based cohort studies; the discrepancy is a matter of concern.7-9\n\nThe management of PCNSL poses a unique challenge in resource-limited settings. First, because of its orphan-disease nature, the lymphoma could easily be missed despite its characteristic radiologic appearance.10 Second, unlike other brain neoplasms, surgical removal of the tumor is unnecessary and histopathologic diagnosis is mandatory by stereotactic needle biopsy, which is not routinely available at many centers.10 Third, PCNSL presents as a periventricular tumor, often with notable vasogenic edema and surrounding mass effect, and the use of corticosteroids to reduce cerebral edema is a common practice in patients with newly diagnosed brain tumors. Corticosteroids cause profound apoptosis of the lymphomatous cells and may obscure as well as delay the ability to make a definitive diagnosis10,11; corticosteroid use has the potential to affect the outcome by not only delaying the diagnosis but also by selecting out the drug-resistant clones. Finally, treatment with HDMTX is risky and requires intensive monitoring and experience.12\n\nCONTEXT\nKey objective\n\nDespite numerous advances in the field of primary CNS lymphoma, there remain notable barriers in the management of this rare and aggressive brain neoplasm.\n\nThere are no population-based data for PCNSL in India. In such a scenario, large hospital-based data may be revealing.\n\nThis is a retrospective study that spanned 17 years, from 2001 to 2017, and was conducted at the All India Institute of Medical Sciences (AIIMS), which is a tertiary care center in the Northern India.\n\nKnowledge generated\n\nPatients were young and immunocompetent and presented with a high-burden disease at baseline.\n\nHigh-dose methotrexate–based polychemotherapy is effective and can be safely given without pharmacokinetic monitoring.\n\nThe outcome of patients who could be treated appears comparable to that of patients from the West.\n\nRelevance\n\nThis is the largest study of PCNSL from India representative of the experiences across all parts of the country and discusses the challenges faced in this country.\n\n\n\nIn India, PCNSL represents approximately 1% of all primary CNS neoplasms according to the hospital-based data reported by many centers, including ours.13-16 In this study, we attempted to characterize the clinical and pathologic profile and the outcome of patients with PCNSL who were treated during a period of 17 years at the All India Institute of Medical Sciences (AIIMS), which is a tertiary care center in Northern India. We also elaborate on the challenges faced during the management of the disease.\n\nMATERIALS AND METHODS\nWe examined the medical records of all patients diagnosed with PCNSL at our center between 2001 and 2017. Ethical clearance was obtained from the institutional ethical review committee. The date of biopsy was taken as the date of diagnosis. Contrast-enhanced magnetic resonance imaging was performed at diagnosis, after induction, after consolidation, then every 3 months during first 2 years, every 6 months for the next 3 years, and annually thereafter.\n\nEach cycle of HDMTX was administered after admission as an inpatient. Each patient received intravenous hydration at a rate of 3 L/m2 and intravenous sodium bicarbonate for urine alkalization. After a urine pH of more than 7.5 had been maintained for two consecutive measures, HDMTX was started and infused over 3 hours. The hydration and alkalinization were maintained for the subsequent 48 to 72 hours. Leucovorin rescue was initiated 24 hours after methotrexate administration at a dosage of 20 mg intravenously (preferably) or orally every 6 hours for 12 doses. Serum creatinine, blood urea, and CBC were monitored daily. Pharmacokinetic monitoring of methotrexate could not be performed, because it is not routinely done at our center.\n\nThe standard dose of WBRT was 45 Gy in 25 fractions over 5 weeks (n = 50) by bilateral parallel opposed skull fields using a German Helmet portal with cobalt-60 gamma rays; the procedure is described in detail elsewhere.17 In a few patients (n = 10), reduced-dose WBRT (23.4 Gy in 13 fractions over 2.5 weeks) was administered, because these patient experienced complete response (CR) as part of a study protocol.4,17,18\n\nχ2 or Fisher’s exact test was used to detect an association between categoric variables. Survival was estimated by the Kaplan-Meier method and compared using the log-rank test. Data were censored on February 15, 2018. A univariable Cox proportional hazard model followed by a multivariable Cox regression analysis were performed to identify the predictors of outcome. Event-free survival (EFS) was calculated from the date of diagnosis to date of disease relapse or progression or of death as a result of any cause. Overall survival (OS) was calculated from the date of diagnosis to date of death as a result of any cause. STATA/SE 13.0 (Stata Corp, College Station, TX) was used for statistical analysis.