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"abstract": "In a two-part process, we assessed elements of the principal hormonal pathway regulating iron homeostasis in human neonates. Part 1: Quantifying erythropoietin (Epo), erythroferrone (ERFE), hepcidin, and relevant serum and erythrocytic iron-related metrics in umbilical cord blood from term (n = 13) and preterm (n = 10) neonates, and from neonates born to mothers with diabetes and obesity (n = 13); Part 2: Quantifying serum Epo, ERFE, and hepcidin before and following darbepoetin administration. Part 1: We measured Epo, ERFE and hepcidin in all cord blood samples. Epo and ERFE levels did not differ between the three groups. Preterm neonates had the lowest hepcidin levels, while neonates born to diabetic women with a very high BMI had the lowest ferritin and RET-He levels. Part 2: Following darbepoetin dosing, ERFE levels generally increased (p < 0.05) and hepcidin levels generally fell (p < 0.05). Our observations suggest that the Epo/ERFE/hepcidin axis is intact in the newborn period.",
"affiliations": "Division of Neonatology, University of Utah Health, Salt Lake City, UT, USA. Electronic address: Tim.Bahr@hsc.utah.edu.;Department of Pathology, University of Utah Health, Salt Lake City, UT, USA; Center for Iron and Heme Disorders, University of Utah, Salt Lake City, UT, USA.;Department of Pathology, University of Utah Health, Salt Lake City, UT, USA.;Division of Neonatology, University of Utah Health, Salt Lake City, UT, USA.;Division of Neonatology, Department of Pediatrics, University of Washington, Seattle, WA, USA.;Division of Neonatology, University of Utah Health, Salt Lake City, UT, USA; Division of Hematology/Oncology, Department of Pediatrics, University of Utah Health, Salt Lake City, UT, USA; Center for Iron and Heme Disorders, University of Utah, Salt Lake City, UT, USA; Women and Newborns Research, Intermountain Healthcare, Murray, UT, USA.",
"authors": "Bahr|Timothy M|TM|;Ward|Diane M|DM|;Jia|Xuan|X|;Ohls|Robin K|RK|;German|Kendell R|KR|;Christensen|Robert D|RD|",
"chemical_list": "C554270:EPO protein, human; C000600298:Erfe protein, human; C578702:HAMP protein, human; D064451:Hepcidins; D036361:Peptide Hormones; D004921:Erythropoietin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bcmd.2021.102536",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-9796",
"issue": "88()",
"journal": "Blood cells, molecules & diseases",
"keywords": "Erythroferrone; Erythropoietin; Hepcidin; Iron; RET-He; Supplementation",
"medline_ta": "Blood Cells Mol Dis",
"mesh_terms": "D004921:Erythropoietin; D005260:Female; D005312:Fetal Blood; D064451:Hepcidins; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D009765:Obesity; D036361:Peptide Hormones; D011247:Pregnancy; D011248:Pregnancy Complications; D011254:Pregnancy in Diabetics; D047928:Premature Birth; D015398:Signal Transduction",
"nlm_unique_id": "9509932",
"other_id": null,
"pages": "102536",
"pmc": null,
"pmid": "33450539",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Is the erythropoietin-erythroferrone-hepcidin axis intact in human neonates?",
"title_normalized": "is the erythropoietin erythroferrone hepcidin axis intact in human neonates"
} | [
{
"companynumb": "US-AMGEN-USASP2021078786",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DARBEPOETIN ALFA"
},
"drugadditional": "3",
... |
{
"abstract": "Rhabdomyolysis is a syndrome characterized by muscle necrosis which causes the release of myoglobin into the bloodstream. The manifestations of this syndrome range from asymptomatic elevation of serum muscle enzymes to life-threatening cases associated with extremely high enzyme levels, electrolyte imbalance, and acute renal failure. Symptoms of rhabdomyolysis include dark urine, muscle weakness, and fatigue. Statins are commonly used drugs for the prevention and management of dyslipidemia. We present an interesting and critical case on statin-induced rhabdomyolysis with renal failure and previously undiagnosed idiopathic hypothyroidism.",
"affiliations": "Department of Critical Care, Dr. L H Hiranandani Hospital, Mumbai, Maharashtra, India.;Department of Critical Care, Dr. L H Hiranandani Hospital, Mumbai, Maharashtra, India.;Department of Critical Care, Dr. L H Hiranandani Hospital, Mumbai, Maharashtra, India.;Lead Medical, Asia Pacific region, Ferring Pharmaceuticals Pvt. Ltd., Mumbai, Maharashtra, India.",
"authors": "Ambapkar|Sachinkumar N|SN|;Shetty|Naresh|N|;Dwivedy|Arpita|A|;Malve|Harshad Onkarrao|HO|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0972-5229.182210",
"fulltext": "\n==== Front\nIndian J Crit Care MedIndian J Crit Care MedIJCCMIndian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine0972-52291998-359XMedknow Publications & Media Pvt Ltd India IJCCM-20-30510.4103/0972-5229.182210Case ReportStatin-induced rhabdomyolysis in patient with renal failure and underlying undiagnosed hypothyroidism Ambapkar Sachinkumar N. Shetty Naresh Dwivedy Arpita Malve Harshad Onkarrao 1From: Department of Critical Care, Dr. L H Hiranandani Hospital, Mumbai, Maharashtra, India1 Lead Medical, Asia Pacific region, Ferring Pharmaceuticals Pvt. Ltd., Mumbai, Maharashtra, IndiaCorrespondence: Dr. Harshad Onkarrao Malve, Ferring Pharmaceuticals Pvt. Ltd., 24th Floor, Sunshine Towers, Senapati Bapat Marg, Elphinstone (West), Mumbai - 400 013, Maharashtra, India. E-mail: dr.harshad.malve@gmail.com5 2016 20 5 305 307 Copyright: © Indian Journal of Critical Care Medicine2016This 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.Rhabdomyolysis is a syndrome characterized by muscle necrosis which causes the release of myoglobin into the bloodstream. The manifestations of this syndrome range from asymptomatic elevation of serum muscle enzymes to life-threatening cases associated with extremely high enzyme levels, electrolyte imbalance, and acute renal failure. Symptoms of rhabdomyolysis include dark urine, muscle weakness, and fatigue. Statins are commonly used drugs for the prevention and management of dyslipidemia. We present an interesting and critical case on statin-induced rhabdomyolysis with renal failure and previously undiagnosed idiopathic hypothyroidism.\n\nAtorvastatinfoot dropmyopathymyositis\n==== Body\nIntroduction\nStatins have become the most widely prescribed drug worldwide since its introduction in 1987.[1] They are effective and generally safe. Rhabdomyolysis though rare is the most severe form of myotoxicity, which can occur with all statins, either in monotherapy or in combination therapy.[23] The US Food and Drug Administration Adverse Event Reporting System database reports rates of statin-induced rhabdomyolysis of 0.3–13.5 cases per 1,000,000 statin prescriptions.[1] We report a case of atorvastatin-induced rhabdomyolysis with renal failure precipitated by underlying undiagnosed hypothyroidism. We also discuss the pathogenesis, clinical features, and management of such cases.\n\nCase Report\nA 74-year-old male patient was admitted with complaints of progressive swelling all over the body associated with pain and stiffness in the limbs for 2 weeks. He had history of oliguria and constipation for 4 days. His past medical history included hypertension, acid peptic disease, and cholecystectomy. Ongoing medications were amlodipine, olmesartan, hydrochlorothiazide, and pantoprazole. Atorvastatin 20 mg was added 15 days prior to his symptom onset. There was no other significant history.\n\nOn examination, he had tachypnea, tachycardia, and high blood pressure. Nonpitting subcutaneous edema with severe muscle tightness and rigidity was noted. Reflexes were suppressed. Other systems were unremarkable. Investigations on admission revealed hemoglobin 14.3 g/dl, hematocrit 42.5%, total leukocyte count 22400/mm3 (neutrophil 90, lymphocyte 9), platelet 2.28 lakhs/mm3, erythrocyte sedimentation rate 5, creatinine 1.13 mg/dl, blood urea nitrogen 12.5 mg/dl, sodium 105.1 mmol/L, potassium 4.5 mmol/L, bilirubin 1.1 mg/dl, total protein 5.1 g/dl, albumin 2.94 g/dl, serum glutamic oxaloacetic transaminase/serum glutamate pyruvate transaminase 2688/468 U/L, calcium 8.84 mg/dl, creatinine phosphokinase (CPK) 192,000 U/L, thyroid-stimulating hormone 70.5 mIU/L, FT3 1.32 nmol/L, and FT4 <0.88 nmol/L. Urine high-colored, positive for protein and red blood cell, urine myogobin-positive, serum antinuclear antibody negative, high anti-thyroperoxidase antibody were observed. Leptospirosis IgM and IgG were negative. Vitamin D was normal.\n\nOn the basis of history, clinical findings, and laboratory reports – diagnosis of atorvastatin-induced rhabdomyolysis with underlying hypothyroidism was made. Hypothyroidism was diagnosed for the first time on the present admission and it was idiopathic. Eltroxin 75 µg OD was added and then increased to 125 µg OD over a few days.\n\nMagnetic resonance imaging was done which showed diffuse swelling and abnormal signal involving almost all muscles of both lower limbs with increased T2/short tau inversion recovery signal intensity and low T1 signal intensity. Areas of breakdown with liquefied necrosis were seen. All these features were consistent with diffuse myositis with muscle necrosis.\n\nAtorvastatin was discontinued; intravenous hydration with alkalization of urine was initiated with electrolyte correction. He was put on thyroxin supplements and symptomatic treatment. He gradually improved with symptoms resolving over next 2 weeks. His CPK levels were serially monitored which normalized to 116 after 1 month. During the course of illness, creatinine increased to 3.95 which eventually normalized over a period of time. Deranged liver enzymes returned to normal limits within 2 weeks. He developed urosepsis which was successfully treated with appropriate antibiotics. His recovery was uneventful except for bilateral foot drop.\n\nDiscussion\nThe clinical spectrum of statin-induced myopathy ranges from myalgia, myositis, and rhabdomyolysis to asymptomatic increase in the concentration of creatine kinase (CK). Symptoms include fatigue, muscle pain, muscle tenderness, muscle weakness, nocturnal cramping, and tendon pain.[2] The muscle symptoms tend to be proximal, generalized, and worse with exercise. The mean duration of statin therapy before onset of symptoms ranges from 1 to 60 days.[2] The mean duration of myalgia after stopping statin therapy ranges from 1 week to 4 months. Risk factors for precipitating myopathy include advanced age, female sex, low body mass index, diminished hepatic and renal function, multiple comorbidities (untreated hypothyroidism, diabetes etc.), medications, excess alcohol, intercurrent infections, surgery or trauma, drug interactions, and dietary effect.[2]\n\nThe mechanism of statin-induced myopathy is unknown. Several theories have been proposed which include impaired synthesis of cholesterol leading to changes in the cholesterol in myocyte membranes and behavior of the membrane. Second, impaired synthesis of compounds in the cholesterol pathway—in particular, deficiency of coenzyme Q10 (CoQ10) (ubiquinone) which could lead to impaired enzyme activity in mitochondria.[4] A third mechanism is depletion of isoprenoids (lipids that are a product of the hydroxymethylglutaryl coenzyme A reductase pathway) which prevents myofibril apoptosis.[4] Furthermore, pharmacodynamic factors, such as transporters affecting the bioavailability of statins, are probably important in determining toxicity although no direct evidence has been found in humans. Drug responses can also be affected by predisposing genetic factors. In vitro and in vivo experiments suggest that lipophilic statins (for example, simvastatin, atorvastatin, lovastatin) are more likely to produce muscular effects than are relatively hydrophilic agents (such as pravastatin, rosuvastatin, and fluvastatin). Lipophilic compounds are more likely to penetrate into muscle tissue, enhancing the potential for myotoxic effects.[34] Therefore, it is prudent to use a more hydrophilic agent in patients with preexisting muscle disease.\n\nFor most patients, myopathy symptoms induced by statin therapy resolve relatively quickly; however, the results of the PRIMO study showed that it may take up to 2 months for resolution of symptoms.[5] There is limited evidence regarding the treatment of statin-associated myopathy. While in most cases myopathy caused by statins is mild and can be reversed when the medication is discontinued, it may present as rhabdomyolysis or severe muscle damage as in the case mentioned. The mainstay of treatment consists of cessation of statins; however, it is prudent for clinicians to rule out other conditions that can cause myopathy and/or CK elevations such as hypothyroidism (as in this case), overt physical activity, and alcohol abuse.[2] Patients who present with clinically significant rhabdomyolysis require hospitalization and intravenous hydration to prevent renal damage.[6]\n\nOnce the patient's muscle symptoms have resolved, clinicians have several options to treat that patient's dyslipidemia, including the use of a lower dose of the same statin, initiation of a different statin, and/or utilization of nonstatin lipid-lowering agents.[6] Failure to achieve the target low density lipoprotein goal with statins can be augmented with drugs such as ezetimibe or bile-acid binding resins. The use of fibrates and niacin as monotherapy has been associated with myopathy. Clinical experience indicates that there may be an increased risk of myotoxicity associated with statin and fibrate combination therapy.[7] Therefore, bile-acid resins may be the optimal choice in those patients without triglyceride abnormalities who cannot tolerate statin therapy.[8] CoQ10 supplementation is tried in experimental studies and found to be successful in significantly reducing CK and aspartate aminotransferase levels in serum.[9] There has also been interest in the use of CoQ10, Chinese red rice yeast, and Vitamin D as prevention and/or management of statin-associated myopathy although there is no definite evidence.\n\nA similar case of statin-induced bilateral foot drop in a case of hypothyroidism is published by Chaudhary et al.[10] The present case study highlights the similar findings, thus warrants precautions for use of statins in such patients.\n\nConclusion\nStatin-induced rhabdomyolysis although rare can sometimes present as a life-threatening condition. Thus, clinicians should be vigilant about this critical complication and associated precipitating factors such as hypothyroidism.\n\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Jukema JW Cannon CP de Craen AJ Westendorp RG Trompet S The controversies of statin therapy: Weighing the evidence J Am Coll Cardiol 2012 60 875 81 22902202 \n2 Mendes P Robles PG Mathur S Statin-induced rhabdomyolysis: A comprehensive review of case reports Physiother Can 2014 66 124 32 24799748 \n3 Holder K Myalgias and myopathies: Drug-induced myalgias and myopathies FP Essent 2016 440 23 7 26734833 \n4 Päivä H Thelen KM Van Coster R Smet J De Paepe B Mattila KM High-dose statins and skeletal muscle metabolism in humans: A randomized, controlled trial Clin Pharmacol Ther 2005 78 60 8 16003294 \n5 Bruckert E Hayem G Dejager S Yau C Bégaud B Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study Cardiovasc Drugs Ther 2005 19 403 14 16453090 \n6 Harper CR Jacobson TA Evidence-based management of statin myopathy Curr Atheroscler Rep 2010 12 322 30 20628837 \n7 Dedhia V Munsi SC Myopathy caused by a combination rosuvastatin and fenofibrate J Assoc Physicians India 2007 55 152 3 17571748 \n8 Bays H Statin safety: An overview and assessment of the data-2005 Am J Cardiol 2006 97 6C 26C \n9 Choi HK Won EK Choungsss SY Effect of coenzyme Q10 supplementation in statin-treated obese rats Biomol Ther (Seoul) 2016 24 171 7 26797109 \n10 Chaudhary N Duggal AK Makhija P Puri V Khwaja GA Statin-induced bilateral foot drop in a case of hypothyroidism Ann Indian Acad Neurol 2015 18 331 4 26425013\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-5229",
"issue": "20(5)",
"journal": "Indian journal of critical care medicine : peer-reviewed, official publication of Indian Society of Critical Care Medicine",
"keywords": "Atorvastatin; foot drop; myopathy; myositis",
"medline_ta": "Indian J Crit Care Med",
"mesh_terms": null,
"nlm_unique_id": "101208863",
"other_id": null,
"pages": "305-7",
"pmc": null,
"pmid": "27275082",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports",
"references": "16581330;20628837;16453090;24799748;17571748;22902202;26425013;16003294;26797109;26734833",
"title": "Statin-induced rhabdomyolysis in patient with renal failure and underlying undiagnosed hypothyroidism.",
"title_normalized": "statin induced rhabdomyolysis in patient with renal failure and underlying undiagnosed hypothyroidism"
} | [
{
"companynumb": "IN-DRREDDYS-USA/IND/16/0080787",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional... |
{
"abstract": "Vancomycin is a first-line drug for treating methicillin-resistant Staphylococcus aureus. Thrombocytopenia is a rare adverse reaction to vancomycin treatment, and there are no reports of vancomycin-induced thrombocytopenia (VIT) in infants. We describe the case of a 3-month-old girl who was diagnosed with purulent meningitis. After 13 days of treatment with vancomycin, her platelet count reduced to 8 × 109/L. Vancomycin was discontinued, and intravenous methylprednisolone was administered. The platelet count returned to normal after 4 days. Patients, especially young children, receiving vancomycin for a long clinical course should undergo careful monitoring of laboratory indicators and blood tests.",
"affiliations": "Department of Pharmacy, Xiamen Maternity and Child Care Hospital, Xiamen, Fujian, China.;Department of Pharmacy, Xiamen Maternity and Child Care Hospital, Xiamen, Fujian, China.;Department of Pharmacy, Xiamen Maternity and Child Care Hospital, Xiamen, Fujian, China.;Department of Pharmacy, Xiamen Maternity and Child Care Hospital, Xiamen, Fujian, China.;Department of Pharmacy, Xiamen Maternity and Child Care Hospital, Xiamen, Fujian, China.",
"authors": "Chen|Quan-Yao|QY|;Wan|Jun|J|;Yang|Jian-Hui|JH|;Lin|Min|M|;Chen|Yao|Y|",
"chemical_list": "D014640:Vancomycin",
"country": "Brazil",
"delete": false,
"doi": "10.1590/0037-8682-0150-2018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0037-8682",
"issue": "51(6)",
"journal": "Revista da Sociedade Brasileira de Medicina Tropical",
"keywords": null,
"medline_ta": "Rev Soc Bras Med Trop",
"mesh_terms": "D005260:Female; D006801:Humans; D007223:Infant; D016920:Meningitis, Bacterial; D012720:Severity of Illness Index; D013921:Thrombocytopenia; D013997:Time Factors; D014640:Vancomycin",
"nlm_unique_id": "7507456",
"other_id": null,
"pages": "873-875",
"pmc": null,
"pmid": "30517547",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Vancomycin-induced severe thrombocytopenia in a young infant.",
"title_normalized": "vancomycin induced severe thrombocytopenia in a young infant"
} | [
{
"companynumb": "CN-MYLANLABS-2019M1002759",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "Dexmedetomidine (DEX) is widely used in pediatric procedural sedation (PPS) by a variety of pediatric subspecialists. The objective of our study was to describe the overall rates of adverse events and serious adverse events (SAEs) when DEX is used by various pediatric subspecialists.\n\n\n\nPatients from the Pediatric Sedation Research Consortium (PSRC) database were retrospectively reviewed and children that received DEX as their primary sedation agent for elective PPS were identified. Demographic and clinical data, provider subspecialty, and sedation-related complications were abstracted. SAEs were defined as death, cardiac arrest, upper airway obstruction, laryngospasm, emergent airway intervention, unplanned hospital admission/increased level of care, aspiration, or emergency anesthesia consult. Event rates and 95% confidence intervals (CIs) were calculated.\n\n\n\nDuring the study period, 13 072 children were sedated using DEX, accounting for 5.3% of all sedation cases entered into the PSRC. Of the sedated patients, 73% were American Society of Anesthesiologists Physical Status class 1 or 2. The pediatric providers responsible for patients sedated with DEX were anesthesiologists (35%), intensivists (34%), emergency medicine physicians (12.7%), hospitalists (1.1%), and others (17%). The overall AE rate was 466/13 072 (3.6%, 95% CI 3.3% to 3.9%). The overall SAE rate was 45/13 072 (0.34%, 95% CI 0.19% to 0.037%). Airway obstruction was the most common SAE: 35/13 072 (0.27%, 95% CI 0.19% to 0.37%). Sedations were successful in 99.7% of cases.\n\n\n\nWe report the largest series of PPS using DEX outside the operating room. Within the PSRC, PPS performed using DEX has a very high success rate and is unlikely to yield a high rate of SAEs.",
"affiliations": "Department of Pediatrics, and.;Department of Pediatrics, and.;Department of Pediatrics, and Divisions of Pediatric Emergency Medicine and.;Department of Pediatrics, and Pediatric Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia;;Department of Pediatrics, Baylor College of Medicine, San Antonio, Texas;;Department of Anesthesiology, Boston Children's Hospital, Boston, Massachusetts; and.;Pediatric Emergency Medicine Associates, Children's Healthcare of Atlanta, Atlanta, Georgia.;Department of Pediatrics, and Pediatric Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia; pradip.kamat@choa.org.",
"authors": "Sulton|Carmen|C|;McCracken|Courtney|C|;Simon|Harold K|HK|;Hebbar|Kiran|K|;Reynolds|Jason|J|;Cravero|Joseph|J|;Mallory|Michael|M|;Kamat|Pradip|P|",
"chemical_list": "D006993:Hypnotics and Sedatives; D020927:Dexmedetomidine",
"country": "United States",
"delete": false,
"doi": "10.1542/hpeds.2015-0280",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2154-1671",
"issue": "6(9)",
"journal": "Hospital pediatrics",
"keywords": null,
"medline_ta": "Hosp Pediatr",
"mesh_terms": "D002170:Canada; D002675:Child, Preschool; D016292:Conscious Sedation; D016208:Databases, Factual; D020927:Dexmedetomidine; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D007223:Infant; D008297:Male; D061214:Patient Safety; D012189:Retrospective Studies; D014481:United States",
"nlm_unique_id": "101585349",
"other_id": null,
"pages": "536-44",
"pmc": null,
"pmid": "27516413",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pediatric Procedural Sedation Using Dexmedetomidine: A Report From the Pediatric Sedation Research Consortium.",
"title_normalized": "pediatric procedural sedation using dexmedetomidine a report from the pediatric sedation research consortium"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201905553",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXMEDETOMIDINE"
},
"drugadditional": "3"... |
{
"abstract": "BACKGROUND\nStimulants are the mainstay therapy for attention deficit/hyperactivity disorder (ADHD) and are associated with adrenergic side effects. There are limited data on the clinical course of patients treated for ADHD who have long-QT syndrome (LQTS), for which β-blockade is the goal of therapy.\n\n\nMETHODS\nLQTS patients from the Rochester-based LQTS Registry (open-enrollment between 1979 and 2003; follow-up from 1979 to present) treated with stimulant or nonstimulant ADHD medications (n = 48) were compared to a 2:1 age-, gender-, and QTc-duration matched LQTS control group not exposed to ADHD medications (n = 96). Kaplan-Meier and Cox proportional hazards regression analyses were used to evaluate risk of cardiac events (syncope, aborted cardiac arrest, and sudden cardiac death) in LQTS patients treated with ADHD medications.\n\n\nRESULTS\nDuring a mean follow-up of 7.9 ± 5.4 years after initiation of ADHD medication at a mean age 10.7 ±7.3 years, there was a 62% cumulative probability of cardiac events in the ADHD treatment group compared to 28% in the matched LQTS control group (P < 0.001). Time-dependent use of ADHD medication was associated with an increased risk for cardiac events (HR = 3.07; P = 0.03) in the multivariate Cox model adjusted for time-dependent β-blocker use and prior cardiac events. Subgroup gender analyses showed that time-dependent ADHD medication was associated with an increased risk in male LQTS patients (HR = 6.80, P = 0.04).\n\n\nCONCLUSIONS\nLQTS patients treated with ADHD medications have increased risk for cardiac events, particularly syncope, and this risk is augmented in males. The findings highlight the importance of heightened surveillance for LQTS patients on ADHD medications.",
"affiliations": "University of Rochester Medical Center, Heart Research Follow-Up Program, Rochester, New York.;University of Rochester Medical Center, Heart Research Follow-Up Program, Rochester, New York.;University of Rochester Medical Center, Heart Research Follow-Up Program, Rochester, New York.;University of Rochester Medical Center, Heart Research Follow-Up Program, Rochester, New York.;University of Rochester Medical Center, Heart Research Follow-Up Program, Rochester, New York.;Metro Health Campus of Case Western Reserve University, Heart and Vascular Research Center, Cleveland, Ohio, USA.",
"authors": "Zhang|Claire|C|;Kutyifa|Valentina|V|;Moss|Arthur J|AJ|;McNitt|Scott|S|;Zareba|Wojciech|W|;Kaufman|Elizabeth S|ES|",
"chemical_list": "D000697:Central Nervous System Stimulants",
"country": "United States",
"delete": false,
"doi": "10.1111/jce.12739",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1045-3873",
"issue": "26(10)",
"journal": "Journal of cardiovascular electrophysiology",
"keywords": "adrenergic side effect; attention deficit hyperactivity disorder; congenital arrhythmia; long-QT syndrome; stimulants",
"medline_ta": "J Cardiovasc Electrophysiol",
"mesh_terms": "D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D002648:Child; D015897:Comorbidity; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D009518:New York; D015995:Prevalence; D011379:Prognosis; D012042:Registries; D018570:Risk Assessment; D017678:Sex Distribution; D015996:Survival Rate; D013575:Syncope; D016896:Treatment Outcome",
"nlm_unique_id": "9010756",
"other_id": null,
"pages": "1039-44",
"pmc": null,
"pmid": "26149510",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "10606113;11136691;11349696;12086544;12709446;12736279;12849668;12862507;15056530;22043968;22161946;22265361;22809800;22906875;23160939;21961773;1884444;8256751;9753711;15581262;15705013;16138075;16182674;16254730;16549404;16951018;17307628;17470695;18055666;18184962;18549912;18676566;18805113;19154426;19165529;19440077;19841298;20141706;21185501;20584517;21206410;21406998;21576311",
"title": "Long-QT Syndrome and Therapy for Attention Deficit/Hyperactivity Disorder.",
"title_normalized": "long qt syndrome and therapy for attention deficit hyperactivity disorder"
} | [
{
"companynumb": "US-JNJFOC-20160809146",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "A 56-year-old female presents to the emergency department 6h after taking an overdose of verapamil MR 120 mg × 28 capsules. She has a past medical history of hypertension and atrial flutter. On admission her GCS is 15, HR 50/min, BP 100/64, Capillary blood glucose(CBG) 10.2. ECG shows sinus bradycardia with prolongation of the PR interval. You estimate her weight to be 60 kg.",
"affiliations": "University Hospitals, Coventry and Warwickshire, UK. tomheaps@hotmail.co.uk",
"authors": "Heaps|Tom|T|",
"chemical_list": "D002121:Calcium Channel Blockers",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1747-4884",
"issue": "10(3)",
"journal": "Acute medicine",
"keywords": null,
"medline_ta": "Acute Med",
"mesh_terms": "D002121:Calcium Channel Blockers; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008875:Middle Aged; D011041:Poisoning",
"nlm_unique_id": "101553725",
"other_id": null,
"pages": "153-5",
"pmc": null,
"pmid": "21904713",
"pubdate": "2011",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Problem-based review: calcium channel blocker (CCB) poisoning.",
"title_normalized": "problem based review calcium channel blocker ccb poisoning"
} | [
{
"companynumb": "PHHY2011GB097998",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"drugadditional": null,
... |
{
"abstract": "Ductus arteriosus is an essential component of fetal circulation. Due to occurring changes in the cardiopulmonary system physiology after birth, ductus arteriosus closes. Patent ductus arteriosus can be closed by medical or invasive (percutaneous or surgical) treatment methods. Percutaneous or surgical closure of patent ductus arteriosus can be performed for the cases that medical closure failed. Surgical treatment is often preferred method for closure of patent ductus arteriosus in the neonatal period. The most common surgical complications are pneumothorax, recurrent laryngeal nerve injury, bleeding, and recanalisation. A very rare surgical complication is left pulmonary artery ligation that has been presented in a few cases in the literature. Echocardiography control should be performed in the early post-operative period, especially in patients with clinical suspicion. If reoperation is required, it should never be delayed. We report a newborn patient whose left pulmonary artery ligated accidentally during patent ductus arteriosus closure surgery and surgical correction of this complication at the early post-operative period.",
"affiliations": "Department of Cardiovascular Surgery, Ondokuz Mayıs University, Samsun, Turkey.;Department of Pediatrics, Division of Pediatric Cardiology, Ondokuz Mayıs University, Samsun, Turkey.",
"authors": "Yucel|Semih Murat|SM|https://orcid.org/0000-0002-8077-828X;Sahin|Irfan Oguz|IO|https://orcid.org/0000-0003-0256-0653",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1017/S1047951120002784",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "30(12)",
"journal": "Cardiology in the young",
"keywords": "Ligation; left pulmonary artery; newborn; patent ductus arteriosus",
"medline_ta": "Cardiol Young",
"mesh_terms": "D004373:Ductus Arteriosus; D004374:Ductus Arteriosus, Patent; D006801:Humans; D007231:Infant, Newborn; D008026:Ligation; D011651:Pulmonary Artery; D014656:Vascular Surgical Procedures",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "1943-1945",
"pmc": null,
"pmid": "32900403",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ligation of left pulmonary artery instead of patent ductus arteriosus.",
"title_normalized": "ligation of left pulmonary artery instead of patent ductus arteriosus"
} | [
{
"companynumb": "TR-APTAPHARMA INC.-2106519",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "3",
... |
{
"abstract": "Teaching point: CT may help distinguishing benign from life-threatening pneumatosis intestinalis.",
"affiliations": "Clinique St Luc, BE.;Clinique Saint-Luc, Bouge, BE.",
"authors": "Vanderschueren|Louis|L|;Coulier|Bruno|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.5334/jbsr.2188",
"fulltext": "\n==== Front\nJ Belg Soc Radiol\nJ Belg Soc Radiol\n2514-8281\nJournal of the Belgian Society of Radiology\n2514-8281 Ubiquity Press \n\n10.5334/jbsr.2188\nImages in Clinical Radiology\nMassive Benign Pneumatosis Intestinalis\nVanderschueren Louis 1 Coulier Bruno bcoulier.md@gmail.com2 1 Clinique St Luc, BE\n2 Clinique Saint-Luc, Bouge, BE\nCorresponding author: Bruno Coulier (bcoulier.md@gmail.com)\n24 11 2020 \n2020 \n104 1 6731 5 2020 03 11 2020 Copyright: © 2020 The Author(s)2020This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. See http://creativecommons.org/licenses/by/4.0/.Teaching point: CT may help distinguishing benign from life-threatening pneumatosis intestinalis.\n\nPneumatosis intestinaliscancer5-Fluorouracilcoloncomputed tomography\n==== Body\nCase report\nA 78-year old woman presented with epigastric pain and non-bloody diarrhea 6 days after a second cure of adjuvant chemotherapy for gastric adenocarcinoma (the FOLFIRI protocol that includes Folinic acid, 5-Fluorouracil (5-FU) and Irinotecan).\n\nMassive Pneumatosis Intestinalis (PI) could be seen (Figure 1, A to E) on the scout view (black arrows on A). On subsequent coronal (B) and axial (C to E) Computed Tomography (CT), colonic submucosal (blue arrows), extensive subserosal, mesenteric (yellow stars) and free posterior retroperitoneal gas (black arrowheads) were depicted. Gas were also found within in a right Grynfelt hernia (orange arrowhead on A, red stars on D). The distal ileum was slightly affected (black arrows on E). Pneumoperitoneum, portal gas, bowel wall thickening, mesenteric fat stranding and ascites were absent. The precise etiology of PI could not be clearly identified, even though contribution of chemotherapy (notably 5-FU) was likely. Given the absence of alarm CT findings, the patient was successfully treated conservatively.\n\nFigure 1 Comment\nPneumatosis intestinalis which is defined as the presence of gas within the digestive tract wall is a radiographic finding resulting of a large spectrum of underlying diseases. The nature and severity of the disease determines the clinical significance of PI, not the amount of air. Initially considered indicative of advanced intestinal infarction, PI may be found in benign conditions such as immunosuppressive states.\n\nPathogenesis of PI is multifactorial but two main theories emerge. The ‘bacterial theory’ hypothesizes the action of gas-forming bacilli entering the submucosa through mucosal breaks or increased mucosal permeability. The ‘mechanical theory’ hypothesizes that increasing of intraluminal bowel pressure with loss of intestinal mucosal integrity allows normal bowel gas to dissect the bowel wall.\n\nRegarding this, patients with cancer have a greater propensity to develop PI - often benign - because they cumulate multiple risk factors (surgery, medical procedures and immunosuppression). Thrombogenic and vasospastic effects of 5-FU on the intestinal epithelium may have played a role in our patient.\n\nIndependently from the clinical status, CT may help differentiate benign from worrisome PI and guide proper clinical treatment [1]. Alarm signs include porto-mesenteric gas, mesenteric stranding, bowel dilatation and thickening, ascites, and confinement of PI to the small bowel. Colonic PI appears more frequently benign. Pneumoperitoneum may be seen in benign PI.\n\nCompeting Interests\nThe authors have no competing interests to declare.\n==== Refs\n1 Steve Lee \nKS , Hwang \nS , Hurtado Rúa \nSM , Janjigian \nYY , Gollub \nMJ . Distinguishing Benign and Life-Threatening Pneumatosis Intestinalis in Patients with Cancer by CT Imaging Features\n. AJR . 2013 ; 200 (5 ): 1042 –47\n. DOI: 10.2214/AJR.12.8942 23617487\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2514-8281",
"issue": "104(1)",
"journal": "Journal of the Belgian Society of Radiology",
"keywords": "5-Fluorouracil; Pneumatosis intestinalis; cancer; colon; computed tomography",
"medline_ta": "J Belg Soc Radiol",
"mesh_terms": null,
"nlm_unique_id": "101698198",
"other_id": null,
"pages": "67",
"pmc": null,
"pmid": "33283147",
"pubdate": "2020-11-24",
"publication_types": "D002363:Case Reports",
"references": "23617487",
"title": "Massive Benign Pneumatosis Intestinalis.",
"title_normalized": "massive benign pneumatosis intestinalis"
} | [
{
"companynumb": "BE-PFIZER INC-2021073510",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": "3",
... |
{
"abstract": "Prolonged immunosuppression or delayed T-cell recovery may favor Epstein-Barr virus (EBV) infection or reactivation after allogeneic hematopoietic stem cell transplantation (HSCT), which can lead to post-transplant lymphoproliferative disease (PTLD) and high-grade malignant B-cell lymphoma. Cytokine-induced killer (CIK) cells with dual specific anti-tumor and virus-specific cellular immunity may be applied in this context.\n\n\n\nCIK cells with EBV-specificity were generated from peripheral blood mononuclear cells (PBMCs), expanded in the presence of interferon-γ, anti-CD3, interleukin (IL)-2 and IL-15 and were pulsed twice with EBV consensus peptide pool. CIK cells with EBV-specificity and conventional CIK cells were phenotypically and functionally analyzed. Additionally, CIK cells with EBV-specificity were applied to a patient with EBV-related PTLD rapidly progressing to highly aggressive B-cell lymphoma on a compassionate use basis after approval and agreement by the regulatory authorities.\n\n\n\nPre-clinical analysis showed that generation of CIK cells with EBV-specificity was feasible. In vitro cytotoxicity analyses showed increased lysis of EBV-positive target cells, enhanced proliferative capacity and increased secretion of cytolytic and proinflammatory cytokines in the presence of EBV peptide-displaying target cells. In addition, 1 week after infusion of CIK cells with EBV-specificity, the patient's highly aggressive B-cell lymphoma persistently disappeared. CIK cells with EBV-specificity remained detectable for up to 32 days after infusion and infusion did not result in acute toxicity.\n\n\n\nThe transfer of both anti-cancer potential and T-cell memory against EBV infection provided by EBV peptide-induced CIK cells might be considered a therapy for EBV-related PTLD.",
"affiliations": "University Hospital Frankfurt, Goethe University, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany. Electronic address: Lisa-Marie.Pfeffermann@kgu.de.;University Hospital Frankfurt, Goethe University, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.;University Hospital Frankfurt, Goethe University, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.;University Hospital Frankfurt, Goethe University, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.;University Hospital Frankfurt, Goethe University, Institute for Transfusion Medicine and Immunohematology and German Red Cross Blood Donor Service Baden-Wuerttemberg-Hessen, Frankfurt am Main, Germany.;University Hospital Frankfurt, Goethe University, Senckenberg Institute of Pathology, Frankfurt am Main, Germany.;University Hospital Frankfurt, Goethe University, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.;University Hospital Frankfurt, Goethe University, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.;University Hospital Frankfurt, Goethe University, Department for Children and Adolescents, Division for Stem Cell Transplantation and Immunology, Frankfurt am Main, Germany.",
"authors": "Pfeffermann|Lisa-Marie|LM|;Pfirrmann|Verena|V|;Huenecke|Sabine|S|;Bremm|Melanie|M|;Bonig|Halvard|H|;Kvasnicka|Hans-Michael|HM|;Klingebiel|Thomas|T|;Bader|Peter|P|;Rettinger|Eva|E|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.jcyt.2018.04.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1465-3249",
"issue": "20(6)",
"journal": "Cytotherapy",
"keywords": "Epstein-Barr virus; cytokine-induced killer cells; cytotoxic T cells; immunotherapy; lymphoma; post-transplantation lymphoproliferative disease",
"medline_ta": "Cytotherapy",
"mesh_terms": "D000293:Adolescent; D002478:Cells, Cultured; D055612:Cytokine-Induced Killer Cells; D020031:Epstein-Barr Virus Infections; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D004854:Herpesvirus 4, Human; D006801:Humans; D007111:Immunity, Cellular; D016219:Immunotherapy, Adoptive; D020014:K562 Cells; D008223:Lymphoma; D013601:T-Lymphocytes; D014775:Virus Activation",
"nlm_unique_id": "100895309",
"other_id": null,
"pages": "839-850",
"pmc": null,
"pmid": "29754771",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Epstein-Barr virus-specific cytokine-induced killer cells for treatment of Epstein-Barr virus-related malignant lymphoma.",
"title_normalized": "epstein barr virus specific cytokine induced killer cells for treatment of epstein barr virus related malignant lymphoma"
} | [
{
"companynumb": "DE-TEVA-2018-DE-936228",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "1",
... |
{
"abstract": "Insulin allergy, one of insulin's adverse effects, is rare, especially in patients with Type 2 diabetes, but management is difficult and no effective strategy has yet been established. We experienced an insulin allergy case successfully managed with a novel combination of insulins.\n\n\n\nA 38-year-old woman started insulin therapy when diabetes was diagnosed at age 19 years. Despite poorly controlled diabetes because of poor adherence, she hoped to conceive a child and continuous subcutaneous insulin infusion was introduced using insulin aspart at age 32 years. One month thereafter, she developed skin reactions at the subcutaneous insulin infusion catheter insertion site. The patient was then tested for all rapid-acting insulin formulations, all of which triggered local reactions. She decided to continue the continuous subcutaneous infusion of human regular insulin, accompanied by oral cetirizine hydrochloride and betamethasone valerate ointment. The patient was admitted to our hospital at age 38 years with high HbA1c levels. She was tested for all long-acting insulin analogues. All results, except for insulin degludec, were positive. She discontinued continuous subcutaneous insulin infusion and switched to insulin degludec combined with liraglutide. The allergic reactions had completely disappeared and her blood glucose was well controlled by the time of discharge.\n\n\n\nOur patient was allergic to all insulin formulations except insulin degludec. Her allergic reactions completely disappeared after switching to insulin degludec. The crystallized structure of this insulin might mask its skin allergen antigenicity. Furthermore, her postprandial hyperglycaemia was successfully controlled with liraglutide. We propose multihexamer-forming ultra-long-acting insulin plus glucagon-like peptide-1 analogues as a therapeutic option for patients with insulin allergy.",
"affiliations": "Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan. midori-tky@umin.ac.jp.;Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.;Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.;Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.;Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.;Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.;Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.;Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.;Department of Diabetes and Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.",
"authors": "Fujishiro|M|M|;Izumida|Y|Y|;Takemiya|S|S|;Kuwano|Y|Y|;Takamoto|I|I|;Suzuki|R|R|;Yamauchi|T|T|;Ueki|K|K|;Kadowaki|T|T|",
"chemical_list": "D001786:Blood Glucose; D006442:Glycated Hemoglobin A; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; C571886:insulin degludec; D000069450:Liraglutide",
"country": "England",
"delete": false,
"doi": "10.1111/dme.12998",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0742-3071",
"issue": "33(11)",
"journal": "Diabetic medicine : a journal of the British Diabetic Association",
"keywords": null,
"medline_ta": "Diabet Med",
"mesh_terms": "D000328:Adult; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2; D004342:Drug Hypersensitivity; D004359:Drug Therapy, Combination; D005260:Female; D006442:Glycated Hemoglobin A; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D049528:Insulin, Long-Acting; D000069450:Liraglutide",
"nlm_unique_id": "8500858",
"other_id": null,
"pages": "e26-e29",
"pmc": null,
"pmid": "26485621",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A case of insulin allergy successfully managed using multihexamer-forming insulin degludec combined with liraglutide.",
"title_normalized": "a case of insulin allergy successfully managed using multihexamer forming insulin degludec combined with liraglutide"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP08288",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INSULIN ASPART"
},
"drugadditional": null,
... |
{
"abstract": "Diffuse large B-cell lymphoma with secondary involvement of the central nervous system (SCNS-DLBCL) is a rare condition carrying a poor prognosis. No optimal therapeutic regimen has been identified. We retrospectively analysed 23 patients with SCNS-DLBCL treated with R-IDARAM (rituximab 375 mg/m(2) IV day 1; methotrexate 12·5 mg by intrathecal injection day 1; idarubicin 10 mg/m(2) /day IV days 1 and 2; dexamethasone 100 mg/day IV infusion over 12 h days 1-3; cytosine arabinoside 1000 mg/m(2) /day IV over 1 h days 1 and 2; and methotrexate 2000 mg/m(2) IV over 2 h day 3. Ten out of 23 (44%) patients had CNS involvement at initial presentation ('new disease'), 10/23 (44%) had relapsed disease and 3/23 (13%) had primary refractory disease. 14/23 (61%) of patients responded - 6 (26%) complete response, 8 (35%) partial response. Grade 3-4 haematological toxicity was seen in all cycles, with no grade 3-4 or long-term neurological toxicity. Median follow-up for surviving patients was 49 months. At 2 years, estimated progression-free survival (PFS) was 39% and overall survival (OS) was 52%. Encouraging outcomes were reported in patients with new disease, with 5-year estimated PFS of 50% and OS 75%. R-IDARAM is a well-tolerated regimen with encouraging efficacy in patients with SCNS-DLBCL, although patients with relapsed or refractory disease continue to fare poorly.",
"affiliations": "Cancer Institute, Department of Haematology, University College London, London, UK.;Department of Haematology, Royal London Hospital, London, UK.;Department of Pharmacy, University College London Hospital, London, UK.;Department of Haematology, University College London Hospital, London, UK.;Department of Haematology, University College London Hospital, London, UK.;Department of Haematology, University College London Hospital, London, UK.;Cancer Institute, Department of Haematology, University College London, London, UK.;Cancer Institute, Department of Haematology, University College London, London, UK.;Cancer Institute, Department of Haematology, University College London, London, UK.;Department of Haematology, University College London Hospital, London, UK.",
"authors": "Maciocia|Paul|P|;Badat|Mohsin|M|;Cheesman|Simon|S|;D'Sa|Shirley|S|;Joshi|Rahul|R|;Lambert|Jonathan|J|;Mohamedbhai|Sajir|S|;Pule|Martin|M|;Linch|David|D|;Ardeshna|Kirit|K|",
"chemical_list": "D003561:Cytarabine; D000069283:Rituximab; D003907:Dexamethasone; D008727:Methotrexate; D015255:Idarubicin",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.13867",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1048",
"issue": "172(4)",
"journal": "British journal of haematology",
"keywords": "CNS relapse; central nervous system; clinical; haematological malignancy; lymphomas",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D003561:Cytarabine; D003907:Dexamethasone; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015255:Idarubicin; D007262:Infusions, Intravenous; D007278:Injections, Spinal; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "545-53",
"pmc": null,
"pmid": "26684148",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Treatment of diffuse large B-cell lymphoma with secondary central nervous system involvement: encouraging efficacy using CNS-penetrating R-IDARAM chemotherapy.",
"title_normalized": "treatment of diffuse large b cell lymphoma with secondary central nervous system involvement encouraging efficacy using cns penetrating r idaram chemotherapy"
} | [
{
"companynumb": "GB-ROCHE-1304152",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nEltrombopag activates the thrombopoietin (TPO) surface receptor on the megakaryocyte, which increases the production of platelets, and rapidly improves circulating platelet numbers in patients with immune thrombocytopenic purpura (ITP). This allows for rapid tapering and/or cessation of corticosteroid therapy. Less is known about the platelet response to this drug in ITP associated with systemic lupus erythematosus (SLE).\n\n\nMETHODS\nA retrospective review was performed of the clinical course of three consecutive patients, each with SLE-associated ITP who were initially treated with corticosteroids or other immunomodulatory therapy. These patients were treated with eltrombopag at the DMC Center for Bleeding Disorders and Thrombosis. Eltrombopag was administered according the package insert, with an initial dose of 50 mg daily, with weekly, then monthly monitoring of platelet counts and dose adjustments. Some immunomodulatory agents (e.g. hydroxychloroquine) were continued to control non hematologic SLE manifestations.\n\n\nRESULTS\nAll three patients maintained acceptable platelet counts (>50,000/mm(3) for >3 years) following tapering and cessation of corticosteroids. The drug was well-tolerated and there were no adverse events, and specifically no thrombotic events.\n\n\nCONCLUSIONS\nEltrombopag is effective as a rapidly acting corticosteroid sparing therapy for patients with ITP associated with SLE. This is important in reducing corticosteroid related side effects and morbidities in treating SLE patients with ITP. Larger studies are needed to ascertain safety and efficacy of eltrombopag in SLE patients with ITP, particularly those with coexisting antiphospholipid antibodies.",
"affiliations": "Internal Medicine Department, Rheumatology Division, Wayne State University, Detroit, MI, USA mmaroun@med.wayne.edu.;Medicine and Oncology Department, Wayne State University School of Medicine, Karmanos Cancer Institute, USA.;Medicine and Oncology Department, Wayne State University School of Medicine, Karmanos Cancer Institute, USA.;Internal Medicine Department, Rheumatology Division, Wayne State University, Detroit, MI, USA Internal Medicine Department, Central Michigan University, MI, USA.",
"authors": "Maroun|M-C|MC|;Ososki|R|R|;Andersen|J C|JC|;Dhar|J P|JP|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; D013926:Thrombopoietin; C520809:eltrombopag",
"country": "England",
"delete": false,
"doi": "10.1177/0961203314559632",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "24(7)",
"journal": "Lupus",
"keywords": "Systemic lupus erythematosus; eltrombopag; immune thrombocytopenia",
"medline_ta": "Lupus",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D001565:Benzoates; D005260:Female; D006801:Humans; D006834:Hydrazines; D008180:Lupus Erythematosus, Systemic; D008875:Middle Aged; D016553:Purpura, Thrombocytopenic, Idiopathic; D011720:Pyrazoles; D053628:Receptors, Thrombopoietin; D012189:Retrospective Studies; D013926:Thrombopoietin",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "746-50",
"pmc": null,
"pmid": "25416695",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Eltrombopag as steroid sparing therapy for immune thrombocytopenic purpura in systemic lupus erythematosus.",
"title_normalized": "eltrombopag as steroid sparing therapy for immune thrombocytopenic purpura in systemic lupus erythematosus"
} | [
{
"companynumb": "PHHY2017US059309",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPiperacillin-tazobactam is common empiric antibiotic therapy. Hematologic laboratory test abnormalities were documented but rare in premarketing studies, and whether these alterations are of clinical significance has been studied little. Very few cases of piperacillin-induced bleeding, thrombocytopenia, or both have been reported; aberrations in platelet function have not been implicated.\n\n\nMETHODS\nA 55-year old Vietnamese man with hypertension presented for treatment of an Intracranial hemorrhage. Platelet function assays (PFAs) at the time of external ventricular drain and quad-lumen bolt placement were normal, and imaging showed no hemorrhage after placement. The patient was later started on empiric piperacillin-tazobactam due to high suspicion for aspiration pneumonia. After removal of the quad-lumen bolt and external ventricular drain on separate days, both follow-up computed tomography scans showed new hematomas in the devices' tracts, with significant intraventricular hemorrhage. Repeat PFAs were abnormally prolonged, representing a distinct change from baseline. A trend toward normalization of PFAs was observed 6 hours after discontinuation of piperacillin-tazobactam with progression toward baseline thereafter.\n\n\nCONCLUSIONS\nThis is unique in that the significant bleeding that occurred was attributable to platelet dysfunction rather than thrombocytopenia. This is the first reported case of intracranial (periprocedural) hemorrhage potentially related to piperacillin-tazobactam; further research into this drug's impact upon qualitative platelet function is needed.",
"affiliations": "School of Medicine, UC Irvine Health, Irvine, California, USA. Electronic address: bowerm1@uci.edu.;School of Medicine, UC Irvine Health, Irvine, California, USA.;Department of Neurology, UC Irvine, Orange, California, USA.;Department of Neurology, UC Irvine, Orange, California, USA.;UC Irvine Health, Orange, California, USA.",
"authors": "Bower|Matthew|M|;Borders|Candace|C|;Schnure|Andrew|A|;Groysman|Leonid|L|;Tran|Minh-Ha|MH|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin",
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"issue": "114()",
"journal": "World neurosurgery",
"keywords": "Adverse drug reaction; Intracranial hemorrhage; Platelets",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001791:Blood Platelet Disorders; D001792:Blood Platelets; D002543:Cerebral Hemorrhage; D003422:Critical Care; D036262:Empirical Research; D006801:Humans; D008297:Male; D008875:Middle Aged; D010397:Penicillanic Acid; D010878:Piperacillin; D000077725:Piperacillin, Tazobactam Drug Combination; D016896:Treatment Outcome",
"nlm_unique_id": "101528275",
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"pages": "204-210",
"pmc": null,
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"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Platelet Dysfunction and Intracerebral Hemorrhage in a Patient Treated with Empiric Piperacillin-Tazobactam in the Neurocritical Care Unit.",
"title_normalized": "platelet dysfunction and intracerebral hemorrhage in a patient treated with empiric piperacillin tazobactam in the neurocritical care unit"
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"abstract": "In several medico-legal cases, bone samples analysis may provide the only source of toxicological information. This case study reports the analysis of a human bone specimen, belonging to a 46-year-old man, found 3 months after his death due to cervical-thoracic injuries in a motorcycle accident. Bone specimen was the only available material for toxicological analysis, among few skull hair and rotten skin. Analysis was performed by a newly developed and validated ultra-high-pressure liquid chromatography-mass spectrometry/mass spectrometry (UHPLC-MS/MS) method, following simple and efficient sample pretreatment. The results were in accordance with the man's medical record: Alprazolam and zolpidem were found at 2.2 and 5.4 ng/g of bone, respectively. Both these drugs were prescribed to the deceased.",
"affiliations": "Laboratory of Forensic Medicine & Toxicology, Medical School, Aristotle University Thessaloniki, Thessaloniki, 54124, Greece.;Laboratory of Forensic Medicine & Toxicology, Medical School, Aristotle University Thessaloniki, Thessaloniki, 54124, Greece.;Laboratory of Forensic Service of Ministry of Justice of Thessaloniki, Thessaloniki, 54628, Greece.;Laboratory of Forensic Service of Ministry of Justice of Thessaloniki, Thessaloniki, 54628, Greece.;Laboratory of Forensic Medicine & Toxicology, Medical School, Aristotle University Thessaloniki, Thessaloniki, 54124, Greece.",
"authors": "Orfanidis|Amvrosios|A|;Gika|Helen|H|;Zaggelidou|Eleni|E|;Mastrogianni|Orthodoxia|O|;Raikos|Nikolaos|N|",
"chemical_list": "D006993:Hypnotics and Sedatives; D000077334:Zolpidem; D000525:Alprazolam",
"country": "United States",
"delete": false,
"doi": "10.1111/1556-4029.13890",
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"issn_linking": "0022-1198",
"issue": "64(2)",
"journal": "Journal of forensic sciences",
"keywords": "alprazolam; bones; femur; forensic science; liquid chromatography-mass spectrometry/mass spectrometry; skeletal tissue; zolpidem",
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000063:Accidents, Traffic; D000525:Alprazolam; D000071298:Body Remains; D002851:Chromatography, High Pressure Liquid; D005269:Femur; D006197:Hair; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D009049:Motorcycles; D011180:Postmortem Changes; D012867:Skin; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D000077334:Zolpidem",
"nlm_unique_id": "0375370",
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"pubdate": "2019-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Alprazolam and Zolpidem in Skeletal Tissue of Decomposed Body Confirms Exposure.",
"title_normalized": "alprazolam and zolpidem in skeletal tissue of decomposed body confirms exposure"
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"abstract": "BACKGROUND\nSexually transmitted Human Papilloma Virus (HPV) infection is a known risk factor for cancer of the anal canal in both men and women.\n\n\nMETHODS\nWe describe a report of synchronous carcinoma of the anal canal in a heterosexual couple. High risk type 16 HPV DNA was detected in both tumors.\n\n\nCONCLUSIONS\nLongstanding sexual partners may share risk of HPV-associated anal canal cancer.",
"affiliations": "Department of Radiation Oncology, Sunnybrook Health Sciences Centre T-Wing, University of Toronto, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada.;Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Canada.;Division of Medical Oncology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada.;Department of Radiation Oncology, Sunnybrook Health Sciences Centre T-Wing, University of Toronto, 2075 Bayview Ave, Toronto, ON, M4N 3M5, Canada. shun.wong@sunnybrook.ca.",
"authors": "Mendez|Lucas C|LC|;Hsieh|Eugene|E|;Earle|Craig C|CC|;Wong|Shun|S|",
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"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 478510.1186/s12885-018-4785-8Case ReportSynchronous anal canal carcinoma in a heterosexual couple Mendez Lucas C. lucascastro.mendez@sunnybrook.ca 1Hsieh Eugene Eugene.hsieh@suunybrook.ca 23Earle Craig C. craig.earle@ices.on.ca 45Wong Shun shun.wong@sunnybrook.ca 11 0000 0001 2157 2938grid.17063.33Department of Radiation Oncology, Sunnybrook Health Sciences Centre T-Wing, University of Toronto, 2075 Bayview Ave, Toronto, ON M4N 3M5 Canada 2 0000 0000 9743 1587grid.413104.3Division of Anatomic Pathology, Department of Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Canada 3 0000 0001 2157 2938grid.17063.33Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada 4 0000 0001 2157 2938grid.17063.33Division of Medical Oncology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Canada 5 0000 0000 8849 1617grid.418647.8Institute of Clinical Evaluative Sciences, Toronto, Canada 10 9 2018 10 9 2018 2018 18 88418 6 2018 30 8 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nSexually transmitted Human Papilloma Virus (HPV) infection is a known risk factor for cancer of the anal canal in both men and women.\n\nCase presentation\nWe describe a report of synchronous carcinoma of the anal canal in a heterosexual couple. High risk type 16 HPV DNA was detected in both tumors.\n\nConclusion\nLongstanding sexual partners may share risk of HPV-associated anal canal cancer.\n\nKeywords\nHPV infectionAnal canal cancerHeterosexualityissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nOver 8,000 new cases of cancer of the anal canal are expected in the United States in 2017, with 2/3 of them in women [1]. The incidence of anal cancer continues to grow in both sexes, with a more pronounced increase in the male population [2]. Infection by the human papilloma virus (HPV) is strongly associated with anal cancer, with almost all cases associated with this virus [3]. Sexually transmitted disease, immunosuppression such as HIV infection, tobacco use and previous history of cervical, vaginal or vulvar cancer are known risk factors for the disease [4–6]. Men who have sex with men are at higher risk of developing anal canal cancer than heterosexual men [7]. Here we reported synchronous presentation of squamous cell carcinoma of the anal canal in a heterosexual couple.\n\nCase presentation\nCase 1\nA 60-year-old woman sought medical attention after a 2-month history of minor rectal bleeding and an anal nodule. On physical examination, a 3-cm mobile anterior ulcerative mass in the anal canal was palpable, beginning at 1 cm from the anal verge with no extension to the anorectal junction. No nodes were appreciated in the inguinal regions. A biopsy revealed an invasive squamous cell carcinoma, well-differentiated (Fig. 1a). Staging computerized tomography (CT) of the thorax/abdomen/pelvis did not show any lymphadenopathy or distant metastatic disease. Pelvic magnetic resonance imaging (MRI) demonstrated a 3-cm mass in the anal canal extending to the anorectal junction (Fig. 2a and b). There was no pelvic or inguinal lymphadenopathy. Her laboratory investigations including HIV-1 and HIV-2 serology were negative. A recent Papanicolau smear of the cervix was reported to be negative for intraepithelial lesion or malignancy.Fig. 1 The biopsy of the anal lesion of the female revealed a well-differentiated squamous cell carcinoma (a), and the male had a poorly differentiated squamous cell carcinoma (b) with a prominent lymphoid infiltrate (*), hematoxylin and eosin staining. Both lesions (c, d) demonstrate strong and diffuse p16 immunoreactivity (brown) and there is no p16 expression in the adjacent rectal glands (*). Magnification X 200\n\nFig. 2 T2-weighted MRI of the pelvis of the female case shows a 3-cm lesion in the anal canal extending into the anorectal junction (a. sagittal, b. axial). MRI of the male case also demonstrates a T2 lesion measuring about 3 cm beginning at 2 cm from the anal verge (c. sagittal, d. axial)\n\n\n\nThe patient had a past medical history remarkable for an in-situ cervical carcinoma treated with laser therapy over 20 years ago with no subsequent recurrence. She also underwent a right salpingo-oophorectomy for an endometriotic cyst of the right ovary 8 years prior to her anal canal cancer diagnosis. She is a life-time non-smoker and social alcohol drinker. There was no past history of any autoimmune disorders.\n\nFor her T2N0M0 anal cancer, the patient underwent a course of chemo-radiotherapy as per institutional protocol. The total dose was 54 Gy in 30 daily fractions to the primary and elective nodal irradiation consisted of 36 Gy in 20 fractions to the inguinal/femoral, mesorectal, presacral and external/internal iliac nodal regions. The radiation treatment was delivered using volumetric modulated arch therapy (VMAT) technique. The chemotherapy regimen consisted of mitomycin C (10 mg/m2 on day 1) and infusional 5-fluorouracil (1000 mg/m2/day for 4 days), given concurrently on week 1 and week 5 of radiation. The patient developed RTOG grade 3 skin and perineal reactions. She had an episode of fever without neutropenia managed by oral antibiotics.\n\nCase 2\nWhile the female was undergoing chemoradiation, her husband, with whom she has been married for over 30 years, requested a screening colonoscopy during his regular urological follow-up. The investigation revealed an anal mass that was biopsied and demonstrated a poorly-differentiated squamous cell carcinoma with prominent lymphoid infiltration (Fig. 1b). This 63 year-old man was largely asymptomatic. After diagnosis, he was referred to the same cancer centre where his wife received oncological care. On physical examination, an ulcerative exophytic mass was seen, measuring approximately 3 cm in maximum dimension, located over the posterior third of the anal canal at 2 cm from the verge. The mass extended to the anorectal junction. No inguinal nodes were clinically suspicious. Staging CT and MRI revealed at least four suspicious mesorectal nodes and a 1.8-cm left external iliac lymph node. There was no evidence of distant metastatic disease. On MRI, the maximum tumor dimension of the primary was 3 cm (Fig. 2c and d). Similar to his wife, this man’s HIV serology was negative. He was a non-smoker. There was no previous history of sexually transmissible disease, and he denied any receptive anal intercourse or sex with men. He was on tamsulosin 0.4 mg and dutasteride 0.5 mg for benign prostatic hyperplasia.\n\nThis patient was treated with the same institutional protocol of chemoradiation for his T2 N2 anal cancer with a total dose of 54 Gy to the primary and the involved nodes plus concurrent chemotherapy with 5-fluorouracil and mitomycin C. The elective nodal irradiation dose was 36 Gy. The patient developed neutropenia and thrombocytopenia, diarrhea, oral mucositis and the usual perianal/perineal skin reaction.\n\nThe immunohistochemical profiles of both the wife’s and husband’s lesions were similar. Both tumours demonstrated diffuse and strong immunoreactivity for p16 (Fig. 1c-d) suggesting high-risk HPV infection [8] and neither exhibited p53 overexpression or p53 loss. PCR for HPV genotype was performed using the Cobas 4800 HPV Test System [9]. HPV16 DNA was detected in both lesions. The two lesions were negative for HPV18 and also negative for HPV31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66 and 68.\n\nDiscussion and conclusion\nTwo-thirds of anal canal cancer cases are seen in females and the incidence among men is about 20 times higher in men who have sex with men [5]. Therefore, little attention has been focused on heterosexual men in regard to cancer in the anal region. However, up to 12–24% of heterosexual men have been reported to harbor HPV infection in the anal canal [10, 11]. It is expected that some of these patients, as described here, may develop anal carcinoma.\n\nThis report brings to light two interesting points. First, the route of HPV transmission to the anal canal in men who do not have receptive anal sex is not yet fully understood. One possible route of transmission is self-contamination from genital or perianal sites that may occur with either sexual or non-sexual behavior. An association between genital and anal canal HPV co-infection has been described [4]. In fact, multiple overlapping risk factors, such as increasing number of female sex partners and short duration of the relationship have been reported as risk factors for both penile and anal cancers [10, 12]. Non-sexual routes of transmission may also explain anal canal infection in men that do not have sex with men, especially for patients without genital HPV infection. Previous studies have identified HPV-DNA in fingers [13], various objects such as gloves and biopsy forceps [14], suggesting that multiple items could serve as a potential vehicle for HPV transmission. It is not clear, however, if exposure to these fomites could result in actual infection. This concept also strengthens the idea of self-contamination. Finally, under reporting of receptive anal intercourse is another possible explanation as patients may refuse to disclose this information due to embarrassment and stigma.\n\nThe second learning point illustrated by this report of the 2 cases relates to the theoretical higher risk of development of HPV-related cancers in partners of patients with cancers associated with this virus. Recently, a systematic review suggested a 2–3 fold increase risk of HPV-related cancer in spouses of patients with previous HPV-related malignancies [15]. Similar to the two cases described here, Andrews et al. provided an example of this notion in a report of two heterosexual couples diagnosed with HPV-related oropharyngeal carcinomas within a time frame of one year [16]. Interestingly, both husbands and wives in this report were also found to have HPV16-associated tumors. We did not perform deep sequencing of the HPV16 genome in the couple in the present study. Although sequence concordance may lend further evidence for partner-to-partner transmission, the HPV genome is known to exhibit genetic diversity generated through interactions with host cell DNA-editing enzymes [17]. It may thus be difficult to prove partner-to-partner transmission definitively.\n\nAnal canal cancer is an uncommon entity that most frequently affects women or men who have sex with men. This report suggests that men who have sex with women may be at risk of cancer of the anal region. In conclusion, both male and female partners of patients with HPV-related cancers are at increased risk of malignancies associated with this virus, including carcinoma of the anal canal.\n\nAbbreviations\nCTComputerized tomography\n\nHIVHuman immunodeficiency virus\n\nHPVHuman papilloma virus\n\nMRIMagnetic resonance imaging\n\nVMATVolumetric modulated arch therapy\n\nAuthor’s contribution\nConception and design: SW. Development of methodology: LM, SW. Acquisition of data: EH, CE, SW. Data analysis and interpretation: LM, EH, CE, SW. Writing, review, and/or revision of the manuscript: All. Administrative, technical, or material support: EH, SW. Study supervision: SW. Other (oversight of every aspect of the research): SW. All authors have read and approved this manuscript.\n\nEthics approval and consent to participate\nThis is a case-report with ethics approval waived. Both patients have consented to have their data published.\n\nConsent for publication\nBoth patients provided consent for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interest\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Siegel R Miller KD Ahmedin J Cáncer statistics Ca Cáncer J 2017 67 1 7 30 10.3322/caac.21387 \n2. Shiels MS Kreimer AR Coghill AE Darragh TM Devesa SS Anal cancer incidence in the United States, 1977-2011: distinct patterns by histology and behavior Cancer Epidemiol Biomark Prev 2015 24 10 1548 1556 10.1158/1055-9965.EPI-15-0044 \n3. Hoots BE Palefsky JM Pimenta JM Smith JS Human papillomavirus type distribution in anal cancer and anal intraepithelial lesions Int J Cancer 2009 124 10 2375 2383 10.1002/ijc.24215 19189402 \n4. Jiménez W Paszat L Kupets R Wilton A Tinmouth J Presumed previous human papillomavirus (HPV) related gynecological cancer in women diagnosed with anal cancer in the province of Ontario Gynecol Oncol [Internet] 2009 114 3 395 398 10.1016/j.ygyno.2009.05.006 \n5. Daling JR Madeleine MM Johnson LG Schwartz SM Shera KA Wurscher MA Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer Cancer 2004 101 2 270 280 10.1002/cncr.20365 15241823 \n6. Sunesen KG Nørgaard M Thorlacius-Ussing O Laurberg S Immunosuppressive disorders and risk of anal squamous cell carcinoma: a nationwide cohort study in Denmark, 1978-2005 Int J Cancer 2010 127 3 675 684 10.1002/ijc.25080 19960431 \n7. Daling JR Weiss NS Klopfenstein LL Cochran LE Chow W Daifuku R Correlates of homosexual behavior and the incidence of anal Cancer JAMA J Am Med Assoc 1982 247 14 1988 1990 10.1001/jama.1982.03320390050042 \n8. Klussmann JP Gültekin E Weissenborn SJ Wieland U Dries V Dienes HP Expression of p16 protein identifies a distinct entity of tonsillar carcinomas associated with human papillomavirus Am J Pathol 2003 162 3 747 753 10.1016/S0002-9440(10)63871-0 12598309 \n9. Kerr DA Sweeney B Arpin RN Ring M Pitman MB Wilbur DC Automated extraction of formalin-fixed, paraffin-embedded tissue for high-risk human papillomavirus testing of head and neck squamous cell carcinomas using the Roche Cobas 4800 system Arch Pathol Lab Med [Internet] 2016 140 8 844 848 10.5858/arpa.2015-0272-OA \n10. Nyitray A Nielson CM Harris RB Flores R Abrahamsen M Dunne EF Prevalence of and risk factors for anal human papillomavirus infection in heterosexual men J Infect Dis 2008 197 12 1676 1684 10.1086/588145 18426367 \n11. Nyitray AG Smith D Villa L Lazcano-Ponce E Abrahamsen M Papenfuss M Prevalence of and risk factors for anal human papillomavirus infection in men who have sex with women: a cross-National Study J Infect Dis [Internet] 2010 201 10 1498 1508 10.1086/652187 \n12. Daling JR Madeleine MM Johnson LG Schwartz SM Shera KA Wurscher MA Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease Int J Cancer 2005 116 4 606 616 10.1002/ijc.21009 15825185 \n13. Sonnex C Strauss S Gray JJ Detection of human papillomavirus DNA on the fingers of patients with genital warts Sex Transm Infect 1999 75 5 317 319 10.1136/sti.75.5.317 10616355 \n14. Ferenczy, A Bergeron C, Richart RM. Human papillomavirus DNA in fomites on objects used for management of patients with genital human papillomavirus infection Obs Gynecol 1989;74:950–954.\n15. Mirghani H Sturgis EM Aupérin A Monsonego J Blanchard P Is there an increased risk of cancer among spouses of patients with an HPV-related cancer: A systematic review Oral Oncol [Internet] 2017 67 138 145 10.1016/j.oraloncology.2017.02.024 \n16. Andrews E Shores C Hayes DN Couch M Southerland J Morris D Concurrent human papillomavirus–associated tonsillar carcinoma in 2 couples J Infect Dis [Internet] 2009 200 6 882 887 10.1086/605442 \n17. Hirose Y Onuki M Tenjimbayashi Y Mori S Ishii Y Takeuchi T Crossm Within-Host Variations of Human Papillomavirus Reveal APOBEC Signature Mutagenesis in the Viral Genome J Virol 2018 92 12 1 14 10.1128/JVI.00017-18\n\n",