\n\nRESULTS\nPatient Characteristics\nWe identified 99 occurrences of PCNSL during the years 2001 to 2017 (Table 1). Only a single patient was positive for HIV serology. The median age at presentation was 50 years (range, 13 to 70 years), and the ratio of men to women was 1.9:1. The median duration of symptoms before diagnosis was 3.5 months (range, 0.5 to 48 months); common symptoms were motor abnormality (60.6%) followed by features of raised intracranial tension (49.5%) and abnormality of higher mental function (47.4%). Ocular and leptomeningeal involvement (positive CSF cytology) at presentation were found in 19.4% and 15.8% of patients, respectively. An Eastern Cooperative Oncology Group performance status (PS) of 3 or more at presentation was found in 58.5% of patients.\n\nTABLE 1 Baseline Characteristics\n\nTumor Characteristics\nThe histopathology was DLBCL in 97.7% of patients (87 of 89 patients; Table 2). The histologic diagnosis was established by biopsy (stereotactic or open) in 49 patients and by surgery in 40 patients. In 10 patients (approximately 10%), the diagnosis was entirely based on the typical radiographic appearance, because biopsy could not be obtained or was inconclusive. Multiple intracranial lesions were found in 81.8% of patients; these occurred predominantly in the frontal lobe (52.53%) followed by the parietal lobe (49.49%), and involvement of deep structures (basal ganglia/thalamus) was seen in 51.5% of patients.\n\nTABLE 2 Diagnosis, Pathology, and Treatment\n\nTreatment and Outcome\nTwenty-two of 99 patients did not receive any therapy, so they were excluded from the outcome analysis (Fig 1). Of 77 patients, 73 patients received MVP ± R (HDMTX, vincristine, and procarbazine, with or without rituximab), as suggested by DeAngelis et al,3 or its modification (Table 2).3,4 The median numbers of MVP ± R cycles was five (range, two to five cycles). Rituximab was used in patients who could afford it (n = 27).\n\nFIG 1 Flow diagram. Ara-C, cytarabine; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone, CR, complete response; HDMTX, high-dose methotrexate; IT MTX, intrathecal methotrexate; LAMA, left against medical advice; LFU, lost to follow-up; MVP, methotrexate, vincristine, and procarbazine; PR, partial response; SD, stable disease; WBRT, whole-body radiotherapy.\n\nThe objective response rate (ORR) to chemotherapy was 81.8%; 46.8% had CR. Seven (9%) of 77 patients had progressive disease (PD); among them, three could receive WBRT as salvage. The final response after consolidation (WBRT and/or high-dose cytarabine) was 80.5%, and 67.5% had CR. Nine patients had PD, and all except one patient died as a result. In five patients, WBRT was avoided in view of advanced age (older than 60 years). In a single case, the reason for the omission of WBRT could not be ascertained.\n\nThe median duration of follow-up for the whole cohort was 34 months. The median EFS and OS were 20.4 months and 31.7 months, respectively (Figs 2A and 2B). In the multivariable analysis, the absence of resection, infratentorial involvement, and low serum albumin (< 3.5 g/dL) were independent predictors of both EFS and OS (Tables 3 and 4).\n\nFIG 2 Kaplan-Meier survival estimates: (A) event-free survival; and (B) overall survival.\n\nTABLE 3 Univariable and Multivariable Analysis for EFS\n\nTABLE 4 Univariable and Multivariable Analysis for Overall Survival\n\nIn 56 (72.7%) of 77 patients, the International Extra-Nodal Lymphoma Staging Group risk score could be calculated; patients in low-risk (n = 4), intermediate-risk (n = 32), and high-risk (n = 20) groups represented 7.1%, 57.1%, and 35.7% of the total, respectively (Table 1). The 2-year EFS for high-risk patients versus non-high-risk patients (n = 36) was 22% versus 65.7% (P = .006); the 2-year OS for high-risk versus non–high-risk patients (n = 36) was 32.7% versus 80.9% (P = .001).\n\nWe also did a subgroup analysis to evaluate the impact of rituximab (n = 27; 36.9%) when added to the MVP regimen (n = 73). Addition of rituximab resulted in higher ORR (88.9% v 73.9%; P = .12) and better achievement of CR (81.5% v 56.5%; P = .03). The median follow-up times in the MVP cohort with rituximab and in the MVP-only cohort were 20.7 months and 48.27 months, respectively. The 2-year EFS was better in the rituximab cohort (57.3% v 40.4%; P = .02), as was the 2-year OS (61.6% v 53.4%; P = .056).\n\nThere were 36 deaths in the whole cohort, of which 26 patients (72.2%) died as a result of either relapse or progression of PCNSL. Seven patients died as a result of unrelated or unknown causes, and three patients died as a result of chemotherapy-related toxicity. Among 17 patients who experienced disease relapse, 15 had local recurrences, and two had both local and systemic relapse. Most of the recurrences (12 of 17, or 70.6%) occurred within 2 years of diagnosis.\n\nTreatment-related late neurotoxicity was observed in eight patients (10%) and was severe in two patients; in the rest, it was mild to moderate and was reversible in one case (normal pressure hydrocephalus, improved with ventriculoperitoneal shunt). In this cohort, late neurotoxicity was seen predominantly in the patients who received combined modality treatment (six of eight patients); five (62.5%) of the eight patients were age 60 years or older.\n\nDISCUSSION\nThis single-center retrospective study is, to our knowledge, the largest study to be reported from India, and it illustrates the difficulties and the challenges faced in the treatment of PCNSL in a developing country. The study is somewhat representative of the experiences across all parts of the country.13,15,16,19-22\n\nIn this study, 22 patients (22.2%) did not receive treatment because of poor PS (n = 14), refusal to take treatment (n = 5), or loss to follow-up (n = 3). The non-treatment rate is slightly more than the 8% to 15.3% rate reported in different studies from India.19-21 We noticed that the rate gradually decreased from 9% between 2001 and 2005 to 2% between 2016 and 2017; the reasons could be multiple (eg, timely diagnosis, better general condition, or PS).\n\nIn this study, we had only a single case of HIV-associated PCNSL (approximately 1%), which is similar to rates from many other reports from India—from 0% to 8.6%—including one autopsy study,13-16,19-23 and which is far less than the US incidence—from 26.2% (1980 to 2007) to 36.3% (1992 to 2011).1 The most plausible explanation is the earlier death of these patients as a result of opportunistic infections and tuberculosis.16,23\n\nThe median age among the immunocompetent patients in this study was 50 years; median ages reported by other centers in India, though, ranged from 42 to 59 years14-16,19-22,24 and reports from the West suggest that those patients are a decade older as well.25,26 This difference could be a result of the different age structure in India (only approximately 8% of the population is older than 60 years) or from the referral bias, but contribution of environmental or genetic factors cannot be excluded.\n\nIn this study, most of the occurrences were DLBCL (97.7%), and this was similar to other reports from India.13-16,19-21 By Han’s classification, non-germinal center type (56.4%) was more common in this study, but this was a small sample size (Table 2) (n = 39). A similar trend was also reported previously by us and others.21,22,24,27\n\nIn this study, the majority of the lesions were located in the supratentorial region, and the frontal lobe was the most common site—again similar to what is reported from other Indian studies11,15,16,22 and from Western literature.25,26 In this cohort, there were higher number of patients with high-burden disease compared with the Western literature, including multiple intracranial lesions (81.8% v 34%) and higher incidence of high intracranial tension features (49.4% v 33%) that reflected in the incidence of poor PS at presentation (PS of 4: 40.4% v 12%) in this study.25,26 The incidence of multiple intracranial lesions varied between 15% and 77% among different retrospective series from India14,15,19-21; in a prospective study from our center, multiple lesions were found in 75% of cases and reflected the influence of referral bias among different institutions across India.17\n\nThe rate of surgical resection in this study appears high (n = 40, or 45%) and mostly as a result of suspicion of glioma or other brain tumors (n = 36, 90%). In the rest, resection was performed because of the requirement of urgent decompression to improve the sensorium. A better EFS and OS was observed in the patients who underwent surgical resection in this study , as reported by a few other studies also,28,29 and the elimination of drug-resistant clones by surgical removal10 could be a theoretical cause. Better survival in patients who underwent surgical resection as compared with biopsyin the present study, is most likely due to a selection bias, and we refrain from deriving any conclusion from this finding and discourage resections in PCNSL, which is an infiltrative neoplasm.30\n\nToxicity from HDMTX and its relation to serum methotrexate concentrations is not as clear in PCNSL as it is in other malignancies, like osteosarcoma.12 At our center, we could not monitor methotrexate levels, because it is not available routinely. Thus, we had to rely entirely on adequate hydration, urine alkalinization, leucovorin, and monitoring of renal function and CBC. The mortality related to HDMTX in this study was 3.9%, which is comparable to another study (approximately 2.5% mortality) in which methotrexate levels were monitored prospectively in patients with PCNSL.31\n\nIn this study, the response to HDMTX-based chemotherapy with or without WBRT was 80.5% (CR, 67.5%), which is comparable to that of Western studies.3,4 There was an improvement in response rates—especially CR; EFS; and, to some extent, OS—in patients who received rituximab in addition to MVP. This improvement was similar to that seen in other reports, but longer follow-up is required for confirmation.5,6 At a median follow-up period of 34 months, the median EFS and OS were 20.4 months and 31.7 months, respectively. The outcome in this cohort was modest and can be improved upon. The impact of corticosteroids on delay of diagnosis and on the survival outcome in this cohort could not be formally addressed because of the lack of information about corticosteroid use. However, at least two thirds of patients had a history of prior use of corticosteroids, and these data will be prospectively analyzed. A better understanding of the molecular architecture of PCNSL may help integrate small molecules, especially ibrutinib, into the therapeutic armamentarium.32\n\nDespite several inherent limitations related to the retrospective study design, this study demonstrated that most patients were young and immunocompetent but presented with a higher disease burden. The survival looks comparable to that of patients in the West but can still be improved upon with early diagnosis. However, it may be desirable to monitor the serum levels of methotrexate; at centers with no such facilities, HDMTX can still be administered safely but only with careful monitoring. At present, we need to put more effort into diagnosis of PCNSL in these patients early, which would certainly improve the outcome.