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"issn_linking": "1471-2407",
"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "Anal canal cancer; HPV infection; Heterosexuality",
"medline_ta": "BMC Cancer",
"mesh_terms": "D001005:Anus Neoplasms; D001706:Biopsy; D005260:Female; D020010:Heterosexuality; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary; D027383:Papillomaviridae; D030361:Papillomavirus Infections; D012747:Sexual Partners; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100967800",
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"title": "Synchronous anal canal carcinoma in a heterosexual couple.",
"title_normalized": "synchronous anal canal carcinoma in a heterosexual couple"
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"abstract": "Drug-resistant paediatric tuberculosis (TB) is an overlooked global problem. In Italy, the epidemiology of TB has recently changed and data regarding drug-resistant forms in the paediatric setting is scanty. The aim of this case series was to report the cases of drug-resistant TB, diagnosed between June 2006 and July 2010 in four Italian tertiary centres for paediatric infectious diseases, in children and adolescents living in Italy. Twenty-two children were enrolled, of these 17 were resistant to one or more drugs and five had multidrug-resistant TB. All but one child were either foreign born or had at least one foreign parent. Twenty-one patients completed their treatment without clinical or radiological signs of activity at the end of treatment, and one patient was lost to follow up. The outcomes were good, with few adverse effects using second-line anti-TB drugs. Although this series is limited, it might already reflect the worrisome increase of drug-resistant TB, even in childhood.",
"affiliations": "Department of Paediatrics, Infectious Diseases Unit,University of Turin,Regina Margherita Children's Hospital, Turin,Italy.;TB Reference Centre/Villa Marelli Institute, Department of Pneumology, Niguarda Hospital, Milan,Italy.;Department of Paediatrics, Infectious Diseases Unit,University of Turin,Regina Margherita Children's Hospital, Turin,Italy.;Department of Paediatrics, Infectious Diseases Unit,University of Turin,Regina Margherita Children's Hospital, Turin,Italy.;Paediatrics and Infectious Disease Unit, Ospedale Pediatrico Bambino Gesù, Rome,Italy.;TB Reference Centre/Villa Marelli Institute, Department of Pneumology, Niguarda Hospital, Milan,Italy.;Department of Paediatrics, Infectious Diseases Unit,University of Turin,Regina Margherita Children's Hospital, Turin,Italy.;Paediatrics and Infectious Disease Unit, Ospedale Pediatrico Bambino Gesù, Rome,Italy.;Department of Maternal and Paediatric Sciences,Università degli Studi di Milano, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico,Milan,Italy.;Department of Paediatrics, Infectious Diseases Unit,University of Turin,Regina Margherita Children's Hospital, Turin,Italy.;TB Reference Centre/Villa Marelli Institute, Department of Paediatrics, Niguarda Hospital, Milan,Italy.;Department of Paediatrics, Infectious Diseases Unit,University of Turin,Regina Margherita Children's Hospital, Turin,Italy.",
"authors": "Mignone|F|F|;Codecasa|L R|LR|;Scolfaro|C|C|;Raffaldi|I|I|;Lancella|L|L|;Ferrarese|M|M|;Garazzino|S|S|;Marabotto|C|C|;Esposito|S|S|;Gabiano|C|C|;Lipreri|R|R|;Tovo|P-A|PA|",
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"title": "The spread of drug-resistant tuberculosis in children: an Italian case series.",
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"abstract": "The gestational trophoblastic neoplasia (GTN) patients with the International Federation of Gynecology and Obstetrics (FIGO) score≥12 are defined as ultra high-risk GTN. This study aims to investigate the clinical characteristics, the treatment efficiency, and the prognosis of ultra high-risk GTN patients.\n\n\n\nBetween January 2002 and December 2015, medical record data of 143 GTN patients with FIGO score≥12 at Peking Union Medical College Hospital (PUMCH) were reviewed. Ratios were compared using chi-square test, and prognostic risk factors were analyzed by univariate analysis and multivariate analysis.\n\n\n\nAmong the 143 ultra high-risk GTN patients, 94 (65.7%) patients had achieved complete remission and 15.9% (15/94) patients relapsed after complete remission. The 5-year overall survival (OS) rate of the entire cohort approached 67.9%. The results of the multivariate analysis revealed that non-molar antecedent pregnancy [Relative risk (RR) 4.689, 95% CI 1.448-15.189, P=0.010], brain metastases (RR 2.280, 95% CI 1.248-4.163, P=0.007), previous failed multiagent chemotherapy (RR 5.345, 95% CI 2.222-12.857, P=0.000) and surgery (RR 0.336, 95% CI 0.177-0.641, P=0.001) all had influence on the prognosis of ultra high-risk GTN patients.\n\n\n\nGTN patients with FIGO score≥12 have a poor prognosis. More emphasis should be placed on non-molar antecedent pregnancy, brain metastases, and previous multiagent chemotherapy failure. Moreover, salvage surgery may improve the prognosis. Floxuridine-based multiagent chemotherapy is effective with manageable toxicity for ultra high-risk GTN patients.",
"affiliations": "Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, 100730 Beijing, PR China.;Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, 100730 Beijing, PR China. Electronic address: yangjunjun@pumch.cn.;Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, 100730 Beijing, PR China.;Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, 100730 Beijing, PR China. Electronic address: zhaojun@pumch.cams.cn.;Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, 100730 Beijing, PR China.;Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, 100730 Beijing, PR China.;Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, 100730 Beijing, PR China.;Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, 100730 Beijing, PR China. Electronic address: fengfz1969@sina.com.;Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, 100730 Beijing, PR China. Electronic address: wanxr@pumch.cn.;Departments of Obstetrics and Gynecology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No.1 Shuaifuyuan, Wangfujing, Dongcheng District, 100730 Beijing, PR China. Electronic address: XiangY@pumch.cn.",
"authors": "Kong|Yujia|Y|;Yang|Junjun|J|;Jiang|Fang|F|;Zhao|Jun|J|;Ren|Tong|T|;Li|Jie|J|;Wang|Xiaoyu|X|;Feng|Fengzhi|F|;Wan|Xirun|X|;Xiang|Yang|Y|",
"chemical_list": "D005467:Floxuridine; D003609:Dactinomycin; D014750:Vincristine; D005047:Etoposide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.ygyno.2017.04.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-8258",
"issue": "146(1)",
"journal": "Gynecologic oncology",
"keywords": "Chemotherapy; Gestational trophoblastic neoplasia; Prognosis; Survival; Ultra high-risk",
"medline_ta": "Gynecol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D003609:Dactinomycin; D005047:Etoposide; D005260:Female; D005467:Floxuridine; D031901:Gestational Trophoblastic Disease; D006801:Humans; D008875:Middle Aged; D011247:Pregnancy; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D016879:Salvage Therapy; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "0365304",
"other_id": null,
"pages": "81-86",
"pmc": null,
"pmid": "28461032",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical characteristics and prognosis of ultra high-risk gestational trophoblastic neoplasia patients: A retrospective cohort study.",
"title_normalized": "clinical characteristics and prognosis of ultra high risk gestational trophoblastic neoplasia patients a retrospective cohort study"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201706516",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DACTINOMYCIN"
},
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{
"abstract": "Intracranial dural arteriovenous fistulas (DAVFs), constituting approximately 10 to15% of intracranial vascular malformations, are anomalous direct connections between dural arteries and venous sinuses, meningeal veins, or cortical veins; the arterial feeders are various, usually fed by branches of internal carotid, external carotid, or vertebral artery (Santillan et al. CNN 115(3):241-251, 2013; Holoekamp et al. JN 124(6):1752-65, 2016; Terada T et al. JN 80(5):884-9, 1994). Spectrums of clinical presentations are widespread, arranging from pulsatile tinnitus to intracranial hemorrhage. Such DAVFs with rapidly progressive dementia as primary presentation, which has been reported in several literature, are still extremely scarce (Santillan et al. CNN 115(3):241-251, 2013; Holoekamp et al JN 124(6):1752-65, 2016). Up to 2015, similar reports are less than 20 cases (Holoekamp et al. JN 124(6):1752-65, 2016). Herein, we report a patient who was misdiagnosed with encephalitis, presented thalamic dementia, and was ultimately diagnosed of DAVFs.",
"affiliations": "Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.;Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China. tujianglong85@126.com.;Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.;Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, China.",
"authors": "Cheng|Zhi-Juan|ZJ|http://orcid.org/0000-0001-9823-9375;Tu|Jiang-Long|JL|;He|Jian-Le|JL|;Li|Juan|J|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-018-3292-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "39(7)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": null,
"medline_ta": "Neurol Sci",
"mesh_terms": "D001921:Brain; D020785:Central Nervous System Vascular Malformations; D060825:Cognitive Dysfunction; D003704:Dementia; D003937:Diagnosis, Differential; D003951:Diagnostic Errors; D018450:Disease Progression; D004660:Encephalitis; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "1293-1296",
"pmc": null,
"pmid": "29480338",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": "8169629;19690848;19155381;23287743;26587655",
"title": "Rapidly progressive cognitive impairment caused by intracranial dural arteriovenous fistulas (DAVFs): a case report.",
"title_normalized": "rapidly progressive cognitive impairment caused by intracranial dural arteriovenous fistulas davfs a case report"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201808536",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional":... |
{
"abstract": "Hypersensitivity reactions to radiocontrast media (RCM) are common and in severe cases may present a challenge for treating physician in cases when premedication fails or the patient presents with severe comorbidities. We describe two cases in need of radiocontrast media after a severe reaction on previous exposure to iohexol. One presented anaphylactic reaction to RCM despite premedication and another presented with angina. Both cases were treated with a desensitization protocol to iodixanol. In conclusion, desensitization to radiocontrast media may be considered in patients with previously unsuccessful premedication and/or severe acute comorbidities.\n14.",
"affiliations": "Mona Al-Ahmad, Department of Microbiology,, Faculty of Medicine, Kuwait University,, PO Box 24923,, Safat 13110, Kuwait, T: +965-24636515, F: +965-25332719, Alahmadm@hsc.edu.kw, ORCID: orcid.org/0000-0003-3720-7032.",
"authors": "Al-Ahmad|Mona|M|;Bouza|Tito Rodriguez|TR|",
"chemical_list": "D003287:Contrast Media; D007472:Iohexol",
"country": "Saudi Arabia",
"delete": false,
"doi": "10.5144/0256-4947.2017.333",
"fulltext": "\n==== Front\nAnn Saudi MedAnn Saudi MedAnnals of Saudi Medicine0256-49470975-4466King Faisal Specialist Hospital and Research Centre 2876103410.5144/0256-4947.2017.333asm-37-4-333Case-ReportSuccessful desensitization to radiocontrast media in two high-risk cardiac patients Al-Ahmad Mona http://orcid.org/0000-0003-3720-7032aBouza Tito Rodriguez b\na Department of Microbiology, Kuwait University Faculty of Medicine, Safat, Al Asimah, Kuwait\nb Drug Allergy Unit, Department of Allergy, Al-Rashed Allergy Centre, Sulaibikhat, KuwaitCorrespondence: Mona Al-Ahmad, Department of Microbiology, Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait, T: +965-24636515, F: +965-25332719, Alahmadm@hsc.edu.kw, ORCID: orcid.org/0000-0003-3720-7032Jul-Aug 2017 37 4 333 335 © 2017 Annals of Saudi Medicine2017This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.Hypersensitivity reactions to radiocontrast media (RCM) are common and in severe cases may present a challenge for treating physician in cases when premedication fails or the patient presents with severe comorbidities. We describe two cases in need of radiocontrast media after a severe reaction on previous exposure to iohexol. One presented anaphylactic reaction to RCM despite premedication and another presented with angina. Both cases were treated with a desensitization protocol to iodixanol. In conclusion, desensitization to radiocontrast media may be considered in patients with previously unsuccessful premedication and/or severe acute comorbidities.\n==== Body\nHypersensitivity reactions to iodinated radiocontrast media (RCM) are common in daily practice. Reactions to RCM can be related to their chemical properties and are therefore dose-dependent (chemotoxic) or related to mast cell release of mediators (anaphylaxis IgE/non-IgE).1 While American guidelines consider all reactions as anaphylaxis IgE/non-IgE, European studies show a possible role for Ig-E and skin testing.1\n\nManagement of patients with a previous anaphylactic reaction to RCM includes pretreatment regimes that may reduce, although not fully prevent severe reactions.1,2 Rapid desensitization is a procedure that allows the gradual reintroduction of first-line medications to patients by providing a temporary tolerance to the drug. This is used solely in cases where no alternative of similar efficacy is available. This procedure has been proven effective for Ig-E mediated reactions where in vitro studies have determined a role for desensitization in avoidance of FcɛRI receptor internalization and therefore mast cell activation.3 Although the exact pathophysiology of the immediate type reaction to RCM is not clearly understood as an IgE-mediated reactions, few successful examples of desensitization to RCM have been published.4\n\nCASE 1\nA 79-year-old non-atopic middle-eastern female was referred to the allergy department for evaluation of an anaphylactic history to radiocontrast media (RCM). History was significant for metastatic endometrial carcinoma under treatment with taxol, carboplatin and radiotherapy, and severe aortic stenosis requiring valve replacement. Despite several asymptomatic previous exposures to RCM, five months prior she underwent a routine CT chest scan and within two minutes of the RCM, iohexol infusion, presented with sudden of shortness of breath, wheezing, diffuse flushing and urticaria. She received intravenous fluids and hydrocortisone, oxygen therapy and a bronchodilator through a nebulizer. The reaction resolved within few hours. Three months later, a second CT scan of the chest was planned, and the patient was premedicated with oral prednisolone 60 mg a day for two days, then 20 mg 1 hour prior to the procedure, along with ranitidine 150 mg, and cetirizine 10 mg. Within two minutes of RCM infusion (50 mL iohexol), she presented shortness of breath and wheezing with sudden decrease of O2 saturation to 87%, increased heart rate to 134 bpm and blood pressure of 156/74 mm Hg (from previous 124/48) along with dizziness and flushing in the back and shoulders that required admission to the intensive care unit and ventilation via continuous positive airway pressure (CPAP). She was resuscitated with intravenous hydrocortisone 200 mg, oxygen therapy and nebulized bronchodilator and then discharged from the intensive care unit after 2 days. Serum tryptase was not taken during any of the reactions. Two months later, her cardiac status progressed, and she was referred for evaluation of RCM hypersensitivity prior to a transcatheter aortic valve implantation (TAVI), and coronary angiography, requiring about 300 mL of RCM administration. Because the patient had failed premedication, desensitization was proposed and a protocol was generated.\n\nCASE 2\nA 66-year-old middle-eastern female was referred to the allergy department for evaluation of an anaphylactic history to RCM. History was significant for bronchial asthma under control, chronic urticaria, type II diabetes, and hypertension. Ten years before, a coronary angiography was performed with iohexol, and presented after 2 hours with flushing, facial angioedema, throat tightness, and shortness of breath followed by loss of consciousness which was treated in the emergency department with fluid therapy, bronchodilators and corticosteroids. At the time of referral, the patient was in need of new coronary angiography due to Canadian Cardiovascular Society class IV angina. Due to the severity of the previous reaction in a symptomatic patient requiring urgent coronary angiography, desensitization was proposed and a protocol was generated.\n\nDesensitization\nBoth patients were informed and signed consent for the desensitization procedure. The procedure was done in the intensive care unit, 4 hours before coronary angiography and TAVI procedures. In both cases, premedication was given after consultation with treating cardiologist and included an oral prednisolone 50 mg, ranitidine 150 mg and cetirizine 10 mg tablets at 24, 13, 7, and 1 hour before the procedure, montelukast 10 mg at 24 hour, and 1 hour before the procedure. A skin prick test with undiluted iohexol (Omnipaque GE healthcare, Cork, Ireland), and iodixanol (Vispaque, GE healthcare, Cork, Ireland) was negative as well as intradermal testing with 1/10 dilution. The desensitization protocol was performed as shown in Table 1. Neither patient reported symptoms during the entire protocol receiving a total of 16.67 grams iodixanol (320 mg/mL) with stable vital signs. In case 1 surgery was delayed for 4 hours and the patient received 320 mL of iodixanol in several boluses for a total of 370 mL. The aortic valve was successfully replaced and the patient was extubated 8 hours later. In case 2 coronary angiography was performed after 30 minutes and the patient received 300 mL of iodixanol with stent placement. Tryptase was drawn before the desensitization protocol and additional samples were taken in case 1 after 30 minutes, 5 hours and 8 hours, and in case 2 after 1 hour, without significant changes for both patients. Repeated skin testing 4 months after desensitization with 1/10 and 1/1 concentration to iodixanol and iohexol was negative.\n\nDISCUSSION\nRCM hypersensitivity reactions can be immediate or a delayed. Following the introduction of nonionic low-osmolarity RCM in the 1970s, the rates of reactions to RCM with non-ionic low-osmolar agents use have been reduced from 3.8–12.7% to 0.7–3.1%, and ten-fold reductions from 0.1–0.4% with severe reactions, but reactions including death are still reported.2,5\n\nWe describe one case that, where despite premedication, the patient presented with anaphylactic reactions to RCM and one case of a patient with angina present at rest in need of RCM after anaphylaxis. Both patients tolerated a successful desensitization protocol, and underwent a coronary angiogreaphy, followed by transaortic valve implantation surgery or stent with no complications.\n\nReports of positive skin, basophil activation tests (BAT), RCM specific Ig-E and mast cell release of mediators like histamine and tryptase support a role for Ig-E mediated mechanisms in some patients.2 An in vivo role for complement activation and bradykinin activation remains unclear. The pathophysiologic mechanisms may resemble the ones involved in the reactions following administration of taxanes, where a mechanism remains to be established and skin testing shows controversial results.6 Recently, there was a report of an 81-year-old female who presented with anaphylaxis to iodixanol despite intensive pretreatment. She was desensitized to iodixanol in 1 hour and 50 minutes via an 11-step doubling dose protocol up to a final step of 5 mL undiluted iodixanol.4\n\nRapid desensitization is a procedure that can be used to provide a temporary tolerance to a first-line drug when no alternative is available. There is high cross-reactivity between different types of RCM agents in patients presenting with anaphylaxis, and a positive skin test.7 In a recent meta-analysis,8 cross reactivity between iohexol and iodixanol was reported as 10% (5–23%) based on results of skin test-positive patients, but data is scarce regarding cross-reactivity between iohexol and iodixanol in patients with negative skin testing. Therefore, it is difficult to determine the role of performing desensitization with iodixanol instead of the initial culprit agent, iohexol. Despite incomplete understanding of the mechanisms involved in RCM anaphylactic reactions, desensitization can be considered where no alternative is available to the use of RCM.\n\nSIMILAR CASES PUBLISHED: 14\n\nTable 1 Iodixanol desensitization protocol.\n\nStep\tSolution\tRate (mL/hr)\tTime (min)\tVolume (mL)\tDose step (mg)\tCumulative (mg)\t\n\n\t\n1\t1\t2.5\t15\t0.625\t0.104\t0.104\t\n2\t1\t5\t15\t1.25\t0.208\t0.312\t\n3\t1\t10\t15\t2.5\t0.416\t0.729\t\n4\t1\t20\t15\t5\t0.833\t1.562\t\n5\t2\t2.5\t15\t0.625\t2.082\t3.644\t\n6\t2\t5\t15\t1.25\t4.164\t7.808\t\n7\t2\t10\t15\t2.5\t8.329\t16.137\t\n8\t2\t20\t15\t5\t16.658\t32.794\t\n9\t3\t5\t15\t1.25\t41.644\t74.438\t\n10\t3\t10\t15\t2.5\t83.288\t157.726\t\n11\t3\t20\t15\t5\t166.575\t324.301\t\n12\t3\t40\t15\t10\t333.150\t657.451\t\n13\t4\t10\t15\t2.5\t800.002\t1457.453\t\n14\t4\t20\t15\t5\t1600.005\t3057.458\t\n15\t4\t40\t15\t10\t3200.010\t6257.468\t\n16\t4\t80\t24.3\t32.5\t10400.032\t16657.500\t\nSolution 1: 0.167 mg/mL; Solution 2: 3.332 mg/mL; Solution 3: 33.315 mg/mL; Solution 4: undiluted iodixanol (320 mg/mL)\n==== Refs\nREFERENCES\n1 Demoly P Adkinson NF Brockow K Castells M Chiriac AM Greenberger PA International Consensus on drug allergy Allergy 2014 69 4 420 37 10.1111/all.12350 24697291 \n2 Brockow K Sanchez-Borges M Hypersensitivity to contrast media and dyes Immunology and allergy clinics of North America 2014 34 3 547 64 viii 10.1016/j.iac.2014.04.002 25017677 \n3 Sancho-Serra Mdel C Simarro M Castells M Rapid IgE desensitization is antigen specific and impairs early and late mast cell responses targeting FcepsilonRI internalization European journal of immunology 2011 41 4 1004 13 10.1002/eji.201040810 21360700 \n4 Gandhi S Litt D Chandy M Nguyen BM Jindal NL Tarlo SM Successful rapid intravenous desensitization for radioiodine contrast allergy in a patient requiring urgent coronary angiography The journal of allergy and clinical immunology In practice 2014 2 1 101 2 10.1016/j.jaip.2013.06.016 24565778 \n5 Kim MH Lee SY Lee SE Yang MS Jung JW Park CM Anaphylaxis to iodinated contrast media: clinical characteristics related with development of anaphylactic shock PloS one 2014 9 6 e100154 10.1371/journal.pone.0100154 24932635 \n6 Picard M Castells MC Re-visiting Hypersensitivity Reactions to Taxanes: A Comprehensive Review Clinical reviews in allergy & immunology 2014 10.1007/s12016-014-8416-0 24740483 \n7 Ahn YH Koh YI Kim JH Ban GY Lee YK Hong GN The potential utility of iodinated contrast media (ICM) skin testing in patients with ICM hypersensitivity Journal of Korean medical science 2015 30 3 245 51 10.3346/jkms.2015.30.3.245 25729245 \n8 Yoon SH Lee SY Kang HR Kim JY Hahn S Park CM Skin tests in patients with hypersensitivity reaction to iodinated contrast media: a meta-analysis Allergy 2015 70 6 625 37 10.1111/all.12589 25649510\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0256-4947",
"issue": "37(4)",
"journal": "Annals of Saudi medicine",
"keywords": null,
"medline_ta": "Ann Saudi Med",
"mesh_terms": "D000368:Aged; D000707:Anaphylaxis; D000787:Angina Pectoris; D003287:Contrast Media; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007472:Iohexol",
"nlm_unique_id": "8507355",
"other_id": null,
"pages": "333-335",
"pmc": null,
"pmid": "28761034",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25649510;24565778;24740483;25729245;24932635;25017677;24697291;21360700",
"title": "Successful desensitization to radiocontrast media in two high-risk cardiac patients.",
"title_normalized": "successful desensitization to radiocontrast media in two high risk cardiac patients"
} | [
{
"companynumb": "KW-BAUSCH-BL-2017-036474",
"fulfillexpeditecriteria": "1",
"occurcountry": "KW",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "Purpose: To compare the incidence of oversedation between oral and parenteral diphenhydramine therapy for treatment of opioid-induced pruritus in patients with sickle cell disease vaso-occlusive crisis (SCD VOC). Methods: This retrospective, single-center, cohort study included patients greater than or equal to 18 years old with sickle cell disease admitted for vaso-occlusive crisis who received either intravenous or oral diphenhydramine for opioid-induced pruritus. Patients were identified through ICD-9 and ICD-10 codes from June 1, 2016 through July 1, 2017. Rates of oversedation were compared between the 2 formulations. Secondary endpoints included length of stay, amount and duration of diphenhydramine, rate of acute chest and indication for IV therapy. Results: Fifty unique patients were included in the analysis representing 121 admissions. Seven patients received both formulations on separate admissions and were included in both groups. Twenty-nine percent of patients in the IV diphenhydramine group experienced oversedation (12/42) versus 13% in the oral diphenhydramine group (2/15, P = .312). The average number of admissions was significantly higher in the IV versus oral group (2.45 vs 1.20; P = .005) with average and median length of stay also significantly higher in the IV versus oral group (30.57, 16.0 vs 10.67, 10.0; P = .003). Conclusion: While there was no statistically significant difference in the rates of oversedation with use of IV versus oral diphenhydramine formulations, patients with SCD VOC who received IV diphenhydramine had more frequent admissions and a longer length of stay. Clinicians may consider oral diphenhydramine preferentially in appropriate patients over IV administration.",
"affiliations": "Department of Pharmacy, Atrium Health, Charlotte, NC, USA.;Memorial Sloan Kettering Cancer Center, New York, NY, USA.;Department of Pharmacy, Atrium Health, Charlotte, NC, USA.;Department of Pharmacy, Atrium Health, Charlotte, NC, USA.;Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.;Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.;Levine Cancer Institute, Atrium Health, Charlotte, NC, USA.",
"authors": "Rector|Katherine|K|;Merchant|Shelby|S|;Crawford|Rachel|R|;Arnall|Justin R|JR|https://orcid.org/0000-0003-0901-4866;Symanowski|James|J|;Veeramreddy|Padmaja|P|;Osunkwo|Ifeyinwa|I|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0018578720954171",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0018-5787",
"issue": "56(6)",
"journal": "Hospital pharmacy",
"keywords": "analgesics; disease management; intravenous therapy; pain management",
"medline_ta": "Hosp Pharm",
"mesh_terms": null,
"nlm_unique_id": "0043175",
"other_id": null,
"pages": "725-728",
"pmc": null,
"pmid": "34732930",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "19282436;10735342;24799810;22382792;21690248;12694022;29627799",
"title": "Evaluation of Intravenous Diphenhydramine Use in Patients with Sickle Cell Vaso-Occlusive Crisis.",
"title_normalized": "evaluation of intravenous diphenhydramine use in patients with sickle cell vaso occlusive crisis"
} | [
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"companynumb": "US-JNJFOC-20200943938",
"fulfillexpeditecriteria": "1",
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{
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"activesubstance": {
"activesubstancename": "PROMETHAZINE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Nanoparticle albumin-bound paclitaxel(nab-PTX)is effective as second-line chemotherapy for advanced gastric cancer. Long-term administration is generally impossible because of peripheral sensory neuropathy. However, we report 2 cases that were treated with>35 cycles of nab-PTX with dose reduction to control disease progression, which appears to be the highest number cycles so far reported. Case 1 was a male patient in his 70s, with distant lymph node metastases and an advanced primary lesion(tub2). He received 6 cycles S-1/CDDP and achieved a partial response; however, the treatment was changed to second-line chemotherapy with nab-PTX because of adverse effects; the dose of nab-PTX was reduced by 60% every 3 weeks. At the time of writing, 36 cycles have been administered and disease control has been maintained, with Grade 2 peripheral sensory neuropathy. Case 2 was another male patient in his 70s, who underwent total gastrectomy for gastric cancer(mucinous adenocarcinoma). Virchow metastasis was detected 6months after surgery. He received 1 cycle S-1/CDDP and achieved a partial response; however, treatment was changed to second-line chemotherapy with nab-PTX because of adverse effects; the dose of nab-PTX was reduced by 60% every 3 weeks. At the time of writing, 41 cycles have been administered and disease control has been maintained, with Grade 2 peripheral sensory neuropathy.",
"affiliations": "Dept. of Surgery, Yamagata Saisei Hospital.",
"authors": "Kawaguchi|Kiyoshi|K|;Urayama|Masahiro|M|;Fujimoto|Hiroto|H|;Isobe|Hideki|H|;Fuse|Akira|A|;Ohta|Keiji|K|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "46(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000418:Albumins; D005743:Gastrectomy; D006801:Humans; D008297:Male; D017239:Paclitaxel; D013274:Stomach Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1569-1572",
"pmc": null,
"pmid": "31631141",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two Cases of Long-Term Control of Advanced Gastric Cancer Treated with>35 Cycles of Low-Dose Nab-Paclitaxel.",
"title_normalized": "two cases of long term control of advanced gastric cancer treated with 35 cycles of low dose nab paclitaxel"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-20191101448",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Teriflunomide is indicated for the treatment of adult patients with relapsing-remitting multiple sclerosis.\n\n\nMETHODS\nWe present a rare intoxication with a high dose (672 mg) of teriflunomide. According to its product label, the only known treatment is the administration of colestyramine and activated carbon (charcoal). No serious adverse events occurred during the time the patient was admitted (<24 h). No long-term overdose-related symptoms or complaints were reported.\n\n\nCONCLUSIONS\nThe fact that after the acute overdose both adverse events and laboratory parameters were acceptable, prescribing colestyramine and activated carbon, as well as monitoring of laboratory parameters such as full blood count, liver and kidney values and QTc, seems sufficient during the early stage (<24 h after intake) of teriflunomide overdose.",
"affiliations": "Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede, The Netherlands.;Department of Internal Medicine, Medisch Spectrum Twente, Enschede, The Netherlands.;Department of Internal Medicine, Medisch Spectrum Twente, Enschede, The Netherlands.;Department of Clinical Pharmacy, Medisch Spectrum Twente, Enschede, The Netherlands.",
"authors": "Mian|Paola|P|https://orcid.org/0000-0002-3551-1201;van Haaften|W Tobias|WT|;Assink|Marijke|M|;van Drie-Pierik|Regine J H M|RJHM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.13360",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "46(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "MS; teriflunomide; toxicology",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": null,
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "1784-1786",
"pmc": null,
"pmid": "33421160",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Acute teriflunomide overdose with relatively mild symptoms: A case report.",
"title_normalized": "acute teriflunomide overdose with relatively mild symptoms a case report"
} | [
{
"companynumb": "NL-TEVA-2021-NL-1874565",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE"
},
"drugadditional": null,... |
{
"abstract": "Meningitis due to Mycoplasma hominis in adults is rarely described, with only three cases having been reported to date. A case of fatal meningitis in a 39-year-old patient after a neurosurgical procedure for a subarachnoid haemorrhage is reported herein. Identification and treatment were significantly delayed because of the rarity of the aetiology and difficulty identifying this organism with the routinely used conventional methods, such as Gram staining and agar growth on standard agar plates. Clinical procedures and the treatment of 'culture-negative' central nervous system infections is a real challenge for clinical microbiologists and clinicians, and M. hominis has to be considered as a potential, although very uncommon, pathogen.",
"affiliations": "Department of Microbiology, CHU de Caen, Av. Côte de Nacre, 14033 Caen Cedex 9, France.;Department of Anaesthesiology and Critical Care Medicine, CHU de Caen, Caen, France.;Department of Microbiology, CHU de Caen, Av. Côte de Nacre, 14033 Caen Cedex 9, France.;Department of Anaesthesiology and Critical Care Medicine, CHU de Caen, Caen, France.;Department of Virology, CHU de Caen, Caen, France.;University of Bordeaux, INRA, USC EA 3671 Mycoplasma and Chlamydia Infections in Humans, Bordeaux, France; Department of Bacteriology, CHU de Bordeaux, Bordeaux, France.;Department of Microbiology, CHU de Caen, Av. Côte de Nacre, 14033 Caen Cedex 9, France.;Department of Microbiology, CHU de Caen, Av. Côte de Nacre, 14033 Caen Cedex 9, France. Electronic address: isnard-c@chu-caen.fr.",
"authors": "Reissier|Sophie|S|;Masson|Romain|R|;Guérin|François|F|;Viquesnel|Gérald|G|;Petitjean-Lecherbonnier|Joëlle|J|;Pereyre|Sabine|S|;Cattoir|Vincent|V|;Isnard|Christophe|C|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "48()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Central nervous system; Meningitis; Molecular identification; Mycoplasma hominis; Nosocomial",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D003428:Cross Infection; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D016920:Meningitis, Bacterial; D009175:Mycoplasma Infections; D019535:Mycoplasma hominis; D013345:Subarachnoid Hemorrhage",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "81-3",
"pmc": null,
"pmid": "27208637",
"pubdate": "2016-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Fatal nosocomial meningitis caused by Mycoplasma hominis in an adult patient: case report and review of the literature.",
"title_normalized": "fatal nosocomial meningitis caused by mycoplasma hominis in an adult patient case report and review of the literature"
} | [
{
"companynumb": "FR-BAYER-2016-128755",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
... |
{
"abstract": "Oxaliplatin is one of the most commonly used drugs for patients with colorectal cancer. It has rarely been associated with disseminated intravascular coagulation (DIC) with only 3 previously reported cases. In all those instances, the patients had started receiving oxaliplatin, developed evidence of DIC during the course of planned treatment, and recovered with supportive care. We report a case of a 71-year-old man with colorectal cancer treated successfully with an oxaliplatin-based regimen who had disease relapse after 3 years. When treated again with oxaliplatin, he developed signs of an acute hypersensitivity reaction, and eventually had signs and symptoms consistent with DIC despite appropriate management. This case is unique in that a DIC reaction evolving from a hypersensitivity reaction occurred after the patient had already tolerated the drug years earlier. It suggests a possible immune-mediated etiology to this rare occurrence that should be kept in mind while utilizing this commonly employed drug.",
"affiliations": "Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA.",
"authors": "Waddle|Mark|M|;Irvin|Myra|M|;Gupta|Eva|E|;Gibbs|Martin|M|;Kakar|Tanya S|TS|;Gannon|Nicole A|NA|;Arthurs|Jennifer R|JR|;Fischer|Deborah L|DL|;Ailawadhi|Sikander|S|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D003404:Creatinine; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000471844",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-3157",
"issue": "62(5)",
"journal": "Chemotherapy",
"keywords": "Colorectal cancer; Disseminated intravascular coagulation; Oxaliplatin",
"medline_ta": "Chemotherapy",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003110:Colonic Neoplasms; D003404:Creatinine; D004211:Disseminated Intravascular Coagulation; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008207:Lymphatic Metastasis; D008297:Male; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012008:Recurrence",
"nlm_unique_id": "0144731",
"other_id": null,
"pages": "295-300",
"pmc": null,
"pmid": "28505615",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Disseminated Intravascular Coagulation after Oxaliplatin Infusion.",
"title_normalized": "acute disseminated intravascular coagulation after oxaliplatin infusion"
} | [
{
"companynumb": "US-PFIZER INC-2017384483",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "OBJECTIVE\nTo describe the clinical, pathological and genomic characteristics of pancreatic cancer with DNA mismatch repair deficiency (MMRD) and proficiency (MMRP).\n\n\nMETHODS\nWe identified patients with MMRD and MMRP pancreatic cancer in a clinical cohort (N=1213, 519 with genetic testing, 53 with immunohistochemistry (IHC)) and a genomic cohort (N=288 with whole-genome sequencing (WGS)).\n\n\nRESULTS\n12 out of 1213 (1.0%) in the clinical cohort were MMRD by IHC or WGS. Of the 14 patients with Lynch syndrome, 3 (21.4%) had an MMRP pancreatic cancer by IHC, and 4 (28.6%) were excluded because tissue was unavailable for testing. MMRD cancers had longer overall survival after surgery (weighted HR after coarsened exact matching 0.11, 95% CI 0.02 to 0.78, p=0.001). One patient with an unresectable MMRD cancer has an ongoing partial response 3 years after starting treatment with PD-L1/CTLA-4 inhibition. This tumour showed none of the classical histopathological features of MMRD. 9 out of 288 (3.1%) tumours with WGS were MMRD. Despite markedly higher tumour mutational burden and neoantigen loads, MMRD cancers were significantly less likely to have mutations in usual pancreatic cancer driver genes like KRAS and SMAD4, but more likely to have mutations in genes that drive cancers with microsatellite instability like ACV2RA and JAK1. MMRD tumours were significantly more likely to have a basal-like transcriptional programme and elevated transcriptional markers of immunogenicity.\n\n\nCONCLUSIONS\nMMRD pancreatic cancers have distinct clinical, pathological and genomic profiles. Patients with MMRD pancreatic cancer should be considered for basket trials targeting enhanced immunogenicity or the unique genomic drivers in these malignancies.",
"affiliations": "Ontario Institute for Cancer Research, Toronto, Ontario, Canada.;Ontario Institute for Cancer Research, Toronto, Ontario, Canada.;Ontario Institute for Cancer Research, Toronto, Ontario, Canada.;Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.;Ontario Institute for Cancer Research, Toronto, Ontario, Canada.;Ontario Pancreas Cancer Study, Mount Sinai Hospital, Toronto, Ontario, Canada.;Ontario Pancreas Cancer Study, Mount Sinai Hospital, Toronto, Ontario, Canada.;Pancreas Centre BC, Vancouver, Ontario, Canada.;Ontario Institute for Cancer Research, Toronto, Ontario, Canada.;Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.;Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.;Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.;Pancreas Centre BC, Vancouver, Ontario, Canada.;Pancreas Centre BC, Vancouver, Ontario, Canada.;Goodman Cancer Research Centre, Montreal, Quebec, Canada.;Goodman Cancer Research Centre, Montreal, Quebec, Canada.;Department of Oncology, Queen's University, Kingston, Ontario, Canada.;NYU Langone Health, New York City, New York, USA.;Pancreas Centre BC, Vancouver, Ontario, Canada.;Ontario Institute for Cancer Research, Toronto, Ontario, Canada.;Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.;Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Hospital Cancer Centre, Toronto, Ontario, Canada.;Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.;Ontario Institute for Cancer Research, Toronto, Ontario, Canada Steven.Gallinger@uhn.ca.",
"authors": "Grant|Robert C|RC|http://orcid.org/0000-0002-9821-0377;Denroche|Robert|R|;Jang|Gun Ho|GH|;Nowak|Klaudia M|KM|;Zhang|Amy|A|;Borgida|Ayelet|A|;Holter|Spring|S|;Topham|James T|JT|;Wilson|Julie|J|;Dodd|Anna|A|;Jang|Raymond|R|;Prince|Rebecca|R|;Karasinska|Joanna M|JM|;Schaeffer|David F|DF|;Wang|Yifan|Y|;Zogopoulos|George|G|;Berry|Scott|S|;Simeone|Diane|D|;Renouf|Daniel J|DJ|;Notta|Faiyaz|F|;O'Kane|Grainne|G|;Knox|Jennifer|J|;Fischer|Sandra|S|;Gallinger|Steven|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/gutjnl-2020-320730",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-5749",
"issue": "70(10)",
"journal": "Gut",
"keywords": "cancer genetics; cancer immunobiology; cancer syndromes; molecular genetics; pancreatic cancer",
"medline_ta": "Gut",
"mesh_terms": null,
"nlm_unique_id": "2985108R",
"other_id": null,
"pages": "1894-1903",
"pmc": null,
"pmid": "32933947",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma.",
"title_normalized": "clinical and genomic characterisation of mismatch repair deficient pancreatic adenocarcinoma"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-333549",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"dru... |
{
"abstract": "Nonconvulsive status epilepticus (NCSE) and acute repetitive seizures (ARS) are associated with significant morbidity and mortality. Due to the lack of randomized-controlled trials of intravenous antiepileptic drugs (AEDs) in these conditions, trials of a new generation of AEDs in this aspect are needed. A prospective interventional study was conducted in children under 18 years of age with NCSE or ARS who either had contraindication to or were refractory to first-line AEDs and received intravenous lacosamide. Demographic data, the efficacy of treatment, and adverse effects were recorded. Eleven patients with a median age of 11 years, predominantly female (72.7%), were enrolled. Average loading dose was 227 mg (8.3 mg/kg/dose) and average daily maintenance dose was 249 mg (4.6 mg/kg/dose). All patients (100%) experienced a reduction in seizure frequency within 24 hours. Eight of eleven patients (72.7%) experienced a reduction in seizure frequency of more than 50% by the end of the study, and one patient became seizure-free. In terms of adverse events, one patient had a bradycardia without prolongation of the PR interval. Interestingly, there was a case of neuronal ceroid lipofuscinosis in which a significant improvement in seizure control was achieved. The results indicate that intravenous lacosamide may be an alternative treatment for NCSE or ARS in children. To our knowledge, this is the first study on the use of intravenous lacosamide in Asian children. This study is registered to Thai Clinical Trials Registry (TCTR) and the trial registration number is TCTR20180508004.",
"affiliations": "Neurology Division, Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand.;Neurology Division, Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand.;Department of Pharmacology, Phramongkutklao College of Medicine, Bangkok, Thailand.;Neurology Division, Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand.",
"authors": "Ngampoopun|Monsicha|M|;Suwanpakdee|Piradee|P|0000-0001-9814-3867;Jaisupa|Nattapon|N|;Nabangchang|Charcrin|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2018/8432859",
"fulltext": "\n==== Front\nNeurol Res IntNeurol Res IntNRINeurology Research International2090-18522090-1860Hindawi 10.1155/2018/8432859Research ArticleEffectiveness and Adverse Effect of Intravenous Lacosamide in Nonconvulsive Status Epilepticus and Acute Repetitive Seizures in Children Ngampoopun Monsicha \n1\nhttp://orcid.org/0000-0001-9814-3867Suwanpakdee Piradee piradee@pedpmk.org\n1\nJaisupa Nattapon \n2\nNabangchang Charcrin \n1\n\n1Neurology Division, Department of Pediatrics, Phramongkutklao Hospital, Bangkok, Thailand\n2Department of Pharmacology, Phramongkutklao College of Medicine, Bangkok, ThailandAcademic Editor: Vincenzo Di Lazzaro\n\n2018 10 6 2018 2018 843285923 1 2018 4 4 2018 6 5 2018 Copyright © 2018 Monsicha Ngampoopun 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.Nonconvulsive status epilepticus (NCSE) and acute repetitive seizures (ARS) are associated with significant morbidity and mortality. Due to the lack of randomized-controlled trials of intravenous antiepileptic drugs (AEDs) in these conditions, trials of a new generation of AEDs in this aspect are needed. A prospective interventional study was conducted in children under 18 years of age with NCSE or ARS who either had contraindication to or were refractory to first-line AEDs and received intravenous lacosamide. Demographic data, the efficacy of treatment, and adverse effects were recorded. Eleven patients with a median age of 11 years, predominantly female (72.7%), were enrolled. Average loading dose was 227 mg (8.3 mg/kg/dose) and average daily maintenance dose was 249 mg (4.6 mg/kg/dose). All patients (100%) experienced a reduction in seizure frequency within 24 hours. Eight of eleven patients (72.7%) experienced a reduction in seizure frequency of more than 50% by the end of the study, and one patient became seizure-free. In terms of adverse events, one patient had a bradycardia without prolongation of the PR interval. Interestingly, there was a case of neuronal ceroid lipofuscinosis in which a significant improvement in seizure control was achieved. The results indicate that intravenous lacosamide may be an alternative treatment for NCSE or ARS in children. To our knowledge, this is the first study on the use of intravenous lacosamide in Asian children. This study is registered to Thai Clinical Trials Registry (TCTR) and the trial registration number is TCTR20180508004.\n==== Body\n1. Introduction\nNonconvulsive status epilepticus (NCSE) and acute repetitive seizures (ARS) are associated with significant morbidity and mortality and require prompt and effective treatment. Benzodiazepine, phenytoin, valproic acid, and phenobarbital are the first-line antiepileptic drugs for status epilepticus (SE) and ARS. If the seizure is refractory to the first-line treatment, the use of high dose barbiturates, propofol, or midazolam is recommended [1]. Adverse effects of these substances on consciousness and respiration may require ICU admission and artificial ventilation. Therefore, drugs with better adverse effect profiles may be beneficial for patients [2].\n\nLacosamide (LCM) is a novel agent that has been approved by the US Food and Drug Administration for individuals aged 4 years and older for partial-onset seizures as monotherapy or adjunctive therapy. Intravenous (i.v.) LCM has safety and tolerability similar to that of oral LCM [3]. Lacosamide has a novel dual mode of action. First, it has a functionalized amino acid that selectively enhances slow inactivation of voltage-gated sodium channels, increasing the proportion of sodium channels unavailable for depolarization. Such unavailability reduces pathological hyperexcitability without affecting normal physiological activity of neurons. Second, LCM binds to collapsin response mediator protein-2 (CRMP2), which enhances the drug's antiepileptic activity. However, this mechanism has recently been questioned [4].\n\nLacosamide is eliminated by the kidneys and has not been shown to affect CYP enzymes or biotransformation in the liver. It has a half-life of approximately 13 hours and is minimally (less than 15%) bound to serum proteins [4]. It is relatively well-tolerated. Common side effects include dizziness, headache, nausea, vertigo, somnolence, ataxia, and, in a small number of patients, a prolongation of the PR interval and atrioventricular block on electrocardiography [5, 6].\n\nMany clinical studies had shown that LCM has a good response rate in adults with epilepsy and has a favorable side-effect profile [7, 8]. However, there is limited data on the efficacy of intravenous LCM in the pediatric population, especially in Asian children [9–12]. Therefore, a single center, prospective interventional study of the efficacy and tolerability of intravenous LCM as adjunctive treatment or monotherapy in Thai children aged less than 18 years with nonconvulsive status epilepticus or acute repetitive seizures was conducted.\n\n2. Patients and Methods\nThis single center, prospective, interventional, open-label study was conducted between April 2016 and March 2018 in the Phramongkutklao Hospital, Thailand. The study protocol, amendments, and informed consent were approved by the Institutional Review Board of the Royal Thai Army Medical Department. All patients or their legal representatives signed written informed consent before the participation in the study.\n\nPatients were selected based on the following criteria: (i) patients with status epilepticus and/or acute repetitive seizures aged less than 18 years; (ii) patients who had uncontrollable seizures after first-line antiepileptic drug therapies; and (iii) patients with a contraindication to first-line antiepileptic drugs (allergy to drugs, comorbidity, drug interaction, and risk of side effects). The electrocardiogram and tests of kidney and liver function were done before the enrollment to rule out atrioventricular heart block and severe liver and renal diseases. Lacosamide therapy would be terminated if a patient experienced intolerable side effects or seizure aggravation.\n\nFor the purposes of this study, acute repetitive seizures (ARS) were defined as two or more seizures in 24 hours, with self-limited seizures, and patients resuming their normal state after each seizure. Convulsive status epilepticus (CSE) was defined as continuous convulsive seizures lasting more than 5 min or two or more seizures during which the patient did not return to baseline consciousness. Nonconvulsive status epilepticus (NCSE) was defined as a change in mental status from baseline for more than 30 min with ictal discharge on the electroencephalogram (EEG) [2].\n\nThe data and clinical findings were recorded including sex, age, etiology, epilepsy history, seizure type, onset of seizure, order in which AEDs were administered, loading and maintenance doses of intravenous LCM, and concomitant AEDs, as well as the responsiveness to the LCM therapy and adverse events.\n\nIntravenous LCM was added to the medications administered as a part of a standard protocol, including a sequence of benzodiazepine, phenytoin, valproic acid, and/or phenobarbital. Thus the seizures in these patients were refractory to conventional treatments. The starting loading dose of LCM was 10 mg/kg/dose (maximal dose of 400 mg/dose) followed by the maintenance dose of 1-10 mg/kg/day which was administered twice per day for three days. LCM was given orally after the discontinuation of LCM i.v. Cessation of seizures was defined as the disappearance of EEG seizure activity (all patients with a diagnosis of nonconvulsive status epilepticus underwent continuous EEG monitoring) or the disappearance of previous ictal symptoms without any suspicion of ongoing subclinical seizure.\n\nThe response to the treatment was defined by a comparison of baseline seizure frequency 1 month prior to the study to the frequency during i.v. LCM treatment at 24 hours and 1 week. It was classified as seizure-free, >75% reduction, >50% reduction in seizures, and ineffectiveness (all patients with less than 50% reduction). Children and adolescents with more than 50% reduction in seizure frequency during a minimum period of 1 week were considered responders. Wilcoxon rank test was used for statistical comparison between seizure frequency 1 month before the study and after using LCM i.v. for 24 hours and 1 week. Immediate side effects within 48 hours and short-term side effects (within 1 week) of i.v. LCM administration were also noted.\n\n3. Results\nTwelve patients met the inclusion criteria, but one was excluded from the study due to a noncompliance. Therefore, eleven patients were included in the study. Nine patients (81.8%) had acute repetitive seizures, and two (18.2%) had nonconvulsive status epilepticus. The demographic data are shown in the Table 1. The patients were aged 7-16 years (median age 11 years) and were predominantly female (72.7%). Most patients (90.9%) had underlying preexisting epilepsy including focal epilepsy of unknown etiology (36.3%) and Lennox-Gastaut syndrome (27.2%) and had received a median of 3.5 AEDs (range 2-5) concomitantly. The mean age at seizure onset was 4.4 ± 4.3 years. Lacosamide was administered as the second-order and third-order antiseizure medication in 5 of 11 (45.4%) and 4 of 11 (36.4%) patients, respectively.\n\nThe average loading dose was 227 mg (8.3 mg/kg/dose) and average maintenance dose was 125 mg, prescribed twice per day (4.6 mg/kg/dose). Intravenous LCM was found to be efficacious in every patient (100%) with a reduction in seizure frequency within 24 hours of administration. Eight patients (72.7%) were considered responders at the end of the study, and one of them became seizure-free. There was statistically significant reduction in seizure frequency after i.v. LCM (p < 0.05; Figure 1.)\n\nIn terms of adverse effects, one patient experienced bradycardia without the prolongation of the PR interval. No other adverse effects and no hemodynamic instability during the infusion were documented in this study. Interestingly, there was one patient who was diagnosed with neuronal ceroid lipofuscinosis (NCL), which is generally refractory to other AEDs; this patient showed significant improvement in seizure frequency as described below.\n\n3.1. Patient Data\nA 9-year-old boy with a history of neuronal ceroid lipofuscinosis with acute repetitive seizures, in bedridden status, was admitted to the Phramongkutklao Hospital due to community-acquired pneumonia and had myoclonic seizures more than 100 times per day. Despite antiepileptic treatment which included topiramate 10 mg/kg/day, clonazepam 6 mg/kg/day, levetiracetam 40 mg/kg/day, valproic acid 60 mg/kg/day, and lamotrigine 6 mg/kg/day, the epilepsy was poorly controlled. At admission, intravenous benzodiazepine was started, followed by intravenous levetiracetam at 30 mg/kg/dose. Despite the treatment, the patient continued to have ARS, and therefore intravenous LCM was initiated (loading dose 8 mg/kg/dose followed by maintenance dose 5 mg/kg/dose twice per day). The patient experienced an 85% decrease in seizure frequency in 24 hours and a 70% decrease by the end of the study.\n\n4. Discussion\nIntravenous LCM is known to be an effective and well-tolerated treatment for SE and ARS in hospitalized adult patients [13]. Currently, there are only limited data from retrospective trials in children. Arkilo et al. published a retrospective study of 47 pediatric patients who received intravenous LCM. The initial dose ranged from 2 to 10 mg/kg, with the effectiveness of 65%. Sedation was noted in 5 children without any other identified adverse events [14]. Grosso et al. published a retrospective case study of 11 pediatric patients with status epilepticus who were administered intravenous LCM as third or higher line of antiseizure medications. Seizure cessation was observed in 45% of patients, with no identified serious adverse effects with high loading dose up to 14 mg/kg/day [15]. Poddar et al. published a retrospective study of 9 pediatric patients receiving intravenous LCM for the treatment of status epilepticus. In this study, the success rate was 77.8%, and 44.4% of patients became seizure-free. Better outcomes were observed when LCM i.v. was given earlier with adequate dosing. The mean initial loading dose was 8.7 mg/kg. Bradycardia occurred in one patient within 24 hours after initiating LCM, but no other adverse effects were reported [16]. Sample sizes in our study are similar to those in previously published studies, and our results support earlier findings regarding the efficacy and adverse effect profile of LCM. No significant adverse reactions or drug-drug interactions were observed. One patient from our cohort had transient bradycardia, which resolved without intervention, and the patient was hemodynamically stable. Extending previous reports, our study also demonstrated statistically significant reduction in seizure frequency at 24 hours and 1 week after initiation of i.v. treatment with LCM.\n\nThere is a recent study on the possible association between LCM treatment and a change in CRMP2 function [17]. The exact contribution of this reorganization to epileptogenesis is not yet fully understood. In a mouse model, CRMP2 has been associated with neurodegenerative diseases including NCLs [18]. Due to this association, LCM may be a therapeutic option for NCLs or other neurodegenerative diseases, but available clinical data is limited. Interestingly, our study included one patient with the NCL who had favorable outcome in seizure frequency. We followed up with this patient every week for two months. His mother reported that the seizure frequency decreased more than 50% while the patient continued to take LCM orally. Therefore, our observation can provide a foundation for future use of LCM as an antiepileptic drug for the treatment of this particular disease.\n\nThe strength of our study is its prospective design and statistical significance in seizure cessation. However, the limitations include a small sample size, the variability in concomitant antiepileptic drugs, and the absence of patients with convulsive status epilepticus. Therefore, a larger prospective clinical study with more types of seizures needs to be conducted to establish the efficacy of i.v. LCM in SE or ARS in children.\n\n5. Conclusions\nOur prospective study demonstrated that intravenous LCM is safe and efficacious in NCSE or ARS in children. Our findings suggest that i.v. LCM can be a good alternative treatment before considering anesthetic agents, especially when ICU bed availability is limited.\n\nAbbreviations\nSE:Status epilepticus\n\nNCSE:Nonconvulsive status epilepticus\n\nARS:Acute repetitive seizures\n\nNCL:Neuronal ceroid lipofuscinosis\n\nAEDs:Antiepileptic drugs\n\nIV:Intravenous\n\nLCM:Lacosamide\n\nLEV:Levetiracetam\n\nCZP:Clonazepam\n\nVPA:Valproic acid\n\nTPM:Topiramate\n\nDZP:Diazepam\n\nCLB:Clobazam\n\nPPN:Perampanel\n\nLTG:Lamotrigine\n\nPHT:Phenytoin\n\nPB:Phenobarbital\n\nCBZ:Carbamazepine.\n\nData Availability\nThe datasets generated during and/or analysed during the study are available from the corresponding author on reasonable request.\n\nConflicts of Interest\nThere are no conflicts of interest among all coauthors regarding doing this study or publishing it.\n\nFigure 1 Comparison between seizure baseline 1 month before IV LCM and after IV LCM at 24 hours and 1 week.\n\nTable 1 Patient\tAge/sex\tEtiology\tOther AEDs\tOrder of IV LCM\tLoading/maintenance dose (MKDose)\t% seizure reduction in 24 hr\tEfficacy (% seizure reduction)\tSide effect\t\n\n1\n\t\n10 Y\n\t\nTraumatic brain injury\n\t\nLEV, CZP, VPA, TPM\n\t\n3\n\t\n10/6.6\n\t\n85.71\n\t\nNo change\n\t\nNo\n\t\n\n2\n\t\n12 M\n\t\nLennox-Gastaut syndrome\n\t\nLEV, DZP, CLB, TPM, PPN\n\t\n2\n\t\n10/5\n\t\n75\n\t\n>50%\n\t\nbradycardia\n\t\n\n3\n\t\n15 Y\n\t\nAnti NMDAR encephalitis\n\t\nLEV, TPM\n\t\n1\n\t\n6.7/2.2\n\t\n100\n\t\nSeizure free\n\t\nNo\n\t\n\n4\n\t\n9 M\n\t\nneuronal ceroid lipofusinosis\n\t\nLEV, CZP, VPA, TPM, LTG\n\t\n3\n\t\n8/5\n\t\n85\n\t\n>50%\n\t\nNo\n\t\n\n5\n\t\n9 Y\n\t\nfocal epilepsy of unknown etiology \n\t\nLEV, PHT\n\t\n4\n\t\n4.7/4.7\n\t\n100\n\t\nNo change\n\t\nNo\n\t\n\n6\n\t\n14 Y\n\t\nfocal epilepsy of unknown etiology \n\t\nLEV, VPA, TPM\n\t\n3\n\t\n5/2.5\n\t\n100\n\t\n>50%\n\t\nNo\n\t\n\n7\n\t\n14 Y\n\t\nLennox-Gastaut syndrome\n\t\nLEV, TPM, CLB, PB\n\t\n2\n\t\n9/4.5\n\t\n90\n\t\n>75%\n\t\nNo\n\t\n\n8\n\t\n10 Y\n\t\nfocal epilepsy of unknown etiology\n\t\nVPA, TPM, CBZ\n\t\n2\n\t\n9/4.5\n\t\n100\n\t\n>75%\n\t\nNo\n\t\n\n9\n\t\n7 Y\n\t\nSchizencephaly\n\t\nTPM, DZP, PB\n\t\n3\n\t\n10/5\n\t\n66.67\n\t\n>75%\n\t\nNo\n\t\n\n10\n\t\n16 Y\n\t\nfocal epilepsy of unknown etiology\n\t\nPHT, TPM, CZP\n\t\n2\n\t\n10/5\n\t\n100\n\t\nNo change\n\t\nNo\n\t\n\n11\n\t\n8 M\n\t\nLennox-Gastaut syndrome\n\t\nLEV, PPN, LTG, PB\n\t\n2\n\t\n8.7/5.2\n\t\n71.42\n\t\n>75%\n\t\nNo\n\t\nAEDs: antiepileptic drugs; IV: Intravenous; LCM: lacosamide; LEV: levetiracetam; CZP: clonazepam; VPA: valproic acid; TPM: topiramate; DZP: diazepam; CLB: clobazam; PPN: perampanel; LTG: lamotrigine; PHT: phenytoin; PB: phenobarbital; CBZ: carbamazepine.\n==== Refs\n1 Brophy G. M. Bell R. Claassen J. Guidelines for the evaluation and management of status epilepticus Neurocritical Care 2012 17 1 3 23 10.1007/s12028-012-9695-z 2-s2.0-84864280308 22528274 \n2 Garces M. Villanueva V. Mauri J. A. Suller A. Garcia C. Lopez Gonzalez F. J. Factors influencing response to intravenous lacosamide in emergency situations: LACO-IV study Epilepsy & behavior: E & B 2014 36 144 \n3 Biton V. Rosenfeld W. E. Whitesides J. Fountain N. B. Vaiciene N. Rudd G. D. Intravenous lacosamide as replacement for oral lacosamide in patients with partial-onset seizures Epilepsia 2008 49 3 418 424 2-s2.0-39749167069 10.1111/j.1528-1167.2007.01317.x 17888078 \n4 Finsterer J. Frank M. Beneficial effect of lacosamide for mitochondrial epilepsy Epilepsy Research 2018 140 95 96 10.1016/j.eplepsyres.2017.12.015 29316502 \n5 Pasha I. Kamate M. Suresh D. K. Safety of lacosamide in children with refractory partial epilepsy Saudi Pharmaceutical Journal 2015 23 5 556 561 2-s2.0-84943583344 10.1016/j.jsps.2015.01.006 26594123 \n6 Yildiz E. P. Ozkan M. U. Bektas G. Lacosamide treatment of childhood refractory focal epilepsy: the first reported side effect in paediatric patients Child's Nervous System 2017 33 11 2023 2027 2-s2.0-85028970328 10.1007/s00381-017-3586-8 \n7 Kellinghaus C. Berning S. Besselmann M. Intravenous lacosamide as successful treatment for nonconvulsive status epilepticus after failure of first-line therapy Epilepsy & Behavior 2009 14 2 429 431 2-s2.0-59749093137 10.1016/j.yebeh.2008.12.009 19130901 \n8 Höfler J. Unterberger I. Dobesberger J. Kuchukhidze G. Walser G. Trinka E. Intravenous lacosamide in status epilepticus and seizure clusters Epilepsia 2011 52 10 e148 e152 2-s2.0-80053575364 10.1111/j.1528-1167.2011.03204.x 21801171 \n9 Shiloh-Malawsky Y. Fan Z. Greenwood R. Tennison M. Successful treatment of childhood prolonged refractory status epilepticus with lacosamide Seizure 2011 20 7 586 588 2-s2.0-79960926642 10.1016/j.seizure.2011.03.005 21474342 \n10 Casas-Fernandez C. Martinez-Bermejo A. Rufo-Campos M. Smeyers-Dura P. Herranz-Fernandez JL. Ibanez-Mico S. Efficacy and tolerability of lacosamide in the concomitant treatment of 130 patients under 16 years of age with refractory epilepsy: a prospective, open-label, observational, multicenter study in Spain Drugs in R & D 2012 12 187 97 10.2165/11636260-000000000-00000 23193979 \n11 Pasha I. Kamate M. Didagi S. K. Efficacy and tolerability of lacosamide as an adjunctive therapy in children with refractory partial epilepsy Pediatric Neurology 2014 51 4 509 514 2-s2.0-84908120416 10.1016/j.pediatrneurol.2014.07.004 25266613 \n12 Yorns W. R. Khurana D. S. Carvalho K. S. Hardison H. H. Legido A. Valencia I. Efficacy of lacosamide as adjunctive therapy in children with refractory epilepsy Journal of Child Neurology 2014 29 1 23 27 2-s2.0-84891770237 10.1177/0883073812462887 23143718 \n13 Miró J. Toledo M. Santamarina E. Efficacy of intravenous lacosamide as an add-on treatment in refractory status epilepticus: A multicentric prospective study Seizure 2013 22 1 77 79 2-s2.0-84872129823 10.1016/j.seizure.2012.10.004 23127776 \n14 Arkilo D. Gustafson M. Ritter F. J. Clinical experience of intravenous lacosamide in infants and young children European Journal of Paediatric Neurology 2016 20 2 212 217 2-s2.0-84957431010 10.1016/j.ejpn.2015.12.013 26810009 \n15 Grosso S. Zamponi N. Bartocci A. Lacosamide in children with refractory status epilepticus. A multicenter Italian experience European Journal of Paediatric Neurology 2014 18 5 604 608 2-s2.0-84906936353 10.1016/j.ejpn.2014.04.013 24836405 \n16 Poddar K. Sharma R. Ng Y.-T. Intravenous Lacosamide in Pediatric Status Epilepticus: An Open-Label Efficacy and Safety Study Pediatric Neurology 2016 61 83 86 2-s2.0-84969921725 10.1016/j.pediatrneurol.2016.03.021 27241232 \n17 Wilson S. M. Khanna R. Specific Binding of Lacosamide to Collapsin Response Mediator Protein 2 (CRMP2) and Direct Impairment of its Canonical Function: Implications for the Therapeutic Potential of Lacosamide Molecular Neurobiology 2015 51 2 599 609 2-s2.0-84939894431 10.1007/s12035-014-8775-9 24944082 \n18 Sarkar C. Chandra G. Peng S. Zhang Z. Liu A. Mukherjee A. B. Neuroprotection and lifespan extension in Ppt1-/- mice by NtBuHA: Therapeutic implications for INCL Nature Neuroscience 2013 16 11 1608 1617 2-s2.0-84886949159 10.1038/nn.3526 24056696\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-1860",
"issue": "2018()",
"journal": "Neurology research international",
"keywords": null,
"medline_ta": "Neurol Res Int",
"mesh_terms": null,
"nlm_unique_id": "101543314",
"other_id": null,
"pages": "8432859",
"pmc": null,
"pmid": "29984000",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "24944082;25266613;23127776;28884208;23143718;17888078;19130901;29316502;27241232;21801171;24056696;21474342;23193979;24922617;26810009;24836405;22528274;26594123",
"title": "Effectiveness and Adverse Effect of Intravenous Lacosamide in Nonconvulsive Status Epilepticus and Acute Repetitive Seizures in Children.",
"title_normalized": "effectiveness and adverse effect of intravenous lacosamide in nonconvulsive status epilepticus and acute repetitive seizures in children"
} | [
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"companynumb": "TH-UCBSA-2018032856",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOBAZAM"
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{
"abstract": "Lupus anticoagulant hypoprothrombinemia syndrome (LA-HPS) is a rare condition that may predispose both to thrombosis and bleeding due to positive lupus anticoagulant (LA) and factor II (FII) deficiency. It can be seen in association with infections or systemic lupus erythematosus (SLE) and may require glucocorticoids (GCs) and/or immunosuppressive medications. Pediatric LA-HPS cases in the literature and three cases that received only rituximab (RTX) for LA-HPS (in addition to GCs) at two institutions between January 2010 and June 2017 were analyzed descriptively. Pediatric LA-HPS cases (≤18 years) with bleeding or thrombotic events were included. Information obtained included demographics, presenting symptoms, diagnoses, treatments, pre-/post-treatment prothrombin time (PT)/partial thromboplastin time (PTT)/LA/FII levels, and outcomes. In addition to three LA-HPS cases identified at our institutions, as of June 2017, 37 articles reported 54 pediatric LA-HPS cases (mean age: 8 years (0.9-17 years); female/male: (2:1); viral illness 27 (50%), SLE 20 (37%), and other six (11%)). All cases had a positive LA and FII deficiency (range: 0%-40%). All cases presented with bleeding diathesis and were treated with various regimens, but there was no reported use of RTX. The purpose of this report is to describe the novel use of RTX as a steroid-sparing agent in three pediatric SLE cases and to systematically review the literature on pediatric cases of LA-HPS.",
"affiliations": "1 Department of Pediatric Rheumatology, 25050 Steven and Alexandra Cohen Children's Medical Center , Lake Success, NY, USA.;2 Department of Pediatric Rheumatology, 25062 Hospital for Special Surgery -Weill Cornell Medical Center, New York, NY, USA.;3 Department of Pediatric Rheumatology, 20666 Children's Hospital of The King's Daughters , Norfolk, VA, USA.",
"authors": "Cetin Gedik|K|K|;Siddique|S|S|;Aguiar|C L|CL|",
"chemical_list": "D016682:Lupus Coagulation Inhibitor; D053482:beta 2-Glycoprotein I; D000069283:Rituximab",
"country": "England",
"delete": false,
"doi": "10.1177/0961203317751853",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0961-2033",
"issue": "27(7)",
"journal": "Lupus",
"keywords": "Lupus anticoagulant; hypoprothrombinemia; rituximab",
"medline_ta": "Lupus",
"mesh_terms": "D000293:Adolescent; D002648:Child; D005260:Female; D006801:Humans; D007020:Hypoprothrombinemias; D016682:Lupus Coagulation Inhibitor; D008297:Male; D010314:Partial Thromboplastin Time; D011517:Prothrombin Time; D000069283:Rituximab; D053482:beta 2-Glycoprotein I",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "1190-1197",
"pmc": null,
"pmid": "29320972",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Rituximab use in pediatric lupus anticoagulant hypoprothrombinemia syndrome - report of three cases and review of the literature.",
"title_normalized": "rituximab use in pediatric lupus anticoagulant hypoprothrombinemia syndrome report of three cases and review of the literature"
} | [
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"companynumb": "PHHY2018US023649",
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"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
... |
{
"abstract": "The acquired form of 5-oxoproline (pyroglutamic acid) metabolic acidosis was first described in 1989 and its relationship to chronic acetaminophen ingestion was proposed the next year. Since then, this cause of chronic anion gap metabolic acidosis has been increasingly recognized. Many cases go unrecognized because an assay for 5-oxoproline is not widely available. Most cases occur in malnourished, chronically ill women with a history of chronic acetaminophen ingestion. Acetaminophen levels are very rarely in the toxic range; rather, they are usually therapeutic or low. The disorder generally resolves with cessation of acetaminophen and administration of intravenous fluids. Methionine or N-acetyl cysteine may accelerate resolution and methionine is protective in a rodent model. The disorder has been attributed to glutathione depletion and activation of a key enzyme in the γ-glutamyl cycle. However, the specific metabolic derangements that cause the 5-oxoproline accumulation remain unclear. An ATP-depleting futile 5-oxoproline cycle can explain the accumulation of 5-oxoproline after chronic acetaminophen ingestion. This cycle is activated by the depletion of both glutathione and cysteine. This explanation contributes to our understanding of acetaminophen-induced 5-oxoproline metabolic acidosis and the beneficial role of N-acetyl cysteine therapy. The ATP-depleting futile 5-oxoproline cycle may also play a role in the energy depletions that occur in other acetaminophen-related toxic syndromes.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Baylor University Medical Center, Dallas, Texas.",
"authors": "Emmett|Michael|M|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen; D000255:Adenosine Triphosphate; D005978:Glutathione; D003545:Cysteine; D011761:Pyrrolidonecarboxylic Acid",
"country": "United States",
"delete": false,
"doi": "10.2215/CJN.07730713",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1555-9041",
"issue": "9(1)",
"journal": "Clinical journal of the American Society of Nephrology : CJASN",
"keywords": null,
"medline_ta": "Clin J Am Soc Nephrol",
"mesh_terms": "D000082:Acetaminophen; D000136:Acid-Base Equilibrium; D000138:Acidosis; D000255:Adenosine Triphosphate; D018712:Analgesics, Non-Narcotic; D000818:Animals; D003545:Cysteine; D004734:Energy Metabolism; D005978:Glutathione; D006801:Humans; D011041:Poisoning; D011379:Prognosis; D011761:Pyrrolidonecarboxylic Acid; D015219:Substrate Cycling",
"nlm_unique_id": "101271570",
"other_id": null,
"pages": "191-200",
"pmc": null,
"pmid": "24235282",
"pubdate": "2014-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "20826575;3567011;10890623;2751957;239948;2570295;16221705;1757400;11215692;18053525;21519223;18338302;17397529;18158646;9474033;9665429;2572924;18072147;22761219;6911;3393065;20925168;21296238;17594793;2567460;22378043;22986610;45011;15983950;20971602;15983968;20413906;9797643;2702756;21978879;1847941;19166318;19815612;4256952;22256446;20876840;18809985;18601945;16702335;21988557;20020268;17610529;18796312;20207721;5274454;2246862;16439602;23324093;10094443;20157498;16922670;8373447;18809984;17699243;18635433;22569027",
"title": "Acetaminophen toxicity and 5-oxoproline (pyroglutamic acid): a tale of two cycles, one an ATP-depleting futile cycle and the other a useful cycle.",
"title_normalized": "acetaminophen toxicity and 5 oxoproline pyroglutamic acid a tale of two cycles one an atp depleting futile cycle and the other a useful cycle"
} | [
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"companynumb": "US-JNJFOC-20140107674",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Bleeding and need for blood products are major complications associated with extracorporeal membrane oxygenation (ECMO) use. This study evaluated bleeding complications with low and standard heparinization protocols in the maintenance of venoarterial (VA)-ECMO.\n\n\n\nA retrospective comparison was performed of 2 methods of heparinization in a contemporaneous series of adult patients supported with VA-ECMO at Rush University Medical Center, between November 2011 and November 2016. CentriMag (Thoratec, Pleasanton, CA) pumps, Quadrox (Maquet, Wayne, NJ) oxygenators, and heparin-bonded circuitry were used in all patients. Group 1 was a control group of 50 patients who had ECMO support with an initiation dose of 5,000 U of heparin, followed by standard heparinization at a goal activated clotting time of 180 to 220 seconds. Group 2 comprised 52 adult patients supported with a \"low heparin protocol\" ECMO, receiving a standard heparin bolus of 5,000 U for cannulation but without subsequent, ongoing heparin administration. Acuity of illness was similar in both groups as assessed by the Mortality Probability Model (59% in Group 1 vs 62.9% in Group 2, p = 0.08). Data were submitted to the Extracorporeal Life Support Organization prospectively. Clots in the circuit, limb ischemia, oxygenator failure, and embolic complications were recorded.\n\n\n\nWeaning off ECMO was successful in 26 patients (50%) in Group 2 compared with 18 (36%) in Group 1 (p = 0.05). Hemorrhage from the cannulation site occurred in 11 (21%) in Group 2 vs 21 (42%) in Group 1 and from the surgical site in 11 (21%) in Group 2 vs 18 (36%) in Group 1. Severe bleeding complications were higher in the control group (Group 1, 32%) compared with Group 2 (11.5%; p = 0.012).\n\n\n\nMaintenance with low heparin is safe in patients supported by VA-ECMO. This strategy may reduce risk of severe bleeding and associated complications.",
"affiliations": "Division of Cardiothoracic Surgery, Oregon Health & Science University, Portland, Oregon. Electronic address: ramanj@ohsu.edu.;Department of Medicine, Rush University Medical Center, Chicago, Illinois.;Department of Medicine, Rush University Medical Center, Chicago, Illinois; Department of Surgery, Boston University Medical Center, Boston, Massachusetts.;Department of Medicine, Rush University Medical Center, Chicago, Illinois.;Department of Surgery, George Washington University Medical Center, Washington, DC.",
"authors": "Raman|Jaishankar|J|;Alimohamed|Mazahir|M|;Dobrilovic|Nikola|N|;Lateef|Omar|O|;Aziz|Salim|S|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.healun.2019.01.1313",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-2498",
"issue": "38(4)",
"journal": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",
"keywords": "ECMO; anti-coagulation; bleeding complications; low heparin; thromboembolic complications",
"medline_ta": "J Heart Lung Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001158:Arteries; D015199:Extracorporeal Membrane Oxygenation; D005260:Female; D006470:Hemorrhage; D006493:Heparin; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D014680:Veins; D055815:Young Adult",
"nlm_unique_id": "9102703",
"other_id": null,
"pages": "433-439",
"pmc": null,
"pmid": "30744940",
"pubdate": "2019-04",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "A comparison of low and standard anti-coagulation regimens in extracorporeal membrane oxygenation.",
"title_normalized": "a comparison of low and standard anti coagulation regimens in extracorporeal membrane oxygenation"
} | [
{
"companynumb": "US-PFIZER INC-2019069067",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "We describe a 69-year-old man with a non-small cell carcinoma of the lung, stage III B, who developed bilateral multiple erythematous lesions in the abdominal-inguinal area following treatment with gemcitabine. Histologically, the lesion was characterized by a heavy lymphocytic infiltrate with large CD30+ cells. The lesion was highly suggestive of cutaneous involvement by malignant lymphoma, but complete regression was observed after cessation of gemcitabine. Although rarely reported, gemcitabine therapy can induce skin lesions. Pathologists should be aware of this possibility in order to avoid a misdiagnosis.",
"affiliations": "Section of Anatomic Pathology, Department of Oncology, University of Bologna, Bellaria Hospital, via Altura 3, 40139 Bologna, Italy.",
"authors": "Marucci|G|G|;Sgarbanti|E|E|;Maestri|A|A|;Calandri|C|C|;Collina|G|G|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D016827:CD8 Antigens; D017730:Ki-1 Antigen; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.1046/j.1365-2133.2001.04461.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-0963",
"issue": "145(4)",
"journal": "The British journal of dermatology",
"keywords": null,
"medline_ta": "Br J Dermatol",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D016827:CD8 Antigens; D003841:Deoxycytidine; D003875:Drug Eruptions; D006801:Humans; D017730:Ki-1 Antigen; D008297:Male; D019310:Pseudolymphoma",
"nlm_unique_id": "0004041",
"other_id": null,
"pages": "650-2",
"pmc": null,
"pmid": "11703296",
"pubdate": "2001-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gemcitabine-associated CD8+ CD30+ pseudolymphoma.",
"title_normalized": "gemcitabine associated cd8 cd30 pseudolymphoma"
} | [
{
"companynumb": "IT-PFIZER INC-2017293514",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Cardiogenic shock due to hypertrophic obstructive cardiomyopathy (HoCM) crisis presents a clinical challenge as pharmacologic vasopressor and/or inotropic support can compromise hemodynamics and acute afterload reduction worsens left ventricular outflow tract (LVOT) obstruction. Hypertensive hypertrophic obstructive cardiomyopathy (HHoCM) is an entity mostly affecting elderly hypertensive women and could present with a clinical phenotype similar to HoCM crisis. We present a case of an 81-year-old female patient with HHoCM complicated by severe mitral regurgitation, in cardiogenic shock, in whom hemodynamic stability was restored with transvenous pacing guided by bedside echocardiography to optimize rate, left ventricle (LV) filling time, and cardiac output.",
"affiliations": "Department of Internal Medicine, University of Louisville, Louisville, KY, USA.;Department of Cardiovascular Medicine, University of Louisville, Louisville, KY, USA.;Department of Cardiovascular Medicine, University of Louisville, Louisville, KY, USA.",
"authors": "Spindel|Jeffrey F|JF|0000-0001-5143-1431;Mathbout|Mohammad|M|;Ghafghazi|Shahab|S|0000-0001-5061-6119",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/echo.14969",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0742-2822",
"issue": "38(2)",
"journal": "Echocardiography (Mount Kisco, N.Y.)",
"keywords": "cardiomyopathy hypertrophic; elderly; hypertrophic cardiomyopathy; left ventricular outflow obstruction; mitral regurgitation; transthoracic echocardiography",
"medline_ta": "Echocardiography",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D002312:Cardiomyopathy, Hypertrophic; D004452:Echocardiography; D005260:Female; D006352:Heart Ventricles; D006439:Hemodynamics; D006801:Humans; D014694:Ventricular Outflow Obstruction",
"nlm_unique_id": "8511187",
"other_id": null,
"pages": "347-350",
"pmc": null,
"pmid": "33492740",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Hypertensive hypertrophic obstructive cardiomyopathy crisis resolved with transvenous pacing guided by bedside echocardiography.",
"title_normalized": "hypertensive hypertrophic obstructive cardiomyopathy crisis resolved with transvenous pacing guided by bedside echocardiography"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2021SP004510",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERAPAMIL HYDROCHLORIDE"
},
"dr... |
{
"abstract": "BACKGROUND\nThere are limited data from resource-limited settings on antiretroviral resistance mutations that develop in patients failing second-line PI ART.\n\n\nMETHODS\nWe performed a cross-sectional virological assessment of adults on second-line ART for ≥6 months between November 2006 and December 2011, followed by a prospective follow-up over 2 years of patients with virological failure (VF) at the Hospital for Tropical Diseases, Vietnam. VF was defined as HIV RNA concentrations ≥1000 copies/mL. Resistance mutations were identified by population sequencing of the pol gene and interpreted using the 2014 IAS-USA mutation list and the Stanford algorithm. Logistic regression modelling was performed to identify predictors of VF.\n\n\nRESULTS\nTwo hundred and thirty-one patients were enrolled in the study. The median age was 32 years; 81.0% were male, 95.7% were on a lopinavir/ritonavir-containing regimen and 22 (9.5%) patients had VF. Of the patients with VF, 14 (64%) carried at least one major protease mutation [median: 2 (IQR: 1-3)]; 13 (59%) had multiple protease mutations conferring intermediate- to high-level resistance to lopinavir/ritonavir. Mutations conferring cross-resistance to etravirine, rilpivirine, tipranavir and darunavir were identified in 55%, 55%, 45% and 27% of patients, respectively. Higher viral load, adherence <95% and previous indinavir use were independent predictors of VF. The 2 year outcomes of the patients maintained on lopinavir/ritonavir included: death, 7 (35%); worsening virological/immunological control, 6 (30%); and virological re-suppression, 5 (25%). Two patients were switched to raltegravir and darunavir/ritonavir with good HIV control.\n\n\nCONCLUSIONS\nHigh-prevalence PI resistance was associated with previous indinavir exposure. Darunavir plus an integrase inhibitor and lamivudine might be a promising third-line regimen in Vietnam.",
"affiliations": "Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.;Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.;Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.;Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.;Hawaii Center for AIDS, University of Hawaii at Manoa, Honolulu, HI, USA.;Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.;Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.;Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK.;The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia.;Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK Hawaii Center for AIDS, University of Hawaii at Manoa, Honolulu, HI, USA thuyl@oucru.org.",
"authors": "Thao|Vu Phuong|VP|;Quang|Vo Minh|VM|;Day|Jeremy N|JN|;Chinh|Nguyen Tran|NT|;Shikuma|Cecilia M|CM|;Farrar|Jeremy|J|;Van Vinh Chau|Nguyen|N|;Thwaites|Guy E|GE|;Dunstan|Sarah J|SJ|;Le|Thuy|T|",
"chemical_list": "D017320:HIV Protease Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkv385",
"fulltext": "\n==== Front\nJ Antimicrob ChemotherJ. Antimicrob. ChemotherjacjacJournal of Antimicrobial Chemotherapy0305-74531460-2091Oxford University Press 10.1093/jac/dkv385dkv385Original ResearchHigh prevalence of PI resistance in patients failing second-line ART in Vietnam Thao Vu Phuong 1Quang Vo Minh 2Day Jeremy N. 13Chinh Nguyen Tran 2Shikuma Cecilia M. 4Farrar Jeremy 13Van Vinh Chau Nguyen 2Thwaites Guy E. 13Dunstan Sarah J. 5Le Thuy 134*1 Wellcome Trust Major Overseas Programme, Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam2 Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam3 Centre for Tropical Medicine and Global Health, Nuffield Department of Medicine, University of Oxford, Oxford, UK4 Hawaii Center for AIDS, University of Hawaii at Manoa, Honolulu, HI, USA5 The Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria, Australia* Corresponding author. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, 764 Vo Van Kiet, District 5, Ho Chi Minh City, Vietnam. Tel: +84-8-3838-4010; Fax: +84-8-3923-8904; E-mail: thuyl@oucru.org3 2016 11 12 2015 11 12 2015 71 3 762 774 13 7 2015 21 8 2015 12 10 2015 16 10 2015 © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nThere are limited data from resource-limited settings on antiretroviral resistance mutations that develop in patients failing second-line PI ART.\n\nMethods\nWe performed a cross-sectional virological assessment of adults on second-line ART for ≥6 months between November 2006 and December 2011, followed by a prospective follow-up over 2 years of patients with virological failure (VF) at the Hospital for Tropical Diseases, Vietnam. VF was defined as HIV RNA concentrations ≥1000 copies/mL. Resistance mutations were identified by population sequencing of the pol gene and interpreted using the 2014 IAS-USA mutation list and the Stanford algorithm. Logistic regression modelling was performed to identify predictors of VF.\n\nResults\nTwo hundred and thirty-one patients were enrolled in the study. The median age was 32 years; 81.0% were male, 95.7% were on a lopinavir/ritonavir-containing regimen and 22 (9.5%) patients had VF. Of the patients with VF, 14 (64%) carried at least one major protease mutation [median: 2 (IQR: 1–3)]; 13 (59%) had multiple protease mutations conferring intermediate- to high-level resistance to lopinavir/ritonavir. Mutations conferring cross-resistance to etravirine, rilpivirine, tipranavir and darunavir were identified in 55%, 55%, 45% and 27% of patients, respectively. Higher viral load, adherence <95% and previous indinavir use were independent predictors of VF. The 2 year outcomes of the patients maintained on lopinavir/ritonavir included: death, 7 (35%); worsening virological/immunological control, 6 (30%); and virological re-suppression, 5 (25%). Two patients were switched to raltegravir and darunavir/ritonavir with good HIV control.\n\nConclusions\nHigh-prevalence PI resistance was associated with previous indinavir exposure. Darunavir plus an integrase inhibitor and lamivudine might be a promising third-line regimen in Vietnam.\n\nWellcome Trust http://dx.doi.org/10.13039/100004440\n==== Body\nIntroduction\nThe WHO endorses ritonavir-boosted PI (PIr)-based ART as an efficacious second-line treatment after failure of NNRTI-based first-line therapy in resource-limited settings.1 PIr-based therapy is highly potent in ART-naive patients participating in clinical trials2–4 and has a high efficacy as a second-line therapy in resource-limited settings.5,6 Nevertheless, ≤20% of patients in resource-rich and 27% of patients in resource-limited settings develop virological failure (VF) on PIr-based ART.4,6,7 PI resistance is rarely observed in patients failing PIr-based therapy in clinical trials3,4,8,9 and, similarly, is uncommon (range: 0%–7%) in PI-naive patients failing second-line therapy in sub-Saharan Africa.10–14 However, studies from Cambodia15 and India16 have reported PI-resistance-mutation prevalences of 40% and 70% in patients failing second-line ART, respectively. There are few data regarding the prevalence of and risk factors for PI resistance developed on second-line ART in Asia. Significant uncertainty exists regarding the risk factors for PI resistance in programmatic settings, the contribution of HIV-1 subtypes to mutation development and the clinical outcomes in patients with PI resistance on long-term second-line ART. HIV-1 subtype CRF01_AE accounts for 99% of HIV infections in Vietnam,17–21 which is among the Asian countries with the highest numbers of HIV infections.22,23 Of the 90 000 people on ART, 3% are on second-line therapy.23Because of its costs, viral load monitoring of HIV is not performed routinely. Therefore, data on virological outcome and drug resistance in patients on second-line therapy are lacking. To this end, we aimed to generate data on antiretroviral resistance profiles of HIV-1 CRF01_AE-infected patients with viraemia on second-line PI therapy at the largest HIV treatment centre in Vietnam. Our objectives were: (i) to identify the risk factors for resistance development; (ii) to describe the long-term clinical outcomes of patients with resistance maintained on a failing second-line regimen; and (iii) to investigate cross-resistance to second-generation NNRTIs and PIs to inform national policy on third-line therapy.\n\nMethods\nStudy setting and design\nThe study was conducted at the Hospital for Tropical Diseases (HTD) in Ho Chi Minh City (HCMC). The HTD is the largest centre for HIV care in southern Vietnam, providing ART for more than 5000 patients according to the national ART programme. Until the de-centralization of care in 2011–12, the HTD had been the primary provider of second-line ART for patients living in the 17 southern provinces of Vietnam. First-line therapy was administered according to national and international guidelines and at the time of the study consisted of two NRTIs (lamivudine in combination with either zidovudine or stavudine) and one NNRTI—either nevirapine or efavirenz. Indinavir was generically and locally produced (STADA, Vietnam) during this time and was prescribed (without ritonavir boosting) in public and private settings for patients with treatment failure or intolerance on nevirapine before efavirenz became available in 2004.24 In 2011, tenofovir disoproxil fumarate replaced stavudine as a preferred NRTI backbone drug. Patients in the national programme were required to attend monthly appointments for clinical and adherence evaluation. CD4 cell count was performed every 6 months. HIV load testing was performed to confirm treatment failure when the WHO's defined clinical and/or immunological failure criteria were met.25,26 HIV genotyping was performed to diagnose antiretroviral resistance prior to therapy switch, and results were reported to treating clinicians. Second-line therapy included nelfinavir prior to 2006 and lopinavir/ritonavir thereafter, in combination with tenofovir disoproxil fumarate and/or zidovudine plus lamivudine.27,28\n\nThis study consisted of a cross-sectional survey of adult patients (age ≥15 years) who had been on second-line ART for at least 6 months and were on active care to identify those with VF and their drug resistance development, followed by a prospective follow-up over 2 years of patients with VF. VF was defined as at least two viral loads ≥1000 copies/mL measured 1–3 months apart after intensive adherence counselling. The patients who had been on second-line therapy for <6 months at the time of study assessment, who died or who switched therapy due to drug intolerance were excluded. The study was conducted between December 2011 and June 2014.\n\nData collection\nClinical data, including demographic information, HIV risk factors, ART history, CD4 counts, HIV viral load, genotyping results at the time of therapy switch (if available), AIDS events and therapy adherence, were obtained both retrospectively and prospectively from patients' charts and from one-on-one interviews.\n\nART adherence evaluation\nTreating clinicians routinely assessed adherence according to the national guidelines at all clinic visits; adherence was recorded either as an estimated percentage of pills taken or as a qualitative assessment of ‘good’, ‘average’ or ‘poor’, corresponding to ≥95%, 80%–94% or <80% adherence, respectively.26 Additionally, for this study, adherence was evaluated over the 6 months preceding the time of study assessment using a simple self-reported visual analogue scale (VAS).29 For analysis, sub-optimal adherence was defined as having at least one adherence score of <95% by pill count or by the VAS and/or receiving at least one qualitative adherence assessment of ‘average’ or ‘poor’ over the preceding 6 months prior.\n\nHIV RNA measurement and antiretroviral resistance testing\nAt the time of enrolment, 5 mL of EDTA blood was collected for viral load measurement using the Abbott m2000rt Real Time HIV-1 assay (limit of detection of 150 copies/mL) (Abbott Laboratories, Abbott Park, IL, USA). Antiretroviral resistance testing was performed for patients with VF using an in-house population sequencing and sequence analysis protocol as previously described, with bidirectional coverage of the complete protease gene and reverse transcriptase codons 10–300.18 The sequences were analysed using SeqScape (Applied Biosystems). Nucleotide changes were determined by comparison with the consensus sequence pNL4-3 for HIV-1 subtype B (GenBank accession number M19921). Antiretroviral resistance mutations were identified based on the 2014 IAS-USA mutation list.30 The antiretroviral resistance profile of each patient was predicted using the Stanford resistance interpretation algorithm (http://hivdb.stanford.edu). The Rega HIV-1 subtyping tool was used to determine the HIV-1 subtype of each patient sample.31\n\nStatistical analyses of predictors of VF\nThe following pre-defined covariates were included in the logistic regression model: CD4 cell count and (log10-transformed) HIV RNA load at therapy switch, history of indinavir use, second-line therapy delay (defined as time in months from first detection of failure of first-line ART to time of second-line therapy initiation) and an overall measure of therapy adherence (<95% versus ≥95%). The chosen covariates were either established risk factors for ART outcome5,32–36 or were based on clinicians' observations (i.e. previous indinavir use). Both univariate and multivariable analyses were performed.\n\nFollow-up of patients with VF\nThe results of viral load and resistance testing were reported to the treating clinicians. Patients with VF then received intensive adherence counselling. As third-line therapy was not available through the national programme, these patients were continued on the current treatment according to national guidelines. The clinical and immunological outcomes of these patients over the following 24 months were evaluated. HIV RNA load was re-tested at month 24, and repeat genotype testing was performed if HIV RNA concentrations were ≥1000 copies/mL, to evaluate the evolution of resistance mutations in these patients.\n\nEthics\nThe study was approved by the scientific and ethics committee of the HTD. All patients gave written consent prior to study enrolment.\n\nResults\nStudy population and characteristics\nFigure 1 describes the study participants, virological outcome and follow-up of the patients with VF maintained on the failing second-line regimen. Of 373 patients who started second-line ART between November 2006 and December 2011, 44 (11.8%) had died, 2 had been lost to follow-up and 51 (13.7%) had been transferred to other provincial clinics by the time of the study. Forty-one (11.0%) patients who had been on second-line ART for <6 months and four patients who switched therapy due to first-line therapy intolerance were excluded. The remaining 231 patients were enrolled into the study. Table 1 shows the characteristics of the 231 patients. The median age was 32 years; 81% were men. The median CD4 cell count and HIV RNA concentration at the time of therapy switch were 44 cells/mm3 and 5.1 log10 copies/mL, respectively. The median time on second-line ART was 29 months (IQR: 16–43 months). Nelfinavir was the starting PI in 10 (4.3%) patients, but it was replaced by lopinavir/ritonavir within 12 months for all patients. A total of 36 (17.1%) patients had a history of treatment with indinavir, which was frequently prescribed at 800 mg twice daily or 400 mg three times daily. Sub-optimal adherence was identified in 12.1% patients.\nTable 1. Characteristics of 231 patients on second-line ART in HCMC\n\nCharacteristic\t\t\nMale, n (%)\t187 (81.0)\t\nAge (years), median (IQR)\t32 (28–36)\t\nPrevious history of injecting drug use, n (%); N = 230\t93 (40.4)\t\nCD4 count (cells/mm3), median (IQR); N = 227\t44 (17–84)\t\nHIV RNA concentration (log10 copies/mL), median (IQR); N = 215\t5.1 (4.6–5.5)\t\nPrevious indinavir use, n (%); N = 211\t36 (17.1)\t\nTime on second-line therapy (months), median (IQR)\t29 (16–43)\t\nSecond-line regimens, n (%)\t\n initial regimens\t\n TDF/3TC/LPVr\t112 (48.5)\t\n TDF/3TC/LPVr + AZT\t82 (35.5)\t\n LPVr + other NRTIsa\t27 (11.7)\t\n NFV + other NRTIsa\t10 (4.3)\t\n regimens at time of study assessment\t\n TDF/3TC/LPVr\t128 (55.4)\t\n TDF/3TC/LPVr + AZT\t88 (38.1)\t\n LPVr + other NRTIsa\t15 (6.5)\t\nAdherence, n (%)\t\n ≥95%\t203 (87.9)\t\n <95%\t28 (12.1)\t\nTDF, tenofovir disoproxil fumarate; 3TC, lamivudine; LPVr, lopinavir/ritonavir; AZT, zidovudine; NFV, nelfinavir.\n\naOther NRTIs include two or three of the following drugs: abacavir, didanosine, zidovudine, lamivudine, stavudine or tenofovir disoproxil fumarate.\n\n\nFigure 1. Flow chart of the study participants, virological outcome and follow-up of patients with VF maintained on the failing second-line ART. *24 months follow-up. DRVr, ritonavir-boosted darunavir; RAL, raltegravir; 3TC, lamivudine.\n\n\n\nAntiretroviral resistance mutations detected in patients prior to second-line therapy switch\nBecause of cost constraints, HIV genotyping was performed only for 173 of 231 (74.9%) patients prior to therapy switch. Figure 2 shows the mutations and prevalences detected in these patients. Mutations conferring high-level resistance to NRTIs were detected in 168 of 173 (97.1%) patients, and to NNRTIs in 163 of 173 (94.2%) patients. High-level resistance to PIs was detected in 4 of 173 (2.3%) patients. Resistance mutations to both NRTIs and NNRTIs were present in 161 of 173 (93.1%) patients and to all three drug classes in 6 of 173 (3.5%) patients. The most common NRTI resistance mutations were M184I/V (86.1%), thymidine analogue mutations M41L, D67N, K70E/R, T215F/Y and K219E/Q (33%–57%), Q151M (22.5%) and K65R (16.2%). One hundred and forty-two (82.1%) patients harboured multiple thymidine analogue mutations and multiple NRTI resistance mutations (Q151M complex). Two patients had a T69 insertion mutation. The most common NNRTI resistance mutations were Y181C/I/V (48.6%), G190A/S (42.8%) and K103N (30.1%). At least three major NNRTI resistance mutations were present in 55 of 173 (31.8%) patients. Eight patients carried at least one major PI resistance mutation. The most common protease mutations were M46I/L (2.9%), L90M (1.7%) and V82A (1.2%).\nFigure 2. Prevalence of antiretroviral resistance mutations in 173 patients at the time of switch to second-line therapy in HCMC.\n\n\n\nPredicted resistance to second-line ART regimen\nThe predicted susceptibilities to the national second-line regimens containing tenofovir disoproxil fumarate, lamivudine and lopinavir/ritonavir were evaluated for the 173 patients who had genotype results using the Stanford HIV Drug Resistance algorithm. Intermediate- to high-level resistance to tenofovir disoproxil fumarate was present in 120 of 173 (69.4%), to lamivudine in 165 of 173 (95.4%) and to lopinavir/ritonavir in 2 of 173 (1.2%).\n\nThe numbers of patients predicted to receive one, two and three fully active drugs were 138 of 173 (79.8%), 25 of 173 (14.5%) and 4 of 173 (2.3%), respectively.\n\nVirological outcome\nThe virological outcomes of the 231 patients are shown in Figure 1. Twenty-two (9.5%) patients had confirmed VF with a median HIV RNA concentration of 4.75 log10 copies/mL (IQR: 3.92–5.01 log10 copies/mL). Five of 231 (2.2%) patients had HIV RNA concentrations between 400 and <1000 copies/mL, 4 (1.7%) patients had HIV RNA concentrations between 150 and <400 copies/mL and the remaining 200 (86.6%) patients had undetectable viral loads.\n\nHIV subtypes, antiretroviral resistance mutations and predicted susceptibility of the 22 patients with VF\nOf the 22 patients with VF, 21 (95%) were infected with HIV-1 subtype CRF01_AE; a single patient was infected with HIV-1 CRF01_AE/B recombinant. Table 2 shows the mutation profiles of the 22 patients prior to therapy switch and at VF. The majority of the NRTI and NNRTI resistance mutations detected prior to therapy switch remained detectable at therapy failure, with the NNRTI resistance mutations persisting up to 45 months off NNRTI therapy. Major PI resistance mutations developed in 14 (64%) patients; within this subgroup of patients, the median number of PI resistance mutations was 2 (IQR: 1–3 mutations). The most common PI resistance mutations were V82A/F (64%), M46I/L (57%), I84V (29%) and L76V (21%). Five patients had only one PI resistance mutation; the remaining nine had multiple PI resistance mutations. Minor or accessory PI resistance mutations developed in five patients. Three patients did not have any PI resistance mutations.\nTable 2. Antiretroviral history, drug resistance profile and 2 year outcomes of 22 patients with VF on second-line ART in HCMC\n\nPatient\tTime on second-\nline ART (months)\tAt time of therapy switch\tPrior PI use\tMutations at time of therapy switch\tAt time of VF\tMutations at time of VF\tTwo year outcomes\t\nCD4 count (cells/mm3)\tviral load (copies/mL)\tNRTIs\tNNRTIs\tPIs\tCD4 count (cells/mm3)\tviral load (copies/mL)\tNRTIs\tNNRTIs\tPIs\t\n1\t15\t79\t4 720 000\tno\tL74V, M184I\tK101E, K103N, G190A, M230L\t\t191\t289 000\tD67N, K70R, L74V, M184I, K219Q\tK101E, K103N,\nE138G, G190A,\nM230L\tL10I, V82A\tvirological re-suppression\t\n2\t18\t2\t7 590 000\tNA\tNA\tNA\tNA\t2\t1 630 000\tM184V\tK103N, V108I, Y181C\t\tdeath\t\n3\t19\t13\t170 000\tIDV\tNA\tNA\tNA\t50\t402 194\tT215S\t\tG16E, K20I, M36I, M46L, I54V, H69K, V82A, L89M\tdeath\t\n4\t18\t74\t118 000\tIDV\tM41L, D67N, K70R, V75M, M184V, T215F, K219Q\tK101P, K103N\t\t303\t1574\tM41L, D67N, K70R, V75M, M184V, T215F, K219Q\tK101P, K103N\tL10I, G16E, K20I, M36I, H69K, L89M\ttransferred to other clinic\t\n5\t18\t45\t435 000\tIDV\tA62V, K65N, T69S, V75M, F77L, Q151M, M184V\tV106I, Y181C, Y188L, H221Y\tI54V, N83D, I84R\t152\t1184\tV75M, M184V, T215F\tV106I, Y181C, Y188L, H221Y\tL10I, K20I, M36I, M46L, F53L, I54V, H69K, V82A, L89I\tworsening virological/immunological control\t\n6\t29\t5\t365 000\tno\tK65R, Q151M\tY181C, G190A\tL33F, I84L\t143\t5490\tK65R, Q151M\tY181C, G190A\tK20R, L33F, M36I, M46I, I62V, H69K, L76V, I84V, L89M\tworsening virological/immunological control\t\n7\t6\t6\t190 000\tIDV\tA62V, D67N, T69P, V75I, F77L, F116Y, Q151M, M184I, T215S, K219Q\tK101E, Y181C, G190A\tL10V\t293\t3910\tD67N, V75I, F77L, F116Y, Q151M, M184I, K219Q\tK101E, Y181C, G190A\tL10V, G16E, M36I, H69K, V82A, L89M\tvirological re-suppression\t\n8\t31\t40\t184 000\tno\tM41L, D67N, T69N, K70R, L74I, M184V, T215F, K219Q\tV108I,\nG190A\tL10IV\t546\t1520\tM41L, D67N, K70R, L74I, M184V, T215F, K219Q\tG190A\tL10V, G16E, L33F, M36I, I54V, V82A, L89I\tvirological re-suppression\t\n9\t47\t8\t253 000\tIDV\tM41L, D67N, T69N, K70R, L74I, M184V, T215F, K219Q\tA98G, K103N, G190A\t\t171\t37 379\tM41L, D67N, K70R, M184V, T215F, K219Q\tK103N, G190A\tL10V, K20I, L33F, M36L, M46I,\nI47V, I54V, H69K, T74P,\nV82F, L89M\tworsening virological/immunological control\t\n10\t8\t21\t752 000\tNA\tNA\tNA\tNA\t152\t16 582\tK65R, V75M\tV179F, Y181C, H221Y\tM36I, H69K, L89M\tvirological re-suppression\t\n11\t45\t21\t867 000\tno\tM41L, E44AD, D67N, L74V, V75M, V118I, M184V, L210W, T215Y, K219N\tA98G, L100I, K101P, G190A\t\t121\t96 147\tM41L, D67N, V75M, M184V, L210W\tA98G, G190A\tM36I, H69K, V82I, L89M\tdeath\t\n12\t43\t1\t132 000\tno\tD67N, K70R, M184V, L210W, T215F, K219W\tK103N, V108I, Y181C, G190A\t\t11\t22 600\tM184V\t\t\tdeath\t\n13\t50\t113\t38 238\tIDV\tM41L, D67N, T69P, K70R, M184V, L210W, T215F, K219E\t\t\t57\t319 798\tM41L, D67N, K70R, M184V, L210W, K219QE\t\tL10V, G16E, K20V, L33F, M36I, I47V, I54V, H69K, A71V, I84V, L89M\tworsening virological/immunological control\t\n14\t12\t25\t693 000\tno\tNA\tNA\tNA\t48\t875 664\t\t\tL10I, K20R, M36I, H69K, L89M\tvirological re-suppression\t\n15\t29\t211\t189 000\tIDV\tT69N, V75M\t\tV32I, M46I, Q58E\t253\t64 262\tK70R, V75M, M184V, K219E\tV90I\tL10I, G16E, K20I, M36I, M46I, I54A, Q58E, H69K, K70R, V82A, L89I\tworsening virological/immunological control\t\n16\t47\t44\t139 000\tIDV\tM41L, T69N, V75M, F77L, F116Y, Q151M, M184V, T215Y\tA98G, L100I, K103N\t\t154\t34 900\tM41L, V75M, F77L, M184V, T215Y\tA98G\tL10I, G48A, I54V, A71V, V82A\tRAL + DRVr + 3TC\t\n17\t43\t64\t174 550\tIDV\tM41L, D67N, K70R, L74V, M184V, T215F, K219Q\tY181C, G190S\tM36I\t67\t47 500\tM41L, D67N, K70R, L74V, M184V, T215F, K219Q\tA98G, Y181C, G190S\tL10I, L33F, M46I, I54M, A71V, G73S, I84V\tdeath\t\n18\t23\t41\t377 000\tno\tK65R, V75M\tK103N\t\t6\t67 934\t\t\tM36I, H69K, V82I, L89M\tworsening virological/immunological control\t\n19\t17\t40\t590 000\tno\tD67N, T69N, K70R, L74I, V75M, M184V, T215F, K219E\tK101P, Y181C, G190S\t\t352\t3776\tD67N, K70R, V75M, M184V, T215F, K219E\tK101Q, Y181C, G190A\tK20R, M36I, M46I, L63P, H69K, A71V, L76V,\nI84V, L89M\ttransferred to other clinic\t\n20\t30\t3\t948 909\tNA\tNA\tNA\tNA\t98\t103 000\tK70R, T215F, K219E\tA98G, K101E, Y181C, Y188L, G190A\tL10I, I54V, N83D\tdeath\t\n21\t45\t113\t2 470 000\tIDV\tM41L, D67N, V75M, V118I, M184V, L210W, T215F, K219W\tK101P, V108I, G190A\tL10F\t173\t79 800\tM41L, D67N, V75M, M184V, T215Y\tA98G\tL10F, M46L, I54V, L76V,\nV82A, L89V\tRAL + DRVr + 3TC\t\n22\t26\t14\t81 422\tIDV\tNA\tNA\tNA\t28\t83 300\tK65R\tK101E, Y181C, G190A\t\tdeath\t\nIDV, indinavir; RAL, raltegravir; DRVr, darunavir/ritonavir; 3TC, lamivudine; NA, not applicable (as data are unknown).\n\nBold: major drug resistance mutations according to the IAS-USA 2014.\n\n\n\nFigure 3 shows the predicted resistance profiles of the 22 patients based on their individual genotype profiles. Mutations conferring intermediate- to high-level resistance to the second-line drugs tenofovir disoproxil fumarate, lamivudine and lopinavir/ritonavir were detected in 13 (59%), 18 (82%) and 13 (59%) patients, respectively. Cross-resistance to the second-generation NNRTIs etravirine and rilpivirine was intermediate to high level, and cross-resistance to both was present in 12 (55%) patients. Cross-resistance to the second-generation PIs tipranavir and darunavir was present in 10 (45%) and 6 (27%) patients, respectively. Cross-resistance to darunavir was present only at an intermediate level.\nFigure 3. Predicted antiretroviral susceptibility among 22 patients experiencing VF on second-line ART in HCMC using the Stanford algorithm. AZT, zidovudine; d4T, stavudine; 3TC, lamivudine; FTC, emtricitabine; ABC, abacavir; ddI, didanosine; TDF, tenofovir disoproxil fumarate; EFV, efavirenz; NVP, nevirapine; ETR, etravirine; RPV, rilpivirine; LPV, lopinavir; IDV, indinavir; NFV, nelfinavir; ATV, atazanavir; FPV, fosamprenavir; SQV, saquinavir; TPV, tipranavir; DRV, darunavir; r, ritonavir-boosted.\n\n\n\nPredictors of second-line virological outcome\nTable 3 lists the data for the five covariates entered into the logistic regression model and the results of the univariate and multivariate analyses. The most frequently missing covariates were history of indinavir use (8.7% missing) and viral load (6.9% missing); other covariates were missing in ≤2% of patients. Higher viral load, sub-optimal adherence and previous indinavir use predicted VF in both univariate and multivariate analyses [multivariate ORs: 2.7 (95% CI: 1.1–7.4), P = 0.039; 7.8 (95% CI: 2.1–31.0), P = 0.002; and 12.8 (95% CI: 3.7–49.8), P < 0.001, respectively]. Multivariate analysis shown in Table 3 was based on an analysis excluding missing data.\nTable 3. Factors associated with VF in 231 patients on second-line ART in HCMC\n\nCovariate\tPatients without VF (N = 209)\tPatients with VF (N = 22)\tUnivariate effect\tMultivariate effect\t\nOR (95% CI)\tP\tOR (95% CI)\tP\t\nCD4 counta (by −50 cells/mm3)\t47 (17–88); N = 205b\t33 (9–59)\t1.39 (0.92–2.38)\t0.184\t1.52 (0.84–3.45)\t0.248\t\nHIV RNA concentrationa (by +log10 copies/mL)\t5.1 (4.6–5.5); N = 194b\t5.6 (5–5.9); N = 21b\t3.14 (1.56–6.69)\t0.002\t2.70 (1.08–7.35)\t0.039\t\nTime on failing first-line ART (months)\t9 (5–15); N = 206b\t9 (3–21)\t1.01 (0.97–1.05)\t0.537\t1.01 (0.95–1.07)\t0.786\t\nAdherence <95% (yes)\t21 (10%)\t7 (32%)\t4.18 (1.46–11.16)\t0.005\t7.81 (2.06–31.00)\t0.002\t\nPrior indinavir use (yes)\t27 (14%); N = 192b\t9 (47%); N = 19b\t5.50 (2.02–14.91)\t<0.001\t12.80 (3.69–49.80)\t<0.001\t\nData are presented as absolute numbers (%) for categorical variables and median (IQR) for continuous variables.\n\nBold: results with statistical significance.\n\naAt time of therapy switch.\n\nbNumber of patients with complete data on a covariate.\n\n\n\nWe performed ad hoc univariate and multivariate analyses of factors associated with the development of PI resistance. The three covariates identified to be independent predictors of VF were entered into the logistic regression model. Higher viral load and previous indinavir exposure remained independent predictors of PI resistance in both univariate [ORs: 2.7 (95% CI: 1.1–6.5), P = 0.03; and 9.7 (95% CI: 3.0–34.2), P < 0.001, respectively] and multivariate [ORs: 4.3 (95% CI: 1.5–14.8), P = 0.01; and 13.6 (95% CI: 3.6–61.3), P < 0.001, respectively] analyses. Adherence did not predict PI resistance in the univariate or multivariate analyses.\n\nTwo year follow-up of patients with VF maintained on the failing second-line therapy\nThe clinical outcomes of the 22 patients with VF are shown in Figure 1 and are also reported along with their treatment history and resistance profiles in Table 2. Seven patients died after a median duration of 8 months (IQR: 8–16 months) from the time of study enrolment: four of tuberculosis and three of severe wasting syndrome. Of the 15 patients who remained alive, two patients were transferred to provincial clinics and declined study follow-up visits. Two patients were switched to raltegravir and darunavir/ritonavir (purchased privately from Thailand for $600 US/month) and remained on lamivudine. The remaining 11 patients were maintained on the lopinavir/ritonavir-based regimen. Viral load testing was performed at 24 month in the 13 patients in active follow-up. Virological re-suppression was achieved in the two patients who switched to raltegravir and darunavir/ritonavir and in five patients maintained on lopinavir/ritonavir. The CD4 cell counts of the five patients with virological re-suppression on lopinavir/ritonavir increased to a mean of 611 cells/mm3 (range: 384–942 cells/mm3). Of these five patients, two had no major PI resistance mutations and three had only one major mutation—V82A—at VF. The remaining six patients had persistent viral replication (mean HIV RNA concentration: 5.2 log10 copies/mL; range: 4.79–5.70 log10 copies/mL). Table 4 shows the evolution of antiretroviral resistance mutations of these six patients. Patient 18 had no major drug resistance mutations, and the other five had multiple major PI resistance mutations at VF and continued to accumulate NRTI resistance mutations (in five patients) and PI resistance mutations (in two patients). All six patients had worsening immunological control (mean CD4 count: 97 cells/mm3, range: 0–177 cells/mm3); however, there were no AIDS events over the 24 months of follow-up.\nTable 4. Evolution of resistance mutations in six patients with worsening HIV control who were maintained on a failing second-line regimen\n\nPatient\tTime on second-line ART (months)\tAt time of VF\tMutations at time of VF\tAt 2 year follow-up\tMutations at 2 year follow-up\t\nCD4 count (cells/mm3)\tviral load (copies/mL)\tNRTIs\tNNRTIs\tPIs\tCD4 count (cells/mm3)\tviral load (copies/mL)\tNRTIs\tNNRTIs\tPIs\t\n5\t18\t152\t1184\tV75M, M184V, T215F\tV106I, Y181C, Y188L, H221Y\tL10I, K20I, M36I, M46L, F53L, I54V, H69K, V82A, L89I\t77\t93 500\tA62V, K65N, V75M, F77L, Q151M, M184V\tV106I, Y181C, Y188L, H221Y\tL10F, K20I, M36I, M46L, F53L, I54V, H69K, V82A, L89I\t\n6\t29\t143\t5490\tK65R, Q151M\tY181C, G190A\tK20R, L33F, M36I, M46I, I62V, H69K, L76V, I84V, L89M\t177\t164 000\tK65R,\nD67N, T69d, Q151M, K219E\tY181C, G190A\tL10F, K20R, L33F, M36I, M46I, I62V, H69K, L76V, V82A, T74S, I84V, L89M\t\n9\t47\t171\t37 379\tM41L, D67N, K70R, M184V, T215F, K219Q\tK103N, G190A\tL10V, K20I, L33F, M36L, M46I,\nI47V, I54V, H69K, T74P,\nV82F, L89M\t159\t61 100\tM41L, D67N, T69N, K70R, V75M, M184V, L210W, T215F, K219Q\tV106I, G190A\tL10V, K20I, L33F, M36L, M46I, I47V, I54V, H69K, T74P, V82F, L89M\t\n13\t50\t57\t319 798\tM41L, D67N, K70R, M184V, L210W, K219QE\t\tL10V, G16E, K20V, L33F, M36I, I47V, I54V, H69K, A71V, I84V, L89M\t10\t498 000\tM41L, D67N, K70R, M184V, L210W, T215Y, K219D\t\tL10V, G16E, K20V, L33F, M36I, M46I, I47V, I54V, H69K, A71V, G73T, L76M, I84V, L89T\t\n15\t29\t253\t64 262\tK70R, V75M, M184V, K219E\tV90I\tL10I, G16E, K20I, M36I, M46I, I54A, Q58E, H69K, K70R, V82A, L89I\t159\t97 100\tD67H, T69G, K70R, V75M, M184V, T215I, K219E\tV90IV\tL10I, G16E, K20I, L33F, M36I, M46I, I54A, Q58E, H69K, K70R, V82A, L89I\t\n18\t23\t6\t67 934\t\t\tM36I, H69K, V82I, L89M\t0\t279 000\t\tV106I\tM36I, H69K, V82I, L89M\t\nBold: major drug resistance mutations.\n\n\n\nDiscussion\nWe report the antiretroviral resistance profiles of patients failing second-line PI-based therapy in Vietnam. The major finding was that amongst the patients experiencing VF, 64% harboured at least one major PI resistance mutation and 60% had mutations that conferred intermediate- to high-level resistance to lopinavir/ritonavir. This level of PI resistance is significantly higher than has been previously reported in either resource-rich or resource-poor settings.3,4,8–15,37 Ritonavir-boosted PIs are known to have a high genetic barrier to resistance.8,38 The minimum plasma concentrations of ritonavir-boosted PIs far exceed the levels required to inhibit WT virus replication,39,40 making PIs a durable class of antiretroviral drug to be used across different patient populations. A high prevalence of PI resistance has been reported in four studies, two of which studied populations from Asia, specifically, from Cambodia (N = 71, 40%)15 and India (N = 45, 73%).16 The other two study populations were from West Africa: Mali (N = 93, 25%)37 and Nigeria (N = 61, 62%).41 Except for the study from India, where indinavir/ritonavir and atazanavir/ritonavir were commonly used, the studies in these other countries used lopinavir/ritonavir for second-line therapy. Previous exposure to generically produced un-boosted indinavir and nelfinavir was implicated in the observed high prevalence of PI resistance mutations in the reports from Asia and Nigeria, although formal analyses were lacking. Our study is the first to systematically link previous PI exposure to VF and PI resistance.\n\nIndinavir was generically produced in Vietnam during the early 2000s. The correct dosing was 800 mg three times daily; however, because of the high rate of side effects, many Vietnamese clinicians prescribed it at 400 mg three times daily or 800 mg twice daily. A combination of high pill burden, short half-life, food restriction, high rate of side effects and inadequate dosing likely led to inadequate plasma drug concentrations and increased the risk of PI resistance in patients. Low plasma indinavir concentration has been shown to increase the risk of developing PI resistance mutations in patients experiencing early VF.42 Further, the most common PI resistance mutations detected in our cohort—M46I/L, I54V, V82A and L90M—were shown to be the first mutations to be sequentially selected by indinavir therapy.43 Cheap generically made indinavir, nelfinavir and saquinavir were available in India, China and south-east Asian countries during the same time.15,44 This availability likely explains the higher prevalence of PI resistance reported in the studies from Cambodia and India and suggests that the scope of PI exposure and resistance in Asia might be larger than is currently appreciated. Another reason for the high level of PI resistance observed in our study as well as these other studies is the lack of viral load monitoring, which leads to late detection of VF and accumulation of PI resistance mutations. Better understanding of the extent and determinants of PI resistance in developing countries is needed.\n\nAmong the next-generation NNRTIs and PIs potentially available as third-line drugs, there was evidence of probable intermediate or high levels of cross-resistance to etravirine, rilpivirine and tipranavir in ∼50% of patients. Cross-resistance to darunavir was less frequent (27%) and was observed only at the intermediate level. These prevalences are noticeably higher than those found in studies in similar settings.15,16,37,41 One reason for the observed high-level etravirine cross-resistance is programmatic. The lack of virological monitoring led to prolonged periods of undetected VF in the presence of the low-genetic-barrier drugs nevirapine and efavirenz and accumulation of resistance mutations. This effect was shown by the extensive NNRTI resistance mutations in our cohort (94% of patients with ≥1 and 32% with ≥3 major NNRTI resistance mutations). NNRTI resistance mutations have been shown to persist up to 45 months after the discontinuation of NNRTI therapy. This finding is due to the low fitness costs of these mutations on viral replication, thus explaining the slow reversion of these mutant viruses to WT in the absence of drug pressure.45,46 The presence of ≥3 IAS-USA-defined NNRTI resistance mutations has been associated with decreased virological response to etravirine in the DUET trials.47,48\n\nAnother reason for high etravirine cross-resistance is the inherent genetic variability of the HIV-1 subtype CRF01_AE in south-east Asia. Etravirine was designed to work against HIV containing the NNRTI signature mutation—K103N—which is highly prevalent in HIV-1 subtype B.49 However the most frequent NNRTI resistance mutations selected in subtype CRF01_AE virus by nevirapine and efavirenz exposure are Y181C and G190A/S, rather than K103N.50,51 In the DUET trials, the presence at baseline of these substitutions was associated with impaired virological response to etravirine.47,48 High prevalence of cross-resistance to etravirine (60%) has been reported in several studies of CRF01_AE-infected patients in Thailand for whom first-line NNRTI-based therapy was failing.52–54 As efficacy data of etravirine use in south-east Asia are lacking, phenotypic assays investigating the in vitro susceptibilities of these clinical isolates would be helpful. Until then, etravirine and rilpivirine should probably be avoided as third-line drugs for patients infected with subtype CRF01_AE in south-east Asia. Our data do not support the 2010 and 2013 WHO recommendations to use etravirine in a third-line ART regimen in resource-limited settings.1,25 The phenotypic susceptibility of tipranavir is not as well predicted as that of darunavir by most genotypic interpretation algorithms, in particular for non-B subtypes.55 However, based on our predicted cross-resistance data, darunavir/ritonavir plus a brand-new class of antiretroviral drug, such as integrase strand transfer inhibitors (INSTIs), combined with lamivudine is a reasonable third-line option for Vietnam. As the need for third-line therapy is imminent in the developing world, clinical trials evaluating cost-effective third-line treatment strategies and regimens are needed.\n\nAmong the 20 patients who were maintained on the failing lopinavir/ritonavir regimen, death or worse virological/immunological control occurred for 13 patients, with accumulation of resistance mutations occurring in those who remained alive at 24 months. This finding is consistent with that of a study from Nigeria showing accumulation of PI resistance mutations in patients maintained on failing second-line therapy.41 However, virological re-suppression and good immune response were achieved in five patients; these patients either had no or only one major PI resistance mutation at VF detection. A strategy combining adherence intervention and close monitoring of patients failing second-line therapy before switching to third-line therapy would be cost saving yet effective in resource-poor settings.\n\nOur study has limitations. The study captured VF at one point in time and only in patients who were in active follow-up. The unavoidable exclusion of the 12% who had died and the 14% who had been transferred to their respective resident provinces reduces the power of our observations. Further, PI resistance might be underestimated due to the lack of data from those who had died. Nevertheless, the study site is the largest centre for second-line therapy in Vietnam. The highly uniform HIV care system along with standardized ART regimens in the national programme allow for reasonable generalizability of our findings. We did not sequence the integrase gene in this cohort, as INSTIs are not yet available in Vietnam.\n\nIn conclusion, we identified a significantly higher prevalence of PI resistance in patients failing second-line therapy in Vietnam, which was associated with previous indinavir exposure. The widespread availability of generically made PIs in Asia suggests that the scope of PI resistance might be underestimated in this region. Our data emphasize the need for viral load monitoring to limit the accumulation of NRTI and NNRTI resistance mutations, thus improving second-line treatment outcome and preserving the limited third-line therapy options. Significant cross-resistance to etravirine is common in subtype CRF01_AE-infected patients failing NNRTI therapy, suggesting that etravirine should be avoided as a third-line therapy drug. Research on cost-effective strategies and timing of third-line therapy switch are now needed.\n\nFunding\nThis work was supported by the Wellcome Trust.\n\nTransparency declarations\nNone to declare.\n\nAuthor contributions\nStudy concept and design: T. L., V. M. Q., C. S., S. D. and J. F. Obtaining funding: T. L., S. D., J. D. and J. F. Acquisition of data: V. P. T., V. M. Q., N. T. C., N. V. V. C. and T. L. Analysis and interpretation of the data: V. P. T. and T. L. Drafting the manuscript: V. P. T. and T. L. Critical revision of the manuscript for important intellectual content: V. M. Q., N. T. C., C. S., J. F., J. D., N. V. V. C., S. D. and G. T. All authors contributed to and approved the final manuscript.\n\nAcknowledgements\nWe would like to thank the patients for their participation in the study and thank the staff in the HIV Outpatient Clinic at the Hospital for Tropical Diseases for their assistance with the enrolment of patients.\n==== Refs\nReferences\n1 WHO . Consolidated Guidelines on the Use of Antiretroviral Drugs for Treating and Preventing HIV Infection . 2013 \nhttp://apps.who.int/iris/bitstream/10665/85321/1/9789241505727_eng.pdf .\n2 Murphy RL , da Silva B a , Hicks CB et al \nSeven-year efficacy of a lopinavir/ritonavir-based regimen in antiretroviral-naïve HIV-1-infected patients . HIV Clin Trials \n2008 ; 9 : 1 –10 .18215977 \n3 Eron JJ , Yeni P , Gathe JJ et al \nThe KLEAN study of fosamprenavir-ritonavir versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial treatment of HIV infection over 48 weeks: a randomised non-inferiority trial . 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AIDS \n2010 ; 24 : 1679 –87 .20453629 \n12 Wallis CL , Mellors JW , Venter WDF et al \nProtease inhibitor resistance is uncommon in HIV-1 subtype C infected patients on failing second-line lopinavir/r-containing antiretroviral therapy in South Africa . AIDS Res Treat \n2011 ; 2011 : 769627 .21490784 \n13 Van Zyl GU , Van Mens TE , Mcilleron H et al \nLow lopinavir plasma or hair concentrations explain second-line protease inhibitor failures in a resource-limited setting . J Acquir Immune Defic Syndr \n2011 ; 56 : 333 –9 .21239995 \n14 Reynolds SJ , Laeyendecker O , Nakigozi G et al \nAntiretroviral drug susceptibility among HIV-infected adults failing antiretroviral therapy in Rakai, Uganda . AIDS Res Hum Retroviruses \n2012 ; 28 : 1739 –44 .22443282 \n15 Nerrienet E , Nouhin J , Ngin S et al \nHIV-1 protease inhibitors resistance profiles in patients with virological failure on LPV/r-based 2nd line regimen in Cambodia . 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Antivir Ther \n2012 ; 17 : 905 –13 .22473024 \n19 Ayouba A , Lien TTX , Nouhin J et al \nLow prevalence of HIV type 1 drug resistance mutations in untreated, recently infected patients from Burkina Faso, Côte d'Ivoire, Senegal, Thailand, and Vietnam: the ANRS 12134 study . AIDS Res Hum Retroviruses \n2009 ; 25 : 1193 –6 .19886834 \n20 Ishizaki A , Cuong NH , Thuc PV et al \nProfile of HIV type 1 infection and genotypic resistance mutations to antiretroviral drugs in treatment-naive HIV type 1-infected individuals in Hai Phong, Viet Nam . AIDS Res Hum Retroviruses \n2009 ; 25 : 175 –82 .19239356 \n21 Phan TTC , Ishizaki A , Phung DC et al \nCharacterization of HIV type 1 genotypes and drug resistance mutations among drug-naive HIV type 1-infected patients in Northern Vietnam . AIDS Res Hum Retroviruses \n2010 ; 26 : 233 –5 .20156106 \n22 UNAIDS . HIV in Asia and the Pacific \n2013 \nhttp://www.unaids.org/sites/default/files/media_asset/2013_HIV-Asia-Pacific_en_0.pdf .\n23 Vietnam Ministry of Health . HIV/AIDS Case Report and Implementation of HIV/AIDS Prevention and Control Programme Till September 2014. 2014 . http://www.bacsisaigon.com/tin-tuc/tinh-hinh-dich-hiv-aids-o-viet-nam-den-het-30-9-2014-va-ket-qua-mot-so-chuong-trinh/ .\n24 Chi NH , Quang VM , Chinh NT \nAntiretroviral therapy in HIV/AIDS patients and the resistance of ARVs . In: Workshop on HIV/AIDS in Vietnam—Organized by Hospital for Tropical Diseases and Harvard Medical School AIDS Initiative in Vietnam \n2012 .\n25 WHO . Antiretroviral Therapy for HIV Infection in Adults and Adolescents: Recommendations for a Public Health Approach: 2010 Revision . 2010 \nhttp://whqlibdoc.who.int/publications/2010/9789241599764_eng.pdf .\n26 Vietnam Ministry of Health . Vietnam National Guidelines for HIV/AIDS Diagnosis and Treatment . In Vietnamese. Published with the Decision No. 3003/QD-BYT dated 19/08/2009 of the Minister of Health \n2011 \nhttp://www.vaac.gov.vn/Cms_Data/Contents/Vaac/Folders/DocumentLaw/Vanban/∼contents/8YUJW54X7VRF64XS/4139-Q-BYT.pdf .\n27 Vietnam Ministry of Health . Vietnam National Guidelines for HIV/AIDS Diagnosis and Treatment . In Vietnamese. Published with the Decision No. 06/2005/QD-BYT dated 07/03/2005 of the Minister of Health \n2005 \nhttp://moj.gov.vn/vbpq/Lists/Vn%20bn%20php%20lut/View_Detail.aspx?ItemID=15388 .\n28 Vietnam Ministry of Health . Vietnam National Guidelines for HIV/AIDS Diagnosis and Treatment . In Vietnamese \n2009 \nhttp://benhnhietdoi.vn/data/files/documents/QD.3003.BYT.19.8.2009_Huong_dan_chan_doan_va_dieu_tri_HIVAIDS.pdf .\n29 Kalichman S , Amaral C , Swetzes C et al \nA simple single item rating scale to measure medication adherence: further evidence for convergent validity . J Int Assoc Physicians AIDS Care \n2011 ; 8 : 367 –74 .\n30 Wensing AM , Calvez V , Günthard HF et al \n2014 update of the drug resistance mutations in HIV-1 . Top Antivir Med \n2014 ; 22 : 642 –50 .25101529 \n31 Pineda-Peña A-C , Faria NR , Imbrechts S et al \nAutomated subtyping of HIV-1 genetic sequences for clinical and surveillance purposes: performance evaluation of the new REGA version 3 and seven other tools . Infect Genet Evol \n2013 ; 19 : 337 –48 .23660484 \n32 Win MM , Maek-A-Nantawat W , Phonrat B et al \nVirologic and immunologic outcomes of the second-line regimens of antiretroviral therapy among HIV-infected patients in Thailand . J Int Assoc Physicians AIDS Care \n2011 ; 10 : 57 –63 .\n33 Fox MP , Ive P , Long L et al \nHigh rates of survival, immune reconstitution, and virologic suppression on second-line antiretroviral therapy in South Africa . J Acquir Immune Defic Syndr \n2010 ; 53 : 500 –6 .19838128 \n34 Hosseinipour MC , Kumwenda JJ , Weigel R et al \nSecond-line treatment in the Malawi antiretroviral programme: high early mortality, but good outcomes in survivors, despite extensive drug resistance at baseline . HIV Med \n2010 ; 11 : 510 –8 .20345885 \n35 Levison JH , Orrell C , Losina E et al \nEarly outcomes and the virologic impact of delayed treatment switching on second-line therapy in an antiretroviral roll-out program in South Africa . Antivir Ther \n2011 ; 16 : 853 –61 .21900717 \n36 Sigaloff KCE , Hamers RL , Wallis CL et al \nSecond-line antiretroviral treatment successfully resuppresses drug-resistant HIV-1 after first-line failure: prospective cohort in sub-Saharan Africa . J Infect Dis \n2012 ; 205 : 1739 –44 .22448003 \n37 Maiga AI , Fofana DBD , Cisse M et al \nCharacterization of HIV-1 antiretroviral drug resistance after second-line treatment failure in Mali, a limited-resources setting . J Antimicrob Chemother \n2012 ; 67 : 2943 –8 .22888273 \n38 Tang MW , Shafer RW \nHIV-1 antiretroviral resistance scientific principles and clinical applications . Drugs \n2012 ; 72 : e1 –25 .22686620 \n39 Hoetelmans R \nPharmacological exposure and the development of drug resistance in HIV . Antiretrovir Ther \n2001 ; 6 : 37 –47 .\n40 Zeldin RK \nPharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients . J Antimicrob Chemother \n2003 ; 53 : 4 –9 .14657084 \n41 Rawizza HE , Chaplin B , Meloni ST et al \nAccumulation of protease mutations among patients failing second-line antiretroviral therapy and response to salvage therapy in Nigeria . PLoS One \n2013 ; 8 : e73582 .24069209 \n42 González de Requena D , Gallego O , de Mendoza C et al \nIndinavir plasma concentrations and resistance mutations in patients experiencing early virological failure . AIDS Res Hum Retroviruses \n2003 ; 19 : 457 –9 .12882654 \n43 Zhang Y , Imamichi H , Imamichi T et al \nDrug resistance during indinavir therapy is caused by mutations in the protease gene and in its Gag substrate cleavage sites . J Virol \n1997 ; 71 : 6662 –70 .9261388 \n44 Boettiger DC , Kerr S , Ditangco R et al \nTrends in first-line antiretroviral therapy in Asia: results from the TREAT Asia HIV observational database . PLoS One \n2014 ; 9 : e106525 .25184314 \n45 Arts EJ , Hazuda DJ \nHIV-1 antiretroviral drug therapy . Cold Spring Harb Perspect Med \n2012 ; 2 : a007161 .22474613 \n46 Jain V , Sucupira MC , Bacchetti P et al \nDifferential persistence of transmitted HIV-1 drug resistance mutation classes . J Infect Dis \n2011 ; 203 : 1174 –81 .21451005 \n47 Tambuyzer L , Vingerhoets J , Azijn H et al \nCharacterization of genotypic and phenotypic changes in HIV-1-infected patients with virologic failure on an etravirine-containing regimen in the DUET-1 and DUET-2 clinical studies . AIDS Res Hum Retroviruses \n2010 ; 26 : 1197 –205 .20854144 \n48 Vingerhoets J , Tambuyzer L , Azijn H et al \nResistance profile of etravirine: combined analysis of baseline genotypic and phenotypic data from the randomized, controlled Phase III clinical studies . AIDS \n2010 ; 24 : 503 –14 .20051805 \n49 Andries K , Azijn H , Thielemans T et al \nTMC125, a novel next-generation nonnucleoside reverse transcriptase inhibitor active against nonnucleoside reverse transcriptase inhibitor-resistant human immunodeficiency virus type 1 . Antimicrob Agents Chemother \n2004 ; 48 : 4680 –6 .15561844 \n50 Zolfo M , Schapiro JM , Phan V et al \nGenotypic impact of prolonged detectable HIV type 1 RNA viral load after HAART failure in a CRF01_AE-infected cohort . AIDS Res Hum Retroviruses \n2011 ; 27 : 727 –35 .20854169 \n51 Chetchotisakd P , Anunnatsiri S , Kiertiburanakul S et al \nHigh rate multiple drug resistances in HIV-infected patients failing nonnucleoside reverse transcriptase inhibitor regimens in Thailand, where subtype A/E is predominant . J Int Assoc Physicians AIDS Care \n2006 ; 5 : 152 –6 .\n52 Teeranaipong P , Sirivichayakul S , Mekprasan S et al \nRilpivirine versus etravirine validity in NNRTI-based treatment failure in Thailand . J Int AIDS Soc \n2014 ; 17 : 19740 .25397485 \n53 Manosuthi W , Butler D , Chantratita W et al \nPatients infected with HIV type 1 subtype CRF01_AE and failing first-line nevirapine- and efavirenz-based regimens demonstrate considerable cross-resistance to etravirine . AIDS Res Hum Retroviruses \n2010 ; 26 : 609 –11 .20507208 \n54 Bunupuradah T , Ananworanich J , Chetchotisakd P et al \nEtravirine and rilpivirine resistance in HIV-1 subtype CRF01_AE-infected adults failing non-nucleoside reverse transcriptase inhibitor-based regimens . Antivir Ther \n2011 ; 16 : 1113 –21 .22024527 \n55 Talbot A , Grant P , Taylor J et al \nPredicting tipranavir and darunavir resistance using genotypic, phenotypic, and virtual phenotypic resistance patterns: an independent cohort analysis of clinical isolates highly resistant to all other protease inhibitors . Antimicrob Agents Chemother \n2010 ; 54 : 2473 –9 .20368406\n\n",