\n\nThere have been numerous advances in the field of PCNSL during the past few decades, but notable barriers still remain with respect to identification and treatment of this rare, aggressive, yet curable brain tumor in the real world. More efforts are required to improve the care by formulating guidelines with respect to suspicion and diagnosis of this malignancy, development of cost-effective treatment protocols, improvement of supportive care, education and support of the community practitioners, and development of multidisciplinary care for these patients.\n\nAUTHOR CONTRIBUTIONS\nConception and design: Mukesh Patekar, Narayan Adhikari, Ahitagni Biswas, Vinod Raina, Lalit Kumar, Ajay Gogia, Atul Sharma, Sreenivas Vishnubhatla, Saphalta Baghmar, Ranjit Kumar Sahoo\n\nCollection and assembly of data: Mukesh Patekar, Narayan Adhikari, Ahitagni Biswas, Vinod Raina, Ajay Gogia, Atul Batra, Sameer Bakhshi, Ajay Garg, Ranjit Kumar Sahoo\n\nData analysis and interpretation: Mukesh Patekar, Narayan Adhikari, Vinod Raina, Bidhu Kalyan Mohanti, Atul Batra, Sameer Bakhshi, Sanjay Thulkar, Mehar Chand Sharma, Sreenivas Vishnubhatla, Ranjit Kumar Sahoo\n\nProvision of study material or patients: Mukesh Patekar, Narayan Adhikari, Vinod Raina, Lalit Kumar, Bidhu Kalyan Mohanti, Atul Batra, Mehar Chand Sharma, Saphalta Baghmar, Ranjit Kumar Sahoo\n\nAdministrative support: Vinod Raina, Lalit Kumar, Atul Batra, Ranjit Kumar Sahoo\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAgree to be accountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST AND DATA AVAILABILITY STATEMENT\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.\n\nAtul Sharma\nResearch Funding: CD Pharma India (Inst)\n\nNo other potential conflicts of interest were reported.\n==== Refs\nREFERENCES\n1. Shiels MS Pfeiffer RM Besson C et al Trends in primary central nervous system lymphoma incidence and survival in the US Br J Haematol 174 417 424 2016 27018254 \n2. Thiel E Korfel A Martus P et al High-dose methotrexate with or without whole brain radiotherapy for primary CNS lymphoma (G-PCNSL-SG-1): A phase 3, randomised, noninferiority trial Lancet Oncol 11 1036 1047 2010 20970380 \n3. DeAngelis LM Seiferheld W Schold SC et al Combination chemotherapy and radiotherapy for primary central nervous system lymphoma: Radiation Therapy Oncology Group Study 93-10 J Clin Oncol 20 4643 4648 2002 12488408 \n4. Morris PG Correa DD Yahalom J et al Rituximab, methotrexate, procarbazine, and vincristine followed by consolidation reduced-dose whole-brain radiotherapy and cytarabine in newly diagnosed primary CNS lymphoma: Final results and long-term outcome J Clin Oncol 31 3971 3979 2013 24101038 \n5. Mocikova H Pytlik R Sykorova A et al Role of rituximab in treatment of patients with primary central nervous system lymphoma: A retrospective analysis of the Czech lymphoma study group registry Leuk Lymphoma 57 2777 2783 2016 27087066 \n6. Song Y Wen Y Xue W et al Effect of rituximab on primary central nervous system lymphoma: A meta-analysis Int J Hematol 106 612 621 2017 28900847 \n7. Zeremski V Koehler M Fischer T et al Characteristics and outcome of patients with primary CNS lymphoma in a “real-life” setting compared to a clinical trial Ann Hematol 95 793 799 2016 26801791 \n8. Shenkier TN Voss N Chhanabhai M et al The treatment of primary central nervous system lymphoma in 122 immunocompetent patients: A population-based study of successively treated cohorts from the British Colombia Cancer Agency Cancer 103 1008 1017 2005 15651059 \n9. Panageas KS Elkin EB DeAngelis LM et al Trends in survival from primary central nervous system lymphoma, 1975-1999: A population-based analysis Cancer 104 2466 2472 2005 16240449 \n10. Carnevale J Rubenstein JL The challenge of primary central nervous system lymphoma Hematol Oncol Clin North Am 30 1293 1316 2016 27888882 \n11. Manoj N Arivazhagan A Mahadevan A et al Central nervous system lymphoma: Patterns of incidence in Indian population and effect of steroids on stereotactic biopsy yield Neurol India 62 19 25 2014 24608449 \n12. Joerger M Huitema ADR Illerhaus G et al Rational administration schedule for high-dose methotrexate in patients with primary central nervous system lymphoma Leuk Lymphoma 53 1867 1875 2012 22530664 \n13. Powari M Radotra B Das A et al A study of primary central nervous system lymphoma in Northern India Surg Neurol 57 113 116 2002 11904205 \n14. Paul T