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"title": "High prevalence of PI resistance in patients failing second-line ART in Vietnam.",
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"abstract": "A 45-year-old male was admitted to our hospital after successful resuscitation of cardiac arrest. Ventricular fibrillation (VF) had occurred during breakfast and was defibrillated by an automated external defibrillator operated by emergency medical service staff. On admission, his ECG demonstrated complete right bundle branch block as the sole abnormality. Intensive examination could not detect any structural disease leading to a diagnosis of idiopathic VF and implantation of an ICD. VF storm occurred one month after hospital discharge and beta-blocker, amiodarone, and sedative administration had no effect on VF. Likewise, catheter ablation for triggering premature ventricular beats failed to control the VF storm. The VF storm then subsided in the following weeks and the patient was discharged on amiodarone. A half month later VF storm recurred and the patient was admitted again. This time, isoproterenol infusion was effective in suppressing VF, and thereafter the patient was administered bepridil and followed up without recurrence of VF for 1.5 years. From these beneficial effects, the VF of the patient was suggested to share common arrhythmogenic characteristics to those of Brugada syndrome or J-wave associated VF.",
"affiliations": "Department of Cardiology, Keio University School of Medicine, Tokyo, Japan.",
"authors": "Aizawa|Yoshiyasu|Y|;Takatsuki|Seiji|S|;Inagawa|Kohei|K|;Katsumata|Yoshinori|Y|;Nishiyama|Takahiko|T|;Kimura|Takehiro|T|;Nishiyama|Nobuhiro|N|;Fukumoto|Kotaro|K|;Tanimoto|Yoko|Y|;Tanimoto|Kojiro|K|;Ogawa|Satoshi|S|;Fukuda|Keiichi|K|",
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"title": "Storms of ventricular fibrillation responsive to isoproterenol in an idiopathic ventricular fibrillation patient demonstrating complete right bundle branch block.",
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"abstract": "Radiocontrast media-induced acute severe thrombocytopenia is a very rare complication and potentially life-threatening. Here, we report the case of a 63-year-old male patient with severe acute thrombocytopenia following first exposure to intravenous non-ionic contrast media without immediate allergic reactions. His platelet count dropped from 107000/μL to 2000/μL after six hours of radiocontrast infusion. After administration of corticosteroid and transfusion of platelet concentrates, the platelet count returned gradually to normal within 5 days. To the best of our knowledge, non-ionic contrast media-induced isolated acute severe thrombocytopenia following no signs or symptoms of immediate allergic reaction has never been described.",
"affiliations": "Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea.;Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea.;Divison of Hematology-Oncology, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea.;Divison of Hematology-Oncology, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea. henkengun@gmail.com.",
"authors": "Park|Mihwa|M|https://orcid.org/0000-0003-2013-0972;Kim|Minjeong|M|;Park|Jisun|J|;Cho|Jinhyun|J|https://orcid.org/0000-0002-0641-5210",
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"doi": "10.3349/ymj.2018.59.1.158",
"fulltext": "\n==== Front\nYonsei Med JYonsei Med. JYMJYonsei Medical Journal0513-57961976-2437Yonsei University College of Medicine 2921479210.3349/ymj.2018.59.1.158Case ReportHematologyLife-Threatening Thrombocytopenia Following Intravenous Contrast Media Infusion https://orcid.org/0000-0003-2013-0972Park Mihwa 1Kim Minjeong 1Park Jisun 2https://orcid.org/0000-0002-0641-5210Cho Jinhyun 21 Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea.2 Divison of Hematology-Oncology, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, Incheon, Korea.Corresponding author: Dr. Jinhyun Cho, Division of Hematology-Oncology, Department of Internal Medicine, Inha University Hospital, Inha University School of Medicine, 27 Inhang-ro, Jung-gu, Incheon 22332, Korea. Tel: 82-32-890-2581, Fax: 82-32-890-2585, henkengun@gmail.com01 1 2018 29 11 2017 59 1 158 161 07 7 2017 20 7 2017 24 7 2017 © Copyright: Yonsei University College of Medicine 20182018Yonsei University College of MedicineThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Radiocontrast media-induced acute severe thrombocytopenia is a very rare complication and potentially life-threatening. Here, we report the case of a 63-year-old male patient with severe acute thrombocytopenia following first exposure to intravenous non-ionic contrast media without immediate allergic reactions. His platelet count dropped from 107000/µL to 2000/µL after six hours of radiocontrast infusion. After administration of corticosteroid and transfusion of platelet concentrates, the platelet count returned gradually to normal within 5 days. To the best of our knowledge, non-ionic contrast media-induced isolated acute severe thrombocytopenia following no signs or symptoms of immediate allergic reaction has never been described.\n\nThrombocytopeniacontrast medianon-ionichypersensitivityInha University Hospital\n==== Body\nINTRODUCTION\nContrast media can occasionally produce allergic reactions, ranging from minor to life-threatening anaphylactoid responses. Intravenous contrast media can also induce acute thrombocytopenia, although it is a very rare complication that has been mostly reported in patients who received ionic contrast media, which was usually used for coronary arteriography.123 Non-ionic contrast-induced acute thrombocytopenia is far more rare and has been usually accompanied by signs or symptoms of immediate allergic reaction, including respiratory distress, chest discomfort, facial flushing, or skin rash.45\n\nHere, we report the case of a 63-year-old male patient with a self-limiting severe acute thrombocytopenia following first exposure to intravenous non-ionic contrast medium without any signs or symptoms of immediate allergic reactions.\n\nCASE REPORT\nA 63-year-old male had visited an outside clinic with easy fatigue. Laboratory evaluation revealed elevation of liver transaminases with alanine aminotransaminase of 47 IU/L, aspartate aminotransferase of 106 IU/L, and gamma-glutamyl trans-peptidase of 935 IU/L. The patient had a history of chronic alcohol intake over 30 years and hypertension for 8 years. His daily medication consisted of felodipine 5 mg, losartan 50 mg, atorvastatin 20 mg, and aspirin 100 mg, and he denied any recent changes in medication.\n\nA non-ionic low osmolarity contrast agent [120 mL, Ioversol (Optiray 350©)] enhanced computed tomography (CT) scan was performed to clarify the cause of abnormal liver function test. During infusion of contrast media, no specific signs or symptoms were observed. CT scan detected chronic liver disease with mild splenomegaly, which was consistent with alcoholic liver disease. The patient returned home with no signs or symptoms of immediate allergic reactions. Six hours after examination, he was admitted to our emergency room (ER) reporting sudden onset bleeding from his intravenous site, along with a huge bruise and hematoma. At presentation to the ER, he had a blood pressure of 105/58 mm Hg, a heart rate of 71/min, and a respiration rate of 18/min. No fever, urticaria, itches, rash, respiratory distress, or chest discomfort was recorded. Laboratory test showed severe thrombocytopenia with a platelet count of 2000/µL, which was 107000/µL at the aforementioned clinic 7 days prior. Mild anemia and elevated liver transaminases were also reported, which were considered to be associated with chronic alcohol intake (Table 1). Other laboratory parameters, including prothrombin time and activated partial thromboplastin time, were within normal limits. Peripheral blood smear showed normal size and shape of white blood and red blood cells, except a markedly decreased number of platelets. Serological studies showed no evidence of viral hepatitis or autoimmune disease, and there were no signs or symptoms of infectious disease.\n\nSince drug-induced thrombocytopenia was highly suspected, the patient received platelet concentrates (10 units) and methylprednisolone (1 mg/kg for 5 days) intravenously. The platelet count returned gradually to baseline by day 5, and no further exacerbation of thrombocytopenia was observed during follow-up (Fig. 1). Liver transaminases were also recovered upon drinking cessation, and there were no significant changes in other laboratory tests. He was discharged on the fifth day.\n\nDISCUSSION\nSince their introduction in the 1920s, radiographic iodinated contrast media have been among the most commonly used drugs in modern medicine. The advent of low-osmolar iodinated contrast media has decreased the overall incidence of contrast-induced adverse events; the majority of adverse effects are mild and self-limited.6 Nonetheless, severe or life-threatening complications, including cardiovascular collapse, bronchospasm, laryngeal edema, loss of consciousness, and seizure, can still occur occasionally. Acute severe thrombocytopenia induced by contrast media is extremely rare, with few cases reported in the literature. Most previous cases were associated with ionic contrast media used for coronary angiography.\n\nIn our case, isolated acute severe thrombocytopenia was caused by non-ionic low osmolar contrast media without any signs or symptoms of immediate allergic reaction, which has never been described before. Three cases of non-ionic contrast-induced acute severe thrombocytopenia have been reported so far: Two cases demonstrated acute thrombocytopenia following symptoms of immediate allergic reaction after contrast infusion (Table 2).45 The other case did not describe whether any signs or symptoms of allergic reaction were observed after contrast infusion or not.7\n\nAdverse reactions to contrast media are typically divided into two categories, chemotoxic reactions and hypersensitivity reactions.89 Chemotoxic reactions are associated with the chemical properties of radiocontrast agent and dependent upon dose and infusion rate. These reactions, including emesis, flushing, warmth, increased vagal tone, and organ toxicities, are relatively common, usually transient, and self-limited. Hypersensitivity reactions are idiosyncratic and dose-independent, which include angioedema, bronchospasm, shock, and loss of consciousness. Several non-IgE mediated mechanisms have been proposed for hypersensitivity reactions.1011 Drug-induced platelet destruction is usually caused by drug-induced antibodies; however, this can be difficult to prove.12 Most instances of drug-induced thrombocytopenia are considered as idiosyncratic, and no predisposing genetic or environmental factors have been identified.13 Although the mechanism of contrast-induced thrombocytopenia remains unclear, an immunological mechanism is also postulated. Furthermore, previous studies demonstrated that radiocontrast media could activate coagulation, kinin, and/or complement cascade,101114 which might result in platelet aggregation with resultant thrombocytopenia. However, in vitro studies evaluating the effects of contrast media on platelets have showed conflicting results.1516 Further investigations are needed to clarify the pathophysiology of contrast-induced thrombocytopenia.\n\nThere is no established treatment for contrast-induced thrombocytopenia because of its rarity and uncertain pathophysiology. In many cases, patients have received treatment with high dose intravenous corticosteroids, which are widely used in management of anaphylaxis. However, the role of corticosteroids in contrast-induced thrombocytopenia has never been studied to date. In our opinion, corticosteroids may be beneficial in preventing or reducing the severity of possible delayed adverse effects of radiocontrast media. Intravenous immune globulin and plasma exchange have been used in management of drug-induced thrombocytopenia, although the benefit of these treatments is still uncertain.\n\nThe present case demonstrated a rare but severe hematologic adverse effect of non-ionic low osmolar contrast media. Contrast-induced acute severe thrombocytopenia can occur even in patients without no symptoms or signs of immediate allergic reactions. Given the wide-spread use of intravenous contrast media, this case reminds clinicians to be aware of a rare, but life-threatening, hematologic complication caused by contrast media.\n\nACKNOWLEDGEMENTS\nThis study was supported by Inha University Hospital Research Grant.\n\nThe authors have no financial conflicts of interest.\n\nFig. 1 Changes in platelet level before and after development of acute thrombocytopenia.\nTable 1 Results of Laboratory Evaluation before and after Development of Acute Thrombocytopenia\n\t7 days before\t1st day\t2nd day\t3rd day\t5th day\tNormal range\t\nWBC (/µL)\t8100\t8750\t8510\t7340\t8610\t4000–10000\t\nHb (g/dL)\t12.7\t13.2\t11.7\t11.0\t12.5\t13.0–17.0\t\nHct (%)\t35.2\t37.2\t32.3\t32\t35.9\t36–51\t\nPLT (×103/µL)\t109\t2\t27\t48\t64\t140–400\t\nMCV (fL)\t-\t94\t93\t96\t95\t83–100\t\nMCH (Pg)\t-\t33.5\t33.6\t33.1\t33.1\t27–34\t\nMCHC (g/dL)\t-\t35.6\t36.3\t34.5\t34.8\t31–35\t\nNeutrophil (%)\t-\t92.6\t81.7\t66.1\t82.1\t40–75\t\nBUN (mg/dL)\t10.9\t19.5\t23.1\t30\t25.1\t6–20\t\nCreatinine (mg/dL)\t0.86\t1.19\t1.35\t1.14\t1.04\t0.5–1.3\t\nTotal bilirubin (mg/dL)\t-\t0.7\t0.9\t0.9\t0.6\t0.0–1.2\t\nAST (IU/L)\t106\t114\t80\t44\t37\t5–40\t\nALT (IU/L)\t47\t22\t21\t17\t16\t5–41\t\nALP (IU/L)\t-\t221\t157\t135\t105\t35–130\t\nPT (INR)\t-\t1.22\t1.19\t-\t1.13\t0.85–1.30\t\naPTT (sec)\t-\t38.1\t40.4\t-\t33.5\t29.0–44.0\t\nWBC, white blood cell; Hb, hemoglobin; Hct, hematocrit; PLT, platelet; MCV, mean cell volume; MCH, mean cell hemoglobin content; MCHC, mean cell hemoglobin concentration; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; ALP, alkaline phosphatase; PT, prothrombin time; aPTT, activated partial thromboplastin time.\n\nTable 2 Reported Cases of Non-Ionic Contrast Media-Induced Acute Thrombocytopenia\nAuthor/contrast media\tAge/sex\tSymptoms and signs of allergic reaction\tOnset of allergic reactions\tNadir platelet counts\t\nBata, et al.4/Ioversol (Optiray 350©)\t72/male\tRespiratory distress, creeps, elevated blood pressure\t40 minutes after contrast infusion\t2×103/µL\t\nMcCaulley, et al.5/Iopamidol\t22/female\tFacial flushing, throat tightness, dyspnea\tDuring contrast infusion\t4×103/µL\t\nSaitoh, et al.7/Iopamidol\t70/male\tNo documentation (abstract only)\t\t5×103/μL\n==== Refs\n1 Chang JC Lee D Gross HM Acute thrombocytopenia after i.v. administration of a radiographic contrast medium Am J Roentgenol 1989 152 947 949 2705351 \n2 Cubero-Gómez JM Guerrero Márquez FJ Diaz-de la-Llera L Fernández-Quero M Guisado-Rasco A Villa-Gil-Ortega M Severe thrombocytopenia induced by iodinated contrast after coronary angiography: The use of gadolinium contrast and intravascular ultrasound as an alternative to guide percutaneous coronary intervention Rev Port Cardiol 2017 36 61.e1 61.e4 27986390 \n3 Wiemer M Kreuzpaintner G Lauer B Kiefel V Schultheiss HP Horstkotte D [Recurrent immune thrombocytopenia: a rare complication after contrast medium injection] Dtsch Med Wochenschr 1995 120 1236 1240 7671781 \n4 Bata P Tarnoki AD Tarnoki DL Horvath E Berczi V Szalay F Acute severe thrombocytopenia following non-ionic low-osmolarity intravenous contrast medium injection Korean J Radiol 2012 13 505 509 22778575 \n5 McCaulley JA Deering SH Pates JA Severe thrombocytopenia after contrast infusion in pregnancy Obstet Gynecol 2013 121 2 Pt 2 Suppl 1 473 475 23344413 \n6 Hunt CH Hartman RP Hesley GK Frequency and severity of adverse effects of iodinated and gadolinium contrast materials: retrospective review of 456,930 doses Am J Roentgenol 2009 193 1124 1127 19770337 \n7 Saitoh T Saiki M Sawada U Kawamura N Tohno H Horie T [Severe thrombocytopenia induced by radiographic non-ionic contrast medium] Rinsho Ketsueki 2001 42 507 511 11505531 \n8 Morcos SK Thomsen HS Adverse reactions to iodinated contrast media Eur Radiol 2001 11 1267 1275 11471623 \n9 Brockow K Ring J Classification and pathophysiology of radiocontrast media hypersensitivity Chem Immunol Allergy 2010 95 157 169 20519888 \n10 Szebeni J Hypersensitivity reactions to radiocontrast media: the role of complement activation Curr Allergy Asthma Rep 2004 4 25 30 14680617 \n11 Szebeni J Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity Toxicology 2005 216 106 121 16140450 \n12 Aster RH Curtis BR McFarland JG Bougie DW Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management J Thromb Haemost 2009 7 911 918 19344362 \n13 Aster RH Bougie DW Drug-induced immune thrombocytopenia N Engl J Med 2007 357 580 587 17687133 \n14 Simon RA Schatz M Stevenson DD Curry N Yamamoto F Plow E Radiographic contrast media infusions. Measurement of histamine, complement, and fibrin split products and correlation with clinical parameters J Allergy Clin Immunol 1979 63 281 288 85650 \n15 Li X Gabriel DA Differences between contrast media in the inhibition of platelet activation by specific platelet agonists Acad Radiol 1997 4 108 114 9061083 \n16 Aspelin P Stacul F Thomsen HS Morcos SK van der ESUR). Effects of iodinated contrast media on blood and endothelium Eur Radiol 2006 16 1041 1049 16395531\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0513-5796",
"issue": "59(1)",
"journal": "Yonsei medical journal",
"keywords": "Thrombocytopenia; contrast media; hypersensitivity; non-ionic",
"medline_ta": "Yonsei Med J",
"mesh_terms": "D000208:Acute Disease; D061605:Administration, Intravenous; D003287:Contrast Media; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D013921:Thrombocytopenia",
"nlm_unique_id": "0414003",
"other_id": null,
"pages": "158-161",
"pmc": null,
"pmid": "29214792",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports",
"references": "17687133;7671781;9061083;11471623;19770337;11505531;23344413;2705351;16140450;14680617;19344362;16395531;22778575;20519888;85650;27986390",
"title": "Life-Threatening Thrombocytopenia Following Intravenous Contrast Media Infusion.",
"title_normalized": "life threatening thrombocytopenia following intravenous contrast media infusion"
} | [
{
"companynumb": "KR-GUERBET-KR-20170088",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IOVERSOL"
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{
"abstract": "BACKGROUND\nMalignancies and cisplatin-based chemotherapy are both known to correlate with a high risk of venous thrombotic events (VTT). In testicular cancer, the information regarding the incidence and reason of VTT in patients undergoing cisplatin-based chemotherapy is still discussed controversially. Moreover, no risk factors for developing a VTT during cisplatin-based chemotherapy have been elucidated so far.\n\n\nMETHODS\nWe retrospectively analyzed 153 patients with testicular cancer undergoing cisplatin-based chemotherapy at our institution for the development of a VTT during or after chemotherapy. Clinical and pathological parameters for identifying possible risk factors for VTT were analyzed. The Khorana risk score was used to calculate the risk of VTT. Student t test was applied for calculating the statistical significance of differences between the treatment groups.\n\n\nRESULTS\nTwenty-six out of 153 patients (17%) developed a VTT during chemotherapy. When we analyzed the risk factors for developing a VTT, we found that Lugano stage ≥IIc was significantly (p = 0.0006) correlated with the risk of developing a VTT during chemotherapy. On calculating the VTT risk using the Khorana risk score model, we found that only 2 out of 26 patients (7.7%) were in the high-risk Khorana group (≥3).\n\n\nCONCLUSIONS\nPatients with testicular cancer with a high tumor volume have a significant risk of developing a VTT with cisplatin-based chemotherapy. The Khorana risk score is not an accurate tool for predicting VTT in testicular cancer.",
"affiliations": "Department of Urology, University Hospital Cologne, Cologne, Germany.",
"authors": "Heidegger|Isabel|I|;Porres|Daniel|D|;Veek|Nica|N|;Heidenreich|Axel|A|;Pfister|David|D|",
"chemical_list": "D002945:Cisplatin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000471888",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-1138",
"issue": "99(1)",
"journal": "Urologia internationalis",
"keywords": "Chemotherapy; Cisplatin; Khorana score; Lugano stage; Pulmonary embolism; Testicular tumor; Thrombosis",
"medline_ta": "Urol Int",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D005858:Germany; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009373:Neoplasms, Germ Cell and Embryonal; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013736:Testicular Neoplasms; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D047368:Tumor Burden; D020246:Venous Thrombosis; D055815:Young Adult",
"nlm_unique_id": "0417373",
"other_id": null,
"pages": "104-109",
"pmc": null,
"pmid": "28514776",
"pubdate": "2017",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Predictive Factors for Developing Venous Thrombosis during Cisplatin-Based Chemotherapy in Testicular Cancer.",
"title_normalized": "predictive factors for developing venous thrombosis during cisplatin based chemotherapy in testicular cancer"
} | [
{
"companynumb": "DE-HQ SPECIALTY-DE-2017INT000355",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nOxaliplatin, a third-generation platinum derivative is commonly used for the treatment of colorectal cancer, pancreatic cancer, upper gastrointestinal cancer, hepatobiliary cancer, and ovarian cancer. Neurotoxicity is the dose limiting toxicity and ototoxicity is very rare, less than 1% of patients.\n\n\nMETHODS\nWe present a case of a female patient with locally advanced unresectable pancreatic cancer who developed hearing loss after receiving oxaliplatin and gemcitabine. The dose of oxaliplatin was reduced but continued due to clinical benefit and radiological response.\n\n\nCONCLUSIONS\nTo the best of our knowledge, this is the third case report of oxaliplatin-induced ototoxicity. Ototoxicity seems to be a rare complication of oxaliplatin therapy. Regardless of its rare occurrence, clinicians should be aware of this severe complication and be diligent in monitoring patients's clinical symptoms.",
"affiliations": "Department of Hematology/Oncology and Experimental Therapeutics, Tufts University School of Medicine. Boston, MA, USA. wsaif@tuftsmedicalcenter.org.",
"authors": "Oh|Sun Young|SY|;Wasif|Nawal|N|;Garcon|Marie Carmel|MC|;Rodriguez|Gladys|G|;Saif|Muhammad Wasif|MW|",
"chemical_list": "D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "Italy",
"delete": false,
"doi": "10.6092/1590-8577/1629",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8577",
"issue": "14(6)",
"journal": "JOP : Journal of the pancreas",
"keywords": null,
"medline_ta": "JOP",
"mesh_terms": "D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D001299:Audiometry; D005260:Female; D034381:Hearing Loss; D006801:Humans; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "101091810",
"other_id": null,
"pages": "676-9",
"pmc": null,
"pmid": "24216561",
"pubdate": "2013-11-10",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Ototoxicity associated with oxaliplatin in a patient with pancreatic cancer.",
"title_normalized": "ototoxicity associated with oxaliplatin in a patient with pancreatic cancer"
} | [
{
"companynumb": "US-ACTAVIS-2014-16050",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "2",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
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... |
{
"abstract": "Post-transplant lymphoproliferative disorder (PTLD) is serious life-threating complication of transplantation. The clinical picture differs from lymphomas observed in the general population, with different manifestation, histopathology, higher aggressiveness with involvement of sites beyond the primary lymph node, and poorer outcome. The objective of the study was to present nine cases of PTLD observed in our centre among the kidney transplant recipient population and discuss the results with up-to-date literature. We performed a retrospective single-centre assessment of PTLD incidence in the cohorts of kidney transplant recipients followed by our centre. We found nine cases of PTLD, five men and four woman, aged from 26 to 67 years at the time of diagnosis (mean [SD] 48 [5] years), transplanted between 1997 and 2013. The disease was diagnosed between 2002 and 2017, from 6 to 440 months after transplantation (mean [SD] 96 [137] months). A diffuse large B-cell lymphoma was found in seven cases early as well as late after transplantation, and two patients presented T-cell lymphoma. Five patients achieved complete remission with no relapses after 6 to 13 months of treatment. In three cases the remission was achieved by switching to mammalian target of rapamycin inhibitors (mTORi) only. Four recipients died from 2 weeks to 15 months after PTLD was diagnosed. Although the diagnostic criteria of different forms of PTLD are commonly known, rapid and correct diagnosis is not easy. PTLD is a relatively a rare disease, so there are too few studies and little consensus on the optimal treatment.",
"affiliations": "Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.;Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.;Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.;Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland.;Faculty of Natural Sciences and Technology, Karkonosze College, Jelenia Gora, Poland.;Department of Nephrology, Institute of Medicine, University of Opole, Opole, Poland.",
"authors": "Kamińska|Dorota|D|;Krajewska|Magdalena|M|;Mazanowska|Oktawia|O|;Poznański|Paweł|P|;Boratyńska|Maria|M|;Klinger|Marian|M|",
"chemical_list": null,
"country": "Poland",
"delete": false,
"doi": "10.5114/ceji.2020.103427",
"fulltext": "\n==== Front\nCent Eur J Immunol\nCent Eur J Immunol\nCEJI\nCentral-European Journal of Immunology\n1426-3912 1644-4124 Termedia Publishing House \n\n43217\n10.5114/ceji.2020.103427\nCase Report\nPost-transplant lymphoproliferative disorder in adult renal transplant recipients: case series and review of literature\nKamińska Dorota 1 Krajewska Magdalena 1 Mazanowska Oktawia 1 Poznański Paweł 1 Boratyńska Maria 2 Klinger Marian 3 1 Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, Wroclaw, Poland\n2 Faculty of Natural Sciences and Technology, Karkonosze College, Jelenia Gora, Poland\n3 Department of Nephrology, Institute of Medicine, University of Opole, Opole, Poland\nCorrespondence: Dorota Kamińska, MD, PhD, Department of Nephrology and Transplantation Medicine, Wroclaw Medical University, e-mail: dorota.kaminska@umed.wroc.pl\n30 1 2021 \n2020 \n45 4 498 506\n26 9 2018 28 10 2019 Copyright © 2020 Termedia2020This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0). License (http://creativecommons.org/licenses/by-nc-sa/4.0/)Post-transplant lymphoproliferative disorder (PTLD) is serious life-threating complication of transplantation. The clinical picture differs from lymphomas observed in the general population, with different manifestation, histopathology, higher aggressiveness with involvement of sites beyond the primary lymph node, and poorer outcome.\n\nThe objective of the study was to present nine cases of PTLD observed in our centre among the kidney transplant recipient population and discuss the results with up-to-date literature. We performed a retrospective single-centre assessment of PTLD incidence in the cohorts of kidney transplant recipients followed by our centre. We found nine cases of PTLD, five men and four woman, aged from 26 to 67 years at the time of diagnosis (mean [SD] 48 [5] years), transplanted between 1997 and 2013.\n\nThe disease was diagnosed between 2002 and 2017, from 6 to 440 months after transplantation (mean [SD] 96 [137] months). A diffuse large B-cell lymphoma was found in seven cases early as well as late after transplantation, and two patients presented T-cell lymphoma. Five patients achieved complete remission with no relapses after 6 to 13 months of treatment. In three cases the remission was achieved by switching to mammalian target of rapamycin inhibitors (mTORi) only. Four recipients died from 2 weeks to 15 months after PTLD was diagnosed.\n\nAlthough the diagnostic criteria of different forms of PTLD are commonly known, rapid and correct diagnosis is not easy. PTLD is a relatively a rare disease, so there are too few studies and little consensus on the optimal treatment.\n\nlymphomapost-transplant lymphoproliferative diseasekidney transplantation\n==== Body\nIntroduction\nThe cumulative incidence of cancers is high among solid organ recipients and exceeds 4% over a five-year period. The incidence of particular types of cancers varies between the type of transplanted organ with the highest incidence for lung recipients and the lowest incidence for kidney transplant recipients [1]. The most commonly observed cancers in kidney transplant recipients are skin cancers, followed by kidney cancer, colorectal cancers, bladder cancers, breast cancer, prostate cancer, and lung cancers [2].\n\nPost-transplant lymphoproliferative disorder (PTLD) is the term introduced in 1984 by Thomas Starzl [3] describing serious life-threating complications of solid and bone-marrow transplantation. The incidence of post-transplant lymphomas in solid organ recipients is 3- to 21-fold higher than that in the general population. The incidence of non-Hodgkin lymphomas varies from 0.09% to 3.8% and is highest in thoracic organ recipients [1, 5].\n\nIn kidney transplant recipients the risk of lymphoma was 11.8-fold higher than that in a matched non-transplanted population, with the highest incidence in the first post-transplant year and varying from 1 to 3% [6]. A previously published paper of our kidney transplant cohort in the years 1983–2006 reported that non-Hodgkin lymphoma and PTLD comprised 16% of neoplasms in kidney transplant recipients [7]. The clinical picture differs from lymphomas observed in the general population with different manifestation, histopathology, higher aggressiveness with involvement of sites beyond the primary lymph node, and poorer outcome [8].\n\nIn this paper we present nine cases of PTLD observed in our centre among a kidney transplant recipient population (about 1100 recipients) and discuss the results with up-to-date literature.\n\nCase report\nWe performed a retrospective single-centre assessment of PTLD incidence in the cohorts of kidney transplant recipients followed by our centre (around 1100 recipients) in the last 20 years (1997 to 2017). The recipients lost to follow-up because of graft failure or transfer to another transplant centre were excluded from the study. We found nine cases of PTLD. They were five men and four woman, aged from 26 to 67 years at the time of diagnosis (mean/SD: 49/16 years). They were transplanted between 1997 and 2013; for three of the recipients it was a second kidney transplantation. None of the recipients presented any rejection episode before PTLD diagnosis. Pretransplant Epstein-Barr virus (EBV) status was positive for five recipients and corresponding donors. One recipient presented EBV-negative status before transplantation (the data of corresponding donor were not known). He developed diffuse B-cell lymphoma 35 months after transplantation. Five patients suffered from chronic hepatitis B, and three recipients suffered from hepatitis C before diagnosis. Two recipient survived cytomegalovirus (CMV) after transplantation.\n\nDemographic features of the patients, transplant course, and immunosuppression are presented in Table 1.\n\nTable 1 Demographics and post-transplant clinical course of the recipients\n\nRecipient\tYear\nof tx\tAge\nat tx\n(years)\tPrimary kidney disease\teGFR before PTLD\n(ml/min/\n1.73 m2)\tImmunosup-\npression\tDonor EBV\tRecipient EBV\tHBV/HCV/\nCMV\t\nRecipient 1\t2003\t22\tDiabetes\t50\tTAC/MMF/PRED\t+\t+\tHBV/CMV\t\nRecipient 2\t2000\t30\tGlomerulonephritis\t29\tCSA/AZA/PRED\t+\t+\tHBV\t\nRecipient 3\t2003\n(previous tx 1987)\t50\tUnknown\t49\tCSA/AZA/PRED\t+\t+\tHBV\t\nRecipient 4\t1998\t41\tChronic pyelonephritis\t60\tCSA/AZA/PRED\t\t\tHCV\t\nRecipient 5\t2011\n(previous tx 2003)\t64\tChronic pyelonephritis\t40\tTAC/MMF/PRED\t\t–\t\t\nRecipient 6\t2013\n(previous tx 2003)\t58\tGlomerulonephritis\t49\tTAC/MMF/PRED\t+\t–\tHBV\t\nRecipient 7\t2001\t40\tGlomerulonephritis\t70\tTAC/MMF/PRED\t\t+\tHCV\t\nRecipient 8\t1997\t28\tGlomerulonephritis\t65\tCSA/MMF/PRED\t\t\t\t\nRecipient 9\t1997\t41\tUnknown\t30\tCSA/MMF/PRED\t\t+\tHCV/\nHBV/\nCMV\t\n* tx – kidney transplantation, PTLD – post-transplant lymphoproliferative disorder, TAC– tacrolimus, CSA – cyclosporine A, MMF – mycophenolate mofetil, AZA – azathioprine, PRED – prednisone, eGFR – estimated glomerular filtration rate\n\nPrimary clinical symptoms\nThe disease was diagnosed between 2002 and 2017, from 6 to 440 months after transplantation (mean/SD: 96/137 months) – in most cases between 35 and 50 months after transplantation.\n\nPatient No. 1 was admitted to hospital due to fever, throat-ache, and tonsillar enlargement with cervical lymphadenopathy. Imaging examination revealed mediastinal lymphadenopathy and splenomegaly.\n\nPatient No. 2 suffered from malaise, night sweats, fever, abdominal pain, and weight loss. Imaging diagnostics revealed enlargement of the spleen and liver as well as cervical, supraclavicular, mediastinal, and abdominal lymph nodes.\n\nPatient No. 3 in control imaging examination presented nodular mass from liver to stomach (dimensions: 9.6 × 5.5 cm) and para-aortic nodules.\n\nPatient No. 4 was admitted to the hospital due to three-day appendicitis-like symptoms: pain in right lower abdominal quadrant, subfebrile temperature (37.5˚C), and general malaise. Imaging studies showed an oval hypoechogenic capsulated lesion (42 × 49 × 39 mm) in the inferior pole of the graft. Intraoperatively, an organised abscess-like mass was removed with pain disappearance as well as normalisation of temperature and laboratory markers of inflammation.\n\nPatient No. 5 was admitted to the hospital because of severe diarrhoea (10 or more bowel movements per day) and weight loss (6 kg). Microbiological tests for bacterial as well as viral infections were negative. Gastroscopy revealed Helicobacter pylori presence with antral erosion and active gastritis with some plasma cells. Imagine examination (USG, chest X-ray) as well as colonoscopy showed no abnormalities. The symptoms diminished when mycophenolate sodium was replaced by azathioprine. Three months later the patient presented subcutaneous tumour in the right hypochondrium. Computed tomography (CT) scan revealed extensive infiltrative changes including the following: hepatic flexure of the colon, part prepyloric and antrum of the stomach, porta hepatis, and visceral adipose tissue. Numerous intra-abdominal lymph nodes were also observed.\n\nPatient No. 6 developed fever, malaise, abdominal pain, and weight loss. Computed tomography scans showed a nodular tumour between the liver and stomach (96 × 55 mm) and para-aortic lymph node enlargement.\n\nPatient No. 7 presented with skin infiltrates forming tumours on calves bilaterally, with no bone marrow, lymph node, or other organ involvement.\n\nPatient No. 8 developed sudden jaundice; ultrasonography and magnetic resonance revealed a massive tumour behind the pancreas, 120 × 110 mm in size, with enlarged abdominal lymph nodes with no bone marrow involvement.\n\nPatient No. 9 (described previously) [9] presented worsening of general condition, nausea, diarrhoea, sudden appearance of memory disorders, and speech abnormalities. Computed tomography without contrast showed nonspecific changes in the left temporal-parietal-occipital region, which were later described in the magnetic resonance imaging as possibly caused by progressive multifocal leukoencephalopathy. Autopsy revealed monomorphic primary central nervous system post-transplant lymphoproliferative disorder (M-PCNS-PTLD) presenting itself as spreading destructive lymphocytic lesions in the structures of central nervous system with angiocentric pattern of brain infiltrates.\n\nDiagnosis\nThe diagnosis, clinical course, and treatment of PTLD are summarised in Table 2. In three cases the diagnosis was based on the histological examination of lymph nodes (Patient No. 1, 3, and 6), in the remaining cases (Patient No, 2, 4, 5, 7, and 8) the diagnosis was established based on histology of the removed tumour and in one case (Patient No. 9) during autopsy.\n\nA diffuse large B-cell lymphoma was found in five cases early as well as late after transplantation, monomorphic B-cell lymphoma EBV-positive in one case and Burkitt lymphoma in one case, whereas Patient No. 2 and 7 presented T-cell lymphoma 50 and 47 months after transplantation, repsectively.\n\nTable 2 Diagnosis, clinical course, and treatment of post-transplant lymphoproliferative disorder (PTLD)\n\nRecipient\tYear of PTLD\tAge at PTLD (years)\tTime from tx to PTLD (months)\tOrgan involvement\tHistological diagnosis\tAnn Arbor staging/international Prognostic Index\tTreatment\tPTLD outcome\teGFR after PTLD (ml/min/1.73 m2)\t\n1\t2003\t26\t6\tFever, throat-ache, tonsillar enlargement, cervical and mediastinal lymphadenopathy, splenomegaly\tDiffuse large B-cell lymphoma, [CD20 (+), CD3 (–); Ki-67 (+)]\tIV/3\tSwitch to sirolimus and prednisone\tResolved after 5 months\t50\t\n2\t2004\t34\t50\tCervical, supraclavicular, mediastinal, abdominal noduled, splenomegaly, hepatomegaly\tT-cell lymphoma, [CD 3 (+),\nCD 43 (+); Ki-67 (+) in 2%\nof cells; Bcl-2 (+/–)]\tIII/3\tSwitch to sirolimus and prednisone than CHOP\tDied after 14 months\tGraft loss after 3 months\t\n3\t2006\t53\t34\tNodular mass from liver to stomach and para-aortic nodules\tDiffuse large B-cell lymphoma, [CD 20 (+), LCA (+), CD3 (–); Ki-67 (+) – in most of the CD20 cells; Bcl-2 (–)]\tII/2\tSwitch to sirolimus and prednisone\tResolved\t48\t\n4\t2012\t55\t168\tOval hypoechogenic capsulated lesion in the inferior pole of the graft\tMonomorphic B-cell lymphoma [CD20 + in 100% cells, CD3 (+) in 1% cells, CD79a (+), 5-8% of tumour cells EBV positive, Ki-67 (+) in 2–3% cells,\nBcl-2 (–)]\tIE/1\tSwitch to everolimus and prednisone – relapse added rituximab – PTLD progression – VAD\tResolved in 13 months\t50\t\n5\t2014\t67\t35\tInfiltrative changes included: colon, stomach, liver, visceral adipose tissue, numerous intra-abdominal lymph nodes\tDiffuse B-cell lymphoma\n[CK7 (–), CK20 (–), CD20 (+), CD3 (–); Ki-67 (+) in 87% of cells, Bcl-2 (+)]\tIV/5\tSwitch to sirolimus and prednisone\tDied after 3 months\t–\t\n6\t2015\t61\t38\tNodular tumour between liver and stomach and para-aortic lymph nodes\tDiffuse large B-cell lymphoma, [CD20 (+), CD3 (–); Ki-67 (+) in most of the cells, Bcl2 (–), LCA (+)]\tII/2\tSwitch to sirolimus and prednisone\tResolved in 6 months\t50\t\n7\t2005\t44\t47\tSkin tumours on both calves\tT-cell lymphoma\n[CD 3 (+), CD 43 (+); Ki-67 (+) in 2% of cells; Bcl-2 (+/–)]\tIV/3\tSwitch to sirolimus and prednisone, then surgery\tResolved in 12 months\t55\t\n8\t2002\t33\t43\tAbdominal tumour behind pancreas\tBurkitt lymphoma, [CD20 (+); CD79a (+); CD3 (–);\nCD45RO (–); Tdt (+/–)]\tIV/4\tDiscontinuation of MMF, cyclosporine and prednisone continued\tDied in 2 weeks\t–\t\n9\t2017\t61\t440\tDestructive lymphocytic lesions in the in the left temporal-parietal-occipital region\tLarge B-cells lymphoma\tV/6\tSwitch to methylprednisolone only\tDied in 3 weeks\t–\t\n* Tx – kidney transplantation, CHOP – cyclophosphamide/doxorubicin/vincristine/prednisone, VAD – vincristine/doxorubicin/dexamethasone, eGFR – estimated glomerular filtration rate\n\nTreatment\nIn eight cases primary immunosuppression was switched to mammalian target of rapamycin inhibitors (mTORi) (sirolimus in six cases, trough levels 5-8 ng/ml, everolimus in one case – Patient No. 4) and prednisone. The change of immunosuppression alone was successful in three recipients, leading to complete remission within 5-12 months (Patients No. 1, 3, 6 and 7). Patient No. 8 and 9 died shortly after diagnosis, before treatment was introduced.\n\nPatient No. 5 lost his kidney allograft shortly after diagnosis and died due to disease progression three months after diagnosis being haemodialysed.\n\nIn Patient No. 2 (T-cell lymphoma) abdominal pain vanished and the general condition improved after switch of immunosuppression, but allograft function gradually deteriorated, and three months later the recipient returned to haemodialysis treatment. Sirolimus therapy was discontinued from the beginning of haemodialysis therapy. The lymphoma progressed in spite of the introduction of chemotherapy (CHOP – cyclophosphamide, doxorubicin, vincristine, and prednisone), and the patient died 15 months later from diagnosed PTLD.\n\nPatient No. 4, after removal of a graft tumour (monomorphic B-cell lymphoma) and switch of immunosuppression, presented no allograft rejection signs and no infiltrates in terms of CD20 or EBV-positive cells in control graft biopsy. Four months after diagnosis local recurrence in the previously affected area was observed in USG and CT with two focal lesions localised in the right lung just above the diaphragm. Rituximab treatment (375 mg/m2, weekly, for four weeks) was started with no side effects. After six months CT revealed disappearance of lesions localised in the right lung but progression of infiltration in the area of the lower pole of the transplanted kidney located in the right iliac fossa (39 × 53 × 47 mm) with enlarged inguinal lymph node round up to 14 mm below the graft. Chemotherapy with vincristine, doxorubicin, and dexamethasone (VAD) protocol was introduced with no complications (for five months). Follow-up imaging dia-gnostics at the end of the chemotherapy course showed complete regression of graft infiltration with no further recurrence after the next 40 months.\n\nPatient No. 8 died two weeks after diagnosis before treatment was introduced, and Patient No. 9 died three weeks after diagnosis.\n\nOutcome\nFive patients achieved complete remission with no relapses after 6 to 13 months of treatment (four with B-cell and one with T-cell lymphoma). In three cases the remission was achieved by switch to mTORi only (all the three cases of diffuse large B-cell lymphoma). Four recipients (aged 33, 61, 34, and 67 years) died – from 2 weeks to 15 months after PTLD was diagnosed.\n\nThe allograft function within normal limits before PTLD was diagnosed in five cases (estimated glomerular filtration rate [eGFR] from 40 to 70 ml/min) and deteriorated in one case (Patient No. 2 – eGFR 28 ml/min). All patients who died lost their graft functions shortly after switch of immunosuppression. In the three recipients who died within three months of diagnosis of PTLD the graft loss was caused by lymphoma progression and multiorgan failure rather than graft rejection. In Patient No. 2, with a survival time of 15 months, the deleterious effect of immunosuppression reduction and lymphoma invasion was added to the nephrotoxic effect of chemotherapy with CHOP. In the remaining five survivors the allograft function did not change significantly during the time (mean eGFR 52 vs. 50 ml/min). However, in Patient No, 6, irrespective of stable graft function with GFR around 50 ml/min, proteinuria rose up to 4-6 g/24 h after conversion. No anti-rejection treatment was applied due to malignant process. After two years the graft function deteriorated and the patient returned to haemodialysis treatment (eight years after KTx). He was haemodialysed for 24 months and received the third kidney allograft in 2015 with immunosuppression consisted of basiliximab, tacrolimus, mycophenolate mofetil, and prednisone. The graft function was normal with GFR above 50 ml/min with no proteinuria and no symptoms PTLD recurrence.\n\nDiscussion\nPost-transplant lymphoproliferative disorder is one of the unsolved problems among solid organ recipients. In the era of modern, strong immunosuppression, the rising incidence of this complication leads to the death of 30-60% of affected solid organ transplant recipients.\n\nRisk factors\nAmong the risk factors of PTLD, EBV infection and immunosuppressive treatment are the most recognised. PTLD is associated with EBV infection in the majority of cases – 80% of B-cell origin PTLD and less in T-cell proliferations. After infection, B-cells incorporate EBV DNA into the cellular genome, which leads to decreased rate of apoptotic cell death through Bcl-2 induction and stimulates extensive proliferation of B-cells leading to lymphoblastic transformation. EBV-transformed B-lymphocytes in the transplant recipients under immunosuppressive treatment escape from the surveillance of T-lymphocytes and expand to various forms of PTLD [10]. EBV-negative PTLD was more likely to have monomorphic histology (90% vs. 65%) but was not more likely to be associated with high-risk clinical features. Paediatric recipients – very frequently EBV-negative – are especially prone to developing PTLD, and the incidence of PTLD among them varies from 0.4 to 10%, compared to adults at 1-2.3%. However, there are conflicting data regarding EBV-matching of donor and recipient in relation to PTLD development. Donor EBV-positive status as well as recipient EBV-negative status increases the risk of PTLD development five times in comparison to those matched for EBV sero-status [11]. However, more current wide studies did not recognise EBV status as a risk factor for PTLD in the European population [12, 13]. In our cohort two out of six recipients were EBV-negative with EBV-positive donors. They both developed PTLD in the form of diffuse B-cell lymphoma, 35 and 38 months after transplantation.\n\nThe other well-recognised risk factor of PTLD is immunosuppressive therapy. Whereas therapy with OKT3 or ATG, but not with anti-IL2 receptor antibodies, increases the risk of PTLD [6, 14], the reports of other types of drugs are conflicting. In the era of dual immunosuppressive therapy with azathioprine and prednisone incidence of PTLD was very low, and it increased with an introduction of calcineurin inhibitors and mycophenolate. Also, the treatment of acute rejection episodes with OKT3 or ATG increased the risk in patients who did not receive antibody in induction after transplantation. Moreover, in patients who received polyclonal antibodies in induction, rejection treatment (ATG or OKT3) further attenuated the already increased lymphoma risk [15]. The use of belatacept was related to increased incidence of PTLD, especially with central nervous system localisation [16, 17]. The data from large transplant registries show that incidence of PTLD in patients treated with tacrolimus and an antimetabolite was two-fold higher compared to cyclosporine-based immunosuppression [18]. A significantly decreased risk of late-onset PTLD was seen in recipients treated with corticosteroid maintenance [19]. Surprisingly, in an investigation of 114,000 kidney transplant recipients, treatment with an mTORi together with tacrolimus increased the risk of PTLD compared to mycophenolate with tacrolimus [20].\n\nCurrently, the total immunosuppressive load rather than the use of any particular agent is thought to be critical for the development of PTLD [21-23]. In our cohort none of the recipients received mono- or polyclonal therapy in induction of immunosuppression. They were all treated with calcineurin inhibitor (cyclosporine – 5, tacrolimus – 4) with antiproliferative drugs (azathioprine – 3, mycophenolate – 3) and prednisone [9]. None of the recipients received steroids or polyclonal antibodies in the treatment of rejection episodes. The total burden of immunosuppression in the Polish population is lower than standard protocols used in western Europe and especially the US, which at least partially can explain the low number of PTLD cases in our cohort.\n\nNone of the minor risk factors including HTLV-1, BK, and CMV infection was shown to increase the incidence of PTLD. Neither HBV nor HCV contribute to non-Hodgkin lymphoma development in immunocompromised individuals [24]; however, in a Swedish population of transplant recipients there was an association between EBV-negative lymphoma and HCV infection [25]. In our group seven patients were HBV/HCV positive and two recipients survived CMV infection after transplantation.\n\nTiming\nThe time period after transplantation influences the PTLD course. Early PTLD related to immunosuppression intensity is usually associated with EBV infection frequently located in the graft, among young recipients. The late PTLD is less frequently associated with EBV infection in older patients and is frequently extranodal [26]. Quinlan et al. in their analysis considered 762 cases of PTLD among 156,740 kidney transplant recipients and showed that for early-onset PTLD, significantly increased risk was associated with young age at transplantation (HR 3.97 for < 20 vs. 20-50 years), non-Hispanic white race/ethnicity, and seronegativity for EBV and CMV at transplantation. Those associations were not seen in late-onset PTLD. For late-onset PTLD, higher risk with older age reflected lymphoma patterns in the general population [19].\n\nLocalisation\nPTLD can be localised in any organ. EBV-positive lymphomas more frequently involved the allograft (lung/liver/kidney), more rarely in bone marrow [25]. The potential mechanism leading to a preferential allograft localisation may include the effect of chronic antigen stimulation, presence of passenger lymphocytes in the graft, or development of lymphoma from donor lymphocytes. In kidney transplant recipients the transplanted organ is not the most frequent localisation, with gastrointestinal tract involvement in about 15% and relatively often involvement of the central nervous system [18, 27]. In our cohort isolated lymphadenopathy was seen in two recipients, four recipients presented intra-abdominal tumours, one recipient presented a tumour in the graft accompanied by enlargement of lymph nodes, one recipient presented brain infiltrates, and one recipient presented skin tumours.\n\nHistopathology\nThere are several classifications of PTLD due to its heterogeneous morphological picture [8]. The newest WHO classification describes four main histological types with many subtypes [28, 29]. They are as follows:\n\nEarly lesions (florid follicular hyperplasia, plasmacytic hyperplasia, infectious mononucleosis-like lesion).\n\nPolymorphic PTLD.\n\nMonomorphic PTLD:\nB-cell neoplasms: diffuse large B cell lymphoma, Burkitt lymphoma, plasma cell myeloma, plasmacytoma-like lesion,\n\nT-cell neoplasms: peripheral T cell lymphoma, NOS, hepatosplenic T-cell lymphoma.\n\n\n\nClassical Hodgkin lymphoma type PTLD.\n\n\n\nMost B-cell PTLD were related to positive EBV status, in contrast to T-cell PTLD, which were less frequently attributed to EBV infection. The 2016 classification of the World Health Organisation of EBV-related lymphoproliferative disorders showed that EBV led to a wide range of B-cell lymphoproliferative disorders whereas T-cell lymphoproliferative disorders included peripheral T-cell lymphomas, angioimmunoblastic T-cell lymphomas, extranodal nasal natural killer/T-cell lymphomas, and other rare histotypes [30]. After organ transplantation more than 85% of PTLDs derive from B-cells, 14% from T-cells, and about 1% from natural killer cells [21]. Early-onset PTLD (i.e. within the first two years after transplant, N = 361) was more likely to be monomorphic than polymorphic, and late-onset PTLD (more than two years after transplant) was shown to be even more likely to have monomorphic pathology [31]. In our cohort two cases of T-cell lymphoma developed 50 and 47 months after transplantation occurred in EBV-positive recipients who received a kidney from an EBV-positive donor. The remaining recipients presented monomorphic B-cell lymphomas.\n\nTreatment\nThere is no consensus about the optimal treatment of PTLD, with a lack of randomised phase III trials. Several therapies are used, and most of them start from immunosuppressive therapy reduction. The underlying idea is the restoration of the recipient’s immunity to limit the EBV infection. In a retrospective study the response rate to reduction of immunosuppression alone was reported in 45% with the relapse rate of 17% and the risk of acute rejection above 30% [32]. Conversely, in a small prospective study a response to immunosuppression reduction was seen in only 6% of cases with no complete remission [33].\n\nCurrent guidelines recommend discontinuation of antimetabolites, reduction of calcineurin inhibitors, and maintenance of corticosteroids. However, the effect of particular immunosuppressive agents on PTLD outcome is unclear. European best practice guidelines for renal transplantation from 2002 recommended reduction of calcineurin-inhibitor by 50%, cessation of all other IS, and maintenance of steroids [34]. The recent version published in 2009 recommends reduction or cessation of immunosuppressive medication with no further details [35].\n\nA switch to proliferation signal inhibitors is often used when PTLD is diagnosed. In vitro data on Burkitt lymphoma-derived cells showed that the combination of cyclosporin A with everolimus is preferred to the combination of tacrolimus and everolimus [36]. Conversion to everolimus was shown to be effective in preservation of graft function and control of disease progression [37]. In a study of PTLD among liver transplant recipients, switching from calcineurin inhibitor to sirolimus at the time of diagnosis improved survival compared with only decreasing immunosuppression [38]. A series case report also showed that sirolimus induces remission of PLTD [39]. However, another study reported that mTORi use after transplantation does not decrease the risk of PTLD [20], and other studies showed conflicting results [40-42].\n\nIt was observed that reduction of immunosuppression together with removal of neoplastic B cells by rituximab and chemotherapy are the most effective modalities for long-term survival. Reduced immunosuppression during chemotherapy was shown not to increase the risk of graft function deterioration [43]. Management of PTLD should be based on histological assessment of its subtypes. In early type of PTLD presenting 100% association with EBV infection, reduction of immunosuppression alone causes complete regression, and rituximab is used for non-responding patients. Polymorphic PTLD respond well to reduction of immunosuppression with rituximab monotherapy. Conversely, monomorphic PTLD rarely responds to reduction of immunosuppression with rituximab and usually requires treatment with parallel or sequential use of chemotherapy. Most centres use anthracycline-based drug combinations, such as CHOP with granulocyte colony-stimulating factor support.\n\nAnti-CD20 monoclonal antibody – rituximab – is widely used to treat PTLD and was shown to be effective and safe in retrospective and prospective studies on PTLD treatment, especially when combined with chemotherapy. The first study by Fisher showed its efficacy in treatment of polymorphic forms of PTLD and lack of effect in monomorphic forms with fatal outcome [44]. Some studies have shown that rituximab monotherapy has higher response rate for PTLD than in immunocompetent patients of the nontransplant population. Some small studies showed its usefulness as first-line therapy [45-47]. It was shown that EBV status has no impact on response to therapy including reduction of immunosuppression alone and chemotherapy or survival from the time of diagnosis [48]. Earlier EBV-negative recipients were reported to respond poorly to rituximab, which was not confirmed in a more recent prospective trial [49, 50]. We, like other authors, showed no correlation between the recipient’s EBV status and response to therapy. The good and bad responses were observed in both EBV-positive and EBV-negative groups.\n\nSurgical resection or radiation therapy may be used as adjunctive therapy in cases of advanced stage of the disease. Early surgery is recommended in the case of localised lesions (tonsillectomy, lung or liver resection with eventual re-transplantation). Radiotherapy is used in central nervous system involvement and in the rare cases of the extranodal NK/T-cell lymphomas (the only form in which radiotherapy appears to yield favourable outcomes).\n\nThe novel T-cell-based immune therapies, such as donor lymphocyte infusions and the adoptive transfer of EBV-specific cytotoxic T-lymphocytes (CTLs), are rarely used to treat PTLD. EBV-transformed B-lymphoblastoid cell lines are ideal antigen-presenting cells for the activation of T-cells used in immunotherapy expressing the same 10 viral antigens. The potential methods include the following: donor unmanipulated lymphocyte infusions or donor EBV-specific CTLs infusions, mostly studied in haematopoietic stem cell transplantation recipients. Very few attempts were performed in solid transplant recipients with promising effects [51]. Antiviral agents were used in a limited number patients, which precludes definitive conclusions. It seems reasonable to use ganciclovir in the case of prevention of PTLD in EBV-seronegative patients and/or overimmunosuppressed recipients, but there is still insufficient evidence to support this thesis.\n\nOutcome\nAlthough the histopathological types of PTLD reflect the types of lymphoma in immunocompetent patients, PTLD after solid organ transplantation may carry a poorer prognosis than lymphoma in immunocompetent individuals. The study of Trusson et al. showed that the response to first-line chemotherapy and overall survival are similar in PTLD and non-transplant patients. However cause of death in immunocompetent patients due to progression of the disease concerned 94% of them whereas transplant recipients died mostly of infectious other treatment-related complications [52]. In the analysis of 135 lymphomas after solid organ transplantation the five-year overall survival was 42% in all treated patients. The poor prognostic factors were older age, systemic symptoms of fever, night sweats, weight loss, poor Eastern Cooperative Oncology Group Performance Status, kidney/pancreas/heart recipients (probably due to higher immunosuppression burden compared to kidney transplant recipients), T-cell lymphoma, and HCV-infection [25].\n\nConclusions\nAlthough the diagnostic criteria of different forms of PTLD are commonly known, rapid and correct diagnosis is not always easy. PTLD may appear at any time after transplantation, and it is often presented in a non-specific way – regular physical examination and imaging diagnostics should be performed as well as regular EBV infection monitoring, especially in patients with high immunosuppressive burden.\n\nPTLD is a relatively a rare disorder, so there are too few studies and little consensus on the optimal treatment. Because the origin of PTLD is not exactly known, it is difficult to generate new treatments, and therefore large, randomised trials should be conducted.\n\nThe authors declare no conflict of interest.\n==== Refs\n1 Hall \nEC , Pfeiffer \nRM , Segev \nDL , et al (2013 ): Cumulative incidence of cancer after solid organ transplantation\n. Cancer \n119 : 2300 -2308\n.23559438 \n2 Pendón-Ruiz de Mier \nV , Navarro Cabello \nMD , Martínez Vaquera \nS , et al (2015 ): Incidence and long-term prognosis of cancer after kidney transplantation\n. 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Am J Hematol \n86 :206 -209\n.21264909 \n32 Reshef \nR , Vardhanabhuti \nS , Luskin \nMR , et al (2011 ): Reduction of immunosuppression as initial therapy for post-transplantation lymphoproliferative disorder\n. Am J Transplant \n11 : 336 -347\n.21219573 \n33 Swinnen \nLJ , Le Blanc \nM , Grogan \nTM , et al (2008 ): Prospective study of sequential reduction in immunosuppression, interferon alpha-2b, and chemotherapy for post-transplantation lymphoproliferative disorder\n. Transplantation \n86 : 215 -222\n.18645482 \n34 EBPG Expert Group on Renal Transplantation . (2002 ): European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment\n. Nephrol Dial Transplant \n17 : 31 -36\n.\n35 Heemann \nU , Abramowicz \nD , Spasovski \nG , et al (2011 ): Endorsement of the Kidney Disease Improving Global Outcomes (KDIGO) guidelines on kidney transplantation: a European Renal Best Practice (ERBP) position statement\n. Nephrol Dial Transplant \n26 : 2099 -2106\n.21555392 \n36 Wowro \nSJ , Schmitt \nKRL , Tong \nG , et al (2016 ): Effects of mTOR and calcineurin inhibitors combined therapy in Epstein-Barr virus positive and negative Burkitt lymphoma cells\n. Int Immunopharmacol \n30 : 9 -17\n.26613512 \n37 Chiurchiu \nC , Carreño \nCA , Schiavelli \nR , et al (2010 ): Results of the conversion to everolimus in renal transplant recipients with post-transplantation malignancies\n. Transplant Proc \n42 : 277 -279\n.20172329 \n38 Mumtaz \nK , Faisal \nN , Marquez \nM , et al (2003 ): Post-transplant lymphoproliferative disorder in liver recipients: characteristics, management, and outcome from a single-centre experience with > 1000 liver transplantations\n. Can J Gastroenterol Hepatol \n29 : 417 -422\n.\n39 Boratyńska \nM , Smolska \nD (2008 ): Inhibition of mTOR by sirolimus induces remission of post-transplant lymphoproliferative disorders\n. Transpl Int \n21 : 605 -608\n.18282244 \n40 Kirk \nAD , Cherikh \nWS , Ring \nM , et al (2007 ): Dissociation of depletional induction and post-transplant lymphoproliferative disease in kidney recipients treated with alemtuzumab\n. Am J Transplant \n7 : 2619 -2625\n.17868060 \n41 Caillard \nS , Dharnidharka \nV , Agodoa \nL , et al (2005 ): Post-transplant lymphoproliferative disorders after renal transplantation in the United States in era of modern immunosuppression\n. Transplantation \n80 : 1233 -1243\n.16314791 \n42 Kauffman \nHM , Cherikh \nWS , Cheng \nY , et al (2005 ): Maintenance immunosuppression with target-of-rapamycin inhibitors is associated with a reduced incidence of de novo malignancies\n. Transplantation \n80 : 883 -889\n.16249734 \n43 Taylor \nE , Jones \nM , Hourigan \nMJ , et al (2015 ): Cessation of immunosuppression during chemotherapy for post-transplant lymphoproliferative disorders in renal transplant patients\n. Nephrol Dial Transplant \n30 : 1774 -1779\n.26188340 \n44 Fischer \nA , Blanche \nS , Le Bidois \nJ , et al (1991 ): Anti-B-cell monoclonal antibodies in the treatment of severe B-cell lymphoproliferative syndrome following bone marrow and organ transplantation\n. N Engl J Med \n324 : 1451 -1456\n.2023604 \n45 Choquet \nS , Oertel \nS , LeBlond \nV , et al (2007 ): Rituximab in the management of post-transplantation lymphoproliferative disorder after solid organ transplantation: proceed with caution\n. Ann Hematol \n86 : 599 -607\n.17522862 \n46 Allen \nUD , Preiksaitis \nJK , AST Infectious Diseases Community of Practice (2013 ): Epstein-Barr virus and post-transplant lymphoproliferative disorder in solid organ transplantation\n. Am J Transplant \n13 : 107 -120\n.23465004 \n47 Trappe \nR , Oertel \nS , Leblond \nV , et al (2012 ): Sequential treatment with rituximab followed by CHOP chemotherapy in adult B-cell post-transplant lymphoproliferative disorder (PTLD): the prospective international multicentre phase 2 PTLD-1 trial\n. Lancet Oncol \n13 : 196 -206\n.22173060 \n48 Luskin \nMR , Heil \nDS , Tan \nKS , et al (2015 ): The Impact of EBV status on characteristics and outcomes of post-transplantation lymphoproliferative disorder HHS public access\n. Am J Transpl \n15 : 2665 -2673\n.\n49 Oertel \nSHK , Verschuuren \nE , Reinke \nP , et al (2005 ): Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD)\n. Am J Transplant \n5 : 2901 -2906\n.16303003 \n50 González-Barca \nE , Domingo-Domenech \nE , Capote \nFJ , et al (2007 ): Prospective phase II trial of extended treatment with rituximab in patients with B-cell post-transplant lymphoproliferative disease\n. Haematologica \n92 : 1489 -1494\n.18024397 \n51 Bollard \nCM , Rooney \nCM , Heslop \nHE (2012 ): T-cell therapy in the treatment of post-transplant lymphoproliferative disease\n. Nat Rev Clin Oncol \n9 : 510 -519\n.22801669 \n52 Trusson \nR , Serre \nJE , Szwarc \nI , et al (2016 ): Treatment response and outcomes in post-transplantation lymphoproliferative disease vs. lymphoma in immunocompetent patients\n. Transplant Proc \n48 : 1927 -1933\n.27569924\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "45(4)",
"journal": "Central-European journal of immunology",
"keywords": "kidney transplantation; lymphoma; post-transplant lymphoproliferative disease",
"medline_ta": "Cent Eur J Immunol",
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"nlm_unique_id": "9702239",
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"title": "Post-transplant lymphoproliferative disorder in adult renal transplant recipients: case series and review of literature.",
"title_normalized": "post transplant lymphoproliferative disorder in adult renal transplant recipients case series and review of literature"
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"abstract": "We present the first report of bilateral knee and left ankle osteonecrosis in a 58-year-old female patient on long-term intranasal corticosteroids. Initially, our patient presented with progressive disabling knee pain with normal radiographs. The patient was presumed to have mild degenerative joint disease; therefore, she was treated conservatively. Then, the patient developed severe left ankle pain, and she was thought to have L5/S1 radiculopathy; therefore, she underwent epidural steroid injection that did not provide any benefit. However, extensive bilateral osteonecrosis of the medial tibial plateau in addition to osteonecrosis of the talus bone of left ankle were later diagnosed by MRI. The patient underwent staged bilateral total knee arthroplasty. In conclusion, the diagnosis of osteonecrosis might be challenging because of overlapping clinical presentation with other disorders particularly in the early stage of the disease with normal radiographs. Therefore, a high index of suspicion and thorough history with supplemental MRI imaging are essential for the assessment of patients presented with atypical refractory joint pain particularly in the presence of risk factors.",
"affiliations": "From the Department of Orthopedic Surgery, University of Massachusetts Medical School, Worcester, MA (Dr. Yousef and Dr. Ayers), and the Department of Orthopaedic Surgery, Sohag University, Sohag, Egypt (Dr. Yousef).",
"authors": "Yousef|Mohamed A|MA|0000-0002-3593-2452;Ayers|David C|DC|",
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"fulltext": "\n==== Front\nJ Am Acad Orthop Surg Glob Res Rev\nJ Am Acad Orthop Surg Glob Res Rev\nJAAOS Glob Res Rev\nJAAOS Glob Res Rev\nJAAOS Glob Res Rev\nJAAOS Global Research & Reviews\n2474-7661 Wolters Kluwer Philadelphia, PA \n\nJAAOSGlobal-D-20-00095\n10.5435/JAAOSGlobal-D-20-00095\n00007\nCase Report\nMultiple Joint Osteonecrosis in a Patient on Long-term Intranasal Corticosteroids\nhttp://orcid.org/0000-0002-3593-2452Yousef Mohamed A. MD, PhD Ayers David C. MD From the Department of Orthopedic Surgery, University of Massachusetts Medical School, Worcester, MA (Dr. Yousef and Dr. Ayers), and the Department of Orthopaedic Surgery, Sohag University, Sohag, Egypt (Dr. Yousef).\nCorrespondence to Dr. Yousef: Mohamed.yousef@umassmed.edu\n11 2020 \n12 11 2020 \n4 11 e20.0009526 5 2020 24 9 2020 Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Orthopaedic Surgeons.2020American Academy of Orthopaedic SurgeonsThis is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present the first report of bilateral knee and left ankle osteonecrosis in a 58-year-old female patient on long-term intranasal corticosteroids. Initially, our patient presented with progressive disabling knee pain with normal radiographs. The patient was presumed to have mild degenerative joint disease; therefore, she was treated conservatively. Then, the patient developed severe left ankle pain, and she was thought to have L5/S1 radiculopathy; therefore, she underwent epidural steroid injection that did not provide any benefit. However, extensive bilateral osteonecrosis of the medial tibial plateau in addition to osteonecrosis of the talus bone of left ankle were later diagnosed by MRI. The patient underwent staged bilateral total knee arthroplasty. In conclusion, the diagnosis of osteonecrosis might be challenging because of overlapping clinical presentation with other disorders particularly in the early stage of the disease with normal radiographs. Therefore, a high index of suspicion and thorough history with supplemental MRI imaging are essential for the assessment of patients presented with atypical refractory joint pain particularly in the presence of risk factors.\n\nOPEN-ACCESSTRUE\n==== Body\nOsteonecrosis (ON) is a devastating progressive disease that results in debilitating joint degeneration with functional impairment.1 The femoral head is the most common affected site, followed by the humeral head and knee.1 ON of the knee represents 10% of all patients with ON and typically affects the medial femoral condyle.2 Three distinct types of knee ON were described: idiopathic or spontaneous, secondary that occurs in association with identifiable risk factor, and postarthroscopic.3 The diagnosis of ON is often challenging and delayed as well because of overlapping clinical presentation with other conditions. Despite the well-known safety of the intranasal corticosteroids, we present the first report of bilateral ON of the medial tibial plateau and left ankle ON in a 58-year-old female patient on long-term intranasal corticosteroids. The patient was informed that data concerning the case would be submitted for publication, and she provided consent.\n\nCase Report\nA 58-year-old female patient presented to the outpatient clinic complaining of a gradual onset of constant left knee pain of a 9-week duration after several visits to her primary care provider as well as an orthopaedic surgeon without improvement. No history of trauma was noted, and her pain was localized to the medial and anterior aspects of the knee. On examination, the patient walked with antalgic gait. Localized medial tenderness was elicited. No swelling nor signs of internal derangement were noted. She was able to extend to 0° and flex to 135°. Knee radiographs were negative with maintained joint space and without evidence of fracture or notable osteoarthritis (Figure 1, A). The patient was presumed to have mild degenerative joint disease; therefore, she was prescribed naproxen and was sent to physical therapy for 4 weeks. On the follow-up, the pain did not improve, and she started to complain of similar pain affecting her right knee. MRI of the left knee was done that showed a large area of acute bone marrow edema with abnormal signal intensity in the medial tibial plateau measuring 6.5 × 5.2 cm, suggestive of insufficiency fracture (Figure 2, A and B). The knee was placed in a hinged brace, and the patient started to use a walker for protected weight-bearing. Medial history and medications were reviewed. She had hypothyroidism, hypertension, depression, and allergic rhinitis. Her medication included levothyroxine, escitalopram, hydrochlorothiazide, and intranasal corticosteroids (fluticasone propionate [Flonase] two puffs each nostril twice a day) for several years. She never smoked and often drank 1 to 2 glasses of wine a day.\n\nFigure 1 Anteroposterior plain radiograph of both knees done at the initial presentation with normal appearance (A) and at 3 months afterward (B) demonstrating bilateral subchondral sclerotic lesions and collapse of the medial tibial plateau more severe in the right knee.\n\nFigure 2 T1-weighted (A) and T2-weighted (B) MRI images of the left knee demonstrating a large area of acute bone marrow edema with abnormal signal intensity in the medial tibial plateau and irregularly contoured outline between the viable and necrotic bones. T1-weighted (C) and T2-weighted (D) MRI images of the right knee showing similar findings but more extensive to the left knee with partial collapse of the medial tibial plateau.\n\nBecause of persistent pain of the right knee, MRI of the right knee was done that showed similar findings but more extensive compared to the left knee with partial collapse of the medial tibial plateau (Figure 2, C and D). A linear T2-hyperintense signal was identified in the medical and lateral meniscus as well but without definite articular surface tear. At that time, hip radiographs were done that showed no evidence of ON, and new knee radiographs showed bilateral subchondral sclerotic lesions, with collapse of the medial tibial plateau more severe in the right knee (Figure 1, B). She was treated conservatively with ibuprofen, gabapentin, diphosphonate (alendronate 70 mg once a week), and physical therapy. At 8 weeks of follow-up, her knee pain had become less intense, but she started to experience disabling pain in her left ankle. Ankle radiographs were negative. She was thought to have L5/S1 left radiculopathy; therefore, she underwent left L5/S1 transforaminal epidural steroid injection under fluoroscopy, which did not provide any benefit. Because of continuing pain, MRI of the left ankle was done that showed extensive ON involving the talus and navicular bones (Figure 3). The patient received additional tests including connective tissue disease workup (complete blood count, erythrocyte sedimentation rate, C-reactive protein, urine analysis, serum creatinine, rheumatoid factor, antinuclear antibody, antidouble stranded DNA, lupus anticoagulant, and anticardiolipin antibodies), coagulation profile (prothrombin time, international normalized ratio, activated partial thromboplastin time, and fibrinogen), and thrombophilia workup (antithrombin, protein C, protein S, factor V Leiden, and factor VIII) to exclude underlying diseases that were negative.\n\nFigure 3 T1-weighted (A) and T2-weighted (B) MRI images of the left ankle demonstrating area of acute bone marrow edema with abnormal signal intensity affecting the talus and navicular bones.\n\nFollow-up knee radiographs showed progressive collapse of the medial tibial plateau with varus malalignment and secondary osteoarthritis bilaterally. The disease progressed to stage IV according to the Ficat and Arlet classification3 (Figure 4) over 2 years. Staged bilateral total knee arthroplasty (TKA) was performed because of progressively worsening knee pain recalcitrant to conservative treatment (Figure 5). Bone histopathology confirmed bone ON. The patient recovered well after TKA, with great improvement of pain and function at the 6-month follow-up. The mean knee injury and osteoarthritis outcome score (KOOS) pain scale improved from 38 before surgery to 83. Similarly, the mean KOOS function in daily living (ADL) scale improved from 37 before surgery to 85. The patient achieved an active range of knee motion from 0 to 128° of flexion, with no extension lag. The left ankle was treated conservatively with solid ankle-foot orthosis to provide some comfort and to postpone the ankle surgery until she recovers from the TKA. The ankle ON progressed with talar collapse and secondary degenerative arthritis of the tibiotalar and subtalar joints (Figure 6).\n\nFigure 4 Follow-up anterior-posterior weight-bearing plain radiographs of both knees demonstrating progressive collapse of the medial tibial plateau with varus malalignment and secondary osteoarthritis bilaterally more severe on the right.\n\nFigure 5 Postoperative anterior-posterior weight-bearing plain radiograph demonstrating bilateral total knee arthroplasty in good position and alignment.\n\nFigure 6 Anteroposterior (A) and lateral (B) plain radiograph of the left ankle demonstrating extensive mixed area of sclerosis and luscencies within the talus with flattened talar dome, partial talar collapse, and secondary degenerative osteoarthritis of the tibiotalar and subtalar joints.\n\nDiscussion\nAhlback and colleagues were the first to describe the spontaneous type of knee ON in 1968.4 It is the most common form of knee ON.3 Its exact etiology is still unclear; however, it is thought that vascular insufficiency or traumatic event might be implicated in the necrosis of subchondral bone with subsequent development of articular surface collapse and secondary osteoarthritis.5 This clinical entity is often restricted to the medial femoral condyle with particular unilateral affection of the epiphysis and without other joint involvement or associated comorbidity. It affects older individuals older than 55 years.3 While secondary knee ON usually affects the epiphysis, metaphysis, and even diaphysis, are found in patients younger than 55 years. It is characterized by the presence of bilateral multiple lesions that affect the hip in 90% of the patients.3 It occurs in association with steroid use, alcoholism, connective tissue disease, sickle cell disease, thrombophilia, and in patients with organ transplantation.1,3\n\nPatients with allergic rhinitis represent approximately 10% to 30% of the general population, and the prevalence tends to increase progressively across the world.6 Although the use of intranasal corticosteroids is considered safe, occasional adverse events have been reported such as adrenal suppression, increased intraocular pressure, and growth suppression.7 Although it was shown that 90% of patients with knee ON have a history of steroid use, data on the dose, route of administration, and length of treatment that can cause ON are remarkably variable.8,9 Although long-term high-dose steroid therapy is a major risk factor for ON,9 ON can develop after short-term low-dose therapy,10 intra-articular injection,11 or inhalational steroid.12 It is believed that steroids increase the bone marrow adipocyte cell size with elevation of the intraosseous pressure and subsequent impairment of the blood flow.13,14 The combined use of alcohol and steroids is shown to have an additive effect in causing ON.15 We feel that despite the low systemic bioavailability of the intranasal corticosteroids, they can cause ON in the presence of increased alcohol intake.\n\nPatients usually present with gradual onset of severe medial knee pain that is often worse at night or with weight-bearing.3 The diagnosis of knee ON is often challenging because it is assumed that the knee pain might be due to meniscal injury or early arthritic changes.8 Diagnostic workup including connective tissue screening tests and thrombophilia tests can be considered in patients with ON.16,17 However, their role in patient management is not clear. The plain radiographs are completely normal initially; therefore, high index of clinical suspicion and thorough history are important to identify possible risk factors. Later on, radiographs show subchondral radiolucent areas and eventual articular surface collapse with arthritic changes as the disease progresses.3 At early stage disease, MRI is the modality of choice to establish the diagnosis.18 It provides detailed information about the extension of the lesion and any other associated intra-articular lesions. MRI is also an important screening imaging tool in high-risk patients, regardless of the symptoms.14 Although bone scintigraphy is an effective diagnostic tool, it has a much lower sensitivity of 64% compared with 100% reported using MRI beside its limited value in patients with multifocal disease.18 The duration from the start of symptoms to the time of diagnosis is variable ranging from two weeks to 24 months.6 In our patient, the diagnosis was made 13 weeks after the pain started. Early diagnosis is important to avoid mistreatment and to avoid or delay the need for arthroplasty especially in younger patients.\n\nAlthough it is difficult to differentiate between spontaneous and secondary knee ON based on the clinical presentation, demographic and radiological findings can help identify the type of knee ON. A relatively young patient with multiple joints involvement and underlying risk factors, as is the case with our patient, makes the diagnosis of secondary ON more likely. In addition, MRI findings are useful to identify the type of knee ON particularly those with notably larger lesions in patients with secondary ON and with the presence of irregular well-demarcated line between the necrotic and viable bone.1 Only few cases of bilateral knee ON have been reported in the literature with affection of the patella12,19 and the lateral femoral condyle.20,21 The lesions in our case were localized to the medial tibial plateau bilaterally, which is unusual. All cases shared the same risk factor of steroid use that varied from the typical oral form20 to the inhaled form.12 In our case, intranasal corticosteroids were responsible for ON.\n\nThe conservative treatment of knee ON, which included protected weight-bearing and the use of analgesics and diphosphonate, was unsuccessful. Because the disease continued to progress rapidly, joint-preserving procedures such as core decompression and/or impacted bone grafting were not an option for this patient. Because of extensive bone involvement, we proceeded with TKA, which provides excellent results–comparable with those reported in patients with osteoarthritis--in patients with ON, rather than unicompartmental arthroplasty.22 Our patient's KOOS pain and function scores improved greatly after TKA. The management of talus ON is often challenging with suboptimal outcome in large percentage of patients.23 The management options include conservative treatment with protected weight-bearing or surgical treatment with core decompression, vascularized bone grafting, total talar prosthesis, or salvage procedure.23 The surgical treatment for our patient would have been quite extensive requiring a salvage procedure because of the extensive lesions affection the talus and navicular bones.\n\nIn conclusion, bone ON is an unusual, debilitating disease that necessitates early diagnosis. ON should be considered in the differential diagnosis of severe atypical refractory joint pain particularly in the presence of identified risk factors. The diagnosis might be challenging because of overlapping clinical presentation with other disorders particularly in the early stage of the disease with normal radiographs. Therefore, a high index of suspicion and thorough history with supplemental MRI imaging are essential for the diagnosis of such condition to avoid mistreatment or delays in treatment especially in younger patients.\n\nNeither of the following authors nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this article: Dr. Yousef and Dr. Ayers.\n==== Refs\nReferences\n1. Narváez J Narváez JA Rodriguez-Moreno J Roig-Escofet D : Osteonecrosis of the knee: Differences among idiopathic and secondary types\n. Rheumatology (Oxford) \n2000 ;39 :982 -989\n.10986303 \n2. Mankin HJ : Nontraumatic necrosis of bone (osteonecrosis)\n. N Engl J Med \n1992 ;326 :1473 -1479\n.1574093 \n3. Zywiel MG McGrath MS Seyler TM Marker DR Bonutti PM Mont MA : Osteonecrosis of the knee: A review of three disorders\n. Orthop Clin North Am \n2009 ;40 :193 -211\n.19358905 \n4. Ahlbäck S Bauer GC Bohne WH : Spontaneous osteonecrosis of the knee\n. Arthritis Rheum \n1968 ;11 :705 -733\n.5700639 \n5. Juréus J Lindstrand A Geijer M Robertsson O Tägil M : The natural course of spontaneous osteonecrosis of the knee (SPONK): A 1- to 27-year follow-up of 40 patients\n. Acta Orthop \n2013 ;84 :410 -414\n.23799344 \n6. Lohia S Schlosser RJ Soler ZM : Impact of intranasal corticosteroids on asthma outcomes in allergic rhinitis: A meta-analysis\n. Allergy \n2013 ;68 :569 -579\n.23590215 \n7. Bensch GW : Safety of intranasal corticosteroids\n. Ann Allergy Asthma Immunol \n2016 ;117 :601 -605\n.27979016 \n8. Mont MA Baumgarten KM Rifai A Bluemke DA Jones LC Hungerford DS : Atraumatic osteonecrosis of the knee\n. J Bone Joint Surg Am \n2000 ;82 :1279 -1290\n.11005519 \n9. Chan KL Mok CC : Glucocorticoid-induced avascular bone necrosis: Diagnosis and management\n. Open Orthop J \n2012 ;6 :449 -457\n.23115605 \n10. Dilisio MF : Osteonecrosis following short-term, low-dose oral corticosteroids: A population-based study of 24 million patients\n. Orthopedics \n2014 ;37 :e631 -e636\n.24992058 \n11. Yamamoto T Schneider R Iwamoto Y Bullough PG : Rapid destruction of the femoral head after a single intraarticular injection of corticosteroid into the hip joint\n. J Rheumatol \n2006 ;33 :1701 -1704\n.16881128 \n12. Jafri A Burke J Innes AR : Case study: Bilateral avascular necrosis of patellae after inhaled steroid therapy\n. Knee \n2005 ;12 :235 -237\n.15911299 \n13. Miyanishi K Yamamoto T Irisa T : Bone marrow fat cell enlargement and a rise in intraosseous pressure in steroid-treated rabbits with osteonecrosis\n. Bone \n2002 ;30 :185 -190\n.11792583 \n14. Mont MA Marker DR Zywiel MG Carrino JA : Osteonecrosis of the knee and related conditions\n. J Am Acad Orthop Surg \n2011 ;19 :482 -494\n.21807916 \n15. Boskey AL Raggio CL Bullough PG Kinnett JG : Changes in the bone tissue lipids in persons with steroid- and alcohol-induced osteonecrosis\n. Clin Orthop Relat Res \n1983 ;172 :289 -295\n.\n16. Lykissas MG Gelalis ID Kostas-Agnantis IP Vozonelos G Korompilias AV : The role of hypercoagulability in the development of osteonecrosis of the femoral head\n. Orthop Rev (Pavia) \n2012 ;4 :e17 .22802985 \n17. Ekmekci Y Keven K Akar N : Thrombophilia and avascular necrosis of femoral head in kidney allograft recipients\n. Nephrol Dial Transplant \n2006 ;21 :3555 -3558\n.16968732 \n18. Mont MA Ulrich SD Seyler TM : Bone scanning of limited value for diagnosis of symptomatic oligofocal and multifocal osteonecrosis\n. J Rheumatol \n2008 ;35 :1629 -1634\n.18528962 \n19. Mizuta H Kubota K Shiraishi M Kai K Nakamura E Takagi K : Steroid-related bilateral osteonecrosis of the patella\n. Arthroscopy \n1993 ;9 :114 -116\n.8442818 \n20. Havel PE Ebraheim NA Jackson WT : Steroid-induced bilateral avascular necrosis of the lateral femoral condyles. A case report\n. Clin Orthop Relat Res \n1989 ;243 :166 -168\n.\n21. Arnold CA Tavares JO : Long-term follow-up of bilateral steroid-induced osteonecrosis of the lateral femoral condyles in a patient with Crohn's disease\n. Am J Knee Surg \n1998 ;11 :236 -240\n.9854002 \n22. Myers TG Cui Q Kuskowski M Mihalko WM Saleh KJ : Outcomes of total and unicompartmental knee arthroplasty for secondary and spontaneous osteonecrosis of the knee\n. J Bone Joint Surg Am \n2006 ;88 (suppl 3 ):76 -82\n.\n23. Dhillon MS Rana B Panda I Patel S Kumar P : Management options in avascular necrosis of talus\n. Indian J Orthop \n2018 ;52 :284 -296\n.29887631\n\n",
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"title": "Multiple Joint Osteonecrosis in a Patient on Long-term Intranasal Corticosteroids.",
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"abstract": "A 68-year-old male with a past medical history of interstitial pulmonary fibrosis (IPF) on nintedanib and chronic nintedanib-induced diarrhea for three years presented with hematochezia and worsening diarrhea. Diarrhea had persisted despite the use of cholestyramine and oral antidiarrhea medications. As part of the evaluation of diarrhea, he had undergone colonoscopy two years prior, which had shown non-specific moderate diffuse colitis. No significant abnormalities had been noted on physical exam and lab tests. On the present admission, colonoscopy showed diffuse erythematous, friable, and granular mucosa throughout the entire colon. Biopsies were taken and pathology was reported as acute superficial inflammation and possible nintedanib-induced colitis. Since the patient wanted to continue nintedanib as a part of IPF treatment, 9 mg oral budesonide was started, and the patient was followed up after four months. At his follow-up visit, the patient reported that diarrhea had completely resolved. In this report, we illustrate and discuss a case of nintedanib-induced colitis, which can be resistant to oral antidiarrhea medication and cholestyramine. The mechanism of this side effect is not completely understood; however, it may be related to direct inflammation of the intestinal epithelium, given that nintedanib metabolites are excreted primarily in the stool. As a result, it has been hypothesized that steroids could potentially treat this diarrhea by relieving this inflammation. In our patient, we elected to use budesonide due to less associated systemic side effects and possible similarity of inflammation between nintedanib-associated colitis and inflammatory bowel disease.",
"affiliations": "Internal Medicine, St. Luke's Hospital, Chesterfield, USA.;Internal Medicine, St. Luke's Hospital, Chesterfield, USA.;Internal Medicine/Gastroenterology and Hepatology, St. Luke's Hospital, Chesterfield, USA.",
"authors": "Amini|Afshin|A|;Koury|Elliott|E|;Chahla|Elie|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.9489",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.9489\nGastroenterology\nNintedanib-Induced Colitis Treated Effectively With Budesonide\nMuacevic Alexander Adler John R Amini Afshin 1 Koury Elliott 1 Chahla Elie 2 \n1 \nInternal Medicine, St. Luke's Hospital, Chesterfield, USA \n\n2 \nInternal Medicine/Gastroenterology and Hepatology, St. Luke's Hospital, Chesterfield, USA \n\nElie Chahla elie.chahla@gmail.com\n31 7 2020 \n7 2020 \n12 7 e948914 7 2020 31 7 2020 Copyright © 2020, Amini et al.2020Amini et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/37294-nintedanib-induced-colitis-treated-effectively-with-budesonideA 68-year-old male with a past medical history of interstitial pulmonary fibrosis (IPF) on nintedanib and chronic nintedanib-induced diarrhea for three years presented with hematochezia and worsening diarrhea. Diarrhea had persisted despite the use of cholestyramine and oral antidiarrhea medications. As part of the evaluation of diarrhea, he had undergone colonoscopy two years prior, which had shown non-specific moderate diffuse colitis. No significant abnormalities had been noted on physical exam and lab tests. On the present admission, colonoscopy showed diffuse erythematous, friable, and granular mucosa throughout the entire colon. Biopsies were taken and pathology was reported as acute superficial inflammation and possible nintedanib-induced colitis. Since the patient wanted to continue nintedanib as a part of IPF treatment, 9 mg oral budesonide was started, and the patient was followed up after four months. At his follow-up visit, the patient reported that diarrhea had completely resolved.\n\nIn this report, we illustrate and discuss a case of nintedanib-induced colitis, which can be resistant to oral antidiarrhea medication and cholestyramine. The mechanism of this side effect is not completely understood; however, it may be related to direct inflammation of the intestinal epithelium, given that nintedanib metabolites are excreted primarily in the stool. As a result, it has been hypothesized that steroids could potentially treat this diarrhea by relieving this inflammation. In our patient, we elected to use budesonide due to less associated systemic side effects and possible similarity of inflammation between nintedanib-associated colitis and inflammatory bowel disease.\n\nbudesonidenintedanib induced colitisThe 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\nNintedanib, a tyrosine kinase inhibitor, displays antifibrotic activity via blockade of three receptors [platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), and fibroblast growth factor receptor (FGFR)] [1]. This drug was initially developed as an anti-tumor agent but was later recognized for its unique antifibrotic activity [2]. It is mainly cleared by liver metabolism, with most of the metabolites being excreted in the feces (feces: 93.4%, urine: <1%) [3]. The most common adverse effect associated with nintedanib is diarrhea (62%), which has led to a permanent dose reduction in 11% of patients and discontinuation in 5% [4]. In this report, we discuss a case of nintedanib-induced diarrhea with complete clinical resolution after treatment with oral budesonide.\n\nCase presentation\nA 68-year-old male with a past medical history of interstitial pulmonary fibrosis (IPF) and chronic diarrhea for three years was admitted to the hospital with the chief complaints of hematochezia and worsening diarrhea. He denied any abdominal pain or nausea. In the past three years, he had been taking nintedanib (150 mg twice daily) for IPF. For his diarrhea, he had been on cholestyramine twice a day and other antidiarrheals, but his diarrhea had persisted and worsened. A colonoscopy performed two years ago had shown non-specific moderate diffuse colitis.\n\nThe physical examination and vital signs were unremarkable. His blood work, including complete blood count (CBC) and comprehensive metabolic panel (CMP), was within normal limits. His C-reactive protein (CRP) was mildly elevated. Repeat colonoscopy revealed diffuse areas of erythematous, friable, and granular mucosa throughout the entire colon, similar to the previous endoscopic findings (Figure 1). Histopathology showed acute superficial inflammation, and expansion of lamina propria by lymphoplasmacytic infiltrate, raising the possibility of nintedanib-induced colitis (Figure 2).\n\nFigure 1 Colonoscopy view\nThe image shows erythematous, friable, and granular mucosa in the cecum (yellow arrows)\n\nFigure 2 Histopathology of colon biopsy (200x)\nThe image shows acute superficial inflammation, and expansion of lamina propria by lymphoplasmacytic infiltrate\n\nAs it was more pertinent to continue with nintedanib for his IPF, we elected to treat his colitis with budesonide. He was started on 9 mg oral budesonide with the plan to slowly taper it to the minimum effective dose. His diarrhea gradually improved, and at his follow-up visit about four months later, it had completely resolved.\n\nDiscussion\nNintedanib is an effective treatment for IPF and is associated with reduced disease progression. The use of nintedanib in pulmonary fibrosis was evaluated in the “Efficacy and Safety of Nintedanib in Idiopathic Pulmonary Fibrosis” (INPULSIS-1 and INPULSIS-2) clinical trials [4]. These studies evaluated the safety and efficacy of 150 mg of nintedanib twice daily compared with placebo in patients with idiopathic pulmonary fibrosis. Diarrhea was the most frequently reported adverse event in the nintedanib groups in both trials. In both trials, diarrhea was seen in more than 60% of the patients taking nintedanib, as compared to 18% of patients in the placebo group. Diarrhea led to permanent dose reduction in 11% of patients and discontinuation in 5% [4].\n\nIn the “To Improve Pulmonary Fibrosis with BIBF 1120” (TOMORROW) study, a total of 432 patients underwent randomization to receive nintedanib at one of four doses (50 mg once a day, 50 mg twice a day, 100 mg twice a day, or 150 mg twice a day) or placebo for 12 months [5]. The adverse events most frequently leading to discontinuation were diarrhea, nausea, and vomiting. In the group receiving 150 mg twice a day, the rate of diarrhea was 11.8% as compared to 0% in the placebo group. Among the 85 patients in this high-dose group, 47 (55.3%) had diarrhea compared to 15.3% in the placebo group. Four (4.7%) patients had severe diarrhea and three (3.5%) had what was described as serious diarrhea, as compared with zero patients in the placebo group [5].\n\nKato et al. studied 77 patients with IPF who received nintedanib and showed that 27 patients (35.1%) developed diarrhea that was grade 2 or more severe [6]. Among these, 10 patients required discontinuation of nintedanib despite the use of antidiarrheal medications. Additionally, they reported that the use of concomitant prednisolone successfully prevented diarrhea in patients on nintedanib [6].\n\nThe mechanism of nintedanib-induced diarrhea/colitis remains unknown. One of the proposed mechanism involves direct inflammation of the intestinal epithelium induced by nintedanib decomposition products. Nintedanib is primarily cleared via liver metabolism, with most of the metabolites being excreted in the feces [3]. This inflammation, like that of inflammatory bowel disease, may respond to corticosteroid treatment, resulting in the improvement of diarrhea [7].\n\nIn our patient, stopping this medication was not a viable option since it was very effective in reducing disease progression. Instead, we used budesonide, a glucocorticoid with high first-pass metabolism, as its systemic side effects would be less severe as compared with conventional glucocorticoids [7]. The patient had complete clinical remission in less than three months.\n\nConclusions\nDiarrhea and colitis are well-known common side effects of nintedanib and often lead to the discontinuation of this medication. In patients with nintedanib-induced colitis/diarrhea who are resistant to oral antidiarrheal medications, budesonide could be a viable option to cure this common side effect. Further research is needed to help standardize its use and prevent IPF treatment interruption.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 BIBF 1120: triple angiokinase inhibitor with sustained receptor blockade and good antitumor efficacy Cancer Res Hilberg F Roth GJ Krssak M 4774 4782 68 2008 18559524 \n2 Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis J Pharmacol Exp Ther Wollin L Maillet I Quesniaux V Holweg A Ryffel B 209 220 349 2014 24556663 \n3 Nintedanib Aust Prescr Anonymous Anonymous 62 63 39 2016 27340326 \n4 Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis N Engl J Med Richeldi L du Bois RM Raghu G 2071 2082 370 2014 24836310 \n5 Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis N Engl J Med Richeldi L Costabel U Selman M 1079 1087 365 2011 21992121 \n6 Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial Lancet Fuchs CS Tomasek J Yong CJ 31 39 383 2014 24094768 \n7 Crohn's disease evaluation and treatment: clinical decision tool Gastroenterology Sandborn WJ 702 705 147 2014 25046160\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(7)",
"journal": "Cureus",
"keywords": "budesonide; nintedanib induced colitis",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e9489",
"pmc": null,
"pmid": "32766018",
"pubdate": "2020-07-31",
"publication_types": "D002363:Case Reports",
"references": "27340326;24094768;21992121;18559524;24836310;24556663;25046160",
"title": "Nintedanib-Induced Colitis Treated Effectively With Budesonide.",
"title_normalized": "nintedanib induced colitis treated effectively with budesonide"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-042202",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "NINTEDANIB"
},
"... |
{
"abstract": "OBJECTIVE\nTo report a probable association of Stevens-Johnson Syndrome (SJS) with furosemide and suspected cross-sensitivity with lincomycin and silver sulfadiazine cream.\n\n\nCONCLUSIONS\nA 28-year-old Hispanic male was admitted for SJS, with a prolonged hospital course and unclear etiology throughout the majority of the stay. Patient's medications prior to development of SJS symptoms were stable for 3 months and with the exception of furosemide, all were continued throughout the hospitalization while the SJS resolved. During hospitalization, the patient was unintentionally rechallenged with furosemide, after which the rash reappeared and then worsened further with use of silver sulfadiazine cream. At this point in the hospitalization, the prolonged course of the rash prior to admission and the administration of lincomycin 3 days prior to admission were revealed. This suggests the SJS was initially caused by furosemide, a nonaromatic sulfonamide diuretic, with slow progression prior to hospital admission over approximately 7 weeks, followed by an acute worsening caused by lincomycin, a sulfide antibiotic.\n\n\nCONCLUSIONS\nUse of the Naranjo ADR Probability Scale indicates a probable relationship between SJS and furosemide in this patient. Clinicians should be aware of this rare potential adverse effect, even months after the initiation of therapy.",
"affiliations": "University of Oklahoma College of Pharmacy, Oklahoma City, OK, USA.",
"authors": "Wright|Amanda A|AA|;Vesta|Kimi S|KS|;Stark|Jennifer E|JE|;Smith|Winter J|WJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005665:Furosemide; D008034:Lincomycin; D012837:Silver Sulfadiazine",
"country": "United States",
"delete": false,
"doi": "10.1177/0897190010362260",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0897-1900",
"issue": "23(4)",
"journal": "Journal of pharmacy practice",
"keywords": null,
"medline_ta": "J Pharm Pract",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D005665:Furosemide; D006801:Humans; D008034:Lincomycin; D008297:Male; D012837:Silver Sulfadiazine; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "8900945",
"other_id": null,
"pages": "367-70",
"pmc": null,
"pmid": "21507837",
"pubdate": "2010-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Stevens-Johnson syndrome associated with furosemide: a case report.",
"title_normalized": "stevens johnson syndrome associated with furosemide a case report"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-00415",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"dr... |
{
"abstract": "BACKGROUND\nBendamustine, used for the treatment of indolent B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia, is known to cause prolonged myelosuppression and lymphocytopenia and has been associated with the risk of developing serious and fatal infections. While reports of localized CMV infections in asymptomatic patients exist, disseminated CMV disease has not been described.\n\n\nMETHODS\nWe report the first case of disseminated CMV infection in a 75-year-old male diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with massive bone marrow infiltration. Despite 6-cycle R-bendamustine chemotherapy resulted in a good partial response, the patient developed persistent fever and severe weight loss. Analysis of cerebrospinal fluid and peripheral blood revealed the presence of CMV-DNA, while the fundus oculi examination revealed bilateral CMV retinitis. Treatment with induction and maintenance drugs was complicated by neutropenia and deterioration of renal function with electrolyte imbalance. From an immunological standpoint, we observed a profound imbalances in phenotype and function of B- and T-cell subsets, with a high proportion of circulating total, activated CD69+ and CD80+ B-cells, a low γ/δ T-cell frequency with a high proportion of CD69- and CD38-expressing cells, and hyperactivated/exhausted CD4+ and CD8+ T-cell phenotypes unable to face CMV challenge.\n\n\nCONCLUSIONS\nWe hereby describe a severe form of disseminated CMV disease after R-bendamustine treatment. Our observations strongly support the careful clinical monitoring of CMV reactivation/infection in oncologic patients undergoing this therapeutic regimen.",
"affiliations": "Clinic of Infectious Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Via di Rudinì 8, 20142, Milan, Italy.;Clinic of Infectious Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Via di Rudinì 8, 20142, Milan, Italy.;Clinic of Infectious Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Via di Rudinì 8, 20142, Milan, Italy.;Clinic of Infectious Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Via di Rudinì 8, 20142, Milan, Italy.;Department of Medical Oncology, ASST Santi Paolo e Carlo, Milan, Italy.;U.O. Radiologia, Ospedale di Vizzolo Predabissi, Vizzolo Predabissi, Milan, Italy.;Department of Medical Oncology, ASST Santi Paolo e Carlo, Milan, Italy.;Clinic of Infectious Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Via di Rudinì 8, 20142, Milan, Italy.;Clinic of Infectious Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Via di Rudinì 8, 20142, Milan, Italy.;Clinic of Infectious Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Via di Rudinì 8, 20142, Milan, Italy.;Clinic of Infectious Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Via di Rudinì 8, 20142, Milan, Italy. giulia.marchetti@unimi.it.",
"authors": "Cona|Andrea|A|;Tesoro|Daniele|D|;Chiamenti|Margherita|M|;Merlini|Esther|E|;Ferrari|Daris|D|;Marti|Antonio|A|;Codecà|Carla|C|;Ancona|Giuseppe|G|;Tincati|Camilla|C|;d'Arminio Monforte|Antonella|A|;Marchetti|Giulia|G|http://orcid.org/0000-0002-4498-4828",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D000998:Antiviral Agents; D000069461:Bendamustine Hydrochloride; D000077562:Valganciclovir",
"country": "England",
"delete": false,
"doi": "10.1186/s12879-019-4545-7",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 454510.1186/s12879-019-4545-7Case ReportDisseminated cytomegalovirus disease after bendamustine: a case report and analysis of circulating B- and T-cell subsets Cona Andrea andrea.cona@unimi.it 1Tesoro Daniele daniele.tesoro@unimi.it 1Chiamenti Margherita margherita_chiamenti@yahoo.it 12Merlini Esther esther.merlini@gmail.com 1Ferrari Daris daris.ferrari@asst-santipaolocarlo.it 3Marti Antonio 4Codecà Carla carla.codeca@asst-santipaolocarlo.it 3Ancona Giuseppe giuseppe.ancona@unimi.it 1Tincati Camilla camilla.tincati@unimi.it 1d’Arminio Monforte Antonella antonella.darminio@unimi.it 1http://orcid.org/0000-0002-4498-4828Marchetti Giulia +390281843064giulia.marchetti@unimi.it 11 0000 0004 1757 2822grid.4708.bClinic of Infectious Diseases, Department of Health Sciences, ASST Santi Paolo e Carlo, University of Milan, Via di Rudinì 8, 20142 Milan, Italy 2 0000 0004 1763 1124grid.5611.3Department of Diagnostics and Public Health, University of Verona, Gianbattista Rossi Hospital, Piazzale L.A. Scuro, 10, 37134 Verona, Italy 3 Department of Medical Oncology, ASST Santi Paolo e Carlo, Milan, Italy 4 grid.476841.8U.O. Radiologia, Ospedale di Vizzolo Predabissi, Vizzolo Predabissi, Milan, Italy 22 10 2019 22 10 2019 2019 19 88130 4 2019 9 10 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nBendamustine, used for the treatment of indolent B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia, is known to cause prolonged myelosuppression and lymphocytopenia and has been associated with the risk of developing serious and fatal infections. While reports of localized CMV infections in asymptomatic patients exist, disseminated CMV disease has not been described.\n\nCase presentation\nWe report the first case of disseminated CMV infection in a 75-year-old male diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with massive bone marrow infiltration. Despite 6-cycle R-bendamustine chemotherapy resulted in a good partial response, the patient developed persistent fever and severe weight loss. Analysis of cerebrospinal fluid and peripheral blood revealed the presence of CMV-DNA, while the fundus oculi examination revealed bilateral CMV retinitis. Treatment with induction and maintenance drugs was complicated by neutropenia and deterioration of renal function with electrolyte imbalance. From an immunological standpoint, we observed a profound imbalances in phenotype and function of B- and T-cell subsets, with a high proportion of circulating total, activated CD69+ and CD80+ B-cells, a low γ/δ T-cell frequency with a high proportion of CD69- and CD38-expressing cells, and hyperactivated/exhausted CD4+ and CD8+ T-cell phenotypes unable to face CMV challenge.\n\nConclusions\nWe hereby describe a severe form of disseminated CMV disease after R-bendamustine treatment. Our observations strongly support the careful clinical monitoring of CMV reactivation/infection in oncologic patients undergoing this therapeutic regimen.\n\nKeywords\nBendamustineDisseminated CMVLymphomaB-cellsT-cellsissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nBendamustine is a highly efficacious chemotherapeutic alkylating drug used as monotherapy or in combination with rituximab (R), for the treatment of indolent B-cell non-Hodgkin lymphoma and chronic lymphocytic leukemia.\n\nIt is known to cause prolonged myelosuppression and lymphocytopenia [1] and has thus been associated with the risk of developing serious and fatal infections [2], although a recent meta-analysis did not show a higher frequency of infections when using bendamustine compared with other alkylating drugs [3]. In particular, reports of localized CMV infections (i.e. retinitis, gastritis) as well as positive CMV antigenemia in asymptomatic patients [4–6] exist in the literature, yet disseminated CMV disease has not been described.\n\nCase presentation\nWe report the case of a patient who developed systemic CMV infection with encephalitis, retinitis, gastritis and colitis after treatment with R-bendamustine. The patient’s clinical history was collected from the electronic medical chart upon signed written informed consent, approved by our Ethics Committee (Helsinki Declaration).\n\nA 75-year-old male was diagnosed with lymphoplasmacytic lymphoma/Waldenström macroglobulinemia with massive bone marrow infiltration in 2016. Past medical history was unremarkable, except for IgM monoclonal gammopathy since 1995.\n\nA 6-cycle R-bendamustine chemotherapy resulted in a good partial response, defined as no extramedullary symptoms with a normal bone marrow biopsy and a reduced, but still detectable, monoclonal IgM protein.\n\nThree months after treatment completion, the patient developed persistent fever and severe weight loss. Laboratory and radiological investigations excluded bacterial infections and extranodal lymphoma localizations. An abdominal CT scan showed parietal thickening of the ileo-caecal region (Fig. 1), and endoscopy revealed mucosal ulcers of both the oesophagus and the colon. Biopsies yielded CMV intracytoplasmic inclusions. HIV antibody testing was negative.\nFig. 1 Abdominal CT scan. The arrow shows parietal thickening of the ileo-caecal region\n\n\n\nThe patient underwent lumbar puncture for the onset of confusion with an abnormal EEG activity, consistent with an acute encephalopathy, despite aspecific dura mater enhancement upon brain MRI imaging, and was thus transferred to our clinical centre. He subsequently developed floaters and blurred vision; fundus oculi examination revealed bilateral CMV retinitis. CMV-DNA PCR was positive in both the peripheral blood (8200 cp/mL) and the CSF (34,500 cp/mL), thus a diagnosis of disseminated CMV infection was made with gastrointestinal, brain and ocular involvement. Induction treatment with ganciclovir (5 mg/Kg q12h) was started, soon after replaced by foscarnet (120 mg/Kg daily) due to the development of severe neutropenia on day 12. Foscarnet was suspended after 2 weeks of treatment due to the deterioration of renal function and electrolyte imbalances. After a 23-day cycle of induction therapy, despite residual plasmatic CMV-DNA (125 cp/mL), maintenance treatment with valganciclovir (900 mg/day) was started, subsequently reduced to 450 mg/day and finally stopped on day 15 because of neutropenia without complete suppression of CMV-viremia (CMV-DNA 399 cp/ml). T-lymphocyte immunephenotype performed 5 months after the last R-bendamustine cycle revealed severe CD4+ depletion (44 cells/μl, 16%), a CD8+ T-cell count of 158/μl (57%), and subversion of the CD4+/CD8+ ratio (0.28) (Fig. 2a).\nFig. 2 CMV-DNA and CD4+ T-cell count and characterization of B−/T-cell subsets. a Shows the trend of plasmatic CMV-DNA (cp/ml) and the trend of CD4 T-cell count (cell/μl). b-e shows flow cytometry results. Compared to healthy donors (n = 13; data presented as mean + SD value) the patient showed (i) higher proportion of circulating total B cells, CD69+, CD80+ and CXCR3+ B cells; (ii) lower frequency of circulating γ/δ T-cells, with higher proportion of CD69+ and CD38+ γ/δ T-cells; (iii) hyper-activated HLA-DR + CD38+ CD4 and CD8 T-cells (b). The study subject patient also featured an altered T-cell maturation profile, with massive loss of naïve (CCR7 + CD45RA+) and concomitant increase of terminally differentiated (CCR7-CD45RA+) CD4 and CD8 T-cells, with no substantial differences in central memory (CCR7 + CD45RA-) and effector memory (CCR7-CD45RA-) subpopulations compared to healthy donors (c). Staphylococcal Enterotoxin B (SEB_superantigen, blue) exposure resulted in high CD4+ T-cell expression of HLA-DR + CD38+ (1.71% vs 1.55), CD39+ (2.78% vs 1.03%) and PD-1+ (3.59% vs 1.27) compared to CMV stimulation (purple) (d; results are displayed after subtraction of “medium alone” condition). SEB, yet not CMV, also resulted in high CD8+ T-cell expression of HLA-DR + CD38+ (0.78% vs 0.28), CD39+ (1.57% vs 0.35%) and PD-1+ (0.84% vs 0) as well as IL2 + IFNγ+ (0.02% vs 0), IL2-IFNγ+ (4.40% vs 0.13%), TNFα+ (4.56% vs 0.25%) and CD107a (95.78% vs 35.43%) (e). Comparable levels of Granzyme B (73.2% vs 75.51%) and Perforin (72.85% vs 70.11%) were detected following both stinuli (e)\n\n\n\nThree months later the patient experienced reduced visual acuity and visual hallucinations. The fundus oculi examination revealed bilateral retinitis reactivation while no signs of encephalitis were found on brain-MRI. Hallucinations were accounted for as a side effect of levetiracetam, which was promptly discontinued. Plasmatic CMV-DNA resulted positive (487 cp/ml) and induction therapy with valganciclovir (900 mg q12h) was re-started. After 2 weeks, negativization of plasmatic CMV-DNA was observed and valganciclovir was reduced (900 mg/day). After the introduction of valganciclovir and discontinuation of levetiracetam, hallucinations resolved and visual acuity partially recovered as confirmed by the ophthalmologic evaluation that showed no signs of active lesions. At the beginning of suppressive maintenance therapy (9 months after chemotherapy) the CD4+, CD8+ T-cell counts and the CD4+/CD8+ T-cell ratio were 151 cells/μl, 578 cells/μl and 0.25 respectively (Fig. 2a).\n\nLymphoplasmacytic lymphoma/Waldenström macroglobulinemia is a B-cell lymphoma characterized by an infiltrate of heterogeneous B-cells and IgM hypersecretion [7]. Current therapeutic interventions target only lymphoplasmacytic cells [8], raising questions about the fate of the remaining B-cell subsets. We investigated the B-cell immune profile in this subject, finding a higher proportion of circulating total, activated CD69+ and CD80+ B-cells when compared to our in-house healthy control group (Fig. 2b). We also found a high proportion of B-cells expressing the chemokine receptor CXCR3 (Fig. 2b), known to regulate T-cell chemotaxis and to be expressed by B-cells in some subtypes of B-cell lymphoma [9], as further evidence of the profound imbalance within the B-lymphocyte compartment.\n\nGiven the development of disseminated CMV and the persistent CD4+ lymphopenia following a 6-cycle of R-bendamustine, we also sought to investigate T-cell immune-phenotype and function. We first assessed γ/δ T-cells, given their role in the immune response to CMV infection [10] and found a low γ/δ T-cell frequency with a high proportion of CD69- and CD38-expressing cells, suggesting a consumed, yet activated γ/δ compartment (Fig. 2b).\n\nThe assessment of CD4+ and CD8+ T-cells revealed a hyperactivated phenotype coupled with an altered distribution of memory and naïve subsets (Fig. 2b-c), compared to in-house healthy donors. Given that our patient displayed a hyperactivated T lymphocyte cell compartment, we next asked whether such generalized T-cell hyperactivation might also specifically affect the patient’s CMV-specific responses. Aiming to specifically dissect CMV-specific response, we therefore comparatively investigated functionally different CD4+/CD8+ T-cell subsets that have been demonstrated to play a central role in CMV-specific immune response [11].\n\nInterestingly, the patient’s PBMC ex vivo challenge to CMV and bacterial stimuli revealed a different functional profile, with evidences of T-cell activation/exhaustion and IFN-γ/TNF-α release upon bacterial, but not CMV challenge (Fig. 2d-e). Likewise, our patient displayed a low CD107a release specifically after CMV challenge with no other differences in cytolytic activity (Fig. 2e), in all suggesting a selective impairment of CMV-specific immunity.\n\nDiscussion and conclusions\nTo our knowledge, this is the first report of a disseminated CMV disease following treatment with bendamustine. While several case studies of localized CMV disease have been reported [12], no disseminated infection post-bendamustine has been described.\n\nAside from disease severity, the distinctive feature of our case resides in the entity and duration of the immunosuppression, known risk factor for CMV disease reactivation together with positive antibody CMV titres [13]. In particular, low total CD4+ T lymphocyte counts [2, 5], as well as steroid use [5], have been linked to overt clinical CMV disease following bendamustine treatment. In contrast to a report by Saito et al. who described resolution of lymphocytopenia approximately 7–9 months after treatment [1], in the present clinical case, CD4+ T-cells remained below 200/μl as long as 16 months after chemotherapy completion, implying a severe, long-lasting CD4+ depletion. Furthermore, bendamustine is known to affect the cytotoxic potential of CMV-specific CD8+ T-lymphocytes, in turn hampering the immune control over CMV [14]. Accordingly, our findings of a feeble CMV-specific response coupled with a hyperactivated, yet exhausted B- and T-cell phenotype with outgrowth of terminally-differentiated and effector memory at the disadvantage of naïve phenotypes, suggest functional exhaustion, possibly reflecting chronic viral antigenic exposure. Whether CMV infection further promotes the exhaustion of the immune system, or whether the impairment of the latter fuels CMV reactivation, remains to be clarified. Further, our data do not allow for the identification of a definite causal relationship between B/T cell immune pattern and the effects of bendamustine. Indeed, we were able to perform laboratory analyses 14 months following the start of bendamustine treatment and 1 year after the onset of CMV infection, with the patient on suppressive anti-CMV maintenance therapy exhibiting undetectable CMV viremia and a low CD4+ count (< 200 cells/μl). A detailed characterization of B/T lymphocyte homeostasis and function before and after bendamustine treatment should be encouraged to gain the broadest insight into the immune challenges of such therapies, to further assist clinical management of bendamustine-receiving patients.\n\nFrom a clinical standpoint, patients with the above-mentioned characteristics are difficult to treat. Haematological side effects are common during treatment with ganciclovir, valganciclovir and foscarnet, possibly contributing to reduced life expectancy. Accordingly, we were forced to suspend the secondary prophylaxis despite a low level residual CMV viremia due to neutropenia, which contributed to the second disease reactivation.\n\nIn conclusion, we describe a severe form of disseminated CMV disease after bendamustine treatment; our findings support the careful clinical monitoring of CMV reactivation/infection in oncologic patients undergoing this therapeutic regimen. Specifically, monitoring should include: (i) CMV serology prior to the initiation of bendamustine therapy (ii) absolute and CD4+ T lymphocyte counts counts before, during and after bendamustine treatment and (iii) CMV viral load/antigenimia in patients who develop fever and/or clinical signs compatible with CMV infection [2–5, 13].\n\nAbbreviations\nCMVCytomegalovirus\n\nCSFCerebrospinal fluid\n\nCTComputed tomography\n\nCXCR3Chemokine receptor 3\n\nEEGElectroencephalogram\n\nHIVHuman immunodeficiency virus\n\nIFN-γInterferon-γ\n\nIgMImmunoglobulinn M\n\nPBMCPeripheral blood mononuclear cells\n\nPCRPolymerase chain reaction\n\nR-bendamustineRituximab-bendamustine\n\nTNF-αΤumor necrosis factor-α\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAndrea Cona, Daniele Tesoro and Margherita Chiamenti contributed equally to this work.\n\nAcknowledgements\nThe authors wish to thank the patient who participated to the study and the staff of the Clinic of Infectious Diseases and Tropical Medicine at ASST Santi Paolo e Carlo.\n\nAdherence to CARE guidelines\nOur manuscript reporting adheres to CARE guidelines.\n\nAuthors’ contributions\nMC, AC and DT attended the patient, performed the research, analyzed data and wrote the manuscript; EM performed the immune-phenotypical analyses, analyzed the data and helped in writing the paper; DF, CC, CT and GA attended the patient and helped with the research/diagnosis and in finalizing the paper; AM analysed and discussed the patient’s CT images; Ad’AM and GM designed the research study and finalized the paper. All authors have read and approved the final manuscript.\n\nFunding\nThe present study was self-funded.\n\nAvailability of data and materials\nAll relevant data and material are included in this publication.\n\nEthics approval and consent to participate\nWritten informed consent approved by the local ethics committee was obtained from the subject prior to participation.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nCompeting interests\nNone of the authors report competing financial interests in relation to the work described. Giulia Marchetti is a member of the Editorial Board of BMC Infectious Diseases.\n==== Refs\nReferences\n1. Saito H Maruyama D Maeshima AM Makita S Kitahara H Miyamoto K Fukuhara S Munakata W Suzuki T Kobayashi Y Prolonged lymphocytopenia after bendamustine therapy in patients with relapsed or refractory indolent B-cell and mantle cell lymphoma Blood Cancer J 2015 5 e362 10.1038/bcj.2015.86 26495859 \n2. Isono N Imai Y Watanabe A Moriya K Tamura H Inokuchi K Asano C Masuda M Shimura H Mitsuhashi K Cytomegalovirus reactivation in low-grade B-cell lymphoma patients treated with bendamustine Leuk Lymphoma 2016 57 9 2204 2207 10.3109/10428194.2015.1126589 26699798 \n3. Gafter-Gvili A Gurion R Raanani P Shpilberg O Vidal L Bendamustine-associated infections-systematic review and meta-analysis of randomized controlled trials Hematol Oncol 2017 35 4 424 431 10.1002/hon.2350 27734524 \n4. Lim SH Pathapati S Langevin J Hoot A Severe CMV reactivation and gastritis during treatment of follicular lymphoma with bendamustine Ann Hematol 2012 91 4 643 644 10.1007/s00277-011-1307-z 21811782 \n5. Hasegawa T Aisa Y Shimazaki K Nakazato T Cytomegalovirus reactivation with bendamustine in patients with low-grade B-cell lymphoma Ann Hematol 2015 94 3 515 517 10.1007/s00277-014-2182-1 25107463 \n6. Yamasaki S Kohno K Kadowaki M Takase K Iwasaki H Cytomegalovirus retinitis in relapsed or refractory low-grade B cell lymphoma patients treated with bendamustine Ann Hematol 2017 96 1215 1217 10.1007/s00277-017-3005-y 28447162 \n7. Naderi N Yang DT Lymphoplasmacytic lymphoma and Waldenstrom macroglobulinemia Arch Pathol Lab Med 2013 137 4 580 585 10.5858/arpa.2012-0034-RS 23544948 \n8. Barakat FH Medeiros LJ Wei EX Konoplev S Lin P Jorgensen JL Residual monotypic plasma cells in patients with waldenstrom macroglobulinemia after therapy Am J Clin Pathol 2011 135 3 365 373 10.1309/AJCP15YFULCZHZVH 21350089 \n9. Jones D Benjamin RJ Shahsafaei A Dorfman DM The chemokine receptor CXCR3 is expressed in a subset of B-cell lymphomas and is a marker of B-cell chronic lymphocytic leukemia Blood 2000 95 2 627 632 10.1182/blood.V95.2.627 10627472 \n10. Dechanet J Merville P Lim A Retiere C Pitard V Lafarge X Michelson S Meric C Hallet MM Kourilsky P Implication of gammadelta T cells in the human immune response to cytomegalovirus J Clin Invest 1999 103 10 1437 1449 10.1172/JCI5409 10330426 \n11. Ellefsen K Harari A Champagne P Bart PA Sékaly RP Pantaleo G Distribution and functional analysis of memory antiviral CD8 T cell responses in HIV-1 and cytomegalovirus infections Eur J Immunol 2002 32 12 3756 3764 10.1002/1521-4141(200212)32:12<3756::AID-IMMU3756>3.0.CO;2-E 12516570 \n12. Modvig L Boyle C Randall K Borg A Severe cytomegalovirus reactivation in patient with low-grade non-Hodgkin’s lymphoma after standard chemotherapy Case Rep Hematol 2017 2017 5762525 29201472 \n13. Styczynski J Who is the patient at risk of CMV recurrence: a review of the current scientific evidence with a focus on hematopoietic cell transplantation Infect Dis Ther 2018 7 1 1 16 10.1007/s40121-017-0180-z \n14. Hosoda T Yokoyama A Yoneda M Yamamoto R Ohashi K Kagoo T Ueno H Boku S Yano T Bendamustine can severely impair T-cell immunity against cytomegalovirus Leuk Lymphoma 2013 54 6 1327 1328 10.3109/10428194.2012.739285 23072371\n\n",
"fulltext_license": "CC BY",
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"issue": "19(1)",
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"keywords": "B-cells; Bendamustine; Disseminated CMV; Lymphoma; T-cells",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000368:Aged; D018906:Antineoplastic Agents, Alkylating; D000998:Antiviral Agents; D001402:B-Lymphocytes; D000069461:Bendamustine Hydrochloride; D018414:CD8-Positive T-Lymphocytes; D003586:Cytomegalovirus Infections; D017726:Cytomegalovirus Retinitis; D006801:Humans; D008297:Male; D016176:T-Lymphocyte Subsets; D000077562:Valganciclovir; D008258:Waldenstrom Macroglobulinemia",
"nlm_unique_id": "100968551",
"other_id": null,
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"pmid": "31640581",
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"title": "Disseminated cytomegalovirus disease after bendamustine: a case report and analysis of circulating B- and T-cell subsets.",