Challa S Tandon A et al Primary central nervous system lymphomas: Indian experience, and review of literature Indian J Cancer 45 112 118 2008 19018115 \n15. Pasricha S Gupta A Gawande J et al Primary central nervous system lymphoma: A study of clinicopathological features and trend in Western India Indian J Cancer 48 199 203 2011 21768666 \n16. Sarkar C Sharma MC Deb P et al Primary central nervous system lymphoma: A hospital-based study of incidence and clinicopathological features from India (1980-2003) J Neurooncol 71 199 204 2005 15690139 \n17. Adhikari N Biswas A Gogia A et al A prospective phase II trial of response adapted whole-brain radiotherapy after high dose methotrexate based chemotherapy in patients with newly diagnosed primary central nervous system lymphoma: Analysis of acute toxicity profile and early clinical outcome J Neurooncol 139 153 166 2018 29633112 \n18. Shah GD Yahalom J Correa DD et al Combined immunochemotherapy with reduced whole-brain radiotherapy for newly diagnosed primary CNS lymphoma J Clin Oncol 25 4730 4735 2007 17947720 \n19. Agarwal PA Menon S Smruti BK et al Primary central nervous system lymphoma: A profile of 26 cases from Western India Neurol India 57 756 763 2009 20139505 \n20. Puligundla CK Bala S Karnam AK et al Clinicopathological features and outcomes in primary central nervous system lymphoma: A 10-year experience Indian J Med Paediatr Oncol 38 478 482 2017 29333016 \n21. Rudresha AH Chaudhuri T Lakshmaiah KC et al Primary central nervous system lymphoma in immunocompetent patients: A regional cancer center experience South Asian J Cancer 6 165 168 2017 29404295 \n22. Patel B Chacko G Nair S et al Clinicopathological correlates of primary central nervous system lymphoma: Experience from a tertiary care center in South India Neurol India 63 77 82 2015 25751474 \n23. Lanjewar DN Jain PP Shetty CR Profile of central nervous system pathology in patients with AIDS: An autopsy study from India AIDS 12 309 313 1998 9517994 \n24. Mahadevan A Rao CR Shanmugham M et al Primary central nervous system diffuse large B-cell lymphoma in the immunocompetent: Immunophenotypic subtypes and Epstein-Barr virus association J Neurosci Rural Pract 6 8 14 2015 25552844 \n25. Bataille B Delwail V Menet E et al Primary intracerebral malignant lymphoma: Report of 248 cases J Neurosurg 92 261 266 2000 10659013 \n26. Ferreri AJM Reni M Pasini F et al A multicenter study of treatment of primary CNS lymphoma Neurology 58 1513 1520 2002 12034789 \n27. Sharma MC Gupta RK Kaushal S et al A clinicopathological study of primary central nervous system lymphomas and their association with Epstein-Barr virus Indian J Med Res 143 605 615 2016 27488004 \n28. Bellinzona M Roser F Ostertag H et al Surgical removal of primary central nervous system lymphomas (PCNSL) presenting as space occupying lesions: A series of 33 cases Eur J Surg Oncol 31 100 105 2005 15642434 \n29. Weller M Martus P Roth P et al Surgery for primary CNS lymphoma? Challenging a paradigm Neuro-oncol 14 1481 1484 2012 22984018 \n30. Lai R Rosenblum MK DeAngelis LM Primary CNS lymphoma: A whole-brain disease? Neurology 59 1557 1562 2002 12451197 \n31. Ferreri AJM Reni M Foppoli M et al High-dose cytarabine plus high-dose methotrexate versus high-dose methotrexate alone in patients with primary CNS lymphoma: A randomised phase 2 trial Lancet 374 1512 1520 2009 19767089 \n32. Lionakis MS Dunleavy K Roschewski M et al Inhibition of B-cell receptor signaling by ibrutinib in primary CNS lymphoma Cancer Cell 31 833 843.e5 2017 28552327\n\n",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D016543:Central Nervous System Neoplasms; D059248:Chemoradiotherapy; D005260:Female; D006801:Humans; D007194:India; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Primary CNS Lymphoma in India: A 17-Year Experience From the All India Institute of Medical Sciences.",
"title_normalized": "primary cns lymphoma in india a 17 year experience from the all india institute of medical sciences"
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"abstract": "Routine prenatal care in the United States includes screening for asymptomatic bacteriuria (ASB), which occurs in 2 to 7 percent of pregnant women and can cause urinary tract infection and pyelonephritis. We present the case of a pregnant woman affected by multidrug resistant Klebsiella induced ASB during her prenatal screen, which was untreated due to a repeat urine culture showing mixed flora; subsequently, the patient's postpartum course was complicated by pyelonephritis and perinephric abscess, concluding in a radical nephrectomy. Current recommendations are to treat ASB after two consecutive voided urine cultures showing the same bacterial strain in quantitative counts of =/> 10(5) colony forming units (cfu)/mL or a single-catheterized specimen with quantitative count of =/> 10(2) cfu/mL. For women with ASB in their prenatal screen or other high risk factors, consideration should be given to testing urine cultures every trimester until the completion of pregnancy to prevent the complications of persistent bacteriuria.",