"title_normalized": "disseminated cytomegalovirus disease after bendamustine a case report and analysis of circulating b and t cell subsets"
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"abstract": "Patients with delirium may fail to respond to standard therapies. Sixteen patients with management-refractory hyperactive delirium responded to adjunctive valproic acid, with complete resolution of hyperactive delirium in 13 cases. A rationale for using valproic acid in such circumstances is discussed.",
"affiliations": "From the Stanford University School of Medicine, Stanford, CA (YS, AA, JRM); and the George Washington University, Washington, DC (ACM, SL).;From the Stanford University School of Medicine, Stanford, CA (YS, AA, JRM); and the George Washington University, Washington, DC (ACM, SL).;From the Stanford University School of Medicine, Stanford, CA (YS, AA, JRM); and the George Washington University, Washington, DC (ACM, SL).;From the Stanford University School of Medicine, Stanford, CA (YS, AA, JRM); and the George Washington University, Washington, DC (ACM, SL).;From the Stanford University School of Medicine, Stanford, CA (YS, AA, JRM); and the George Washington University, Washington, DC (ACM, SL).",
"authors": "Sher|Yelizaveta|Y|;Miller|Anne Catherine|AC|;Lolak|Sermsak|S|;Ament|Andrea|A|;Maldonado|José R|JR|",
"chemical_list": "D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D014635:Valproic Acid",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018692:Antimanic Agents; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D003693:Delirium; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome; D014635:Valproic Acid",
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"title": "Adjunctive Valproic Acid in Management-Refractory Hyperactive Delirium: A Case Series and Rationale.",
"title_normalized": "adjunctive valproic acid in management refractory hyperactive delirium a case series and rationale"
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"abstract": "Adult and children attention deficit/hyperactivity disorder (ADHD) share similar symptoms and responses to drugs such as methylphenidate (MPH). Yet, in Europe, these drugs remain unlicensed for adults. We aimed to assess the effects of an acute MPH challenge on the four dimensions concentration, impulsivity, tension, and general well-being in ADHD adults, and identify predictors of improvement.\n\n\n\nTherapeutic Drug Monitoring was performed to measure MPH plasma levels. A Visual Analogue Scale was administered to patients before and after the acute MPH challenge to measure self-reported changes in the four dimensions.\n\n\n\nAfter the acute MPH challenge, our 71 patients showed significant improvement in concentration and tension. The MPH challenge dose correlated with lower patients' age, greater side effects, increased concentration (p = .008) and decreased tension (p = .001). At multiple linear regression MPH plasma levels and absence of postdose side effects predicted concentration improvement, MPH plasma levels predicted tension improvement. MPH plasma levels were significantly higher in patients who reported an improvement in concentration, tension, and impulsivity compared to nonimprovers (p's from .001 to .004).\n\n\n\nThese findings point to the efficacy of MPH challenge in improving concentration and tension in adult ADHD, thus emphasizing the need for a broader treatment access for these patients.",
"affiliations": "Department of Psychiatry, Central Hospital, Sanitary Agency of South Tyrol, Bolzano-Bozen, Italy.;NESMOS (Neurosciences, Mental Health, and Sensory Organs) Department, School of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.;NESMOS (Neurosciences, Mental Health, and Sensory Organs) Department, School of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.;Department of Psychiatry, Central Hospital, Sanitary Agency of South Tyrol, Bolzano-Bozen, Italy.;NESMOS (Neurosciences, Mental Health, and Sensory Organs) Department, School of Medicine and Psychology, Sapienza University of Rome, Rome, Italy.;Department of Psychiatry, Central Hospital, Sanitary Agency of South Tyrol, Bolzano-Bozen, Italy.;Klinik für Psychiatrie und Psychotherapie, Universitätsklinikum Mainz, Mainz, Germany.;Department of Psychiatry, Central Hospital, Sanitary Agency of South Tyrol, Bolzano-Bozen, Italy.",
"authors": "Piacentino|Daria|D|0000-0002-9991-7403;De Rossi|Pietro|P|;Kotzalidis|Georgios D|GD|;Maniscalco|Ignazio|I|;Pompili|Maurizio|M|;Giupponi|Giancarlo|G|;Hiemke|Christoph|C|;Conca|Andreas|A|",
"chemical_list": "D000697:Central Nervous System Stimulants; D008774:Methylphenidate",
"country": "England",
"delete": false,
"doi": "10.1002/hup.2740",
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"journal": "Human psychopharmacology",
"keywords": "adults; attention deficit/hyperactivity disorder; challenge test; methylphenidate hydrochloride",
"medline_ta": "Hum Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D004305:Dose-Response Relationship, Drug; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007175:Impulsive Behavior; D008297:Male; D008774:Methylphenidate; D008875:Middle Aged; D055815:Young Adult",
"nlm_unique_id": "8702539",
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"publication_types": "D016428:Journal Article",
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"title": "Methylphenidate challenge test in adults with attention deficit/hyperactivity disorder (ADHD): Clinical effects and their predictors.",
"title_normalized": "methylphenidate challenge test in adults with attention deficit hyperactivity disorder adhd clinical effects and their predictors"
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"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
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"abstract": "Biologics and targeted therapies, such as apremilast, are efficient treatments to manage moderate to severe psoriasis. More information about the risk of serious infection is needed for the newest treatment options in a real-world setting.\nTo assess the risk of serious infection among biologics and apremilast used to treat psoriasis, with etanercept as the comparator.\nThis nationwide cohort study from France involved data from the National Health Data System covering approximately 99% of the French population. All adults with psoriasis, defined as receiving at least 2 prescriptions of a topical vitamin D derivative within a 2-year period, registered in the database between January 1, 2008, and May 31, 2019, were eligible. The study population included those who were new users of biologic agents or apremilast (ie, without any prescriptions of a biologic or apremilast during the previous year). Patients with HIV infection or a history of cancer, transplant, or serious infection were excluded. End of follow-up was January 31, 2020.\nThe primary end point was a serious infection in a time-to-event analysis using propensity score-weighted Cox proportional hazards regression models, estimating weighted hazard ratios (wHRs) and 95% CIs.\nA total of 44 239 new users of biologic treatment were identified (mean [SD] age, 48.4 [13.8] years; 22 866 [51.7%] men; median follow-up, 12 months [interquartile range, 7-24 months]). A total of 29 618 (66.9%) were prescribed a tumor necrosis factor inhibitor first, 6658 (15.0%) an interleukin (IL) 12/23 inhibitor, 4093 (9.3%) an IL-17 inhibitor, 526 (1.2%) an IL-23 inhibitor, and 3344 (7.6%) apremilast. The total number of serious infections was 1656, and the overall crude incidence rate was 25.0 (95% CI, 23.8-26.2) per 1000 person-years. The most frequent serious infections were gastrointestinal infections (645 patients [38.9%]). After adjusting for time-dependent covariables, risk of serious infections was higher for new users of adalimumab (wHR, 1.22; 95% CI, 1.07-1.38) or infliximab (wHR, 1.79; 95% CI 1.49-2.16) vs etanercept, whereas ustekinumab was associated with a lower risk of having a serious infection (wHR, 0.79; 95% CI, 0.67-0.94). Risk of serious infections was not increased for new users of IL-17 and the IL-23 inhibitor guselkumab or apremilast vs etanercept. Risk of serious infections was increased with concomitant nonsteroidal anti-inflammatory drugs or systemic corticosteroids.\nIn this cohort study of individuals with moderate to severe psoriasis, risk of serious infections was increased in new users of infliximab and adalimumab vs etanercept, whereas ustekinumab users had lower risk of having a serious infection but not new users of IL-17 and IL-23 inhibitors or apremilast. Other observational studies are needed to confirm results for the most recent drugs.",
"affiliations": "Groupement d'intérêt scientifique Epidémiologie des produits de santé, L'Agence Nationale de Sécurité du Médicament et des Produits de Santé -Caisse Nationale de l'Assurance Maladie, Paris, France.;Groupement d'intérêt scientifique Epidémiologie des produits de santé, L'Agence Nationale de Sécurité du Médicament et des Produits de Santé -Caisse Nationale de l'Assurance Maladie, Paris, France.;Groupement d'intérêt scientifique Epidémiologie des produits de santé, L'Agence Nationale de Sécurité du Médicament et des Produits de Santé -Caisse Nationale de l'Assurance Maladie, Paris, France.;Epidémiologie en Dermatologie et Evaluation des Thérapeutiques, Université Paris-Est Creteil, Créteil, France.;Groupement d'intérêt scientifique Epidémiologie des produits de santé, L'Agence Nationale de Sécurité du Médicament et des Produits de Santé -Caisse Nationale de l'Assurance Maladie, Paris, France.;Groupement d'intérêt scientifique Epidémiologie des produits de santé, L'Agence Nationale de Sécurité du Médicament et des Produits de Santé -Caisse Nationale de l'Assurance Maladie, Paris, France.",
"authors": "Penso|Laetitia|L|;Dray-Spira|Rosemary|R|;Weill|Alain|A|;Pina Vegas|Laura|L|;Zureik|Mahmoud|M|;Sbidian|Emilie|E|",
"chemical_list": null,
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"doi": "10.1001/jamadermatol.2021.2599",
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"issue": "157(9)",
"journal": "JAMA dermatology",
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"pages": "1056-1065",
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"pubdate": "2021-09-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Association Between Biologics Use and Risk of Serious Infection in Patients With Psoriasis.",
"title_normalized": "association between biologics use and risk of serious infection in patients with psoriasis"
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"companynumb": "FR-JNJFOC-20210753454",
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{
"abstract": "A 19-year-old man presented with acute severe ulcerative colitis. He was taking azathioprine (therapeutic metabolites) and sulphasalazine as well as infliximab with a therapeutic drug level. On day 3 of hydrocortisone therapy, he met day Oxford criteria with >8 bloody stools per day and was given faecal microbiota transplantation and subsequently commenced on dietary therapy combining several strategies-(1) increased intake of fermentable fibres, (2) reduced intake of overall and sulfur-containing protein and (3) restriction of sulfate and sulfite food additives. At week 8 assessment, he was in clinical and endoscopic remission and remained in clinical and endoscopic remission at 12 months.",
"affiliations": "Department of Gastroenterology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia sam.costello@sa.gov.au.;Department of Gastroenterology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia.;Department of Medicine, Monash University, Clayton, Victoria, Australia.;Department of Gastroenterology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia.",
"authors": "Costello|Samuel Paul|SP|http://orcid.org/0000-0002-2857-1812;Day|Alice|A|;Yao|Chu K|CK|;Bryant|Robert Venning|RV|",
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"doi": "10.1136/bcr-2019-233135",
"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2019-233135\n10.1136/bcr-2019-233135\nNovel Treatment (New Drug/Intervention; Established Drug/Procedure in New Situation)\n1506\n1522\n1327\n117\n121\n1560\n1306\nCase reportFaecal microbiota transplantation (FMT) with dietary therapy for acute severe ulcerative colitis\nhttp://orcid.org/0000-0002-2857-1812Costello Samuel Paul 12 Day Alice 12 Yao Chu K 3 Bryant Robert Venning 12 1 Department of Gastroenterology, The Queen Elizabeth Hospital, Woodville South, South Australia, Australia\n2 Department of Medicine, The University of Adelaide Faculty of Health Sciences, Adelaide, South Australia, Australia\n3 Department of Medicine, Monash University, Clayton, Victoria, Australia\nCorrespondence to Dr Samuel Paul Costello; sam.costello@sa.gov.au\n2020 \n24 8 2020 \n24 8 2020 \n13 8 e23313519 6 2020 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.A 19-year-old man presented with acute severe ulcerative colitis. He was taking azathioprine (therapeutic metabolites) and sulphasalazine as well as infliximab with a therapeutic drug level. On day 3 of hydrocortisone therapy, he met day Oxford criteria with >8 bloody stools per day and was given faecal microbiota transplantation and subsequently commenced on dietary therapy combining several strategies—(1) increased intake of fermentable fibres, (2) reduced intake of overall and sulfur-containing protein and (3) restriction of sulfate and sulfite food additives. At week 8 assessment, he was in clinical and endoscopic remission and remained in clinical and endoscopic remission at 12 months.\n\nulcerative colitisgastrointestinal systemspecial-featureunlocked\n==== Body\nBackground\nUp to a quarter of patients with ulcerative colitis (UC) will develop acute severe colitis (ASC) during their disease course, a potentially life-threatening condition.1 Intravenous corticosteroids are the mainstay of therapy; however, approximately 30%–40% of patients progress to second-line (salvage) therapy with infliximab or ciclosporin.2 Despite salvage therapy, long‐term colectomy rates remain high (>50% at 3 years) and new therapeutic options are required.3\n\nCase presentation\nA 19-year-old male carpenter presented to our hospital with ASC. He had a history of UC diagnosed 6 months prior, with poor disease control and four admissions to hospital with colitis requiring intravenous steroid therapy since diagnosis. At diagnosis, he had been commenced on azathioprine 150 mg daily and sulphasalazine 1500 mg two times per day. At his last presentation 10 weeks prior, he was also commenced on infliximab induction therapy with a partial response to therapy with a reduction from 10 bloody bowel motions per day to four non-bloody motions daily. He had completed three doses of induction therapy with infliximab (5 mg/kg) with the last dose 4 weeks prior to this presentation.\n\nOn admission, he reported eight bloody bowel motions per day with associated abdominal pain. On examination, he had mild generalised abdominal tenderness without guarding, pulse rate 114 beats/min, temperature 37.6°C and blood pressure 135/78 mm Hg. He was anaemic with a haemoglobin (Hb) of 131 g/L (135–175 g/L), his albumin was 40 g/dL (34–48) and C-Reactive Protein was 4 mg/L. Stool testing was negative for parasites, bacterial and viral pathogens and Clostridioides difficile toxin on nucleic acid amplification testing. He met Truelove and Witt’s criteria for ASC (≥6 bloody stools per day and two of pulse >90 beats/min, temperature >37.5°C, Hb ≤100 g/L and ESR >30 mm/hr). His thiopurine metabolites levels were therapeutic (6-thioguanine 400, 6-methylmercaptopurine 2907) and infliximab levels supratherapeutic (14.4 mg/L; range 3–7). Flexible sigmoidoscopy 3 days prior to admission had demonstrated moderately-severe colitis (figure 1) with histopathology and immunohistochemistry demonstrating no evidence of cytomegalovirus infection.\n\nFigure 1 Sigmoid colon at week 0 (prior to faecal microbiota transplantation and dietary therapy).\n\nDespite receiving intravenous hydrocortisone 100 mg four times per day for 3 days, his stool frequency and bleeding failed to improve (nine stools per day) and he became more anaemic Hb 120 g/L (135–175 g/L). Infliximab levels were 14.4 mg/L (trough range 3–7 mg/L). The patient met Oxford criteria for ASC (>8 stools per day) and was offered and declined colectomy and was therefore offered donor faecal microbiota transplantation (FMT) with a dietary prescription as salvage therapy. The consent for FMT detailed the experimental nature of FMT in this setting and the greater evidence for surgical colectomy.\n\nSevere confluent colitis (endoscopic Mayo −3) to the descending colon was noted at colonoscopy on day 4 of admission. FMT was delivered to the cecum and repeat FMT was given via enema on days 3 and 7 following colonoscopy as per the Adelaide protocol.4 The FMT had been sourced from a single anonymous stool donor 3 months prior at a stool bank. Fifty grams of donor stool had been processed under anaerobic conditions with 130 mL of normal saline and 20 mL of glycerol to produce a 200 mL suspension and then frozen at −80°C, prior to thawing on the morning of FMT delivery.\n\nDietary therapy was commenced immediately after initial FMT. The dietary prescription consisted of a whole diet approach that was (1) high in fermentable fibres, (2) reduced in overall and sulfur-containing protein, (3) restricted in sulfate and sulfite food additives and (4) was nutritionally replete. Dietary education with comprehensive meal plans and recipes were provided at weeks 0, 4 and 8. Azathioprine 150 mg daily and infliximab (5 mg/kg every eight weeks) therapy were continued during the 12 months follow-up period. Sulfasalazine was ceased by the patient 2 months after receiving FMT therapy.\n\nOutcome and follow-up\nThe patient improved rapidly following the FMT and dietary therapy; stool frequency reduced to 2–3 motions per day without blood after 2 days. At weeks 4 and 8, the patient was opening his bowels every second day without blood. At week 4, flexible sigmoidoscopy demonstrated Mayo-1 colitis and at week 8 there was endoscopic remission (Mayo-0) (figure 2) and histological remission (absence of neutrophilic infiltrate). Dietary tolerability and compliance over the 8-week period was assessed to be excellent and he remained in clinical and endoscopic remission (Mayo-0) (figure 3) 12 months following FMT (faecal calprotectin 4 µg/g).\n\nFigure 2 Sigmoid colon at week 8 post faecal microbiota transplantation and dietary therapy.\n\nFigure 3 Sigmoid colon at 12 months post faecal microbiota transplantation and dietary therapy.\n\nDiscussion\nAlthough the efficacy of FMT is established for remission induction of mild to moderate UC,5 6 FMT is not yet used routinely to treat UC in clinical practice and is not currently included in clinical practice guidelines.7 This is due to a number of factors, including the relatively recent emergence of induction of remission data, a lack of data demonstrating maintenance of remission with FMT, as well as legislative restriction, a lack of funding and poor availability of screened stool from stool banks in many jurisdictions.5 8\n\nThere have been reports of FMT inducing remission in patients with severe UC9–11; however, to our knowledge, this is the first case report of FMT as salvage therapy for ASC meeting Oxford criteria in a patient already receiving infliximab with therapeutic levels. This demonstrated the potential of FMT to alter the severe physiological changes present in ASC refractory to standard therapies. FMT likely acts via different mechanisms4 to current immunologically targeted therapies and thus may offer an adjunctive or alternative salvage therapy in the case of failure of hydrocortisone or infliximab. In this case, the infliximab dose was not increased because the infliximab level was high (14.4 mg/L) ciclosporin was not added as a therapy because there is a significant risk of infective complications with sequential or combination therapy.12 13\n\nThe prompt and durable efficacy of FMT observed in this case may have been augmented by a diet prescription. An excellent clinical and histological response of four patients with active UC to a low sulfur diet was first reported in 1998.14 There is progressively more evidence emerging to indicate dietary therapy alone may influence disease activity in UC.15 There is also evidence that metabolites originating from activities of the colonic microbiota, both beneficial and toxic, can contribute significantly to epithelial defects documented in UC. Specifically, excessive exposure of the colonic epithelium to toxic hydrogen sulfide gas, a by-product of dietary protein and sulfur metabolism, produces biochemical lesions in the epithelium, mimicking those described in UC.16 On the other hand, there is also evidence that the fermentation of resistant starch and other prebiotic fibres by colonic bacteria is critical for enterocyte function and colonic health.17 The delivery of these nutrients to the colon is dictated by dietary intake and their metabolism is largely controlled by the colonic microbiota. Thus, it is likely that FMT and dietary therapy work synergistically. The mechanism by which FMT induces remission in UC is not known; however, in a recent randomised controlled trial of FMT for induction of remission of UC, lamina propria mononuclear cell populations correlated with disease severity (Mayo score) but were not correlated with donor FMT.4 This suggests that FMT may be inducing remission via a mechanism other than direct modulation of the mucosal lamina propria mononuclear cell populations. It is possible that alteration of the metabolic capacity of the microbiome plays a role in FMT-induced mucosal healing in UC. It is also possible that dietary therapy may augment this process by changing substrate availability and therefore, the types of metabolic activities. Further trials are warranted to explore whether FMT may have a place in the therapeutic armamentarium in ASC and whether diet has a role in augmenting and sustaining the efficacy of FMT.\n\nPatient’s perspective\nThe faecal transplant and diet treatment was the last resort and it has paid off in a big way for me. Before the FMT and diet, I was on infliximab, azathioprine and sulfasalazine and I was in a bad way. Within two doses of the FMT, I felt a lot better and I have not had any problems since. It really sorted everything out for me. This was the turning factor for me. The FMT was not difficult or painful, I would do it a hundred times again for this result. The diet took more effort but I have been able to stick to the diet pretty well. I tried to follow the diet closely to help the FMT work.\n\nLearning points\nAcute severe ulcerative colitis (UC) is assessed using Truelove and Witt’s criteria and patients meeting these criteria should be commenced on intravenous hydrocortisone.\n\nPatients who do not respond to intravenous hydrocortisone by day 3 should be offered rescue therapy with either Inflixmab or ciclosporin and assessed for surgical colectomy in case of failure of medical therapy.\n\nThere is evidence that faecal microbiota transplantation can induce remission in UC and further study is required before this therapy should be routinely offered to those patients failing infliximab or ciclosporin rescue therapy.\n\nThere is emerging evidence that dietary therapy may influence UC disease course; however, more research is required.\n\nWe would like to acknowledge the work of Associate Professor WEW Roediger and Professor Peter Gibson whose work contributed to the formulation of the dietary therapy used in this case.\n\nTwitter: @Alice_APD\n\nContributors: SPC managed patient’s care and stool bank, conceived of the idea for co-therapy and wrote the manuscript. AD administered the diet therapy, coordinated patient samples and edited the manuscript. CKY developed the dietary plan and edited the manuscript. RVB managed the patient’s care and stool bank and edited the manuscript.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: SPC reports support from Janssen, Shire, Ferring, Microbiotica and Pfizer. RVB has recieved research support from AbbVie, Emerge Health, Ferring, Janssen, Shire, and Takeda.\n\nPatient consent for publication: Obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Bernstein CN , Ng SC , Lakatos PL , et al \nA review of mortality and surgery in ulcerative colitis: milestones of the seriousness of the disease\n. Inflamm Bowel Dis \n2013 ;19 :2001 –10\n. 10.1097/MIB.0b013e318281f3bb 23624887 \n2 Seah D , De Cruz P \nReview article: the practical management of acute severe ulcerative colitis\n. Aliment Pharmacol Ther \n2016 ;43 :482 –513\n. 10.1111/apt.13491 26725569 \n3 Ordás I , Domènech E , Mañosa M , et al \nLong-Term efficacy and safety of cyclosporine in a cohort of Steroid-Refractory acute severe ulcerative colitis patients from the ENEIDA registry (1989-2013): a nationwide multicenter study\n. Am J Gastroenterol \n2017 ;112 :1709 –18\n. 10.1038/ajg.2017.180 28675163 \n4 Costello SP , Hughes PA , Waters O , et al \nEffect of fecal microbiota transplantation on 8-Week remission in patients with ulcerative colitis: a randomized clinical trial\n. JAMA \n2019 ;321 :156 –64\n. 10.1001/jama.2018.20046 30644982 \n5 Costello SP , Soo W , Bryant RV , et al \nSystematic review with meta-analysis: faecal microbiota transplantation for the induction of remission for active ulcerative colitis\n. Aliment Pharmacol Ther \n2017 ;46 :213 –24\n. 10.1111/apt.14173 28612983 \n6 Haifer C , Kelly CR , Paramsothy S , et al \nAustralian consensus statements for the regulation, production and use of faecal microbiota transplantation in clinical practice\n. Gut \n2020 ;69 :801 –10\n. 10.1136/gutjnl-2019-320260 32047093 \n7 Harbord M , Eliakim R , Bettenworth D , et al \nThird European evidence-based consensus on diagnosis and management of ulcerative colitis. Part 2: current management\n. J Crohns Colitis \n2017 ;11 :769 –84\n. 10.1093/ecco-jcc/jjx009 28513805 \n8 Costello SP , Bryant RV \nFaecal microbiota transplantation in Australia: bogged down in regulatory uncertainty\n. Intern Med J \n2019 ;49 :148 –51\n. 10.1111/imj.14212 30754077 \n9 Moayyedi P , Surette MG , Kim PT , et al \nFecal microbiota transplantation induces remission in patients with active ulcerative colitis in a randomized controlled trial\n. Gastroenterology \n2015 ;149 :102 –9\n. 10.1053/j.gastro.2015.04.001 25857665 \n10 Karakan T , Ibis M , Cindoruk M , et al \nFaecal microbiota transplantation as a rescue therapy for steroid-dependent and/or nonresponsive patients with ulcerative colitis: a pilot study\n. Journal of Crohn's and Colitis \n2016 ;10 :S425 –6\n.\n11 Uygun A , Ozturk K , Demirci H , et al \nFecal microbiota transplantation is a rescue treatment modality for refractory ulcerative colitis\n. Medicine \n2017 ;96 :e6479. 10.1097/MD.0000000000006479 28422836 \n12 Leblanc S , Allez M , Seksik P , et al \nSuccessive treatment with cyclosporine and infliximab in steroid-refractory ulcerative colitis\n. Am J Gastroenterol \n2011 ;106 :771 –7\n. 10.1038/ajg.2011.62 21386832 \n13 Maser EA , Deconda D , Lichtiger S , et al \nCyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis\n. Clin Gastroenterol Hepatol \n2008 ;6 :1112 –6\n. 10.1016/j.cgh.2008.04.035 18928936 \n14 Roediger WE \nDecreased sulphur aminoacid intake in ulcerative colitis\n. Lancet \n1998 ;351 :1555. 10.1016/S0140-6736(05)61120-8 10326542 \n15 Suskind DL , Wu B , Braly K , et al \nClinical remission and normalization of laboratory studies in a patient with ulcerative colitis and primary sclerosing cholangitis using dietary therapy\n. J Pediatr Gastroenterol Nutr \n2018 ;67 :e15 –18\n. 10.1097/MPG.0000000000001966 29570558 \n16 Roediger WEW \nReview article: nitric oxide from dysbiotic bacterial respiration of nitrate in the pathogenesis and as a target for therapy of ulcerative colitis\n. Aliment Pharmacol Ther \n2008 ;27 :531 –41\n. 10.1111/j.1365-2036.2008.03612.x 18194497 \n17 Roediger WE , Millard S \nColonocyte metabolism\n. Gut \n1996 ;38 :792 –3\n. 10.1136/gut.38.5.792-a\n\n",
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"title": "Faecal microbiota transplantation (FMT) with dietary therapy for acute severe ulcerative colitis.",
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"abstract": "We report a case of induction of pseudoseizures by anticonvulsant toxicity in a patient with underlying seizure disorder, hence supporting the argument of an organic subtype of pseudoseizure.",
"affiliations": "Department of Psychiatry and Drug De-addiction, Lady Hardinge Medical College & Smt. Sucheta Kriplani Hospital, New Delhi. Electronic address: hgarekar@gmail.com.;Department of Psychiatry and Drug De-addiction, Lady Hardinge Medical College & Smt. Sucheta Kriplani Hospital, New Delhi.",
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"abstract": "Diabetic ketoacidosis (DKA) is an acute and major life-threatening complication of diabetes mellitus. Fluid resuscitation, insulin therapy, and electrolyte replacement are essential for DKA treatment. Rarely, life threatening allergic reactions might develop in a patient treated with insulin. If anaphylaxis develops after insulin, the DKA treatment options are restricted. A limited number of case reports have been reported in patients with severe anaphylactic reactions to human insulin who were then treated with synthetic insulin analogues. We present a case of a 45-year-old male patient with allergic reactions to human insulin. The patient was successfully treated with insulin aspart and hemodialysis.",
"affiliations": "Dokuz Eylul University, Faculty of Medicine, Department of Emergency Medicine, Balcova, 35340, Izmir, Turkey.;Dokuz Eylul University, Faculty of Medicine, Department of Emergency Medicine, Balcova, 35340, Izmir, Turkey.;Adiyaman University, Training and Research Hospital, Department of Emergency Medicine, Adiyaman, Turkey.;Artvin State Hospital, Department of Emergency Medicine, Artvin, Turkey.;Dokuz Eylul University, Faculty of Medicine, Department of Internal Medicine, Balcova, 35340, Izmir, Turkey.",
"authors": "Oray|Nese Colak|NC|;Bayram|Basak|B|;Altintas|Emel|E|;Sivrikaya|Semra|S|;Savran|Yusuf|Y|",
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"fulltext": "\n==== Front\nTurk J Emerg MedTurk J Emerg MedTurkish Journal of Emergency Medicine2452-2473Elsevier S2452-2473(17)30137-110.1016/j.tjem.2017.07.004Case ReportSevere allergic reaction to human insulin in the patient with diabetic ketoacidosis Oray Nese Colak nese.oray@deu.edu.tra∗Bayram Basak basakdr@yahoo.comaAltintas Emel emel_korkmaz@yahoo.combSivrikaya Semra semra.sivrikaya@deu.edu.trcSavran Yusuf yusufsavran@yahoo.comda Dokuz Eylul University, Faculty of Medicine, Department of Emergency Medicine, Balcova, 35340, Izmir, Turkeyb Adiyaman University, Training and Research Hospital, Department of Emergency Medicine, Adiyaman, Turkeyc Artvin State Hospital, Department of Emergency Medicine, Artvin, Turkeyd Dokuz Eylul University, Faculty of Medicine, Department of Internal Medicine, Balcova, 35340, Izmir, Turkey∗ Corresponding author. nese.oray@deu.edu.tr12 8 2017 3 2018 12 8 2017 18 1 40 41 19 6 2017 17 7 2017 26 7 2017 Copyright © 2017 The Emergency Medicine Association of Turkey. Production and hosting by Elsevier B.V. on behalf of the Owner.2017The Emergency Medicine Association of TurkeyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Diabetic ketoacidosis (DKA) is an acute and major life-threatening complication of diabetes mellitus. Fluid resuscitation, insulin therapy, and electrolyte replacement are essential for DKA treatment. Rarely, life threatening allergic reactions might develop in a patient treated with insulin. If anaphylaxis develops after insulin, the DKA treatment options are restricted. A limited number of case reports have been reported in patients with severe anaphylactic reactions to human insulin who were then treated with synthetic insulin analogues. We present a case of a 45-year-old male patient with allergic reactions to human insulin. The patient was successfully treated with insulin aspart and hemodialysis.\n\nKeywords\nDiabetic ketoacidosisRegular insulinAllergic reactionEmergency treatmentInsulin aspart\n==== Body\n1 Introduction\nDiabetic ketoacidosis (DKA) is a potentially fatal crisis of diabetes mellitus (DM). In the treatment of DKA, fluid resuscitation, insulin therapy, and electrolyte replacement are important. Rarely, insulin allergies can be developed in the patient treated with insulin. The most common symptoms of insulin allergies are localized and limited. Life-threatening allergic reactions are rarely reported. Insulin allergies can be managed safely and successfully by desensitization treatment.1, 2 We present treatment of a patient with DKA who developed an insulin allergy. In this case report, we aimed to discuss DKA treatment options in patient with insulin allergies.\n\n2 Case report\nA 45-year-old male was brought to our emergency department with chest pain and hyperglycemia. He had a history of type 2 DM and had been using an oral antidiabetic drug for two years, but he had been stopped using for a month. HIs past medical history did not show any drug allergies. His vitals were measured: 1.) blood pressure of 166/98 mmHg; 2.) pulse 100/min; 3.) respiration number 24/min; 4.) O2 saturation 98%; and 5.) temperature 36.0 °C. His electrocardiograms (ECG's) were normal. His blood glucose level was 405 mg/dL, urinary ketones 15 mmol/L, pH was 6.8, HCO3 4.7 mmol/L, and lactate 3.6 mmol/L. Regular insulin (0.1unit/kg IV bolus) was initiated in addition to 2000 mL of intravenous saline, and a 0.1 unit/kg/hour infusion was started. He developed a generalized skin rash, hoarseness, and uvular edema at the 30th minute of treatment, which then expanded to the soft palate. The vital findings were normal except for the presence of tachycardia. At that moment his vitals were measured: 1.) blood pressure 126/75 mmHg; 2.) pulse 104/min; 3.) respiration number 24/min; 4.) O2 saturation 99%; and 5.) temperature 36.0 °C. It was discovered that the patient never had insulin in the past. A human insulin-related allergic reaction was proposed, and insulin treatment was ended. Chlorphenoxamine hydrochloride (10mg), ranitidine (50mg), prednisolone (1mg/kg), and 0.1mg (1/10,000) adrenaline was given intravenously. Uvula edema did not resolve. Emergency hemodialysis was performed due to severe metabolic acidosis refractory to intravenous sodium bicarbonate. After hemodialysis, pH was 7.2 and HCO3 was 8.9 mmol/L. Also, his symptoms had not regressed. Antihistamines, steroids, and adrenaline were re-administered. He was intubated in order to secure the airway. Because of the lack of response to treatment, hereditary angioedema was considered, and two units of fresh frozen plasma were given. Subcutaneous insulin aspart (15–20 units; NovoRapid, Novo Nordisk Pharmaceuticals Pty Ltd, Australia) was administered due to ongoing complaints and ketoacidosis. Insulin aspart treatment was continued, and hemodialysis was applied intermittently for metabolic acidosis and acute renal failure. On the 3rd day of follow-up, uvula edema, ketonemia, and metabolic acidosis had completely resolved. The patient was extubated on the 5th day and discharged on the 23rd day with basal insulin glargine and nateglinide treatments.\n\n3 Discussion\nAllergic reaction to the human insulin was rarely (0.1–3%) reported.1 Most of these cases were simple allergic reactions such as an injection site swelling, erythema, and itching. However life-threatening angioedema and anaphylaxis were also reported.2, 4 The patient's past medical history did not indicate any allergies, and this allergic reaction developed after the first contact with human insulin.\n\nDKA is one of the most common complications of DM. Regular insulin is essential for DKA treatment. Despite its uncommon occurrence, an insulin allergy is an important clinical dilemma, both because of its life-threatening anaphylaxis and the effects on diabeticmanagement. Both clinical conditions are mortal when they are not treated. The treatment options are limited in these situations and should involve correcting symptoms and switching insulin preparations.\n\nKaya et al. reported a case in which allergic reaction to human insulin develops after the first dose of regular human insulin. In the patient, desensitization treatment was started. At the follow-up DKA developed, and regular human insulin was re-administered. After that, a severe anaphylactic reaction developed, and the patient died despite all medical interventions.3 We report a case of successful treatment of severe allergic reaction to human insulin in a patient with DKA.\n\nThe first step in the treatment of moderate allergic reactions is discontinuation of the suspect agent and antihistamine administration. Severe allergic reactions may be treated with combinations of antihistamines in addition to systemic steroids and adrenaline. Adrenaline should be administered to the patient with angioedema and/or cardiovascular collapse due to anaphylaxis.\n\nIf the allergen drug must be used in the treatment, another equivalent group of drugs can be applied or started desensitization/immunotherapy. Densensitization treatment/immunotherapy is efficient for diabetic patients with allergies to insulin, however, these treatments are not appropriate for DKA patients.2, 3, 4, 5, 6 On the other hand, these treatment options are not useful in emergency situations. Repeated hemodialysis is another treatment choice for correction of resistant metabolic acidosis and removal of ketone bodies, but it is inadequate overall. A limited number of case reports about severe anaphylactic reactions to human insulin in a diabetic patient treatment with synthetic insulin analogues have been reported.2, 7 Insulin glargine, detemir, and aspart are human insulin analogues. Synthetic insulin analogues decrease the risks of insulin allergies due to their differences at the amino acid level.1, 6 In our case, we have successfully managed by switching to a subcutaneous insulin aspart.\n\nIn summary, life threatening allergic reactions to regular insulin might develop. Synthetic insulin analogues and hemodialysis can be used in DKA patients with insülin allergies.\n\nConflict of interest statement\nThe authors have no commercial associations or sources of support that might pose a conflict of interest.\n\nTransparency document\n \n\nPeer review under responsibility of The Emergency Medicine Association of Turkey.\n\nTransparency document related to this article can be found online at http://dx.doi.org/10.1016/j.tjem.2017.07.004.\n==== Refs\nReferences\n1 Radermecker R.P. Scheen A.J. Allergy reactions to insulin: effects of continuous subcutaneous insulin infusion and insulin analogues Diabetes Metab Res Rev 23 2007 348 355 17216593 \n2 Jacquier J. Chik C.L. Senior P.A. A practical, clinical approach to the assessment and management of suspected insulin allergy Diabet Med 30 8 2013 Aug 977 985 Epub 2013 Apr 19 23601039 \n3 Kaya A. Gungor K. Karakose S. Severe anaphylactic reaction to human insulin in a diabetic patient J Diabetes Complicat 21 2 2007 Mar-Apr 124 127 17331861 \n4 Badik J. Chen J. Letvak K. So T.Y. Hypersensitivity reaction to insulin glargine and insulin detemir in a pediatric patient: a case report J Pediatr Pharmacol Ther 21 1 2016 Jan-Feb 85 91 26997933 \n5 Heinzerling L. Raile K. Rochlitz H. Insulin allergy: clinical manifestations and management strategies Allergy 63 2 2008 148 155 18186805 \n6 Akinci B. Yener S. Bayraktar F. Yesil S. Allergic reactions to human insulin: a review of current knowledge and treatment options Endocrine 37 1 2010 Feb 33 39 Epub 2009 Oct 30 19876775 \n7 Ross J.M. Murali M.R. DeLara T.C. Cheron R.G. Anaphylaxis and immunologic insulin resistance in a diabetic woman with ketoacidosis Diabetes Care 7 3 1984 May-Jun 276 279 6428840\n\n",
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"title": "Severe allergic reaction to human insulin in the patient with diabetic ketoacidosis.",
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"abstract": "Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. Canakinumab, a monoclonal antibody targeting IL-1β is under investigation for the treatment of severe SAR-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. On the next day, diuresis recovered and conditions improved: high IL-6 levels and NK cells expressing CD56 (associated with cytokine relase) were significantly reduced giving rise to NK CD56 . Patient died on day 58 with pulmonary bacterial superinfection and persistent SARS-CoV-2 positivity. In conclusion, canakinumab rescued a high risk, very elderly patient, from multiorgan damage complicating COVID-19. It may represent an useful treatment in severe cases.",
"affiliations": "UOSD Terapia Intensiva Post-Operatoria, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;Intensive Care Unit, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;Intensive Care Unit, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;Intensive Care Unit, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;Intensive Care Unit, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;Intensive Care Unit, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;Intensive Care Unit, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;Dipartimento di Microbiologia e Virologia, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;Central Pharmacy, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;UOC Laboratorio Analisi, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;UOC Laboratorio Analisi, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.;Hematology Unit, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy.",
"authors": "Caracciolo|Massimo|M|;Macheda|Sebastiano|S|;Labate|Demetrio|D|;Tescione|Marco|M|;La Scala|Stefano|S|;Vadalà|Eugenio|E|;Squillaci|Rosalba|R|;D'Aleo|Francesco|F|;Morabito|Antonella|A|;Garreffa|Cristina|C|;Marciano|Maria Concetta|MC|;Oliva|Esther N|EN|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D019002:CD56 Antigen; C508585:IL1B protein, human; C508600:IL6 protein, human; D053583:Interleukin-1beta; D015850:Interleukin-6; C522918:NCAM1 protein, human; C541220:canakinumab",
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fimmu.2020.01942",
"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224 Frontiers Media S.A. \n\n10.3389/fimmu.2020.01942\nImmunology\nCase Report\nCase Report: Canakinumab for the Treatment of a Patient With COVID-19 Acute Respiratory Distress Syndrome\nCaracciolo Massimo 1 Macheda Sebastiano 2 Labate Demetrio 2 Tescione Marco 2 La Scala Stefano 2 Vadalà Eugenio 2 Squillaci Rosalba 2 D’Aleo Francesco 3 Morabito Antonella 4 Garreffa Cristina 5 Marciano Maria Concetta 5 Oliva Esther N. 6* 1UOSD Terapia Intensiva Post-Operatoria, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy\n2Intensive Care Unit, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy\n3Dipartimento di Microbiologia e Virologia, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy\n4Central Pharmacy, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy\n5UOC Laboratorio Analisi, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy\n6Hematology Unit, Grande Ospedale Metropolitano Bianchi Melacrino Morelli, Reggio Calabria, Italy\nEdited by: Suraj P. Parihar, University of Cape Town, South Africa\n\nReviewed by: Robert Wilkinson, Francis Crick Institute, United Kingdom; Jagadeesh Bayry, Institut National de la Santé et de la Recherche Médicale (INSERM), France\n\n*Correspondence: Esther N. Oliva, enoliva@gmail.comThis article was submitted to Vaccines and Molecular Therapeutics, a section of the journal Frontiers in Immunology\n\n\n25 8 2020 \n2020 \n25 8 2020 \n11 194212 6 2020 20 7 2020 Copyright © 2020 Caracciolo, Macheda, Labate, Tescione, La Scala, Vadalà, Squillaci, D’Aleo, Morabito, Garreffa, Marciano and Oliva.2020Caracciolo, Macheda, Labate, Tescione, La Scala, Vadalà, Squillaci, D’Aleo, Morabito, Garreffa, Marciano and OlivaThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. Canakinumab, a monoclonal antibody targeting IL-1β is under investigation for the treatment of severe SAR-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. On the next day, diuresis recovered and conditions improved: high IL-6 levels and NK cells expressing CD56bright (associated with cytokine relase) were significantly reduced giving rise to NK CD56dim. Patient died on day 58 with pulmonary bacterial superinfection and persistent SARS-CoV-2 positivity. In conclusion, canakinumab rescued a high risk, very elderly patient, from multiorgan damage complicating COVID-19. It may represent an useful treatment in severe cases.\n\nCOVID-19SARS-CoV-2canakinumabIL-1IL-6cytokine stormnatural killeracute respiratory distress syndrome\n==== Body\nIntroduction\nSARS-CoV-2 is responsible for the current pandemic of coronavirus disease 2019 (COVID-19). Patients present with fever, dry cough, dyspnea, and pneumonia (1). Some patients (approximately 15%), prevalently elderly and with comorbidities, develop serious multiple organ inflammation and acute respiratory distress syndrome (ARDS) (2–4) and require intensive care unit (ICU) admission (3, 4).\n\nThe immune response, including the release of pro-inflammatory cytokines and activation of T cells, are essential for controlling the viral spread, inflammation, and tissue renewal (5, 6). The damged host cell releases proteins induce the production of pro-inflammatory cytokines by nearby cells. Monocytes, macrophages and T cells are attracted to the site of infection, establishing a pro-inflammatory feedback circuit. When the immune response is hampered, the excessive pro-inflammatory cytokines in the lungs are responsible for lung tissue damage and the cytokine storm (CS), or macrophage activation syndrome (MAS), leading to multi-organ damage.\n\nSevere cases with CS progress to ARDS (7, 8). The mechanisms leading to such complications are complex and still under investigation. Many features of COVID-19 resemble MAS triggered by viral infection (8, 9). In fact, SARS-CoV-2 infection is associated with high levels of cytokines and, interestingly, levels of IL-6 have been reported to be correlated with mortality (10). Furthermore, in severe cases, a reduction of natural killer cells and other T lymphocytes, has been observed. Cytokine levels are inversely correlated with lymphocyte count, therefore CS may be an impediment to the adaptive immune response against SARS-CoV-2 infection (6, 11). Moreover, the severity of COVID-19 is correlated with NK subsets distinguished according to the cell surface density of CD56. In fact, CD56bright subset increases with severity. CD56dim NK cells physiologically comprise around 90% of NK cells in peripheral blood and are frequently described as the most cytotoxic, whereas CD56bright NK cells are abundant cytokine producers (12, 13).\n\nInterleukin-1 (IL-1) activates the expression of several pro-inflammatory genes. IL-1β induces inflammation during infection and autoimmunity (14). IL-1β is released by various cell types, including macrophages (15, 16). Canakinumab, a monoclonal antibody targeting IL-1β, is approved for use in rheumatologic disorders1. Based on the mechanism of action of canakinumab, the drug is under investigation for the treatment of severe SAR-CoV-2 infection.\n\nWe present a case of an 85 year old male presenting with COVID-19, complicated by ARDS and cardiac and renal failure, rescued by canakinumab. An indication for compassionate use for COVID-19 during the current pandemic and approval from the local ethics committee was obtained in our center.\n\nCase Description\nPatient was admitted to hospital on March 23, 2020, presenting with fever (38.5°C), hypoxemia (p02 = 61 mmHg), cough, and dyspnea. Medical history revealed only mild arterial hypertension treated with amlodipine and prostatic hypertrophy not requiring treatment. SARS-CoV-2 swab was positive. Chest X-ray showed an interstitial lung pattern and small left pleural effusion. Renal and liver biochemistry were normal. Noteworthy, the patient presented lymphopenia. Reactive C Protein (RCP) was 139 mg/L. Coagulation tests were normal except for Fibrinogen 619 mg/dL and D-dimers 409 ng/mL. He was at first treated in the COVID ward and received broad spectrum antibiotics, hydroxychloroquine, and oxygen therapy with Venturi mask with 30% FiO2 setting. On day 3, a chest computerized tomography (CT) without contrast showed severe lung injury (Figure 1).\n\nFIGURE 1 CT scan on day 3 showed bilateral, patchy alveolar opacities progressing to diffuse consolidations, with a “white lung” appearance and widespread ground-glass opacities and moderate bilateral pleural effusions.\n\nOn day 4, though the fever had subsided, his respiratory condition deteriorated and continuous positive airway pressure (CPAP) non-invasive ventilation with 40% FiO2 setting and positive end-expiratory pressure (PEEP) 10 cmH20 was initiated, together with azitromicin, enoxaparin sodium and lopinavir/ritonavir. On day 5, tocilizumab 8 mg/kg was administered intravenously (within a clinical trial) repeated after 12 h, while continuing hydroxychloroquine, azitromicin and enoxaparin. On day 23, his conditions precipitated with presentation of ARDS, a PaO2/FiO2 ratio (PF) of 103 (Fi02 setting 60%, p02 62 mmHg) and severe arterial hypertension. He was transferred to the Intensive Care Unit (ICU) in an obnubilated and non-collaborative condition, so that he was sedated with dexmedetomidine while continuing CPAP ventilation. On day 24, patient presented oliguria with acute renal and cardiac failure and progressive respiratory failure. He was intubated and received assisted mechanical ventilation together with furosemide continuous intravenous infusion and vasopressor amines.\n\nOn day 25, the patient’s son was informed of the severity of the patient’s clinical conditions and of the risks and benefits of canakinumab treatment. He signed informed consent to administer treatment, to process and publish all relevant clinical research data and potentially identifying information. Canakinumab was administered at a single 300 mg s.c. dose on days 25 and 31.\n\nDiagnostic Assessment\nTo evaluate the biochemical effects of canakinumab, general laboratory chemistry, IL-6, and immunophenotype were collected before and after first and second administration. The drug was well tolerated in the short term, and on the day following the first administration, the patient’s diuresis normalized and renal function improved gradually without full recovery (on day 53, creatinine level reached 88 μmol/L). The findings are summarized in Table 1.\n\nTABLE 1 The laboratory findings before (day 23) and after the First (day 28) and Second (day 42) administrations of canakinumab.\n\nVariable\tBefore\tAfter First\tAfter Second\t\nHemoglobin (Hb) g/dL\t12.0\t11.3\t8.7\t\nWhite Blood Cell count (WBC) × 109/L\t4.4\t6.5\t12.4\t\nNeutrophils-bands (Neutroph) × 109/L\t3.4\t5.8\t10.3\t\nLymphocytes (Lymph) × 109/L\t0.5\t0.2\t0.5\t\nPlatelet count (PLT) × 109/L\t135\t107\t291\t\nD-dimer (D-d) nmol/L\t2.1\t1.9\t3.2\t\nCreatinine (Cr) μmol/L\t44\t124\t97\t\nCRP mg/L\t3.1\t10.2\t156.0\t\nLactate dehydrogenase (LDH) μkat/L\t5.0\t3.8\t3.8\t\nAlkaline phosphatase μkat/L\t1.6\t1.9\t1.9\t\nAlanine aminotransferase (ALT) μkat/L\t1.0\t0.5\t0.2\t\nAspartate aminotransferase (AST) μkat/L\t0.5\t0.4\t0.4\t\nγ-Glutamyltransferase (GGT) μkat/L\t0.4\t0.4\t0.5\t\nSerum IL-6, IU/ml\t424.6\t46.2\t75.2\t\nImmunophenotype, cells/μL\t\t\t\t\nLymphocyte T\t\t\t\t\nCD3+\t402\t172\t114\t\nCD3+CD4+\t309\t117\t74\t\nCD3+CD8+\t95\t56\t41\t\nLymphocyte B CD19+\t31\t32\t34\t\nLymphocyte NK\t\t\t\t\nCD16+CD56+\t111\t77\t18\t\nNK CD56DIM\t57\t66\t109\t\nNK CD56BRIGHT\t42\t1\t2\t\nCD4/CD8 Ratio\t3\t2\t2\t\nDuring hospitalization, the patient underwent periodical microbiological surveillance tests. SARS-Cov-2 genome was evaluated by the Microbiology and Virology laboratory of our hospital. Samples from upper (nasopharyngeal) and lower (bronchoalveolar, bronchoaspirate, and tracheal aspirate) airways were collected and processed within 24 h. RNA-COVID 19 was evaluated using an Allplex 2019-nCoV assay that identifies three different target genes: E (envelope), RdRp (RNA-dependent RNA polymerase), and N (nucleoprotein gene). Based on the interpretation criteria, detection of one or more genes was interpreted as positive COVID-19. There was a high viral replication persisting on Day 43.\n\nOn day 31, as the respiratory conditions did not improve significantly, the Film Array Pneumonia detected the presence of bacterial infection caused by Acinetobacter C.B. Complex – 107 copies/mL – and Pseudomonas Aeruginosa – 106 copies/mL, treated initially with the association of Piperacillin + Tazobactam together with Cotrimoxazole provided intravenously QID, followed by Colistin 3000000 aerosol BID, then with Ceftazidime/Avibactam intravenous TID and finally with Doxycycline 100 mg intravenous BID (the latter ongoing).\n\nThe initial chest CT scan on Day 13 and X-rays performed before First administration (Day 23) and after Second administration (Day 38) are shown in Figure 2.\n\nFIGURE 2 (A) Before the first administration of canakinumab, the chest X-ray shows interstitial changes, ground glass opacities, and multifocal and bilateral effusions. (B) After second administration, the chest X-ray shows the extensive bilateral opacities and bilateral effusions, concomitant to bacterial superinfection.\n\nDiscussion\nCanakinumab is an IL-1 antagonist indicated to treat autoinflammatory disorders. Severe COVID-19 cases show symptoms associated with an excessive release of cytokines (17, 18).\n\nThe IL-1 cytokine family plays an important role in regulating inflammation and is produced in response to inflammatory stimuli and infections. IL-1 production requires inflammasome/Caspase-1-dependent processing. It mediates its effects by binding to its receptor to activate downstream signaling which activates MAPKs and NF-kappa B, leading to the expression of pro-inflammatory mediators that drives the IL-6 signaling pathway.\n\nIL-6 significantly contributes to MAS. Its levels increase with the severity of COVID-19 (9, 19, 20) and the area of pulmonary infiltration (≥50%) in patients with ARDS, together with specific lymphocyte subsets (21). Though the present case had received tocilizumab prior to canakinumab, IL-6 level remained high, postulating that tocilizumab be insufficient to rescue the patient from the subsequent cytokine storm. In our patient, IL-6 and NK CD56bright both decreased after treatment with canakinumab, suggesting that canakinumab, by interfering with IL-1, reduces IL-6. Following the Second administration, IL-6 and CRP levels increased which can be explained with the development of superimposed pulmonary bacterial infection.\n\nSeveral immunotherapeutic drugs are promising for the treatment of the cytokine storm associated with COVID-19 (22). Amongst these, anakinra, an IL-1 receptor antagonist, saltuximab, an IL-6 antagonist, and sarilumab, an IL-6 receptor antagonist, are undergoing Phase 3 stage development (23).\n\nHowever, canakinumab treatment is associated with adverse events, mainly an increased incidence of serious infections. In fact, IL-1β physiologically contributes to host defense against infection by enhancing the antimicrobial action of phagocytes and inducing Th1 and Th17 adaptive immune responses (24). In our case, the patient survived the MAS, but developed bacterial pulmonary superinfection, which was the final cause of death on day 58. This case represents the first published report of canakinumab for the treatment of multiorgan damage associated with COVID-19.\n\nPatient Perspective\nExcessive cytokine release induces severe complications and worsens the prognosis in COVID-19. There are numerous ongoing trials to find treatments that target virus and/or inflammation. Until an effective treatment is found, in this scenario, Canakinumab due to its blocking action of proinflammatory activity by IL-1β can constitute a potential useful treatment in the modulation of hyperinflammatory symptoms, for a subgroup of patients with COVID-19, that resemble the cytokine storm in patients with MAS. The active involvement of immunologists in the clinic and in clinical trials may improve patient outcomes.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Comitato Etico Sezione Sud – Regione Calabria. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\nMC, EO, and DL drafted the initial manuscript. CG performed flow cytometry. FD’A performed microbiological testing. MM performed cytokine tests. All authors reviewed and revised the manuscript and have read and agreed to the published version of the manuscript to the work reported.\n\nConflict of Interest\nEO reports personal fees from Novartis, during the conduct of the study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nNovartis provided compassionate use of Canakinumab for the case described.\n\n1 https://www.drugs.com/pro/ilaris.html#s-34067-9\n==== Refs\nReferences\n1. Zhou P Yang XL Wang XG Hu B Zhang L Zhang W \nA pneumonia outbreak associated with a new coronavirus of probable bat origin.\n\nNature. (2020 ) 579 :270 –3\n.32015507 \n2. Xu Z Shi L Wang Y Zhang J Huang L Zhang C \nPathological findings of COVID-19 associated with acute respiratory distress syndrome.\n\nLancet Respir Med. (2020 ) 8 :420 –2\n.32085846 \n3. Wang D Hu B Hu C Zhu F Liu X Zhang J \nClinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China.\n\nJAMA. (2020 ) 323 :1061 –9\n.\n4. Guan WJ Ni ZY Hu Y Liang WH Ou CQ He JX \nClinical characteristics of coronavirus disease 2019 in China.\n\nN Engl J Med. (2020 ) 382 :1708 –20\n.32109013 \n5. Ivashkiv LB Donlin LT. \nRegulation of type I interferon responses.\n\nNat Rev Immunol. (2014 ) 14 :36 –49\n. 10.1038/nri3581 \n24362405 \n6. Li G Fan Y Lai Y Han T Li Z Zhou P \nCoronavirus infections and immune responses.\n\nJ Med Virol. (2020) 92 :424 –32\n.31981224 \n7. George MR. \nHemophagocytic lymphohistiocytosis: review of etiologies and management.\n\nJ Blood Med. (2014 ) 5 :69 –86\n.24966707 \n8. Qin C Zhou L Hu Z Zhang S Yang S Tao Y \nDysregulation of immune response in patients with COVID-19 in Wuhan, China.\n\nClin Infect Dis. (2020 ) 12 :ciaa248 .\n9. Wan S Yi Q Fan S Lv J Zhang X Guo L \nCharacteristics of lymphocyte subsets and cytokines in peripheral blood of 123 hospitalized patients with 2019 novel coronavirus pneumonia (NCP).\n\nMedRxiv. (2020 ) [Preprint ]. 10.1101/2020.02.10.20021832 \n10. Perricone C Triggianese P Bartoloni E Cafaro G Bonifacio AF Bursi R \nThe anti-viral facet of anti-rheumatic drugs: lessons from COVID-19.\n\nJ Autoimmun. (2020 ) 17 :102468 . 10.1016/j.jaut.2020.102468 \n32317220 \n11. Pedersen F Ho YC. \nSARS-CoV-2: a storm is raging.\n\nJ Clin Invest. (2020 ) 130 :2202 –5\n.32217834 \n12. Li G Fan Y Lai Y Han T Li Z Zhou P \nCoronavirus infections and immune responses.\n\nJ Med Virol. (2020 ) 92 :424 –32\n.31981224 \n13. Cooper MA Fehniger TA Caligiuri MA. \nThe biology of human natural killer-cell subsets.\n\nTrends Immunol. (2001 ) 22 :633 –40\n.11698225 \n14. Vivier E Tomasello E Baratin M Walzer T Ugolini S. \nFunctions of natural killer cells.\n\nNat Immunol. (2008 ) 9 :503 –10\n.18425107 \n15. Dinarello CA. \nTherapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation.\n\nCurr Opin Pharmacol. (2004 ) 4 :378 –85\n.15251132 \n16. Watkins LR Milligan ED Maier SF. \nGlial proinflammatory cytokines mediate exaggerated pain states: implications for clinical pain.\n\nAdv Exp Med Biol. (2003 ) 521 :1 –21\n.12617561 \n17. Ren K Torres R. \nRole of interleukin-1beta during pain and inflammation.\n\nBrain Res Rev. (2009 ) 60 :57 –64\n. 10.1016/j.brainresrev.2008.12.020 \n19166877 \n18. Zhou F Yu T Du R Fan G Liu Y Liu Z \nClinical course and risk factors for mortality of adult in patients with COVID-19 in Wuhan, China: a retrospective cohort study.\n\nLancet. (2020 ) 395 :1054 –62\n.32171076 \n19. Mehta P McAuley DF Brown M Sanchez E Tattersall RS Manson JJ. \nHLH across speciality collaboration, UK. COVID-19: consider cytokine storm syndromes and immunosuppression.\n\nLancet. (2020 ) 395 :1033 –4\n.32192578 \n20. Lee CR Kang JA Kim HE Choi Y Yang T Park SG. \nSecretion of IL-1β From imatinib-resistant chronic myeloid leukemia cells contributes to BCR-ABL mutation-independent imatinib resistance.\n\nFEBS Lett. (2016 ) 590 :358 –68\n.26831735 \n21. Crayne CB Albeituni S Nichols KE Cron RQ. \nThe immunology of macrophage activation syndrome.\n\nFront Immunol. (2019 ) 10 :119 .\n22. Wang W He J Lie P Huang L Wu S Lin Y \nThe definition and risks of cytokine release syndrome-like in 11 COVID- 19-infected pneumonia critically ill patients: disease characteristics and retrospective analysis.\n\nMedRxiv. (2020 ) [Preprint ]. 10.1101/2020.02.26.20026989 \n23. Bonam SR Kaveri SV Sakuntabhai A Gilardin L Bayry J. \nAdjunct immunotherapies for the management of severely Ill COVID-19 Patients.\n\nCell Rep Med. (2020 ) 1 :100016 . 10.1016/j.xcrm.2020.100016 \n32562483 \n24. Van de Veerdonk FL Netea MG Dinarello CA Joosten LAB. \nInflammasome activation and IL-1β and IL-18 processing during infection.\n\nTrends Immunol. (2011 ) 32 :110 –6\n.21333600\n\n",
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"journal": "Frontiers in immunology",
"keywords": "COVID-19; IL-1; IL-6; SARS-CoV-2; acute respiratory distress syndrome; canakinumab; cytokine storm; natural killer",
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"mesh_terms": "D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000073640:Betacoronavirus; D019002:CD56 Antigen; D000086382:COVID-19; D018352:Coronavirus Infections; D017809:Fatal Outcome; D006801:Humans; D053583:Interleukin-1beta; D015850:Interleukin-6; D007694:Killer Cells, Natural; D008297:Male; D058873:Pandemics; D011024:Pneumonia, Viral; D012128:Respiratory Distress Syndrome; D000086402:SARS-CoV-2; D012720:Severity of Illness Index",
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"title": "Case Report: Canakinumab for the Treatment of a Patient With COVID-19 Acute Respiratory Distress Syndrome.",
"title_normalized": "case report canakinumab for the treatment of a patient with covid 19 acute respiratory distress syndrome"
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"abstract": "Purpose: To present a rare case of scleritis associated with a prior diagnosis of giant cell arteritis (GCA) that was unresponsive to glucocorticoids, nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate, and azathioprine, but reached and maintained a full remission with tocilizumab.Observations: A 62-year-old Caucasian female presented with scleritis and headache. Four years earlier, the patient was diagnosed with GCA. Treatment with topical and systemic NSAIDs, prednisone and diverse disease-modifying antirheumatic drugsonly had a partial effect on the scleritis whilst the arthralgia and headaches increased. Despite the absence of laboratory evidence of active GCA, tocilizumab was started and the scleritis and headaches disappeared within several days. Prednisone could be fully tapered within 3 months and to date, 12 months after the start of tocilizumab, the patient has maintained a sustained remission.Conclusions: Our patient demonstrates that tocilizumab might represent a therapeutic option for scleritis, and its further evaluation for this severe ocular disease is worthwhile.",
"affiliations": "Department of Ophthalmogy, Erasmus MC, Rotterdam, The Netherlands.;Internal Medicine, Section Allergology & Clinical Immunology, Erasmus MC, Rotterdam, The Netherlands.;Department of Ophthalmogy, Erasmus MC, Rotterdam, The Netherlands.",
"authors": "Poelman|Huub J|HJ|;Van Daele|Paul L A|PLA|;Rothova|A|A|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
"country": "England",
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"doi": "10.1080/09273948.2019.1617885",
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"issn_linking": "0927-3948",
"issue": "28(2)",
"journal": "Ocular immunology and inflammation",
"keywords": "Giant cell arteritis; Scleritis; Tocilizumab",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007279:Injections, Subcutaneous; D008875:Middle Aged; D012074:Remission Induction; D015423:Scleritis; D016896:Treatment Outcome",
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"pages": "285-287",
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"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Successful Tocilizumab Treatment for Scleritis.",
"title_normalized": "successful tocilizumab treatment for scleritis"
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"abstract": "Erythema nodosum (EN), is the most common variant of septal panniculitis and is possibly a delayed hypersensitivity reaction triggered by a wide range of antigenic stimuli. Hypersensitivity reactions due to medications have been recognized as a cause of 3-10% of EN cases. Case reports of EN associated with the anti-thyroid drugs are quite rarely reported in the literature even if there is a common use of anti-thyroid drugs. We report an EN case due to methimazole. The complaints of patients arose immediately fifteen days after the beginning of methimazole treatment. To the best of our knowledge, this case report is the first of an erythema nodosum induced by methimazole.",
"affiliations": "Yildirim Beyazit University, Ataturk Training and Research Hospital, Dermatology Clinic, Ankara, Turkey.;Yildirim Beyazit University, Ataturk Training and Research Hospital, Endocrinology Clinic, Ankara, Turkey.;Yildirim Beyazit University, Ataturk Training and Research Hospital, Pathology Department, Ankara, Turkey.;Yildirim Beyazit University, Ataturk Training and Research Hospital, Dermatology Clinic, Ankara, Turkey.;Yildirim Beyazit University, Ataturk Training and Research Hospital, Dermatology Clinic, Ankara, Turkey.",
"authors": "Emre|Selma|S|;Ozdemir|Didem|D|;Orhun|Sibel|S|;Kalkan|Goknur|G|;Sener|Sertac|S|",
"chemical_list": null,
"country": "Saudi Arabia",
"delete": false,
"doi": "10.1016/j.jsps.2016.11.003",
"fulltext": "\n==== Front\nSaudi Pharm JSaudi Pharm JSaudi Pharmaceutical Journal : SPJ1319-01642213-7475Elsevier S1319-0164(16)30132-310.1016/j.jsps.2016.11.003Case ReportA case of severe erythema nodosum induced by methimazole Emre Selma dr_semre@yahoo.coma⁎Ozdemir Didem bOrhun Sibel cKalkan Goknur aSener Sertac aa Yildirim Beyazit University, Ataturk Training and Research Hospital, Dermatology Clinic, Ankara, Turkeyb Yildirim Beyazit University, Ataturk Training and Research Hospital, Endocrinology Clinic, Ankara, Turkeyc Yildirim Beyazit University, Ataturk Training and Research Hospital, Pathology Department, Ankara, Turkey⁎ Corresponding author at: Yildirim Beyazit University, Ataturk Training and Research Hospital, Dermatology Clinic, Bilkent, Ankara, Turkey. Fax: +90 312 2912705.Yildirim Beyazit UniversityAtaturk Training and Research HospitalDermatology ClinicBilkentAnkaraTurkey. dr_semre@yahoo.com12 11 2016 7 2017 12 11 2016 25 5 813 815 3 1 2016 5 11 2016 © 2016 King Saud University2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Erythema nodosum (EN), is the most common variant of septal panniculitis and is possibly a delayed hypersensitivity reaction triggered by a wide range of antigenic stimuli. Hypersensitivity reactions due to medications have been recognized as a cause of 3–10% of EN cases. Case reports of EN associated with the anti-thyroid drugs are quite rarely reported in the literature even if there is a common use of anti-thyroid drugs. We report an EN case due to methimazole. The complaints of patients arose immediately fifteen days after the beginning of methimazole treatment. To the best of our knowledge, this case report is the first of an erythema nodosum induced by methimazole.\n\nKeywords\nAnti-thyroid drugsErythema nodosumMethimazole\n==== Body\n1 Introduction\nErythema nodosum (EN), is the most common variant of septal panniculitis. Cutaneous lesions are usually acute, painful, erythematous, round or oval subcutaneous nodules on the extensor areas of the lower extremities. EN is possibly a delayed hypersensitivity reaction triggered by a wide range of antigenic stimuli. The most common causes include drugs, bacterial, viral and fungal infections, pregnancy, systemic diseases such as sarcoidosis, malignant diseases, and inflammatory bowel diseases. However, in more than 55% cases etiologic factors cannot be cleared and are considered to be idiopathic. Hypersensitivity reactions due to medications have been recognized as a cause of 3–10% of EN cases (Blake et al., 2014, Schwartz and Nervi, 2007). We report an EN case due to methimazole, as an unusual cause. To the best of our knowledge, this case report is the first of an erythema nodosum induced by methimazole.\n\n2 Case\nA 64-year-old female patient was admitted to our outpatient clinic with the complaints of multiple erythematous, painful, nodules on both of the legs for fifteen days (Fig. 1). Laboratory examination revealed normal hepatic and renal functions. Complete blood count showed mild neutrophilia. Skin biopsy was performed from erythematous nodules. Histopathological examination revealed spongiosis in epidermis, mixed type inflammatory cell infiltration and lymphocytic vasculitis in dermis and inflammation consistent with septal panniculitis at the subcutaneous tissue (Figure 2, Figure 3). She was diagnosed as EN based on physical and histopathological examinations. Chest radiography, erythrocyte sedimentation rate, urinalysis, antinuclear antibody, and serum ACE levels were normal. Mantoux test, serology for hepatitis and laboratory tests for other infectious agents were negative. She had essential hypertension for 5 years and was using perindopril 5 mg/day and indapamide 1.25 mg/day. Methimazole 20 mg per day was also started for hyperthyroidism associated with Graves’ disease, a month ago. Her serum free T4 and free T3 levels were in normal limits and TSH was 0.05 mIU/mL (0.27–4.2 mIU/mL) at that time. On the other hand, indomethacin 75 mg/day, and topical corticosteroid creams were prescribed for the treatment of erythema nodosum. Empirical amoxicillin/clavulanic acid (875 mg/125 mg twice daily peroral) was started against possible streptococcal infections before laboratory tests resulted. Elevation and wet dressing were also recommended at the same time. Since laboratory results did not show evidence of any infection, the antibiotic therapy was stopped after three days. We noticed that her complaints were increased at the second follow-up appointment. When we deepened the history of the patient we discovered that her complaints were started fifteen days after the beginning of methimazole treatment. Therefore methimazole was stopped and the lesions improved in one week (Fig. 4). Propylthiouracil was started instead of methimazole and after that time she has not reported any side effects or complaints about this drug during the medication for a year. The consent of the patient was received for this report.Figure 1 Multiple erythematous, nodules on both of the lower legs.\n\nFigure 2 Mixed type inflammatory cell infiltration and lymphocytic vasculitis in dermis. HE, 40×.\n\nFigure 3 There is an inflammation compatible with septal panniculitis in subcutaneous fat tissue. HE, 200×.\n\nFigure 4 The appearance of the legs after healing.\n\n\n\n3 Discussion\nAnti-thyroid drugs (ATDs) that are the members of the thioamide group include methimazole, carbimazole and propylthiouracil have been used in the treatment of the hyperthyroidism for approximately 60 years. Methimazole is active metabolite of carbimazole (Taylor and Vaidya, 2012). The most common side effects of ATDs are skin rash, low grade liver dysfunction, granulocytopenia and arthralgia. Myeloperoxidase antineutrophil cytoplasmic antibody (ANCA) related vasculitis, agranulocytosis and severe hepatotoxicity are rare but serious complications of ATDs (Yang et al., 2015). EN is an immune associated non-specific cutaneous reaction that develops as a response to a specific stimuli. It has been presumed to be a hypersensitivity reaction. Hypersensitivity reactions due to medications have been recognized as a cause of 3–10% of erythema nodosum cases (Schwartz and Nervi, 2007). Case reports of EN associated with the anti-thyroid drugs are quite rarely reported in the literature even if there is a common use of anti-thyroid drugs.\n\nUp to date there are only a few anecdotal cases about these anti-thyroid drugs and EN. Two case reports of EN induced by propylthiouracil have been reported (Keren et al., 1985, Wan et al., 2012). In the EN case induced by propylthiouracil that was reported by Wan et al., ANCA positivity was also accompanied (Wan et al., 2012). The third case of EN induced by ATDs was due to carbimazole. EN, acute pancreatitis and hepatic cholestasis were reported in a 33 year-old female patient using carbimazole. These side effects were observed one month later from the beginning of the carbimazole treatment in this patient (Marazuela et al., 2002). Different from the other cases, our patient was the first case of EN that was observed after the usage of methimazole. In our patient lesions continued to develop by increasing even if there is an adequate treatment for EN in a period of one month and lesions had disappeared by improving fast in one week after the cessation of the treatment. We could not find any other etiologic reasons for EN. Streptococcal infections are one of the most common causes of EN (Chowaniec et al., 2016, Starba et al., 2016). We had prescribed empirical antibiotic therapy against possible streptococcal infections, by the time the laboratory tests resulted. But streptococcal infection was not found on laboratory examinations and we stopped antibiotic therapy. Therefore we thought that these EN lesions were induced by methimazole. The EN lesions were localized on the lower legs typically. While the lesions are present, the methimazole treatment was stopped and propylthiouracil treatment was started. There was no recurrence in a period of 1 year follow-up during propylthiouracil treatment. Since these lesions appeared 2 weeks after the beginning of the methimazole, we think that these EN lesions are idiosyncratic hypersensitivity reaction. Sulfonamides are well-known causes of EN. Marazuela et al. (2002) suggested that the sulphydryl groups that are the components of thioamides can cause hypersensitivity reaction and EN. However, in our case propylthiouracil did not induce EN which was also a member of thioamide group. Probably, in our case methimazole caused immune–mediated reaction by another different way. Therefore we should keep methimazole induced EN in mind in the patients that have EN like lesions that the etiologic factors cannot be illuminated during methimazole treatment.\n\nFinancial disclosure\nNone.\n\nPeer review under responsibility of King Saud University.\n==== Refs\nReferences\nBlake T. Manahan M. Rodins K. Erythema nodosum - a review of an uncommon panniculitis Dermatol. Online J. 20 4 2014 3 \nChowaniec M. Stabra A. Wiland P. Erythema nodosum - review of the literature Reumatologia 54 2 2016 79 82 27407284 \nKeren G. Lehr V. Boichis H. Erythema nodosum related to propylthiouracil treatment for thyrotoxicosis Isr. J. Med. Sci. 21 1 1985 62 63 3838294 \nMarazuela M. Sancehez de Paco G. Jimenez I. Carraro R. Fernandez-Herrera J. Pajares J.M. Gomez-Pan A. Acute pancreatitis, hepatic cholestasis, and erythema nodosum induced by carbimazole treatment for Graves disease Endocr. J. 49 3 2002 315 318 12201214 \nSchwartz R.A. Nervi S.J. Erythema nodosuma sign of systemic disease Am. Fam. Physician 75 5 2007 695 700 17375516 \nStarba A. Chowaniec M. Wiland P. Erythema nodosum - presentation of three cases Reumatologia 54 2 2016 83 85 27407285 \nTaylor P.N. Vaidya B. Side effects of anti-thyroid drugs and their impact on the choice of treatment for thyrotoxicosis in pregnancy Eur. Thyroid J. 1 3 2012 176 185 24783017 \nYang J. Zhang J. Xu Q. Sheng G. Weng W. Dong M. Unusual synchronous methimazole-induced agranulocytosis and severe hepatotoxicity in patient with hyperthyroidisma case report and review of the literature Int. J. Endocrinol. 2015 2015 934726 26060496 \nWan P. Zhao X. Hunasehally R.Y. Shi R. Zheng J. Propylthiouracil-induced ANCA-positive erythema nodosum treated with thalidomide Int. J. Dermatol. 51 3 2012 345 22348574\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1319-0164",
"issue": "25(5)",
"journal": "Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society",
"keywords": "Anti-thyroid drugs; Erythema nodosum; Methimazole",
"medline_ta": "Saudi Pharm J",
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"pages": "813-815",
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"pmid": "28725155",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports",
"references": "27407285;22348574;17375516;24783017;26060496;27407284;24746312;12201214;3838294",
"title": "A case of severe erythema nodosum induced by methimazole.",
"title_normalized": "a case of severe erythema nodosum induced by methimazole"
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"abstract": "Bilateral acute iris depigmentation (BADI) and transillumination (BATI) syndromes have been linked with the use of antibiotics, especially fluoroquinolones. They are characterized by acute onset of pigment dispersion in the anterior chamber, depigmentation of the iris and pigment deposition in the angle and in the posterior surface of the cornea (BADI), with iris transillumination defects and atonic pupil with sphincter paralysis (BATI). The purpose of this paper is to report the development of clinical depigmentation and iris damage similar to BADI and BATI in patients who had undergone uneventful glaucoma surgery with intracameral moxifloxacin as prophylaxis for endophthalmitis.\nFour patients who had undergone Ex-Press implantation (cases 1 and 2) or non-penetrating deep sclerotomy (cases 3 and 4) developed asymptomatic pigment dispersion in the anterior chamber, which cleared after treatment with topical corticosteroids and NSAIDS. However, pupillary damage ensued, with mid-midriasis and pigment deposition under the filtration bleb.\nThis is, to the best of our knowledge, the first report of acute unilateral iris depigmentation and transillumination after intracameral use of moxifloxacin. Moxifloxacin's toxic effect may have been promoted by the subconjuntival mitomycin employed to prevent scarring at the filtration bleb. Surgeons should be aware of these potential side-effects of drugs used as widely as moxifloxacin and mitomycin.",
"affiliations": "Clínica Rementería, Madrid, Spain.;Clínica Rementería, Madrid, Spain.;Clínica Rementería, Madrid, Spain.;Clínica Rementería, Madrid, Spain.",
"authors": "Sánchez-Sánchez|Carmen|C|;Puerto|Beatriz|B|;López-Caballero|Cristina|C|;Contreras|Inés|I|",
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"doi": "10.1016/j.ajoc.2020.100639",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30029-3\n10.1016/j.ajoc.2020.100639\n100639\nCase Report\nUnilateral acute iris depigmentation and transillumination after glaucoma surgery with mitomycin application and intracameral moxifloxacin\nSánchez-Sánchez Carmen a Puerto Beatriz ab López-Caballero Cristina ab Contreras Inés contreras@clinicarementeria.esabc∗∗ a Clínica Rementería, Madrid, Spain\nb Hospital Universitario Ramón y Cajal, Madrid, Spain\nc Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain\n∗ Corresponding author. Clínica Rementería, c/ Almagro 36 Entreplanta Dcha, 28010, Madrid, Spain. contreras@clinicarementeria.es\n27 2 2020 \n6 2020 \n27 2 2020 \n18 10063913 10 2019 22 2 2020 25 2 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nBilateral acute iris depigmentation (BADI) and transillumination (BATI) syndromes have been linked with the use of antibiotics, especially fluoroquinolones. They are characterized by acute onset of pigment dispersion in the anterior chamber, depigmentation of the iris and pigment deposition in the angle and in the posterior surface of the cornea (BADI), with iris transillumination defects and atonic pupil with sphincter paralysis (BATI). The purpose of this paper is to report the development of clinical depigmentation and iris damage similar to BADI and BATI in patients who had undergone uneventful glaucoma surgery with intracameral moxifloxacin as prophylaxis for endophthalmitis.\n\nObservations\nFour patients who had undergone Ex-Press implantation (cases 1 and 2) or non-penetrating deep sclerotomy (cases 3 and 4) developed asymptomatic pigment dispersion in the anterior chamber, which cleared after treatment with topical corticosteroids and NSAIDS. However, pupillary damage ensued, with mid-midriasis and pigment deposition under the filtration bleb.\n\nConclusions and importance\nThis is, to the best of our knowledge, the first report of acute unilateral iris depigmentation and transillumination after intracameral use of moxifloxacin. Moxifloxacin's toxic effect may have been promoted by the subconjuntival mitomycin employed to prevent scarring at the filtration bleb. Surgeons should be aware of these potential side-effects of drugs used as widely as moxifloxacin and mitomycin.\n\nHighlights\n• Moxifloxacin is widely used as prophylaxis for endophthalmitis after cataract surgery.\n\n• Bilateral acute iris depigmentation and transillumination syndromes have been reported after the use of antibiotics.\n\n• We report four cases of similar syndromes in patients undergoing glaucoma surgery after intracameral moxifloxacin.\n\n\n\nKeywords\nIntracameral moxifloxacinGlaucoma surgeryAcute iris transilluminationAcute iris depigmentationMitomycin\n==== Body\n1 Introduction\nBilateral acute iris depigmentation (BADI) and bilateral acute iris transillumination (BATI) syndromes have been linked with the use of systemic antibiotics, most frequently fluoroquinolones.1, 2, 3 BADI is characterized by acute onset of pigment dispersion in the anterior chamber, depigmentation of the iris and pigment deposition in the angle and in the posterior surface of the cornea.1,2 Patients with BADI usually complain of red eye, pain and photophobia. In BATI, in addition to these findings, there are clinically evident iris transillumination defects and atonic pupil with sphincter paralysis.\n\nMore recently, unilateral cases of pigment dispersion similar to BADI and BATI have been reported after topical treatment with moxifloxacin.4 However, no cases have been reported up-to-date after intracameral use of moxifloxacin. The purpose of this paper is to report the development of clinical depigmentation and iris damage in patients who had undergone uneventful glaucoma surgery with intracameral moxifloxacin as prophylaxis for endophthalmitis. Institutional review board approval was obtained and informed consent for patient information and images to be published was provided by the patients.\n\n2 Findings\n2.1 Case 1\nA 52 year old man was diagnosed in 2010 with bilateral open-angle glaucoma. In September 2012 he underwent Ex-press shunt, P50 model (Alcon Laboratories, Fort Worth, TX, USA), implantation due to visual field progression in his left eye. A fornix-based conjunctival flap was made in the superior quadrant, then a 4 × 4 mm square-shaped scleral flap (of approximately one-third of the scleral thickness) was dissected 1.0 mm into the clear cornea. A surgical sponge soaked in 0.2 mg/ml mitomycin C was applied under the conjunctiva, over the scleral flap, for 90 s, followed by thorough irrigation with a balanced salt solution. A 1 mm clear-cornea temporal paracentesis was used to inject sodium hyaluronate 10 mg/mL into the anterior chamber. An incision into the anterior chamber parallel to the iris along the gray line was made with a 25-G needle under the scleral flap and the shunt was inserted using its applicator. The scleral flap was then closed with four 10–0 nylon sutures and the conjunctiva with 8–0 vicryl. At the end of the procedure, 0.1ml of 5mg/ml moxifloxacin was injected through the temporal paracentesis into the anterior chamber. Postoperative treatment prescribed was: moxifloxacin 5mg/ml 1 drop 4 times daily for ten days, diclofenac sodium 1mg/ml 1 drop three times daily for two weeks and prednisolone acetate 10mg/ml starting 6 times daily and tapered 1 drop per week.\n\nOne month after surgery, in a scheduled follow-up visit, pigment was detected in the anterior chamber. The patient was instructed to continue treatment with prednisolone three times daily and to reinitiate diclofenac three times daily. Two weeks later, there was no pigment in the anterior chamber, but there was in the filtration bleb and in the angle surrounding the Ex-press shunt (Fig. 1a and b). Intraocular pressure was 9 mmHg and the patient remained asymptomatic. During follow-up, there have been no further episodes of pigment dispersion. In April 2019, corrected visual acuity was 20/20 and intraocular pressure was 10 mmHg with no treatment. The left pupil was slightly dilated and the iris responded sluggishly to light (Fig. 1c).Fig. 1 Case 1. Six weeks after Ex-press filtration surgery and two weeks after detection of pigment dispersion, there was no pigment in the anterior chamber, but there was in the filtration bleb (A) and in the angle surrounding the shunt (B). Six years after surgery, the left pupil is slightly dilated and responds sluggishly to light, with no transillumination defects and a functioning filtration bleb (C).\n\nFig. 1\n\n2.2 Case 2\nA 65 year-old man with chronic angle closure glaucoma in his left eye was scheduled for glaucoma surgery because he did not tolerate topical treatment. He underwent isolated Ex-press shunt implantation in February 2016 (since he had previously undergone cataract surgery in 2015). Surgery was performed as described above, with the same postoperative treatment regime.\n\nThere were no initial postoperative complications. One week after surgery, the anterior chamber was quiet and intraocular pressure was 6 mmHg. However, two weeks later there was ample pigment in the anterior chamber, with no other inflammatory signs. The patient was by then using only prednisolone 3 times daily; he was told to extend treatment for a further twenty days and to add cyclopentolate 10mg/ml one drop daily for one week. Five weeks after surgery, there was almost no free pigment in the anterior chamber, but there was pigment under the filtering bleb and the pupil was fixed in mid-dilation. Intraocular pressure was 10 mmHg. The patient has been followed-up regularly, with no new episodes of pigment dispersion or inflammation. In March 2019, he remained asymptomatic, corrected visual acuity was 20/25, intraocular pressure remained low with no treatment (14 mmHg), there remained slight pigmentation of the filtering bleb and pupil mid-dilation.\n\n2.3 Case 3\nA 76 year-old woman, who had been diagnosed with glaucoma in 2008, pseudophakic, with Fuchs corneal dystrophy, developed an allergic reaction to timolol and brimonidine and was unable to use brinzolamide due to a very low endothelial count. In November 2016 she underwent uneventful non-penetrating deep sclerotomy (NPDS) in her left eye. A corneal traction suture was placed before dissecting a superior fornix-based conjunctival flap. A 5 × 5 mm square superficial scleral flap was dissected at the superior quadrant and extended anteriorly 1 mm into clear cornea. Then mitomycin C was applied under the conjunctiva for 40 s. A second triangular scleral flap was cut, and dissection continued anteriorly, beyond Schlemm's canal to expose the trabeculo-Descemet membrane. A temporal 1-mm paracentesis was performed to decrease intraocular pressure. The inner wall of Schlemm's canal was peeled with a forceps and the deep scleral flap removed. A supra-ciliary hema implant (Esnoper V-2000, AJL Ophthalmic, Álava, Spain) was sutured in the scleral bed with a 10–0 nylon suture. The superficial scleral flap was closed with two Nylon sutures. At the end of the procedure, 0.1ml of 5mg/ml moxifloxacin was injected through the temporal paracentesis. Postoperative treatment was the same as for Ex-press implantation.\n\nThere was initial corneal edema which resolved after one week. At the one-month follow-up visit, there was pigment in the anterior chamber, significant pigment deposition on the endothelial surface in the visual axis, the iris was dilated and responded poorly to light (Fig. 2a). The patient was using prednisolone thrice daily and diclofenac thrice daily; she was instructed to increase prednisolone to one drop four times daily and to taper it slowly. Two weeks later there was no pigment in the anterior chamber. The iris remained unresponsive. Intraocular pressure was 14 mmHg without treatment and corrected visual acuity was 20/25. In February 2017, the patient was seen with an intraocular pressure of 42 mmHg due to the obstruction of the trabeculo-descemet membrane by pigment deposition. After laser goniopuncture, intraocular pressure dropped to 17 mmHg. The patient was last seen in November 2017. Corrected visual acuity was 20/32, intraocular pressure was 16 mmHg with latanoprost and timolol in a fixed combination and she was being treated with fluormetalone once daily and sodium chloride 5% thrice daily for her corneal decompensation due to Fuchs dystrophy. There was diffuse iris transillumination with a mid-dilated pupil and pigment deposition at the edge of the scleral window (Fig. 2b and c).Fig. 2 Case 3. (A) One month after uneventful non-penetrating deep-sclerotomy there was pigment in the anterior chamber, significant pigment deposition on the endothelial surface in the visual axis, the iris was dilated and responded poorly to light. One year after surgery, there was diffuse iris transillumination with a mid-dilated pupil (B) and pigment deposition at the edge of the scleral window (C).\n\nFig. 2\n\n2.4 Case 4\nA 64 year-old woman, diagnosed with bilateral primary open-angle glaucoma in 2012, was scheduled for glaucoma surgery in her right eye due to visual field progression while treated with maximum topical treatment. In April 2019, NPDS was performed as described above.\n\nThe early postoperative visits were unremarkable, but three weeks after surgery pigment was noted in the anterior chamber and under the filtration bleb. The patient was using prednisolone thrice daily. Diclofenac thrice daily was added. Six weeks after surgery, there was no pigment in the anterior chamber but plenty under the filtration bleb. Corrected visual acuity was 20/20 and intraocular pressure was 12 mmHg. Ten weeks after surgery, the anterior chamber remained quiet, with pigment under the filtration bleb (Fig. 3a), inferior transillumination defects (Fig. 3b), an irregular pupil (Fig. 3c) and controlled intraocular pressure with no topical hypotensive or anti-inflammatory treatment.Fig. 3 Case 4. Three weeks after uneventful non-penetrating deep sclerotomy, pigment was noted in the anterior chamber and under the filtration bleb. Ten weeks after surgery, the anterior chamber remained quiet, with pigment under the filtration bleb (A), inferior transillumination defects (B), an irregular pupil (C).\n\nFig. 3\n\n3 Discussion\nBADI and BATI are clinical entities which have been reported after systemic use of antibiotics, especially fluorquinolones, which share the characteristic of intense pigment release into the anterior chamber. They differ in the main tissue affected: the iris stroma in BADI and the iris pigment epithelium in BATI. Recently, several cases of BADI have been reported after topical treatment with fluorquinolones (with no documented oral intake) with unilateral presentation.4\n\nIn this paper we report four cases of pigment dispersion similar to BADI (cases 1 and 2) and BATI (cases 3 and 4), which developed after uneventful glaucoma surgery with mitomycin C application and intracameral moxifloxacin. Topical moxifloxacin was also used as prophylaxis for endophthalmitis. Patients were asymptomatic, with pigment detected in the anterior chamber during scheduled follow-up visits. Pigment release ceased after 2–3 weeks of treatment with topical steroids and non-steroidal anti-inflammatory drugs, with pigment deposition in the filtration bleb. There were iris transillumination defects in two patients and pupillary damage in all cases, with different degrees of sphincter paralysis. In three cases pupillary mid-dilation did not affect visual acuity and the success of filtration surgery was not compromised. In case 3, the patient had advanced Fuchs dystrophy, which might have increased the clinical repercussion of pigment showering. Pigment deposition in the scleral window led to an intraocular pressure spike, which resolved after goniopuncture. However, in addition of pigment deposition, corneal damage progressed, leading to visual acuity worsening.\n\nIn contrast to previous reports on BADI and BATI, the patients in our series were initially asymptomatic and there were no intraocular pressure rises (except as commented in case 3). This was probably due to the fact that the patients were receiving treatment with topical steroids, which would have limited the inflammatory response to pigment dispersion.\n\nThe mechanism by which moxifloxacin might lead to pigment dispersion is unclear. Several reports have suggested that moxifloxacin might be toxic to iris melanocytes. Mahanty et al. evaluated the toxicity of topical moxifloxacin by measuring both the activity and the presence of the melanogenic enzyme tyrosinase (TYR) in aqueous humor specimens taken just before cataract surgery. Although there was no increase in TYR activity after treatment with moxifloxacin, immunoblotting analysis showed the presence of soluble TYR enzyme.5 The authors speculated that this might be due to the inhibitory effect moxifloxacin has on TYR activity. None of the patients in their series developed any clinically appreciable ocular side effects characteristic of BATI or BADI. Interestingly, the aqueous TYR activity within the group was quite variable possibly due to variability in the effective concentration of antibiotics on iris melanocyte toxicity among the patients.5\n\nPerin et al. reported that moxifloxacin had a significant toxic effect on cultivated human iris pigment epithelium (hIPE) cells: at 100μg/mL, cell viability decreased to 84.12% relative to the control group.6 This toxicity effect increased with greater concentrations, and at 500μg/mL cell viability decreased to 59.09%. Moxifloxacin concentrations might come up to 150μg/mL with intracameral administration.6 However, there must clearly be some other factor influencing moxifloxacin toxicity, since no reports of BATI, BADI, or moxifloxacin-associated uveitis have been reported up-to-date following intracameral administration, in spite of the widespread use of moxifloxacin for endophthalmitis prevention after cataract surgery.7,8 We speculate that in our series, moxifloxacin toxicity may have been promoted by mitomycin C application.\n\nMitomycin C is used in glaucoma surgery to reduce fibroblast activity and postoperative scarring at the site of the scleral flap and the subconjunctival space. It reduces the relative risk of failure of trabeculectomy and leads to a lower intraocular pressure twelve months after filtration surgery compared to surgery performed with no antimetabolite application.9 Although mitomycin C use seems to lead to an increased risk of bleb leak, hypotony and endophthalmitis, no significant increase in permanent sight-threatening complications was detected in a 2015 Cochrane review.9 In a survey completed in 2016 by glaucoma surgeons, 97% reported using mitomycin C when performing trabeculectomy.10 In our center, patients undergoing isolated glaucoma surgery with mitomycin C also receive intracameral moxifloxacin to decrease the risk of endophthalmitis.\n\n4 Conclusion\nWe report four cases of unilateral pigment dispersion, with iris transillumination defects in two of them, and pupillary mid-dilation after uneventful glaucoma surgery with intracameral moxifloxacin. It appears to be a rare side effect which develops in certain patients and of which glaucoma surgeons should be aware.\n\nPatient consent\nInformed consent for patient information and images to be published was provided by the patients.\n\nDeclaration of competing interest\nThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\n\nAcknowledgments and Disclosures section\nNo funding or grant support. The Authors declare that there is no conflict of interest. All authors attest that they meet the current ICMJE criteria for Authorship.\n==== Refs\nReferences\n1 Tugal-Tutkun I. Urgancioglu M. Bilateral acute depigmentation of the iris Graefes Arch Clin Exp Ophthalmol 244 6 2006 742 746 16205935 \n2 Tugal-Tutkun I. Araz B. Taskapili M. Bilateral acute depigmentation of the iris: report of 26 new cases and four-year follow-up of two patients Ophthalmology 116 8 2009 1552 1557 19545903 \n3 Tugal-Tutkun I. Onal S. Garip A. Bilateral acute iris transillumination Arch Ophthalmol 129 10 2011 1312 1319 21987674 \n4 Kawali A. Mahendradas P. Shetty R. Acute depigmentation of the iris: a retrospective analysis of 22 cases Can J Ophthalmol 54 1 2019 33 39 30851772 \n5 Mahanty S. Kawali A.A. Dakappa S.S. Aqueous humor tyrosinase activity is indicative of iris melanocyte toxicity Exp Eye Res 162 2017 79 85 28712540 \n6 Perin A. Lyzogubov V. Bora N. In vitro assessment of moxifloxacin toxicity to human iris pigment epithelium Invest Ophthalmol Vis Sci 56 2015 5729 \n7 Melega M.V. Alves M. Cavalcanti Lira R.P. Safety and efficacy of intracameral moxifloxacin for prevention of post-cataract endophthalmitis: randomized controlled clinical trial J Cataract Refract Surg 45 3 2019 343 350 30691922 \n8 Bowen R.C. Zhou A.X. Bondalapati S. Comparative analysis of the safety and efficacy of intracameral cefuroxime, moxifloxacin and vancomycin at the end of cataract surgery: a meta-analysis Br J Ophthalmol 102 9 2018 1268 1276 29326317 \n9 Wilkins M. Indar A. Wormald R. Intra-operative mitomycin C for glaucoma surgery Cochrane Database Syst Rev 4 2005 CD002897 \n10 Vinod K. Gedde S.J. Feuer W.J. Practice preferences for glaucoma surgery: a survey of the American glaucoma society J Glaucoma 26 8 2017 687 693 28692597\n\n",
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"title": "Unilateral acute iris depigmentation and transillumination after glaucoma surgery with mitomycin application and intracameral moxifloxacin.",
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"abstract": "Medication related osteonecrosis of the jaw (MRONJ) is a commonly observed adverse reaction after taking anti-resorption and anti-angiogenic drugs. As we all know, arsenic compounds are used as drugs for pulp devitalization therapy and its local diffusion can cause osteonecrosis. As the treatment of leukemia, the medical records of osteonecrosis are rarely reported. Arsenic compounds may be a potential risk factor for osteonecrosis, which should be brought to the attention of dentists.",
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"title": "Chemotherapeutics-induced osteonecrosis of the jaw in a patient with acute promyelocytic leukemia: A rare case report.",
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"abstract": "Prescribing patterns and appropriateness of morphine use in a neonatal intensive care unit (NICU) were evaluated in a concurrent drug-use evaluation (DUE). Data were collected for 99 infants who received morphine over a six-month period. Patient charts were reviewed to collect the following data: patient's age, weight, dosage schedule, concurrent sedatives, ventilatory status, whether adequacy of analgesia was documented, and descriptions of adverse drug reactions (ADRs). The physicians' orders were reviewed to determine whether NICU morphine dosage guidelines were followed and whether the indication for use was noted. Seven ADRs occurred in six of the patients; three of the ADRs occurred after ophthalmic cryosurgery. Indications for use were noted in 79 of 285 physician orders (27.7%). The adequacy of sedation or analgesia was documented on 60 of the 360 patient days (16.7%). The DUE results prompted several changes: physicians were asked to select indications from a list in the computerized order-entry system, an analgesia or sedation assessment scale was added to nursing flow sheets, and endotracheal intubation became a requirement before ophthalmic cryosurgery. A follow-up DUE showed nearly complete compliance with the new guidelines for morphine use and a reduction in the number of adverse reactions to morphine. A DUE prompted policy changes that improved documentation of indications for and efficacy of morphine use and reduced adverse reactions to the drug in an NICU.",
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"abstract": "BACKGROUND Fabry disease is a rare and progressive X-linked inherited disorder of glycosphingolipid metabolism that is due to deficient or absent lysosomal a-galactosidase A activity. Among its other associated signs and symptoms, patients present with renal failure and proteinuria, which are markers of disease progression. Renin-angiotensin-aldosterone system (RAAS) blockers can slow the progression of chronic renal failure and proteinuria. In fact, some studies have shown the beneficial effects of paricalcitol on proteinuria. CASE REPORT We present a case of a female patient with the classic variant of Fabry disease. She was treated with a high dose of paricalcitol as an antiproteinuric agent due to unsatisfactory double-RAAS blockage, which resulted in transient worsening of cardiac and renal function. CONCLUSIONS Despite the positive effects of paricalcitol as an antiproteinuric agent, as previously shown by some authors, our case highlights the possible serious adverse effects associated with the use of high doses of this drug.",
"affiliations": "Department of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.;Department of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.;Department of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.;Department of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.;Department of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.;Department of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, Slovenia.",
"authors": "Keber|Tajda|T|;Tretjak|Martin|M|;Cokan Vujkovac|Andreja|A|;Mravljak|Marija|M|;Ravber|Katja|K|;Vujkovac|Bojan|B|",
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"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2859651210.12659/AJCR.903886903886ArticlesParicalcitol as an Antiproteinuric Agent Can Result in the Deterioration of Renal and Heart Function in a Patient with Fabry Disease Keber Tajda ABCDEFTretjak Martin BCDEFVujkovac Andreja Cokan BDEFMravljak Marija DERavber Katja DEVujkovac Bojan ABCDEFGDepartment of Internal Medicine, General Hospital Slovenj Gradec, Slovenj Gradec, SloveniaAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Tajda Keber, e-mail: tajda.keber@sb-sg.si2017 09 6 2017 18 644 648 19 2 2017 28 3 2017 © Am J Case Rep, 20172017This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 44\n\nFinal Diagnosis: Deterioration of renal and heart function\n\nSymptoms: Hypercalcemia\n\nMedication: —\n\nClinical Procedure: Laboratory\n\nSpecialty: Nephrology\n\nObjective:\nRare disease\n\nBackground:\nFabry disease is a rare and progressive X-linked inherited disorder of glycosphingolipid metabolism that is due to deficient or absent lysosomal α-galactosidase A activity. Among its other associated signs and symptoms, patients present with renal failure and proteinuria, which are markers of disease progression. Renin-angiotensin-aldosterone system (RAAS) blockers can slow the progression of chronic renal failure and proteinuria. In fact, some studies have shown the beneficial effects of paricalcitol on proteinuria.\n\nCase Report:\nWe present a case of a female patient with the classic variant of Fabry disease. She was treated with a high dose of paricalcitol as an antiproteinuric agent due to unsatisfactory double-RAAS blockage, which resulted in transient worsening of cardiac and renal function.\n\nConclusions:\nDespite the positive effects of paricalcitol as an antiproteinuric agent, as previously shown by some authors, our case highlights the possible serious adverse effects associated with the use of high doses of this drug.\n\nMeSH Keywords:\n25-Hydroxyvitamin D 2Fabry DiseaseHeart Failure, DiastolicProteinuriaRenal Insufficiency\n==== Body\nBackground\nFabry disease (FD, OMIM ID #301500) is a rare and progressive X-linked inherited disorder of glycosphingolipid metabolism. As a result of deficient or absent lysosomal α-galactosidase A activity, globotriaosylceramide accumulates in the tissues and organs and leads to their functional impairment. Classically, FD affects hemizygous males (severe disease), while heterozygous females present with symptoms that range from very mild to severe disease. The disease presents with neurological pain, diffuse angiokeratoma, proteinuria, progressive kidney failure, cardiomyopathy, and arrhythmia, as well as hearing and cerebrovascular (transient ischemic attack, stroke) symptoms. Diagnosis in males is usually established based on low α-galactosidase A activity, whereas in females, it is confirmed with genetic testing [1,2].\n\nProteinuria is a marker of chronic kidney disease (CKD) progression and can predict cardiovascular disease development or death regardless of the cause of CKD [3]. Renin-angiotensin-aldosterone system (RAAS) blockers represent the basis of anti-proteinuric and renoprotective treatment. Many patients have residual proteinuria despite RAAS blockage, even with double-RAAS blockade [4]. Moreover, vitamin D receptor activators have been used in the management of secondary hyperparathyroidism in CKD for several decades [5]. Short-term studies in humans suggest that treatment with vitamin D receptor activators (such as paricalcitol) can reduce proteinuria [4,6]. These agents are efficient not only as a monotherapy, but also as an adjuvant therapy to conventional RAAS blockers [5]. Several animal studies suggest that the renoprotective properties of vitamin D may be mediated by the suppression of RAAS. Although it primarily functions by suppressing renin production; it has also been suggested that it may also act by reducing renal inflammation and preserving the glomerular slit diaphragm [6,7].\n\nProteinuria is the hallmark of Fabry nephropathy and it presents as the predominant risk factor for CKD progression in FD. It is known that enzyme replacement therapy (ERT) alone does not decrease proteinuria; therefore, it is recommended that patients receiving ERT should also receive RAAS inhibitors [1]. The use of paricalcitol to treat proteinuria was recognized by experts [2,8] as a possible therapeutic approach when administered in combination with RAAS blockers.\n\nIn this report, we present a case of a female patient who presented with the classic variant of FD. She came to our clinic with multi-organ involvement and low α-galactosidase A activity. She was subsequently treated with a high dose of paricalcitol, which was used as an antiproteinuric agent, due to unsatisfactory double-RAAS blockade. The treatment course resulted in the transient and reversible worsening of her cardiac and renal function.\n\nCase Report\nA 55-year-old female, ex-smoker, with arterial hypertension, depression, chronic joint pain, and chronic obstructive pulmonary disease was diagnosed with the classic variant of FD featuring multi-organ involvement at the age of 44. Her genetic tests were positive for the disease, and she also exhibited low α-galactosidase A activity (4.6% of normal enzyme activity). At diagnosis, she was already in the advanced stages of the disease, as she predominantly presented with heart (left ventricular concentric hypertrophy with diastolic dysfunction), renal (a mildly reduced glomerular filtration rate [GFR] and non-nephrotic proteinuria), and nervous system (dizziness and depression) involvement. Signs of the disease in other organs were also present, as her eyes (cornea verticillata), skin (anhidrosis and angiokeratoma), and gastrointestinal tract (occasional diarrhea) were affected. A kidney biopsy revealed extensive typical inclusions of globotriaosylceramide in the podocytes and distal tubules with moderate vascular changes.\n\nShe began ERT with agalsidase alfa at the age of 45 years. She was already receiving an angiotensin-converting enzyme inhibitor as an antihypertensive treatment at the time of diagnosis. A year later, she started treatment with an angiotensin-receptor blocker for additional antiproteinuric effects.\n\nAt the age of 50 years, there was an increase in the protein-uria-to-nephrotic range despite dual RAAS blockage. As such, administration of an additional antiproteinuric agent (paricalcitol, 1 µg/day) was initiated. Two years later, the paricalcitol dose was increased to 2 µg/day in an attempt to lower her further increased levels of proteinuria. We recorded a slight decrease in her proteinuria, but it was still within the nephrotic range. At that point, a kidney biopsy was suggested to exclude other possible causes of her high-grade proteinuria, but she refused. In agreement with the patient, a high dose of paricalcitol was attempted, and the dose was further increased to 4 µg/day. Two weeks later, we noticed a slight increase in her total serum calcium, high-sensitive troponin T (hs-TnT), and N-terminal-pro-brain natriuretic peptide (NTproBNP) levels, whereas ionized calcium remained the same. We continued the treatment since the patient was asymptomatic. She was regularly monitored in clinic every two weeks and she developed no new symptoms. At her next regular laboratory testing, we also performed several functional tests. We noticed a slight decrease in her proteinuria (but it was still within the nephrotic range); however, there was also a further, more prominent increase in the patient’s serum creatinine, cystatin C, calcium, hsTnT, and NTproBNP concentrations. In addition, the patient’s serum intact parathormone (iPTH) levels and measured GFR had markedly decreased. Echocardiography revealed worsening of her diastolic dysfunction and an increase in the left ventricular filling pressure (Table 1). An electrocardiogram showed no changes that were characteristic of hypercalcemia. Despite all of the serological and echocardiographic changes, the patient remained asymptomatic at all times. Furthermore, other potential causes of renal and cardiac function worsening were eliminated and paricalcitol therapy was discontinued.\n\nThe patient’s calcium and iPTH levels normalized within 14 days after paricalcitol discontinuation (Figure 1). There was also a rapid and marked decrease in her serum creatinine levels (Figure 1), and the measured GFR recovered to baseline levels. The NTproBNP levels declined, while the left ventricular filling pressure decreased; however, the patient’s diastolic dysfunction (according to tissue Doppler of the mitral annulus) remained unchanged.\n\nAfter 1.5 years without paricalcitol, the patient is now on 1 µg of paricalcitol a day with close and regular monitoring of her serum calcium, phosphate, and iPTH levels. Due to the marked decrease in her renal function in the last three years, another kidney biopsy was suggested; however, the patient rejected it once more. She is now taking part in a program to prepare her for renal replacement therapy.\n\nDiscussion\nAlthough not registered as a standard antiproteinuric treatment, Pisani et al. have shown that treatment with 1 µg of paricalcitol per day significantly reduced proteinuria in 15 patients with FD nephropathy. These patients were previously on a stable dose of RAAS inhibitors, which was titrated to the maximum tolerated dose [7]. The maximal registered dosage regimen of 2 µg of paricalcitol per day is used for the treatment of secondary hyperparathyroidism [9].\n\nERT with dual RAAS blockage did not prevent or decrease proteinuria in our patient. She also had an unsatisfactory response to a standard regimen of 1 µg/day of paricalcitol. There was a slow progressive increase in the patient’s creatinine, calcium, and NTproBNP levels. We recorded a slight decrease in her proteinuria following the initiation of a higher paricalcitol dose (2 µg), which led to the initiation of a 4 µg paricalcitol treatment regimen in an attempt to further diminish her proteinuria. Soon after, we noticed that the patient developed hypercalcemia, and she also presented with laboratory signs of renal and cardiac function deterioration. Increased hsTnT values could suggest additional myocardial cell damage.\n\nIt has been reported that paricalcitol overdose as a consequence of aggressive treatment can result in increased blood urea and aminotransferases, as well as in hypertension and heart rhythm disorders, which are primarily related to acute hypercalcemia [9]. We did not notice any changes that were characteristic of hypercalcemia on electrocardiogram; furthermore, our patient developed no new symptoms, which suggests that her hypercalcemia was chronic in origin. It is not well established whether her hypercalcemia caused her worsening cardiac and renal function.\n\nThe current literature does not report any long-term associations between paricalcitol treatments and changes in left-ventricular structure, systolic or diastolic function, or NTproBNP levels [10,11]. In fact, Virtanen et al. showed that acute hypercalcemia can impair left-ventricular diastolic function, i.e., by decreasing the peak early diastolic velocity (E) and increasing peak late diastolic velocity (A) in CKD patients, whereas Ohara et al. were able to establish a relationship between changes in diastolic function and high levels of PTH, but not with hypercalcemia [12,13]. In addition, there was no negative impact of paricalcitol on renal function, whereas hypercalcemia can provoke acute renal failure [14–16].\n\nThe literature does not provide enough information on the effects of paricalcitol on renal and cardiac function at doses higher than 1 µg, as used in our patient. The fact that the laboratory findings returned to baseline following paricalcitol discontinuation could suggest that there may be a causal relationship. However, there is also a clear connection between hypercalcemia and renal failure, which may have also resulted in renal impairment in our patient. Hypercalcemia can also lead to worsening cardiac diastolic function, but the precise nature of this relationship remains unclear due to contradictory literature findings.\n\nConclusions\nDespite the positive effects of paricalcitol as an antiproteinuric agent, as previously shown by some authors, our case serves as an example of the possible serious adverse events that may occur when high doses of paricalcitol are used. In this case, only minor antiproteinuric effects were achieved.\n\nOur experience suggests that when used as an antiproteinuric agent, only standard regimen doses of paricalcitol (1 µg/day) should be used. The mechanisms underlying the worsening of cardiac and renal function in our case were not completely understood; however, improvements in the patient’s laboratory and functional findings following paricalcitol discontinuation demonstrated a causal relationship.\n\nBojan Vujkovac, Martin Tretjak, and Andreja Cokan Vujkovac received honoraria, travel, and accommodation funding from the Sanofi Genzyme & Shire companies. Bojan Vujkovac is a member of the EU Advisory Board of the Fabry Registry, which is sponsored by Sanofi Genzyme. English-language editing of this manuscript was provided by Journal Prep.\n\nConflict of interest\n\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1. Proteinuria (from 24-hour urine samples), ionized calcium, creatinine, and NT-pro-BNP levels. The first blue dot represents the initiation of paricalcitol therapy, while the second and third dots mark the increases in the daily dose of paricalcitol. The dashed line represents termination of the paricalcitol treatment. Alcium and creatinine levels are reported in millimoles per liter, while NT-pro BNP is reported in picograms per milliliter.\n\nTable 1. Echocardiographic parameters (obtained by the same echocardiographist). Treatment with paricalcitol was terminated after the November 2014 exam.\n\nDate\tNov. 2012\tNov. 2013\tNov. 2014\tNov. 2015\t\nLA (ml/m2)\t23\t24\t30\t23\t\nE’ (cm/s)\t4.5\t4\t2.9\t3.0\t\nS′ (cm/s)\t6.4\t5.5\t5.1\t5\t\nE/E’\t17\t18\t37\t27\t\nE (m/s)\t0.8\t0.7\t1.1\t0.8\t\nA (m/s)\t0.7\t0.8\t0.9\t0.8\t\nE/A\t1.1\t0.9\t1.2\t1\t\nLA – left atrium; E′ – early diastolic septal tissue Doppler velocity; S′ – systolic septal tissue Doppler velocity; E – early diastolic transmitral velocity; A – late diastolic transmitral velocity.\n==== Refs\nReferences:\n1. Germain DP Fabry disease Orphanet J Rare Dis 2010 5 30 21092187 \n2. Terryn W Cochat P Froissart R Fabry nephropathy: indications for screening and guidance for diagnosis and treatment by the European Renal Best Practice Nephrol Dial Transplant 2013 28 3 505 17 23234755 \n3. Eknoyan G Hostetter T Bakris GL Proteinuria and other marker of chronic kidney disease: a position statement of the national kidney foundation (NKF) and the national institute of diabetes and digestive and kidney diseases (NIDDK) Am J Kidney Dis 2003 42 4 617 22 14520612 \n4. De Lorenzo A Salanova L Bomback AS Oral paricalcitol as antiproteinuric agent in chronic kidney disease Nefrologia 2013 33 5 709 15 24089163 \n5. De Borst MH Hajhosseiny R Tamez H Active vitamin D treatment for reduction of residual proteinuria: A systematic review J Am Soc Nephrol 2013 24 11 1863 71 23929770 \n6. Larsen T Mose FH Bech JN Pedersen EB Effect of paricalcitol on renin and albuminuria in non-diabetic stage III–IV chronic kidney disease: A randomized placebo-controlled trial BMC Nephrology 2013 14 163 23889806 \n7. Pisani A Sabbatini M Duro G Antiproteinuric effect of add-on paricalcitol in Fabry disease patients: A prospective observational study Nephrol Dial Transplant 2015 30 4 661 66 25143556 \n8. Schiffmann R Hughes DA Linthorst GE Screening, diagnosis, and management of patients with Fabry disease: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference Kidney Int 2017 91 2 284 93 27998644 \n9. Zemplar- Summaryof product Characteristics (SPC)- (Emc) medicines.org.uk . 2016 Web. 11 Sep. 2016. Available from: URL: http//www.medicines.org.uk/emc/medicine/20464 \n10. Hansen D Rasmussen K Rasmussen LM The influence of vitamin D analogs on calcification modulators, N-terminal pro-B-type natriuretic peptide and inflammatory markers in hemodialysis patients: a randomized crossover study BMC Nephrology 2014 15 130 25112372 \n11. Wang AYM Fang F Chan J Effect of paricalcitol on left ventricular mass and function in CKD – The OPERA Trial J Am Soc Nephrol 2014 25 1 175 86 24052631 \n12. Virtanen VK Saha HH Grounstroem KW Calcium infusion and left ventricular diastolic function in patients with chronic renal failure Nephrol Dial Transplant 1998 13 2 384 88 9509450 \n13. Ohara N Hiramatsu K Shigematsu S Effect of parathyroid hormone on left ventricular diastolic function in patients with primary hyperparathyroidism Miner Electrolyte Metab 1995 21 1–3 63 66 7565464 \n14. Hadjiyannakos D Filiopoulus V Trompouki S Treatment with oral paricalcitol in daily clinical practice for patients with chronic kidney disease stage 3–4: A preliminary study Clin Kidney J 2013 6 2 164 68 26019845 \n15. Han T Rong G Quan D Meta-analysis: The efficacy and safety of paricalcitol for the treatment of secondary hyperparathyroidism and proteinuria in chronic kidney disease Biomed Res Int 2013 2013 320560 23509710 \n16. Moyses-Neto M Guimaraes FM Ayoub F Acute renal failure and hypercalcemia Ren Fail 2006 28 2 153 59 16538974\n\n",
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"title": "Paricalcitol as an Antiproteinuric Agent Can Result in the Deterioration of Renal and Heart Function in a Patient with Fabry Disease.",
"title_normalized": "paricalcitol as an antiproteinuric agent can result in the deterioration of renal and heart function in a patient with fabry disease"
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"abstract": "Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are well-established means of improving glycemia and preventing cardio-renal events in patients with type 2 diabetes. However, their efficacy and safety have yet to be fully characterized in patients with type 1 diabetes (T1D). We studied patients with T1D who regularly attended one of five diabetes centers and treated with an SGLT2i (ipragliflozin or dapagliflozin) for >52 weeks, and the changes in HbA1c, body mass, insulin dose, and laboratory data were retrospectively evaluated and adverse events (AEs) recorded during December 2018 to April 2021. A total of 216 patients with T1D were enrolled during the period. Of these, 42 were excluded owing to short treatment periods and 15 discontinued their SGLT2i. The mean changes in glycated hemoglobin (HbA1c), body mass, and insulin dose were -0.4%, -2.1 kg, and -9.0%, respectively. The change in HbA1c was closely associated with the baseline HbA1c (p < 0.001), but not with the baseline body mass or renal function. The basal and bolus insulin doses decreased by 18.2% and 12.6%, respectively, in participants with a baseline HbA1c <8%. The most frequent AE was genital infection (2.8%), followed by diabetic ketoacidosis (DKA; 1.4%). None of the participants experienced severe hypoglycemic events. In conclusion, the administration of an SGLT2i in addition to intensive insulin treatment in patients with T1D improves glycemic control and body mass, without increasing the incidence of hypoglycemia or DKA.",
"affiliations": "Yuri Ono Clinic, Diabetes, Internal Medicine, Sapporo 060-0001, Japan.;Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.;Kurihara Clinic, Sapporo 004-0053, Japan.;Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.;Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.;Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.;Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.;Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.;Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.;Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.;Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.;Diabetes Center, Manda Memorial Hospital, Sapporo 060-0062, Japan.;Kurihara Clinic, Sapporo 004-0053, Japan.;Aoki Clinic, Sapporo 003-0023, Japan.;Yuri Ono Clinic, Diabetes, Internal Medicine, Sapporo 060-0001, Japan.;Department of Rheumatology, Endocrinology and Nephrology, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.",
"authors": "Kamoshima|Hikaru|H|;Nomoto|Hiroshi|H|;Yamashita|Kumiko|K|;Takahashi|Yuka|Y|;Tsuchida|Kazuhisa|K|;Kuwabara|Saki|S|;Miya|Aika|A|;Cho|Kyu Yong|KY|;Kameda|Hiraku|H|;Nakamura|Akinobu|A|;Atsumi|Tatsuya|T|;Taneda|Shinji|S|;Kurihara|Yoshio|Y|;Aoki|Shin|S|;Ono|Yuri|Y|;Miyoshi|Hideaki|H|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1507/endocrj.EJ21-0573",
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"issn_linking": "0918-8959",
"issue": null,
"journal": "Endocrine journal",
"keywords": "Diabetic ketoacidosis; Sodium-glucose cotransporter 2 inhibitor; Type 1 diabetes",
"medline_ta": "Endocr J",
"mesh_terms": null,
"nlm_unique_id": "9313485",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34819409",
"pubdate": "2021-11-25",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Do the benefits of sodium-glucose cotransporter 2 inhibitors exceed the risks in patients with type 1 diabetes?",
"title_normalized": "do the benefits of sodium glucose cotransporter 2 inhibitors exceed the risks in patients with type 1 diabetes"
} | [
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"activesubstancename": "DAPAGLIFLOZIN"
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"abstract": "We experienced two cases of flexor tendons rupture after triamcinolone acetate (TA) injection for trigger finger. A 45-year-old man underwent injection of 40 mg of TA and 1 mL of 1% lidocaine solution into his little finger. While playing golf 3 months after the injection, he heard a popping sound, and was unable to flex it. A 57-year-old female nurse had undergone injection of 40 mg of TA and 1 mL of 1% lidocaine solution into her thumb twice at a 2-month interval. Two months after the second injection, she was unable to flex it. Both cases had high concentrated TA injection at trigger digits. The present and previous cases illustrate that when TA is injected into trigger digits, the dose should be low, the safety interval should be long, and refuse injection into the tendon proper.",
"affiliations": "1 Department of Orthopedic Surgery, Kikkoman General Hospital, Chiba, Japan.;1 Department of Orthopedic Surgery, Kikkoman General Hospital, Chiba, Japan.;1 Department of Orthopedic Surgery, Kikkoman General Hospital, Chiba, Japan.;1 Department of Orthopedic Surgery, Kikkoman General Hospital, Chiba, Japan.;1 Department of Orthopedic Surgery, Kikkoman General Hospital, Chiba, Japan.;1 Department of Orthopedic Surgery, Kikkoman General Hospital, Chiba, Japan.",
"authors": "Tanaka|Toshikazu|T|;Ogawa|Takeshi|T|;Yanai|Takaji|T|;Okano|Eriko|E|;Kohyama|Sho|S|;Ochiai|Naoyuki|N|",
"chemical_list": "D005938:Glucocorticoids; D008012:Lidocaine; D014222:Triamcinolone Acetonide",
"country": "Singapore",
"delete": false,
"doi": "10.1142/S0218810417720285",
"fulltext": null,
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"issue": "22(3)",
"journal": "The journal of hand surgery Asian-Pacific volume",
"keywords": "Disruption; Flexor tendon; Injection; Triamcinolone acetonide; Trigger digit",
"medline_ta": "J Hand Surg Asian Pac Vol",
"mesh_terms": "D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007270:Injections, Intra-Articular; D008012:Lidocaine; D008297:Male; D008875:Middle Aged; D012421:Rupture; D013708:Tendon Injuries; D014222:Triamcinolone Acetonide; D052582:Trigger Finger Disorder",
"nlm_unique_id": "101688432",
"other_id": null,
"pages": "380-383",
"pmc": null,
"pmid": "28774233",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disruption of Flexor Tendon after Intrasheath Triamcinolone Acetonide Injection for Trigger Digits: Two Case Reports.",
"title_normalized": "disruption of flexor tendon after intrasheath triamcinolone acetonide injection for trigger digits two case reports"
} | [
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"companynumb": "JP-CMP PHARMA-2019CMP00011",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "LIDOCAINE"
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{
"abstract": "Drug-induced pigmentation accounts for up to 20% of all cases of acquired pigmentation. A thorough review of medical history and previous and ongoing medications as well as a complete skin examination can guide diagnosis. Implicated agents include alkylating/cytotoxic agents, analgesics, antiarrhythmics, anticoagulants, antiepileptics, antimalarials, antimicrobials, antiretrovirals, metals, prostaglandin analogs, and psychotropic agents, among others. Confirming true drug associations can be challenging, especially in the setting of delayed onset of pigmentation and coexisting polypharmacy.",
"affiliations": "Department of Dermatology, Beaumont-Farmington Hills, Farmington Hills, MI, USA.;Department of Dermatology, Henry Ford Hospital, 3031 W. Grand Blvd., Suite 800, Detroit, MI, 48202, USA.;Department of Dermatology, Henry Ford Hospital, 3031 W. Grand Blvd., Suite 800, Detroit, MI, 48202, USA. ihamzav1@hfhs.org.",
"authors": "Nahhas|Amanda F|AF|;Braunberger|Taylor L|TL|;Hamzavi|Iltefat H|IH|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40257-018-0393-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1175-0561",
"issue": "20(1)",
"journal": "American journal of clinical dermatology",
"keywords": null,
"medline_ta": "Am J Clin Dermatol",
"mesh_terms": "D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D017495:Hyperpigmentation; D019338:Polypharmacy; D012880:Skin Pigmentation",
"nlm_unique_id": "100895290",
"other_id": null,
"pages": "75-96",
"pmc": null,
"pmid": "30374894",
"pubdate": "2019-02",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "An Update on Drug-Induced Pigmentation.",
"title_normalized": "an update on drug induced pigmentation"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/19/0109092",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
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... |
{
"abstract": "α-fetoprotein (AFP)-secreting gastric cancer (AFP-GC) is a relatively rare, aggressive malignancy among all GC types. However, no GC case with simultaneous expression of AFP and epidermal growth factor receptor 2 (HER2) has been reported to date. To the best of our knowledge, the present report was the first to describe the use of apatinib to treat a patient with advanced GC characterized by AFP-secretion and HER2-positivity. An 86-year-old man with advanced GC was diagnosed with AFP-secretive and HER2-positive GC with liver metastasis at The Affiliated Hospital of Jiujiang University (Jiujiang, China). The patient received first-line (i.e., S-1 plus oxaliplatin) and second-line (i.e., docetaxel) chemotherapy combined with trastuzumab for two cycles, respectively. However, the disease progressed rapidly. Subsequently, apatinib was administered as third-line therapy. After two cycles of apatinib therapy, the patient reported the disappearance of upper abdominal pain and an improvement in his appetite. Furthermore, the AFP level had sharply decreased to 620 ng/ml. Subsequently, upper abdominal computed tomography imaging revealed that the gastric lesion and liver metastatic lesion had reduced in size by 67% and 24%, respectively, suggesting partial remission. Currently, the patient has continued to receive apatinib therapy. It was speculated that AFP-secretion status could contribute to the chemoresistance of HER2-positive GC. Apatinib may be a promising anticancer agent in the case of advanced AFP-producing and HER2-positive GC.",
"affiliations": "Undergraduate Department, The First Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China.;Department of Hematology and Oncology, The Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi 332000, P.R. China.",
"authors": "Ding|Xinjing|X|;Ding|Jianghua|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2021.2313",