"affiliations": "Mayo Clinic, Department of Obstetrics and Gynecology, Rochester, MN, USA.;Mayo Clinic, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Rochester, MN, USA.;Mayo Clinic, Department of Obstetrics and Gynecology, Rochester, MN, USA.;Mayo Clinic, Department of Obstetrics and Gynecology, Rochester, MN, USA.",
"authors": "Kim|Sharon J|SJ|0000-0003-4151-0069;Parikh|Pavan|P|;King|Amanda N|AN|;Marnach|Mary L|ML|",
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"doi": "10.1155/2018/8924823",
"fulltext": "\n==== Front\nCase Rep Obstet GynecolCase Rep Obstet GynecolCRIOGCase Reports in Obstetrics and Gynecology2090-66842090-6692Hindawi 10.1155/2018/8924823Case ReportAsymptomatic Bacteriuria in Pregnancy Complicated by Pyelonephritis Requiring Nephrectomy http://orcid.org/0000-0003-4151-0069Kim Sharon J. kim.sharon@mayo.edu\n1\nParikh Pavan \n2\nKing Amanda N. \n1\nMarnach Mary L. \n1\n\n1Mayo Clinic, Department of Obstetrics and Gynecology, Rochester, MN, USA\n2Mayo Clinic, Department of Obstetrics and Gynecology, Division of Maternal Fetal Medicine, Rochester, MN, USAAcademic Editor: Seung-Yup Ku\n\n2018 19 9 2018 2018 89248231 4 2018 24 7 2018 Copyright © 2018 Sharon J. Kim et al.2018This 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.Routine prenatal care in the United States includes screening for asymptomatic bacteriuria (ASB), which occurs in 2 to 7 percent of pregnant women and can cause urinary tract infection and pyelonephritis. We present the case of a pregnant woman affected by multidrug resistant Klebsiella induced ASB during her prenatal screen, which was untreated due to a repeat urine culture showing mixed flora; subsequently, the patient's postpartum course was complicated by pyelonephritis and perinephric abscess, concluding in a radical nephrectomy. Current recommendations are to treat ASB after two consecutive voided urine cultures showing the same bacterial strain in quantitative counts of =/> 10(5) colony forming units (cfu)/mL or a single-catheterized specimen with quantitative count of =/> 10(2) cfu/mL. For women with ASB in their prenatal screen or other high risk factors, consideration should be given to testing urine cultures every trimester until the completion of pregnancy to prevent the complications of persistent bacteriuria.\n==== Body\n1. Introduction\nScreening for asymptomatic bacteriuria (ASB) is part of routine prenatal care in the United States, as ASB occurs in 2 to 7 percent of pregnant women [1, 2]. Up to 40% of untreated pregnant women with ASB will develop a urinary tract infection (UTI), including pyelonephritis, with 80 percent risk reduction if bacteriuria is eradicated forming the basis for ACOG treatment recommendations [1–4].\n\nIn the absence of strong risk factors for recurrent or persistent bacteriuria such as sickle cell trait or renal transplantation, there is no guidance available to inform the care of other patients at moderately increased risk. These risk factors include a history of prior UTI, nulliparity, pre-existing diabetes mellitus, smoking, late presentation to care, and low socioeconomic status [3, 5–7]. Herein, we discuss the case of a woman affected by multidrug resistant Klebsiella induced ASB untreated in the antenatal period, leading to pyelonephritis and perinephric abscesses and concluding in radical nephrectomy in the postpartum period.\n\n2. Case Presentation\nThe patient is a 30-year old now gravida 2 para 2, status post complete left nephrectomy in the setting of multidrug resistant Klebsiella urosepsis and left pyelonephritis during her immediate postpartum phase. The Anuak speaking woman immigrated from Kenya to the United States nine months prior to her second pregnancy and presented to care at 15 weeks' gestation. Her history included chronic hypertension without a previous history of UTI.\n\nAt her new obstetrical visit, a urinalysis demonstrated 4-10 white blood cells (WBC) per high power field and gram stain positivity for gram-negative bacilli and gram-positive bacilli. Urine culture yielded multidrug resistant Klebsiella pneumoniae, 10(4) to 10(5) colony forming units (cfu/mL). The organism was susceptible to quinolones, carbapenems, and piperacillin/tazobactam. An Infectious Disease consultation recommended a repeat clean catch culture with treatment using IV ertapenem if the culture showed the same organism. The repeat urine culture showed mixed flora without a specific organism identified. Because the patient remained asymptomatic, she did not have an additional gram stain or urine culture through the remainder of pregnancy.\n\nAt 37 weeks' gestation, the patient developed superimposed preeclampsia and underwent induction of labor with a normal spontaneous vaginal delivery without complications. On postpartum day (PPD) 0, she was afebrile but reported left sided abdominal and flank pain. A urine culture on PPD1 was positive for multidrug resistant Klebsiella/Raoultella species (sp) > 10(5) cfu/mL and sensitive to quinolones, gentamicin, and piperacillin/tazobactam. She began PO ciprofloxacin 500 mg twice daily with creatinine rising to 1.1. By PPD3, she continued to have abdominal and flank pain with creatinine rise to 1.5, and based on urine culture sensitivities, antibiotic was changed from ciprofloxacin to PO levofloxacin 500 mg daily. By PPD4 she developed new onset tachycardia, tachypnea, fever of 38.6 degrees celsius, and continued pain. As such, she was transferred to the intensive care unit with lactate 2.8 and WBC 18,000 and started on IV piperacillin/tazobactam 3.375 grams every 6 hours. A chest computerized tomography (CT) was negative for pulmonary embolism, showing a moderate left pleural effusion, and abdominal/pelvic CT compatible with pyelonephritis but no abscess. Blood cultures were positive for Klebsiella/Raoultella sp. On PPD5, when stable, she was transferred to the postpartum unit and switched to IV meropenem 500 mg every 6 hours due to persistent fevers. On PPD7, with ongoing fevers, tachycardia, and pain, a left kidney ultrasound confirmed a 5.1 cm left subcapsular abscess which was aspirated 30 cc of purulent discharge. An echocardiogram for endocarditis and HIV testing were negative. By PPD9, with continued fevers to 39.3 degrees celsius, abdominal CT imaging was concerning for left renal multifocal infection and parenchymal necrosis (Figure 1). On PPD10, after Urology and Maternal Fetal Medicine consultations, the patient underwent an open left nephrectomy. Pathology confirmed severe diffuse pyelonephritis, multifocal abscesses, and diffuse parenchymal infarction (Figure 2).\n\nThe patient recovered well thereafter with symptom resolution, creatinine 1.0, and was discharged on postoperative day 3 with a 14-day course of IV ertapenem 1 gram daily.\n\n3. Discussion\nWhile our patient's early pregnancy urine culture demonstrated multidrug resistant Klebsiella pneumonia complex at 10(4) to 10(5) cfu/ml, she was not treated antenatally due to a repeat urine culture showing mixed flora likely related to inappropriate collection technique [8]. Through the remainder of her pregnancy, she had no urinary symptoms and no additional gram stain or urine culture was obtained until complaint of left abdominal and flank pain on the night of delivery.\n\nThe immunosuppression of pregnancy, mechanical bladder compression, and ureteral dilatation facilitates the ascent of bacteria resulting in a 20-fold increased risk of pyelonephritis in gravidas [2, 7, 9, 10]. For asymptomatic women, bacteriuria is defined as two consecutive voided urine specimens with isolation of the same bacterial strain in quantitative counts > 10(5) cfu/ml or a single-catheterized urine specimen with one bacterial species isolated in a quantitative count of =/> 10(2) cfu/mL[2]. In typical practice, however, only one voided urine specimen is usually obtained and diagnosis is made with =/> 10(5) cfu/mL without obtaining a confirmatory repeat urine culture. Asymptomatic bacteriuria > 10(5) cfu/ml is treated with an antibiotic tailored to the susceptibility of the isolated organism [4]. The threshold for diagnosis and treatment of asymptomatic bacteriuria due to group B Streptococcus, during pregnancy, is lower at =/> 10(4) cfu/mL [11].\n\nIn this patient's particular case, a repeat culture revealed mixed flora. While the general interpretation of mixed flora is one that does not need to be followed up, it should be emphasized that the more appropriate interpretation is that the culture is contaminated and must be repeated especially in the case with a prior positive test. Further, positive cultures that have been treated should be repeated to ensure appropriate clearance of the pathogen. The timing for this is as yet undetermined [2]; however 1 to 2 weeks following completion of antibiotic therapy is reasonable. In our case, empiric treatment of multidrug resistant Klebsiella would have been inappropriate as it is normal skin flora; yet, ensuring that the culture was truly negative thereafter should have been a priority to reduce the subsequent morbidity experienced by the patient and staying true to the core value of antibiotic stewardship.\n\nProper management of ASB during pregnancy is critical to decrease the risks of maternal and neonatal adverse events. Suspicion for renal or perinephric abscess should arise when there are prolonged fever and flank pain, despite antimicrobial therapy [12]. When renal abscesses are less than 5 cm in diameter, antimicrobial therapy alone may be adequate initial management [13, 14]. When clinical symptoms persist after several days of antimicrobial therapy, percutaneous drainage of abscesses less than 5 cm should be considered. Patients with renal abscesses greater than 5 cm should be managed with percutaneous drainage in conjunction with antimicrobial therapy [14, 15]. In the antepartum period, ultrasound imaging should be considered to evaluate for structural abnormalities. Computed tomography with contrast enhancement is the ideal imaging for assessing a perinephric abscess and the extension of suppuration; however, in the antepartum period, the risks of fetal harm should be weighed [14, 16, 17]. Early surgical consultation is recommended for abscesses not amenable to drainage, anatomic abnormalities, or failed medical treatment.\n\nFor low-risk women with a negative urine test in their initial prenatal visit, rescreening for ASB is not indicated. For women with ASB in their prenatal screen or other risk factors, consideration should be given to urine cultures performed every trimester until the completion of pregnancy.\n\nData Availability\nData sharing is not applicable to this article as no datasets were generated or analyzed for this case report.\n\nConsent\nInformed consent was obtained from the patient included in the study.\n\nConflicts of Interest\nThe authors declare they have no conflicts of interest.\n\nFigure 1 CT of abdomen, axial and sagittal views, with findings of multifocal areas of parenchymal infection and necrosis to left kidney∗.\n\nFigure 2 Renal parenchyma shows severe acute pyelonephritis with multifocal abscess formation and multifocal renal infarction.\n==== Refs\n1 Nicolle L. E. Asymptomatic bacteriuria: when to screen and when to treat Infectious Disease Clinics of North America 2003 17 2 367 394 10.1016/S0891-5520(03)00008-4 2-s2.0-0038270588 12848475 \n2 Nicolle L. E. Bradley S. Colgan R. Rice J. C. Schaeffer A. Hooton T. M. Infectious diseases society of America guidelines for the diagnosis and treatment of asymptomatic bacteriuria in adults Clinical Infectious Diseases 2005 40 5 643 654 10.1086/427507 2-s2.0-15044349313 15714408 \n3 Wing D. A. Fassett M. J. Getahun D. Acute pyelonephritis in pregnancy: An 18-year retrospective analysis American Journal of Obstetrics & Gynecology 2014 210 3 219.e1 219.e6 2-s2.0-84896705919 24100227 \n4 Smaill F. M. Vazquez J. C. Antibiotics for asymptomatic bacteriuria in pregnancy Cochrane Database of Systematic Reviews 2015 2015 8 2-s2.0-84991221072 \n5 Schnarr J. Smaill F. Asymptomatic bacteriuria and symptomatic urinary tract infections in pregnancy European Journal of Clinical Investigation 2008 38 2 50 57 2-s2.0-52649157594 10.1111/j.1365-2362.2008.02009.x 18826482 \n6 Thurman A. R. Steed L. L. Hulsey T. Soper D. E. Bacteriuria in pregnant women with sickle cell trait American Journal of Obstetrics & Gynecology 2006 194 5 1366 1370 2-s2.0-33646114738 10.1016/j.ajog.2005.11.022 16647923 \n7 Farkash E. Weintraub A. Y. Sergienko R. Wiznitzer A. Zlotnik A. Sheiner E. Acute antepartum pyelonephritis in pregnancy: A critical analysis of risk factors and outcomes European Journal of Obstetrics & Gynecology and Reproductive Biology 2012 162 1 24 27 2-s2.0-84859885714 10.1016/j.ejogrb.2012.01.024 22381037 \n8 American College of Obstetrics and Gynecology Committee on Obstetrical Practice ACOG Committee Opinion No. 91: Treatment of urinary tract infections in nonpregnant women Obstetrics & Gynecology 2008 111 3 785 794 10.1097/aog.0b013e318169f6ef 18310389 \n9 Sweet R. L. Bacteriuria and pyelonephritis during pregnancy Semin Perinatol 1977 1 25 218305 \n10 Petersson C. Hedges S. Stenqvist K. Suppressed antibody and interleukin-6 responses to acture pyelonephritis in pregnancy Kidney International 1994 45 2 571 577 10.1038/ki.1994.74 2-s2.0-0027957242 8164447 \n11 American College of Obstetricians and Gynecologists Committee on Obstetric Practice ACOG Committee Opinion no. 485: prevention of early-onset group B streptococcal disease in newborns Obstetrics & Gynecology 2011 117 4 1019 1027 10.1097/AOG.0b013e318219229b 21422882 \n12 Lee B. E. Seol H. Y. Kim T. K. Recent clinical overview of renal and perirenal abscesses in 56 consecutive cases Korean Journal of Internal Medicine 2008 23 3 140 148 2-s2.0-52649167903 10.3904/kjim.2008.23.3.140 18787367 \n13 Lee S. H. Jung H. J. Mah S. Y. Chung B. H. Renal abscesses measuring 5 cm or less: Outcome of medical treatment without therapeutic drainage Yonsei Medical Journal 2010 51 4 569 573 2-s2.0-77956210290 10.3349/ymj.2010.51.4.569 20499424 \n14 Dalla Palma L. Pozzi-Mucelli F. Ene V. Medical treatment of renal and perirenal abscesses: CT evaluation Clinical Radiology 1999 54 12 792 797 2-s2.0-0033385912 10.1016/S0009-9260(99)90680-3 10619293 \n15 Meng M. V. Mario L. A. McAninch J. W. Current treatment and outcomes of perinephric abscesses The Journal of Urology 2002 168 p. 1337 10.1016/S0022-5347(05)64443-6 2-s2.0-0036784309 \n16 Siegel J. F. Smith A. Moldwin R. Minimally invasive treatment of renal abscess The Journal of Urology 1996 155 1 52 55 2-s2.0-0029655812 7490896 \n17 Demertzis J. Menias C. O. State of the art: Imaging of renal infections Emergency Radiology 2007 14 1 13 22 2-s2.0-34147153741 10.1007/s10140-007-0591-3 17318482\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6692",
"issue": "2018()",
"journal": "Case reports in obstetrics and gynecology",
"keywords": null,
"medline_ta": "Case Rep Obstet Gynecol",
"mesh_terms": null,
"nlm_unique_id": "101576454",
"other_id": null,
"pages": "8924823",
"pmc": null,
"pmid": "30327737",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "12352387;26252501;16647923;18310389;21422882;12848475;22381037;7490896;18787367;10619293;24100227;8164447;370987;17318482;20499424;15714408;18826482",
"title": "Asymptomatic Bacteriuria in Pregnancy Complicated by Pyelonephritis Requiring Nephrectomy.",
"title_normalized": "asymptomatic bacteriuria in pregnancy complicated by pyelonephritis requiring nephrectomy"
} | [
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"activesubstancename": "CIPROFLOXACIN HYDROCHLORIDE"
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