"fulltext": "\n==== Front\nMol Clin Oncol\nMol Clin Oncol\nMCO\nMolecular and Clinical Oncology\n2049-9450\n2049-9469\nD.A. Spandidos\n\nMCO-0-0-02313\n10.3892/mco.2021.2313\nArticles\nEffective treatment of apatinib for chemotherapy-refractory advanced gastric carcinoma with AFP-secretion and HER2-positivity: A case report\nDing Xinjing 1\nDing Jianghua 2\n1 Undergraduate Department, The First Clinical Medical College of Nanchang University, Nanchang, Jiangxi 330006, P.R. China\n2 Department of Hematology and Oncology, The Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi 332000, P.R. China\nCorrespondence to: Dr Jianghua Ding, Department of Hematology and Oncology, The Affiliated Hospital of Jiujiang University, 57 Xunyang East Road, Jiujiang, Jiangxi 332000, P.R. China doctor0922@126.com\nAbbreviations: AFP, α-fetoprotein; HER2, epidermal growth factor receptor 2\n\n8 2021\n02 6 2021\n02 6 2021\n15 2 15128 7 2020\n07 5 2021\nCopyright: © Ding et al.\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.\nα-fetoprotein (AFP)-secreting gastric cancer (AFP-GC) is a relatively rare, aggressive malignancy among all GC types. However, no GC case with simultaneous expression of AFP and epidermal growth factor receptor 2 (HER2) has been reported to date. To the best of our knowledge, the present report was the first to describe the use of apatinib to treat a patient with advanced GC characterized by AFP-secretion and HER2-positivity. An 86-year-old man with advanced GC was diagnosed with AFP-secretive and HER2-positive GC with liver metastasis at The Affiliated Hospital of Jiujiang University (Jiujiang, China). The patient received first-line (i.e., S-1 plus oxaliplatin) and second-line (i.e., docetaxel) chemotherapy combined with trastuzumab for two cycles, respectively. However, the disease progressed rapidly. Subsequently, apatinib was administered as third-line therapy. After two cycles of apatinib therapy, the patient reported the disappearance of upper abdominal pain and an improvement in his appetite. Furthermore, the AFP level had sharply decreased to 620 ng/ml. Subsequently, upper abdominal computed tomography imaging revealed that the gastric lesion and liver metastatic lesion had reduced in size by 67% and 24%, respectively, suggesting partial remission. Currently, the patient has continued to receive apatinib therapy. It was speculated that AFP-secretion status could contribute to the chemoresistance of HER2-positive GC. Apatinib may be a promising anticancer agent in the case of advanced AFP-producing and HER2-positive GC.\n\napatinib\ngastric cancer\nα-fetoprotein\nepidermal growth factor receptor 2\nFunding No funding was received.\n==== Body\nIntroduction\n\nGastric cancer (GC) ranks as the second-most prevalent cancer among men and the fifth-most prevalent cancer among women when considering all types of cancer reported in China (1). The presence of human epidermal growth factor receptor 2 (HER2) overexpression accounts for 15-20% of gastric adenocarcinomas. The incorporation of trastuzumab, a monoclonal antibody targeting HER2, into chemotherapy has led to a significant increase in the median overall survival (mOS) as compared with that attributed to chemotherapy alone (2). In particular, alpha-fetoprotein (AFP)-secreting GC (AFP-GC) is a relatively rare, aggressive malignancy with a prevalence of 1.3-15% among all GC cases worldwide. Currently, no standard therapy is available for AFP-GC, which consequently results in extremely poor prognoses for patients afflicted with this condition. Similarly, no standard of care exists for treating patients with advanced GC characterized by AFP- and HER2-positivity.\n\nApatinib, produced by the Hengrui Medicine Company of China, is a small-molecular tyrosine kinase inhibitor administered orally that functions as an antiangiogenesis agent via targeting vascular endothelial growth factor receptor-2 (VEGFR-2). At present, the Chinese Society of Clinical Oncology (CSCO) has recommended apatinib be used as a third-line treatment for advanced GC (3). So far, only one study explored the use of apatinib for GC with AFP-secretion (4). Meanwhile, no investigation has assessed apatinib treatment in AFP-secretive and HER2-positive metastatic GC patients. We herein report that apatinib monotherapy was used to effectively treat a patient with chemotherapy-refractory advanced GC with AFP- and HER2-positivity.\n\nCase report\n\nPatient presentation\n\nAn 86-year-old male patient was referred to The Affiliated Hospital of Jiujiang University (Jiujiang, China) with upper abdominal distention for almost two weeks on November 28, 2019. Contrast-enhanced abdominal computed tomography (CT) revealed a prominent thickening of the gastric wall (4.0x2.5 cm2) near the incisura angularis (Fig. 1). Upper abdominal magnetic resonance imaging (MRI) demonstrated a nodule measuring 1.8x1.6 cm2 in the S6 segment of the liver with the characteristics of a ‘low in, low out’ enhancement mode in the arterial, portal, equilibrium, and delay phases (Fig. 1). Painless gastroscopy revealed an ulcer lesion sized 4.0x2.5 cm2 in the anterior wall of the stomach near the incisura angularis (Fig. 2), while the pathology from the gastric biopsy indicated poorly-moderately differentiated adenocarcinoma of stomach (Fig. 3). The immunohistochemistry (IHC) score of HER2 was equivocal (2+) and was confirmed by detecting HER2 amplification by fluorescence in-situ hybridization (FISH) (Fig. 3). The serum AFP level was extremely high (4,235.0 ng/ml; normal range: 0-25 µg/l) at the time of initial diagnosis; however, IHC suggested that AFP was negative in the gastric biopsy. Then, tumor cells were further found with positive expression of embryonic stem cell markers, i.e., glypican-3 (GPC3) and Sal-like protein 4 (SALL4) by IHC staining (Fig. 3).\n\nFirst-line therapy\n\nAccording to the above findings, the patient was diagnosed with AFP-secretive and HER2-positive advanced GC with liver metastasis. Subsequently, systemic chemotherapy was initiated with the regimen of S-1 (tegafur/gimeracil/oteracil) (80 mg/day for two weeks) and oxaliplatin (100 mg/m2 on day 1 every three weeks), with trastuzumab given at a dose of 8 mg/kg every three weeks on the first day of the first cycle, followed by 6 mg/kg every three weeks, as the first-line treatment. After two cycles, the patient's symptom of upper abdominal distention had not improved significantly. Furthermore, his serum AFP level had markedly increased to 6,856.0 ng/ml. Therefore, the clinical response was determined to be disease progression according to the RECIST 1.1 guidelines.\n\nSecond-line therapy\n\nDue to the adverse event of grade IV myelosuppression during the first attempt at chemotherapy, we moved on to trying second-line therapy with docetaxel (60.0 mg/m2 on day 1 every three weeks) in combination with trastuzumab (6 mg/kg on day 1 every three weeks) for two cycles. At this stage, the patient complained of upper abdominal pain, and his AFP level increased further to 8,675.0 ng/ml. Re-examination CT imaging of the upper abdomen found that the gastric lesion and metastatic liver lesion had increased in size to 7x5 cm2 and 2.5x2.1 cm2, respectively (Fig. 4). Unfortunately, the patient still showed myelosuppression of grade IV and recovered through the use of granulocyte colony-stimulating factor. Disease progression was confirmed as the clinical outcome.\n\nThird-line therapy\n\nThe observation of disease progression with both first- and second-line chemotherapy plus trastuzumab suggested that the patient was refractory to these treatments. At this point, we chose apatinib as third-line therapy based on the 2019 CSCO guideline for GC. Due to the patient's advanced age, the dose of apatinib was adjusted from the standard dose of 850 mg/d down to 500 mg/d (every four weeks/cycle).\n\nGeneral status\n\nAfter two cycles of apatinib treatment, the patient reported the disappearance of upper abdominal pain and an improvement in his appetite. Also, we found that his Eastern Cooperative Oncology Group score had increased from the initial 60 points at diagnosis to 90 points.\n\nSerological marker and imaging finding\n\nTwo cycles of apatinib therapy later, the serum AFP level exhibited a sharp decrease from the previous level of 8,675.0 ng/ml to 620 ng/ml. Additionally, upper abdominal CT imaging revealed that the gastric lesion and the liver lesion had decreased in size to 2.3x1.9 cm2 (by 67%) and 1.9x1.7 cm2 (by 24%), respectively (Fig. 5).\n\nAdverse events\n\nFortunately, the patient only displayed mild hand-foot syndrome and elevated blood pressure, which was ascribed to the reduced dose of apatinib administered. At the same time, the antihypertensive agent of amlodipine was given to deal with hypertension.\n\nClinical efficacy\n\nAccording to the CT imaging findings, the gastric lesion and liver metastatic lesion had decreased in size by 67 and 24%, respectively, as compared with prior to receiving apatinib treatment (Fig. 5). The clinical outcome was designated as partial remission per the RECIST 1.1 guidelines. The patient has continued to receive apatinib therapy and undergo follow-up evaluation.\n\nDiscussion\n\nThe notable feature of AFP-GC is a low rate of surgical success and a high rate of liver and lymph node metastasis, which collectively contribute to a very poor prognosis. Moreover, the majority of patients with AFP-GC presenting at initial diagnosis with an advanced stage of the disease. Due to the rarity of AFP-GC, there is no available standard of care for patients with this condition. The mOS of the patients with AFP-GC is significantly shorter than that of those without AFP-GC (12.6 vs. 22.1 months; P<0.001) (5).\n\nAs an inhibitor of HER2, trastuzumab is well-known as a therapeutic agent for HER2-positive breast cancer. Similarly, trastuzumab's incorporation into chemotherapy as first-line therapy significantly improved the clinical outcome of HER2-positive GC patients. Several clinical studies have reported that the median progression-free survival and mOS lengths of patients with HER2-positive GC ranged from 7.1 to 9.2 months and 13.8 to 19.5 months with first-line treatment, respectively (6-9). However, the role of trastuzumab as a second-line therapy remains unclear (10).\n\nIn this case, IHC and FISH analysis confirmed the HER2/neu-positivity pathologically. Despite the negative IHC staining result for AFP, the serum level of AFP was markedly increased. Notably, sensitive markers of embryonic stem cells, i.e., GPC3 and SALL4, were confirmed to be positive pathologically, which strongly suggested that this patient was diagnosed with AFP-producing GC rather than primary liver cancer. Therefore, the final diagnosis of our patient was advanced AFP-secreting and HER2-positive GC with liver metastasis. Both first- and second-line chemotherapy plus trastuzumab failed to control the disease progression, indicating that the patient was resistant to conventional chemotherapy combined with trastuzumab. This result strongly suggested that the status of AFP-secretion enhanced the drug resistance of HER2-positive GC. In this context, it is imperative to identify novel therapeutic strategies that work against advanced GC characterized by AFP-secretion and HER2-positivity.\n\nTumor neovascularization plays a crucial role in tumorigenesis and tumor progression. Molecular biological studies have reported that the frequency of vascular endothelial growth factor (VEGF)-C expression was significantly greater in AFP-GC patients than in patients without AFP-secretion; however, no significant difference in VEGF expression was recorded between these two groups (11). As a lymphangiogenic factor, VEGF-C is responsible for the generation of excess lymph vessels and the distant metastasis of cancer cells, which could constitute an explanation for the biological behavior of AFG-producing GC, i.e., the high tendency for liver and lymph node metastasis (12,13). As one of the receptors of VEGF-C, VEGF receptor 2 has been considered to be a novel predictor of survival in gastric cancer (14). Of coincidence, apatinib is a very small-molecule tyrosine kinase inhibitor that targets VEGF receptor 2, which has been approved as a third-line agent for advanced GC by CSCO (3). As such, we employed apatinib in the present case found to be resistant to first- and second-line chemotherapy. Encouragingly, apatinib monotherapy displayed incredible efficacy in this advanced AFP-producing and HER2-positive GC case. Also, the patient's serum AFP level was sharply reduced following treatment with apatinib, which furthermore confirmed the good clinical outcome of this therapeutic option.\n\nBased on the case outcome described above, we speculated that AFP-secretion could contribute to the chemoresistance of HER2-positive GC. Apatinib may be a promising anticancer agent against advanced AFP-producing and HER2-positive GC. Whether it is appropriate to use apatinib as first-line therapy to treat this unique type of GC deserves further investigation.\n\nAcknowledgements\n\nNot applicable.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\n\nXD designed and drafted the manuscript. JD revised the manuscript. XD and JD acquired the raw data and figures as the patient's medical intern and primary medical oncologist, respectively. XD and JD confirmed the authenticity of all the raw data. Both authors read and approved the final manuscript.\n\nEthics approval and consent to participate\n\nThe requirement for patient consent for participation was waived by the ethics committee because the patient received the standard third-line treatment of apatinib.\n\nPatient consent for publication\n\nThe requirement for patient consent for publication was waived by the ethics committee because the patient received the standard third-line treatment of apatinib.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nFigure 1 Abdominal CT and MRI findings at the first medical examination. (A) Gastric lesions (4.0x2.5 cm2) on the CT cross-section. (B) Gastric lesions (4.0x2.5 cm2) on the CT coronal section. The arrows indicate the gastric lesions in (A and B) (C) Liver metastasis (1.8x1.6 cm2) on the MRI transaxial section (arterial phase). (D) Liver metastasis on the MRI transaxial section (portal phase). (E) Liver metastasis on the MRI transaxial section (equilibrium phase). (F) Liver metastasis on the MRI coronal section (delay phase). The arrows indicate the liver metastasis in (C-E).\n\nFigure 2 Gastroscopy features of the gastric cancer lesion. An ulcer lesion measuring 4.0x2.5 cm2 was present in the anterior wall of the stomach incisura angularis. (A) Hemorrhage image of gastric cancer lesion after histopathologic examination. (B) Image of gastric cancer lesion during biopsy. (C) Static image of gastric cancer lesion before histopathologic examination. The arrows indicate the gastric cancer lesion.\n\nFigure 3 Pathological image. (A) Hematoxylin and eosin staining. Magnification, x400. The major histological type was adenocarcinoma. (B) Immunohistochemical staining for HER2 in the adenocarcinoma. Magnification, x400. Immunohistochemistry grading was 2+. (C) FISH analysis. Magnification, x400. FISH detection revealed the amplification of HER2/neu (clusters of red signals). (D) Immunohistochemical staining for glypican-3. Magnification, x400. (E) Immunohistochemical staining for Sal-like protein 4. Magnification, x400. HER2, epidermal growth factor receptor 2; FISH, fluorescence in situ hybridization.`\n\nFigure 4 Abdominal CT findings after four cycles of chemotherapy. (A) Gastric lesion increased to 7x5 cm2. The arrows indicate the gastric lesion. (B) Liver lesion increased to 2.5x2.1 cm2. The arrow indicates the liver lesion.\n\nFigure 5 Abdominal CT findings after two cycles of apatinib. (A) Gastric lesion decreased to 2.3x1.9 cm2. The arrows indicate the gastric lesion. (B) Liver lesion decreased to 1.9x1.7 cm2. The arrow indicates the liver lesion.\n==== Refs\nReferences\n\n1 Feng RM Zong YN Cao SM Xu RH Current cancer situation in China: Good or bad news from the 2018 Global Cancer Statistics? Cancer Commun (Lond) 39 22 2019 10.1186/s40880-019-0368-6 31030667\n2 Bang YJ Van Cutsem E Feyereislova A Chung HC Shen L Sawaki A Lordick F Ohtsu A Omuro Y Satoh T Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial Lancet 376 687 697 2010 10.1016/S0140-6736(10)61121-X 20728210\n3 Li J Qin S Xu J Guo W Xiong J Bai Y Sun G Yang Y Wang L Xu N Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: Results from a randomized, placebo-controlled, parallel-arm, phase II trial J Clin Oncol 31 3219 3225 2013 10.1200/JCO.2013.48.8585 23918952\n4 Zhu XR Zhu ML Wang Q Xue WJ Wang YW Wang RF Chen SY Zheng LZ A case report of targeted therapy with apatinib in a patient with advanced gastric cancer and high serum level of alpha-fetoprotein Medicine (Baltimore) 95 e4610 2016 10.1097/MD.0000000000004610 27631210\n5 Bozkaya Y Demirci NS Kurtipek A Erdem GU Ozdemir NY Zengin N Clinicopathological and prognostic characteristics in patients with AFP-secreting gastric carcinoma Mol Clin Oncol 7 267 274 2017 10.3892/mco.2017.1288 28781800\n6 Gong J Liu T Fan Q Bai L Bi F Qin S Wang J Xu N Cheng Y Bai Y Optimal regimen of trastuzumab in combination with oxaliplatin/ capecitabine in first-line treatment of HER2-positive advanced gastric cancer (CGOG1001): A multicenter, phase II trial BMC Cancer 16 68 2016 10.1186/s12885-016-2092-9 26857702\n7 Soularue E Cohen R Tournigand C Zaanan A Louvet C Bachet JB Hentic O Samalin E Chibaudel B de Gramont A André T for GERCOR Efficacy and safety of trastuzumab in combination with oxaliplatin and fluorouracil-based chemotherapy for patients with HER2-positive metastatic gastric and gastro-oesophageal junction adenocarcinoma patients: A retrospective study Bull Cancer 102 324 331 2015 10.1016/j.bulcan.2014.08.001 25744576\n8 Rivera F Romero C Jimenez-Fonseca P Izquierdo-Manuel M Salud A Martinez E Jorge M Arrazubi V Mendez JC Garcia-Alfonso P Phase II study to evaluate the efficacy of Trastuzumab in combination with Capecitabine and Oxaliplatin in first-line treatment of HER2-positive advanced gastric cancer: HERXO trial Cancer Chemother Pharmacol 83 1175 1181 2019 10.1007/s00280-019-03820-7 30927036\n9 Takahari D Chin K Ishizuka N Takashima A Minashi K Kadowaki S Nishina T Nakajima TE Amagai K Machida N Multicenter phase II study of trastuzumab with S-1 plus oxaliplatin for chemotherapy-naive, HER2-positive advanced gastric cancer Gastric Cancer 22 1238 1246 2019 10.1007/s10120-019-00973-5 31102009\n10 Palle J Rochand A Pernot S Gallois C Taieb J Zaanan A Human Epidermal Growth Factor Receptor 2 (HER2) in advanced gastric cancer: Current knowledge and future perspectives Drugs 80 401 415 2020 10.1007/s40265-020-01272-5 32077003\n11 Kamei S Kono K Amemiya H Takahashi A Sugai H Ichihara F Fujii H Matsumoto Y Evaluation of VEGF and VEGF-C expression in gastric cancer cells producing alpha-fetoprotein J Gastroenterol 38 540 547 2003 10.1007/s00535-002-1099-y 12825129\n12 Su JL Yang PC Shih JY Yang CY Wei LH Hsieh CY Chou CH Jeng YM Wang MY Chang KJ The VEGF-C/Flt-4 axis promotes invasion and metastasis of cancer cells Cancer Cell 9 209 223 2006 10.1016/j.ccr.2006.02.018 16530705\n13 Pan Z Lu X Zhao J Gao Q Wang J VEGF-C is positively associated with lymphangiogenesis and lymphatic metastasis in rectal cancer Int J Clin Exp Pathol 11 1777 1783 2018 31938284\n14 Li T Yu J Luo X Ren W Zhang Y Cao B VEGFR-2 as a novel predictor of survival in gastric cancer: A systematic review and meta-analysis Pathol Res Pract 214 560 564 2018 10.1016/j.prp.2018.02.005 29572120\n\n",
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"issue": "15(2)",
"journal": "Molecular and clinical oncology",
"keywords": "apatinib; epidermal growth factor receptor 2; gastric cancer; α-fetoprotein",
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"title": "Effective treatment of apatinib for chemotherapy-refractory advanced gastric carcinoma with AFP-secretion and HER2-positivity: A case report.",
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"abstract": "Accelerated idioventricular rhythm (AIVR) during anesthesia has been described in several drug toxicity such as from cocaine, halothane, desflurane, and propofol. We present the case of a man who developed episodes of AIVR observed under total intravenous anesthesia (TIVA) using remifentanil, propofol, and rocuronium. AIVR during anesthesia was a benign phenomenon, and further examinations after surgery showed no structural heart disease and the daily occurrence of idioventricular arrhythmias. This case suggests that the suppression of sinus and atrioventricular nodal function and the autonomic imbalance caused by propofol and remifentanil may induce AIVR with greater frequency.",
"affiliations": "Department of Anesthesia, Osakafu Saiseikai Noe Hospital, Fruichi 1-3-25, Joto-ku, Osaka City, Osaka Japan.;Department of Anesthesia, Osakafu Saiseikai Noe Hospital, Fruichi 1-3-25, Joto-ku, Osaka City, Osaka Japan.;Department of Anesthesia, Osakafu Saiseikai Noe Hospital, Fruichi 1-3-25, Joto-ku, Osaka City, Osaka Japan.;Department of Anesthesia, Osakafu Saiseikai Noe Hospital, Fruichi 1-3-25, Joto-ku, Osaka City, Osaka Japan.;Department of Anesthesia, Osakafu Saiseikai Noe Hospital, Fruichi 1-3-25, Joto-ku, Osaka City, Osaka Japan.",
"authors": "Nakanishi|Mika|M|;Masumo|Kaoru|K|;Oota|Takako|T|;Kato|Takeshi|T|;Imanishi|Toshihiro|T|",
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"fulltext": "\n==== Front\nJA Clin RepJA Clin RepJa Clinical Reports2363-9024Springer Berlin Heidelberg Berlin/Heidelberg 1610.1186/s40981-015-0016-3Case ReportAccelerated idioventricular rhythm observed under total intravenous anesthesia using remifentanil, propofol, and rocuronium Nakanishi Mika +816-6932-0401mikadairisa@gmail.com Masumo Kaoru aokikaoru426@gmail.com Oota Takako noe.masuika@gmail.com Kato Takeshi take_k@sa2.so-net.ne.jp Imanishi Toshihiro tandk-imanishi@rose.ocn.ne.jp Department of Anesthesia, Osakafu Saiseikai Noe Hospital, Fruichi 1-3-25, Joto-ku, Osaka City, Osaka Japan 7 9 2015 7 9 2015 2015 1 1 1214 7 2015 1 9 2015 © The Author(s) 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Accelerated idioventricular rhythm (AIVR) during anesthesia has been described in several drug toxicity such as from cocaine, halothane, desflurane, and propofol. We present the case of a man who developed episodes of AIVR observed under total intravenous anesthesia (TIVA) using remifentanil, propofol, and rocuronium. AIVR during anesthesia was a benign phenomenon, and further examinations after surgery showed no structural heart disease and the daily occurrence of idioventricular arrhythmias. This case suggests that the suppression of sinus and atrioventricular nodal function and the autonomic imbalance caused by propofol and remifentanil may induce AIVR with greater frequency.\n\nKeywords\nAccelerated idioventricular rhythmTotal intravenous anesthesiaRemifentanilPropofolnakanishi854ᅟNakanishi Mika issue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nAccelerated idioventricular rhythm (AIVR) is a ventricular rhythm comprising three or more consecutive monomorphic beats, with a gradual onset. The discharge rate of the ectopic focus is similar to the sinus rate and between 50 and 120 bpm (isorhythmic). The ectopic focus manifests when the sinus rate slows down (below that of the ectopic focus) or when the ectopic focus accelerates above its intrinsic rate by 30–40 bpm [1]. Nine clinical features are helpful in distinguishing AIVR from ventricular tachycardia (VT): chance discovery; no symptoms; no hemodynamic effects; <10 % of sinus isochronicity; HR < 120 bpm; simple conversion to sinus rhythm; short bursts; no effective drug treatment; and left bundle branch block [2].\n\nAIVR during anesthesia has been described in several drug toxic cases such as from cocaine [3], halothane [4], desflurane [5], and propofol [6]. It might be caused by an electrolyte imbalance, post-resuscitation status after acute myocardial infarction, cardiomyopathy, or arrhythmogenic right ventricular dysplasia (ARVD) during the perioperative period [1]. We report a case of AIVR observed under total intravenous anesthesia using remifentanil, propofol, and rocuronium.\n\nCase presentation\nA 50-year-old man, weighing 74 kg, was scheduled for arthroscopic meniscectomy for a right meniscus injury. He had undergone the same surgery on the other side 1 year prior. The previous general anesthesia was induced with sevoflurane 4 %, propofol 140 mg, fentanil 50 μg, lidocaine 50 mg, and rocuronium 50 mg. Propofol 2–3 mg/kg/h, remifentanil 0.1–0.18 μg/kg/min, and sevoflurane 1 % were maintained. His heart rate (HR) was 40–55 bpm. Atropine 0.5 mg administered intravenously did not increase his HR over 55 bpm. Idioventricular rhythm or anesthetic complication was not observed. In this time a preoperative examination revealed no sign or symptom of cardiovascular disease and he was classified as an American Society of Anesthesiologists’ (ASA) Physical Status Classification 1. A preoperative electrocardiogram (ECG) showed a sinus rhythm of 57 bpm, a QRS duration of 0.11 s, and no ventricular ectopic beat (Fig. 1).Fig. 1 Preoperative record of a 12-lead electrocardiogram, showing a sinus rhythm of 57 bpm\n\n\n\n\nBefore anesthetic induction without premedication, the patient’s arterial blood pressure (BP) was 142/83 mmHg and his HR was 48 bpm. General anesthesia was induced with propofol 180 mg, remifentanil 0.1 μg/kg/min, and rocuronium 30 mg. After laryngeal mask insertion, atropine 0.5 mg was administered because his HR fell to 38 bpm with a sinus rhythm. Nevertheless, despite the administration of atropine 0.5 mg twice, his HR did not increase over 55 bpm. Propofol 4–5 mg/kg/h, remifentanil 0.1–0.2 μg/kg/min, and rocuronium 7 μg/kg/min were continued. His systolic BP was 90–140 mmHg, HR was 35–55 bpm, end-tidal CO2 was 35–40 mmHg, and SpO2 was 99–100 %. About 30 min after induction, ventricular arrhythmia occurred with wide QRS complexes indicative of AIVR (ventricular rhythm at this time was 48 bpm) alternating with a sinus rhythm. Ventricular arrhythmia repeated approximately every 5 min for approximately 1 h and AIVRs continued for approximately 30 s (Fig. 2). Heart rates of the idioventricular rhythms (45–50 bpm) were similar to those of the sinus rhythms at those times. The arrhythmias were independent of electric cautery and surgical procedure. Propofol, remifentanil, and rocuronium were regulated with the rate of administration mentioned above in proportion to the surgical stress. Although direct arterial sphygmomanometry in his left radial artery showed that his systolic BP was 20–30 mmHg lower during AIVRs than during sinus rhythms, his systolic BP was kept 100–120 mmHg during ventricular arrhythmia. Blood gas analyses showed plasma sodium, potassium, calcium, glucose, CO2, O2, and pH values within normal ranges. Although temporary transcutaneous pacing pads combined with a defibrillator were prepared, they were not utilized. His stable hemodynamics and short bursts of arrhythmia did not need them. The anesthetic duration was 2 h 32 min. The last AIVR just appeared when the surgery and administration of the anesthetics were finished. AIVR did not reappear after recovery from anesthesia.Fig. 2 Intraoperative electrocardiogram of III lead approximately 90 min after the anesthesia start under TIVA, documenting AIVRs alternating with sinus rhythms. Ventricular arrhythmia repeated approximately every 5 min and AIVRs continued for approximately 30 s\n\n\n\n\nDuring the following 24-h period, continuous ECG monitoring showed no ventricular rhythm, but sinus bradycardia at 35–50 bpm. He confessed that arrhythmia had been noted in periodical health examinations of the school and the company with no subjective symptoms and he had refused detailed examinations. Echocardiography performed 2 days later showed a normal cardiac structure. A Holter ECG 5 days after surgery showed sinus rhythms from 36–97 bpm and total rates of 0.69 % premature atrial contraction (PAC) and 6.35 % premature ventricular contraction (PVC), including an idioventricular rhythm running for 40 beats continuously. He did not have any subjective symptoms during the Holter ECG recording. The results suggested that his AIVR might have occurred daily. He refused further examinations.\n\nDiscussion\nAtrioventricular (AV) junctional rhythm, another consecutive escaped rhythm, usually has a normal QRS duration without a P wave or with a retrograde P wave. If complicated with a bundle branch block, the QRS duration gets longer. AV junctional rhythm might lack effective atrial contraction and reduce the cardiac output than sinus rhythm, because atrial contraction contributes to approximately 15 to 25 % of the diastolic filling of the ventricle [7]. AIVR originates from the His, the Purkinje system or the working contractile ventricular cells [1]. Ventricular pacing has been shown to result in dyssynchronous left ventricular (LV) electrical activation and mechanical contraction, to worsen LV ejection fraction [8]. AIVR is not artificial ventricular pacing, but its abnormal impulse conducting pathway might cause dyssynchronous LV contraction.\n\nSome anesthetics have been described to be associated with AIVR because of toxicity. Cocaine might induce AIVR either through the production of myocardial ischemia or as a direct result of ion channel alterations [3, 9]. Halothane was reported to be associated with AIVR due to a depressant effect on slow inward calcium current and intracellular calcium accumulation [4]. Desflurane was also reported to induce AIVR because of a sympathetic imbalance [5]. Propofol was publicized to be associated with arrhythmias in humans [10]. In the guinea pig heart, the ionic mechanism underlying the negative chronotropic action of propofol on sinoatrial node (SN) automaticity was associated with propofol-induced bradycardia observed in clinical settings [11]. Similar to propofol, remifentanil also depresses sinus node function and most parameters of atrioventricular (AV) nodal function, causing remifentanil-related severe bradyarrhythmias [12]. In this case, the negative chronotropic action of propofol and remifentanil on sinus and AV nodal function might have induced the ectopic focus more often than usual.\n\nAIVR is also associated with higher vagal tone and lower sympathetic activity [13], and the AIVR related to sympathetic nerve block during spinal anesthesia for cesarean section was reported [14]. Propofol suppresses both sympathetic and parasympathetic tone, but the suppression of sympathetic tone is more than that of parasympathetic tone [15]. Remifentanil also induces higher vagal tone [16]. In this case, superior vagal tone related to propofol and remifentanil might have induced AIVR. However, ventricular rhythm was not detected during the postoperative 24-h period including his sleeping hours, time of the parasympathetic nerve predominance. We did not succeed in clarifying the trigger of the idioventricular rhythm observed in the Holter ECG, but his activity at the time of the record was higher than that at the postoperative 24-h period. Not parasympathetic nerve predominance during sleep but imbalance of the autonomic nerve caused by anesthetics might have induced AIVR more frequently.\n\nNaranjo algorithm is a questionnaire designed by Naranjo et al. for determining the likelihood of whether an adverse drug reaction is actually due to the drug rather than the result of other factors [17]. Probability is assigned via a score termed definite (9–13 points), probable (5–8 points), possible (1–4 points) or doubtful (0 point). On using Naranjo’s scale, we obtained a scale of 5, which makes propofol and remifentanil probable causes for the event. The adverse event appeared after their administration (+2). The adverse event improved when they were discontinued (+1). The reaction was less severe when their doses were decreased (+1), because the surgery 1 year prior had no episode of an AIVR with balanced anesthesia using sevoflurane, remifentanil, and propofol, the doses of which were lower than those at this time. The arrhythmias were objectively recorded on an ECG trace (+1).\n\nMost AIVRs are usually well tolerated and do not need specific treatment. Increasing the sinus rate is the recommended treatment for AIVR, therefore, atropine and atrial pacing rhythm can help to control it [1, 2]. Ephedrine is controversial because it can potentially increase AIVR duration [14].\n\nBenign AIVRs with no structural heart disease and no electrolytic abnormality, such as in this case, usually require no intervention. However, sometimes it can present as a more severe arrhythmia requiring treatment, because AIVR might be induced by reperfusion after acute myocardial infarction, some cardiomyopathies, myocarditis, and in newborn infants with various congenital heart diseases [1, 2].\n\nConclusions\nWe observed AIVR under total intravenous anesthesia using remifentanil, propofol, and rocuronium. The suppression of sinus and atrioventricular nodal function and the autonomic imbalance caused by remifentanil and propofol might have induced AIVR with greater frequency.\n\nConsent\nThe patient’s consent to publish this case report was obtained and documented.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nMN; I anesthetized and examined him after surgery. I wrote this report. KM; She examined him in preoperation. TO; She examined him in preoperation 1 year prior. TK; He anesthetized him this time and 1 year prior. TI; He examined him in preoperation this time and 1 year prior. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Riera AR Barros RB de Sousa FD Baranchuk A Accelerated idioventricular rhythm: history and chronology of the main discoveries Indian Pacing Electrophysiol J 2010 10 40 8 20084194 \n2. Reynolds JL Pickoff AS Accelerated ventricular rhythm in children: a review and report of a case with congenital heart disease Pediatr Cardiol 2001 22 23 8 10.1007/s002460010146 11123122 \n3. Jonsson S O’Meara M Young JB Acute cocaine poisoning. Importance of treating seizures and acidosis Am J Med 1983 75 106 14 10.1016/0002-9343(83)90889-6 6310997 \n4. Chhabra A Subramaniam R Sudden appearance of idioventricular rhythm during inhalational induction with halothane in a child with congenital cataract J Postgrad Med 2008 54 337 9 10.4103/0022-3859.43528 18953165 \n5. Marret E Pruszkowski O Deleuze A Bonnet F Accelerated idioventricular rhythm associated with desflurane administration Anesth Analg 2002 95 319 21 12145043 \n6. Scruggs SM Mama K Bright JM Zirofsky D Accelerated idioventricular rhythm following propofol induction in a dog undergoing ocular surgery Vet Anaesth Analg 2010 37 385 6 10.1111/j.1467-2995.2010.00539.x 20636572 \n7. Healey JS Toff WD Lamas GA Andersen HR Thorpe KE Ellenbogen KA Cardiovascular outcomes with atrial-based pacing compared with ventricular pacing: meta-analysis of randomized trials, using individual patient data Circulation 2006 114 11 7 10.1161/CIRCULATIONAHA.105.610303 16801463 \n8. Sweeney MO Hellkamp AS Ellenbogen KA Greenspon AJ Freedman RA Lee KL Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction Circulation 2003 107 2932 7 10.1161/01.CIR.0000072769.17295.B1 12782566 \n9. Wood DM Dargan PI Hoffman RS Management of cocaine-induced cardiac arrhythmias due to cardiac ion channel dysfunction Clin Toxicol 2009 47 14 23 10.1080/15563650802339373 \n10. Muńoz R Goldberg ME Cantillo L Subramoni J Nemiroff MS Perioperative arrhythmias with a propofol-based anesthetics J Clin Anesth 1991 3 149 52 10.1016/0952-8180(91)90014-E 2039644 \n11. Kojima A Ito Y Kitagawa H Matsuura H Ionic mechanisms underlying the negative chronotropic action of propofol on sinoatrial node automaticity in guinea pig heart Br J Pharmacol 2015 172 799 814 10.1111/bph.12936 25220338 \n12. Zaballos M Jimeno C Almendral J Atienza F Patiño D Valdes E Cardiac electrophysiological effects of remifentanil: study in a close-chest porcine model Br J Anaesth 2009 103 191 8 10.1093/bja/aep131 19457895 \n13. Bonnemeier H Ortak J Wiegand UK Eberhardt F Bode F Schunkert H Accelerated idioventricular rhythm in the post-thrombolytic era: incidence, prognostic implications, and modulating mechanisms after direct percutaneous coronary intervention Ann Noninvasive Electrocardiol 2005 10 179 87 10.1111/j.1542-474X.2005.05624.x 15842430 \n14. Coven G Arpesella R Ciceri M Preseglio I Cardani A Accelerated idioventricular rhythm during spinal anesthesia for cesarean section Int J Obstet Anesth 2003 12 121 5 10.1016/S0959-289X(02)00199-1 15321501 \n15. Liu Q Kong AL Chen R Qian C Liu SW Sun BG Propofol and arrhythmias: two sides of the coin Acta Pharmacol Sin 2011 32 817 23 10.1038/aps.2011.42 21642950 \n16. Fattorini F Romano R Ciccaglioni A Pascarella MA Rocco A Mariani V Effects of remifentanil on human heart electrical system. A transesophageal pacing electrophysiological study Minerva Anestesiol 2003 69 673 9 14564237 \n17. Naranjo CA Busto U Sellers EM Sandor P Ruiz I Roberts EA A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 239 45 10.1038/clpt.1981.154 7249508\n\n",
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"title": "Accelerated idioventricular rhythm observed under total intravenous anesthesia using remifentanil, propofol, and rocuronium.",
"title_normalized": "accelerated idioventricular rhythm observed under total intravenous anesthesia using remifentanil propofol and rocuronium"
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"abstract": "To varying extents, women with pre-existing cardiomyopathies have a limited cardiovascular reserve. The hemodynamic challenges of pregnancy, labor, and delivery pose unique risks to this group of patients, which can result in clinical decompensation with overt heart failure, arrhythmias, and rarely, maternal death. A multidisciplinary team approach and a controlled delivery are crucial to adequate management of patients with underlying heart disease. Pre-conception planning and risk assessment are essential, and proper counseling should be offered to expectant mothers with regard to both the risks that pregnancy poses and the implications for future offspring. In this article, we will review the hemodynamic stressors that pregnancy places upon women with pre-existing cardiomyopathies and risk assessment and discuss what evidence exists with regard to the management of 2 forms of cardiomyopathy during pregnancy, labor, and delivery: dilated and hypertrophic cardiomyopathy.",
"affiliations": "Division of Cardiovascular Disease, Department of Internal Medicine, Stony Brook University Medical Center, Stony Brook, New York, USA. kathleen.stergiopoulos@stonybrook.edu",
"authors": "Stergiopoulos|Kathleen|K|;Shiang|Elaine|E|;Bench|Travis|T|",
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"abstract": "OBJECTIVE\nThe purpose of this study is to describe our experience in cases of tubal ectopic pregnancy with heartbeat, abdominal, interstitial (corneal) and cervical ectopic pregnancies treated with intrasacular injection of methotrexate (MTX) administered under ultrasound guidance associated with a single systemic dose of MTX.\n\n\nMETHODS\nDescriptive retrospective study of 14 cases of extrauterine pregnancies treated with intrasacular injection of MTX under ultrasound control, attended in the Maternal-Fetal Medicine Unit of the Miguel Servet University Hospital, in Zaragoza, Spain, between January of 2009 and June of 2010.\n\n\nRESULTS\nOf the 14 ectopic pregnancies, 7 were tubal with heartbeat, 3 cornual, 2 cervical and 2 abdominal. The average gestational age was 7 + 3 weeks and the average β-hCG value on the date of puncture was 22,885.69 mIU/mL. Surgical treatment was required in two cases, the first due to post-puncture haemoperitoneum and the second as a consequence of the rupture of the corneal ectopic pregnancy. In post-treatment monitoring, an asymptomatic increase of β-hCG on the seventh day post-puncture was observed in two cases. The success rate of the treatment was 92.96%.\n\n\nCONCLUSIONS\nUltrasound guided intrasacular injection of MTX associated with a systemic dose adjusted to the body surface of the patient is a minimally invasive, safe and effective treatment in the cases of tubal ectopic pregnancy with heartbeat, abdominal, cornual or cervical ectopic pregnancy.",
"affiliations": "Department of Obstetrics, Miguel Servet University Hospital, C/Monasterio Ntra. Sra. De los Angeles 3, P4, 2ºA, 50012 Zaragoza, Spain.",
"authors": "Andrés|María P|MP|;Campillos|José M|JM|;Lapresta|María|M|;Lahoz|Isabel|I|;Crespo|Raquel|R|;Tobajas|Javier|J|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D018997:Chorionic Gonadotropin, beta Subunit, Human; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00404-011-2044-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0932-0067",
"issue": "285(2)",
"journal": "Archives of gynecology and obstetrics",
"keywords": null,
"medline_ta": "Arch Gynecol Obstet",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000328:Adult; D002584:Cervix Uteri; D018997:Chorionic Gonadotropin, beta Subunit, Human; D005260:Female; D006801:Humans; D008727:Methotrexate; D011247:Pregnancy; D011269:Pregnancy, Abdominal; D011271:Pregnancy, Ectopic; D011274:Pregnancy, Tubal; D012189:Retrospective Studies; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "8710213",
"other_id": null,
"pages": "529-33",
"pmc": null,
"pmid": "21837423",
"pubdate": "2012-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management of ectopic pregnancies with poor prognosis through ultrasound guided intrasacular injection of methotrexate, series of 14 cases.",
"title_normalized": "management of ectopic pregnancies with poor prognosis through ultrasound guided intrasacular injection of methotrexate series of 14 cases"
} | [
{
"companynumb": "ES-MYLANLABS-2019M1044764",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nCalcium channel blockers (CCBs) are commonly used but have the potential to cause substantial toxicity. One such underreported toxicity of CCB use is the development of acute respiratory distress syndrome (ARDS).\n\n\nMETHODS\n44-year-old previously healthy woman presented to the emergency department (ED) having taken 60 tablets of 125 mg extended-release verapamil and 90 tablets of 0.25 mg clonazepam with the intent to commit suicide. On presentation to the ED, she was sedated and intubated for airway protection. She received aggressive medical resuscitation and was ventilated using low tidal volume mechanical ventilation. The hospital course was complicated by worsening hypoxia and a chest x-ray demonstrating bilateral patchy geographic areas of airspace opacities consistent with ARDS. On day 5 of hospitalization, the patient's clinical status improved significantly, and she was subsequently weaned off vasopressors and extubated.\n\n\nCONCLUSIONS\nCCB toxicity can result in profound hypotension, shock, bradycardia, and conduction blocks, as well as hyperglycemia, acidosis and acute kidney injury, and ARDS. It is important for clinicians to understand the signs and symptoms of CCB toxicity, as well as how to treat it.",
"affiliations": "Marshfield Medical Center, Marshfield, Wisconsin, lodhi.fahad@marshfieldclinic.org.;University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin.;Marshfield Medical Center, Marshfield, Wisconsin.;Fatima Memorial Hospital for Medicine and Dentistry, Lahore, Pakistan.;Marshfield Medical Center, Marshfield, Wisconsin.;Marshfield Medical Center, Marshfield, Wisconsin.",
"authors": "Lodhi|Fahad Aftab Khan|FAK|;Shogren|Sophie L|SL|;Vedre|Jayanth G|JG|;Haque|Najiya|N|;Reriani|Martin|M|;Ali|Rashid|R|",
"chemical_list": "D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D002998:Clonazepam; D014700:Verapamil",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1098-1861",
"issue": "119(1)",
"journal": "WMJ : official publication of the State Medical Society of Wisconsin",
"keywords": null,
"medline_ta": "WMJ",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D002121:Calcium Channel Blockers; D002998:Clonazepam; D062787:Drug Overdose; D005260:Female; D006801:Humans; D012121:Respiration, Artificial; D012128:Respiratory Distress Syndrome; D013406:Suicide, Attempted; D014700:Verapamil",
"nlm_unique_id": "9716054",
"other_id": null,
"pages": "66-68",
"pmc": null,
"pmid": "32348076",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Calcium Channel Blocker Toxicity Causing Acute Respiratory Distress Syndrome: A Commonly Used Drug Triggering a Life-Threatening Condition.",
"title_normalized": "calcium channel blocker toxicity causing acute respiratory distress syndrome a commonly used drug triggering a life threatening condition"
} | [
{
"companynumb": "US-ALEMBIC PHARMACUETICALS LIMITED-2020SCAL000369",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
},
"druga... |
{
"abstract": "The authors present the case of a nulliparous 34-year-old patient. At the tenth week of gestation, she developed phlebothrombosis of veins of the right leg and massive pulmonary embolism. After thrombolytic and heparin therapy she developed rethrombosis and heparin-induced thrombocytopenia type II. Lepirudin was introduced in therapy and in the 12th week of gestation acenocumarol was added. After the 34th week, she received danaparoid sodium. After a week, by cesarean section, a healthy and mature female was delivered.",
"affiliations": "Clinic for Gynecology and Obstetrics, Clinical Center, University of Belgrade, Belgrade, Serbia. plesinac@hotmail.com",
"authors": "Plesinac|S|S|;Babović|I|I|;Karapandzić|V Plesinac|VP|",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006629:Hirudins; D011994:Recombinant Proteins; D003871:Dermatan Sulfate; D006493:Heparin; D002809:Chondroitin Sulfates; D006497:Heparitin Sulfate; C035838:danaparoid; D000074:Acenocoumarol; C083544:lepirudin",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0390-6663",
"issue": "40(2)",
"journal": "Clinical and experimental obstetrics & gynecology",
"keywords": null,
"medline_ta": "Clin Exp Obstet Gynecol",
"mesh_terms": "D000074:Acenocoumarol; D000328:Adult; D000925:Anticoagulants; D002585:Cesarean Section; D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D005260:Female; D005343:Fibrinolytic Agents; D005865:Gestational Age; D006493:Heparin; D006497:Heparitin Sulfate; D006629:Hirudins; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D011655:Pulmonary Embolism; D011994:Recombinant Proteins; D013921:Thrombocytopenia; D020246:Venous Thrombosis",
"nlm_unique_id": "7802110",
"other_id": null,
"pages": "307-8",
"pmc": null,
"pmid": "23971268",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful pregnancy after pulmonary embolism and heparin-induced thrombocytopenia--case report.",
"title_normalized": "successful pregnancy after pulmonary embolism and heparin induced thrombocytopenia case report"
} | [
{
"companynumb": "PHHY2013RS081130",
"fulfillexpeditecriteria": "1",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
"... |
{
"abstract": "In a hepatitis C virus (HCV)/HIV-positive Brazilian cohort, evaluate the safety and efficacy of HCV DAAs, the frequency of resistance substitutions in the HCV NS5A and NS5B genes and identify predictors of treatment failure.Retrospective multicenter study of HCV/HIV patients treated with sofosbuvir (SOF)-based regimens at 10 reference centers in Brazil.Clinical and virological data were collected. Genetic diversity in the NS5A and NS5B genes was assessed by direct nucleotide sequencing. The primary outcome was sustained virological response (SVR) 12 weeks after DAA completion.Of 643 HCV/HIV patients analyzed, 74.7% were male, median CD4+ T cell count was 617 cells/mm, 90% had an undetectable HIV viral load. HCV genotype 1 was detected in 80.2%, and 60% were taking at least 1 medication other than antiretroviral drugs during their DAA therapy. Cirrhosis was present in 42%. An SOF/daclatasvir (DCV) regimen was used in most patients (98%). The frequency of NS5A polymorphisms associated with clinically relevant resistance to DCV was 2%; no relevant NS5B variants were identified. The SVR12 rate was 92.8% in an intention to treat (ITT) analysis and 96% in a modified ITT (m-ITT) analysis. AE occurred in 1.6% of patients. By multivariate analysis, therapeutic failure was associated, in the m-ITT analysis, with concomitant use of anticonvulsant drugs (P = .001), age (P = .04), and female gender (P = .04).SOF/DCV regimens were associated with a high SVR rate in an HCV/HIV population. The use of concurrent anticonvulsant drugs and DAAs decreases the chances of achieving an SVR.",
"affiliations": "University of São Paulo School of Medicine, São Paulo.;State University of Campinas, Campinas.;Center Specialized in Health, Caxias Do Sul.;Infectious Disease Outpatient Clinic, Jundiaí.;Federal University of São Paulo, Infectious Diseases Department, São Paulo.;Centro De Referência e Treinamento - CRT DST-AIDS, São Paulo.;Centro De Referência e Treinamento - CRT DST-AIDS, São Paulo.;Federal University of the State of Rio de Janeiro, Rio de Janeiro.;Emilio Ribas Hospital, São Paulo.;Emilio Ribas Hospital, São Paulo.;Heliópolis Hospital, São Paulo.;Base Hospital- Funfarme, São José Do Rio Preto.;University of São Paulo School of Medicine, São Paulo.;University of São Paulo School of Medicine, São Paulo.;LIM 07, Institute of Tropical Medicine, São Paulo.;University of São Paulo School of Medicine, São Paulo.;Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY.;University of São Paulo School of Medicine, São Paulo.",
"authors": "Machado|Soraia M|SM|0000-0002-9937-3995;Vigani|Aline G|AG|;Leite|Andrea G|AG|;Diaz|Ana Claudia M|ACM|;Ferreira|Paulo Roberto A|PRA|;Carnaúba-Júnior|Dimas|D|;Tenore|Simone B|SB|;Brandão-Mello|Carlos Eduardo|CE|;Gonzalez|Mario P|MP|;Siroma|Fabiana|F|;Prado|Kleber D|KD|;Nunes|Delzi V|DV|;Lisboa-Neto|Gaspar|G|;Pinho|João Renato R|JRR|;Malta|Fernanda M|FM|;Azevedo|Raymundo S|RS|;Witkin|Steven S|SS|;Mendes-Correa|Maria Cássia|MC|",
"chemical_list": "D000998:Antiviral Agents",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000021270",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Wolters Kluwer Health \n\nMD-D-19-07950\n10.1097/MD.0000000000021270\n21270\n4900\nResearch Article\nObservational Study\nEffectiveness of direct-acting antivirals for hepatitis C virus infection in hepatitis C/HIV coinfected individuals\nA multicenter studyhttp://orcid.org/0000-0002-9937-3995Machado Soraia M. MDa∗ Vigani Aline G. b Leite Andrea G. c Diaz Ana Claudia M. d Ferreira Paulo Roberto A. e Carnaúba-Júnior Dimas f Tenore Simone B. f Brandão-Mello Carlos Eduardo g Gonzalez Mario P. h Siroma Fabiana h Prado Kleber D. i Nunes Delzi V. j Lisboa-Neto Gaspar a Pinho João Renato R. ak Malta Fernanda M. k Azevedo Raymundo S. a Witkin Steven S. lm Mendes-Correa Maria Cássia am Zhang. Chiyu a University of São Paulo School of Medicine, São Paulo\nb State University of Campinas, Campinas\nc Center Specialized in Health, Caxias Do Sul\nd Infectious Disease Outpatient Clinic, Jundiaí\ne Federal University of São Paulo, Infectious Diseases Department, São Paulo\nf Centro De Referência e Treinamento - CRT DST-AIDS, São Paulo\ng Federal University of the State of Rio de Janeiro, Rio de Janeiro\nh Emilio Ribas Hospital, São Paulo\ni Heliópolis Hospital, São Paulo\nj Base Hospital- Funfarme, São José Do Rio Preto\nk LIM 07, Institute of Tropical Medicine, São Paulo\nl Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY\nm LIM 52, Institute of Tropical Medicine, São Paulo.\n∗ Correspondence: Soraia M. Machado, Rua Benedito Lopes da Silva, 40, apt 40. Mogi das Cruzes, São Paulo 08773-515, Brazil (e-mail: soraiammachado@hotmail.com).\n24 7 2020 \n24 7 2020 \n99 30 e2127010 10 2019 21 2 2020 12 6 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0Abstract\nIn a hepatitis C virus (HCV)/HIV-positive Brazilian cohort, evaluate the safety and efficacy of HCV DAAs, the frequency of resistance substitutions in the HCV NS5A and NS5B genes and identify predictors of treatment failure.\n\nRetrospective multicenter study of HCV/HIV patients treated with sofosbuvir (SOF)-based regimens at 10 reference centers in Brazil.\n\nClinical and virological data were collected. Genetic diversity in the NS5A and NS5B genes was assessed by direct nucleotide sequencing. The primary outcome was sustained virological response (SVR) 12 weeks after DAA completion.\n\nOf 643 HCV/HIV patients analyzed, 74.7% were male, median CD4+ T cell count was 617 cells/mm3, 90% had an undetectable HIV viral load. HCV genotype 1 was detected in 80.2%, and 60% were taking at least 1 medication other than antiretroviral drugs during their DAA therapy. Cirrhosis was present in 42%. An SOF/daclatasvir (DCV) regimen was used in most patients (98%). The frequency of NS5A polymorphisms associated with clinically relevant resistance to DCV was 2%; no relevant NS5B variants were identified. The SVR12 rate was 92.8% in an intention to treat (ITT) analysis and 96% in a modified ITT (m-ITT) analysis. AE occurred in 1.6% of patients. By multivariate analysis, therapeutic failure was associated, in the m-ITT analysis, with concomitant use of anticonvulsant drugs (P = .001), age (P = .04), and female gender (P = .04).\n\nSOF/DCV regimens were associated with a high SVR rate in an HCV/HIV population. The use of concurrent anticonvulsant drugs and DAAs decreases the chances of achieving an SVR.\n\nKeywords\ndirect acting antiviralseffectivenesshepatitis C treatmenthepatitis C-HIV coinfectionsafetyOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nHepatitis C virus (HCV) and HIV coinfection is a major global public health problem.[1,2] According to the World Health Organization (WHO), there are currently around 71 million individuals chronically infected with HCV, 31 million with HIV, and more than 2 million with HCV-HIV coinfection.[2,3] Since HCV and HIV infections share the same routes of transmission, coinfections are often found with an estimated prevalence of 25% to 30% in the general population of people living with HIV/AIDS. These rates are even higher in specific groups, such as in injection drug users.[4,5] Coinfection adversely affects the natural course of hepatitis C infection, accelerating the progression of liver fibrosis and increasing the risk of hepatic decompensation and hepatocellular carcinoma in cirrhotic patients.[6–8] Currently, end-stage liver disease is one of the leading causes of death in the HCV/HIV population.[5,9,10]\n\nThe advent of direct-action antivirals (DAAs) has substantially changed the HCV therapy scenario, including in the HIV-infected population.[11–13] In the interferon (IFN) treatment era, a minority of individuals could be treated due to the occurrence of significant adverse effects and low sustained virological response (SVR) rates.[12,14,15] With DAAs, especially IFN-free regimens, HCV therapy has been simplified and coinfected patients have achieved high cure rates.[11,12] Randomized clinical trials and real-life studies in different parts of the world have shown SVR rates greater than 90% in patients with HCV/HIV, similar to that reported for patients without HIV coinfection.[16–21]\n\nHowever, conflicting results regarding the impact of HIV and immunosuppression on SVR rate in these patients have been reported.[22–24] In some studies, HIV coinfection has been associated with worse clinical outcomes.[22–25] In addition, for this population, adherence to therapy, the high frequency of comorbidities, the concomitant use of medications with potential drug–drug interactions (DDI) with DAAs, and the impact of the presence of resistance-associated substitutions (RASs) in the HCV genome are additional significant challenges that could interfere with the chances of treatment success.[11,26–29]\n\nIn Brazil, the public health system has provided free-of-charge treatment with IFN-free DAAs regimens beginning in 2015 to all HCV/HIV coinfected patients, irrespective of the degree of liver fibrosis.[30] We now present results of a real-life study in this population with the following objectives: to estimate the real-life safety and efficacy of sofosbuvir (SOF)-based treatment regimens in an HCV/HIV Brazilian cohort; to investigate the frequency of baseline RASs in HCV NS5A and NS5B genes, and to identify predictors of treatment failure.\n\n2 Methods\n2.1 Study design and population\nWe conducted an observational, retrospective, and multicenter study of patients at 10 Brazilian reference centers specialized in the treatment of HCV. These centers are located in 3 Brazilian states: São Paulo, Rio Grande do Sul, and Rio de Janeiro.\n\nEligible subjects were all patients with HCV/HIV coinfection who started HCV therapy with SOF-based regimens between July 2015 and August 2017, according to the Brazilian Ministry of Health's Therapeutic Guidelines.[30] Inclusion criteria were: age ≥ 18 years, having received at least 1 dose of the prescribed treatment regimen, and no history of previous therapy with SOF and/or daclatasvir (DCV) or with any other NS5A antiviral regimen. Patients were not excluded based on the presence of comorbidities.\n\nAccording to the Brazilian Therapeutic Guidelines, the following treatment regimens were administered for the different HCV genotypes (GT): for HCV GT 1 and GT4: SOF and DCV; for GT2: SOF-ribavirin (RBV); for GT3: SOF-DCV combination or SOF plus pegIFN-RBV.[30] The choice of concomitant administration of RBV and/or the treatment of HCV GT3 patients was made at the discretion of the attending physician.\n\nThis study was approved by the Ethics Committee for the Analysis of Research Projects (Comissão de Ética para Análise de Projetos de Pesquisa—CAPPesq—Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo—HC-FMUSP) under protocol no. 46221015.0.0000.0068. All patients provided written informed consent prior to inclusion in the study.\n\n2.2 Data collection\nDemographic, clinical, and laboratory data were collected. Data was obtained from medical files after the end of treatment, by using a standard clinical questionnaire. For staging of liver disease, the results obtained by liver biopsy were considered according to the classification of the METAVIR Co-operative Study Group.[31] Liver elastography was also used for liver fibrosis staging. The corresponding transient elastography cutoff points (FibroScan, Echosens, France) for Metavir were less than 5.5 kPa = F0, 5.6 to 7.0 = F1, 7.1 to 9.4 kPa = F2, 9.5 to 12.4 kPa = F3, and ≥ 12.5 kPa = F4.[32] Cirrhosis was defined by liver biopsy or noninvasive method of liver fibrosis, according to the cut-off values mentioned above, or by clinical signs of portal hypertension. When biopsy or elastography were not available, those with APRI score ≥ 2 and FIB score ≥ 3.25 were also classified as cirrhotic.[33–35] Comorbidity was defined as the presence of any clinical condition that required clinical or pharmacological intervention by the medical team. Known DDI between DAAs and other concomitant medications were identified from the website www.hep-druginteractions.org.\n\n2.3 Outcomes\nThe primary efficacy endpoint was the proportion of patients with SVR, defined as an HCV RNA level below the limit of quantification (HCV RNA PCR <12 IU/mL; Abbot Molecular, Des Plaines, IL) following 12 weeks of treatment among all those who received at least 1 dose of the study treatment (intention-to-treat analysis (ITT)).\n\nWe also analyzed SVR, in a modified intention-to-treat analysis (m-ITT), in which we excluded cases such as loss to clinical follow-up, treatment interruptions, and/or deaths not associated with DAA adverse events.\n\nAn adverse event (AE) was defined as any event during treatment that required a dose change or discontinuation of a drug from HCV therapy regimen or other drug intervention. Serious adverse events (SAE) were defined as those that led to discontinuation of DAA therapy or death.\n\n2.4 Baseline RASs\nWe analyzed for RASs in pretreatment samples. HCV RNA extraction was performed from serum using the QIAamp Viral RNA Kit (Qiagen, Hilden, Germany), followed by amplification using the SuperScript III / Platinum Taq High Fidelity One-Step enzyme (InvitrogenTM, Thermo Fisher Brand, Carlsbad, USA), following the manufacturer's protocol. The amplified samples were submitted to a sequencing reaction (bidirectional) derived from the Sanger methodology.[36] The sequences obtained were initially analyzed using the Electropherogram quality analysis program (http://asparagin.cenargen.embrapa.br/phph/). By aligning the amino acid sequences of each sample with reference sequences, NS5A inhibitor RASs were screened at positions 28, 30, 31, 58, 92, and 93; and for NS5B inhibitors at positions 282, 316, and 321.[29,37,38] In addition, all consensus sequences were submitted to Geno2pheno [hcv] 0.92 (https://hcv.geno2pheno.org/) for confirmation of the results.[39]\n\n2.5 Statistical analysis\nWe used bivariate analyses followed by logistic regression to identify factors associated with lack of a SVR. Categorical variables were compared using χ2 or Fisher exact tests and continuous variables were compared using the Student t or Mann–Whitney test. Variables with P < .10 were selected for logistic regression analysis. Variables with P < .05 in the multiple analysis were retained in the final model. Odds ratios (OR) of each variable were estimated with the corresponding confidence interval (95% CI) at the 5% significance level. IBM-SPSS for Windows version 20.0 software was used to perform the analysis.\n\n3 Results\n3.1 Baseline characteristics\nThe main baseline characteristics of the 643 HCV/HIV coinfected patients who started DAA therapy are presented in Table 1. The majority were male (74.7%), median age 50, 90% with an undetectable HIV viral load and a median CD4 + T cell count of 617/mm3. Liver cirrhosis was identified in 42% of patients, mostly Child-Pugh A (85.3%) and Child-Pugh B (14.7%). There were no subjects with Child-Pugh C cirrhosis in our cohort. About 60% of patients had at least 1 comorbidity, with an average of 2 medical conditions per patient (range 1–9), including extrahepatic manifestations and hepatitis B virus coinfection. One hundred sixteen patients (18%) had 3 or more comorbidities. The most frequent comorbidities observed were: systemic arterial hypertension (n = 150), psychiatric disorders (n = 142), diabetes mellitus (n = 79), and dyslipidemia (n = 72). Twelve patients had hepatitis B virus coinfection (HBsAg positive).\n\nTable 1 Baseline characteristics of 643 Brazilian HCV-HIV patients.\n\nAlmost all patients (n = 636) were taking antiretroviral medication. Antiretroviral treatment therapy (ART) was done according to Brazilian Guidelines. ART was documented and no combination was excluded. Among these patients, 250 (38.9%) had their medication modified prior to initiating DAA to prevent drug–drug interactions. During HCV treatment with DAAs, 376 patients (58.5%) reported the concomitant use of other medications (an average of 3 drugs per patient) that were unrelated to HIV or HCV treatment. Antihypertensive drugs, psychotropic drugs, and those used to treat diabetes were the most commonly used medication classes. Although anticonvulsant medications are generally contraindicated during SOF and DCV treatment due to the risk of adverse interactions, these drugs were prescribed in 9 (1.4%) cases, as follows: carbamazepine (n = 4), phenobarbital (n = 2), phenytoin (n = 2), and oxcarbazepine (n = 1).\n\n3.2 Treatment regimens\nTable 2 presents the DAAs regimens used in this cohort, according to HCV genotypes.\n\nTable 2 Treatment regimens and sustained virologic response rate according HCV genotype.\n\n3.3 Response to treatment\nThe overall rate of SVR in the ITT analysis was 92.8% (n = 597; 95% CI 90.9–94.8). Sixteen subjects (2.5%) did not achieve a virological response. For 30 patients (4.7%) no SVR data was available: 9 subjects (1.4%) discontinued DAAs treatment due to SAE and 21 patients (3.3%) were lost to follow-up, interrupted treatment or died due to different causes not associated with HCV or the use of DAAs. In the m-ITT analysis, the SVR rate was 96% (95% CI 94.4%–97.5%) (Fig. 1).\n\nFigure 1 DAA = direct-acting antiviral, SVR = sustained virological response, AE = adverse event.\n\n(A) = intention-to-treat approach, (B) = modified intention-to-treat approach.\n\nCirrhotic patients achieved lower SVR rates when compared with noncirrhotic patients, but with no significant difference in both analyses (P = .21 and P = .44 in the ITT and m-ITT approaches, respectively). Child-Pugh B cirrhotic patients (N = 35) achieved SVR rates of 88.6% in the ITT analysis and 91.1% in the m-ITT analysis.\n\nSVR rates also did not differ significantly among HCV GTs or between Child-A or Child-B patients. Although cirrhotic patients positive for GT3 had a lower SVR rate (74.1%), this was not significantly different from cirrhotic patients with other HCV genotypes (P = .90).\n\n3.4 Safety\nOne hundred three patients experienced an AE during DAA therapy (AE rate: 16%; 95% CI 13.2–18.9). The most frequent AE was anemia, reported for 90 patients, all of whom were using RBV. The diagnosis of anemia secondary to the use of ribavirin was made by the attending physician, based on a decrease in hemoglobin levels during hepatitis C therapy compared with baseline hemoglobin values. None of the cases with anemia resulted in discontinuation of HCV treatment.\n\nSAE occurred in 10 individuals (1.6%; 95% CI 0.6–2.5), of which 2 died due to liver decompensation; both were Child-Pugh B cirrhotic. The other SAE reported were as follows: decompensation of psychiatric disorder (n = 1), elevation of alanine aminotransferase, and aspartate aminotransferase to a level 10 times the upper limit of normal (n = 1) and gastrointestinal intolerance (n = 6).\n\nAmong the 10 patients with SAE, 1 individual with gastrointestinal intolerance completed 8 weeks of therapy and achieved SVR. The other patients did not achieve SVR.\n\n3.5 HCV gene polymorphisms\nWe analyzed for polymorphisms in the HCV NS5B and NS5BA genes in 261 (40.6%) and 254 (39.5%) patients, respectively. In the analysis of the HCV NS5A region, genetic variants were found in 52 (20.5%) patients, In 5 of these individuals (2.0%) the substitutions conferred clinically relevant resistance to DCV.[40] The amino acid variants identified were: L31 M in 1 patient with HCV GT 1a, Y93C in 1 patient with HCV GT 1a, and Y93H in 3 HCV GT 1b-positive patients.\n\n3.6 Predictors of treatment failure\nIn the final logistic regression model, in both the ITT and m-ITT analyses, the use of drugs with relevant DDI with DAAs was significantly associated with non-SVR (P = .004 and P = .001, respectively). In the ITT analysis, the absence of prior IFN therapy was also associated with therapeutic failure (P = .04), whereas in the m-ITT analysis, female gender and age (> 50 years old) were also predictive of lack of SVR (P = .04 and P = .04, respectively). The m-ITT analysis results are summarized in Table 3.\n\nTable 3 Results of bivariate and multivariate analyses of factors associated with lack of SVR in a modified intention-to-treat approach—643 HCV-HIV coinfected patients.\n\nTo evaluate whether characteristics associated with HIV infection could interfere with the likelihood of obtaining SVR, we performed additional analyses on patients with known CD4 + T lymphocyte counts, HIV viral load, and a CDC clinical classification for AIDS. In bivariate and multivariate analysis of these 520 HCV/HIV coinfected individuals, only the use of drugs with significant DDI was associated with treatment failure (P = .01). The results are presented in Table 4.\n\nTable 4 Results of bivariate and multivariate analyses of factors associated with lack of SVR for 520 HCV-HIV coinfected patients with complete data on HIV infection.\n\n4 Discussion\nIn a cohort of 643 HCV-HIV coinfected patients from 10 centers in Brazil, the SVR rate was 96% following SOF and DCV-based therapy. Using a modified-ITT analysis, therapeutic failures were associated with the concomitant use of anticonvulsant drugs (P = .001), age above 50 years old (P = .04), and female gender (P = .04). Regarding drug safety, less than 2% of patients discontinued therapy due to AE. Factors related to HIV immunosuppression were not associated with lower rates of a therapeutic response. Lastly, the frequency of baseline mutations in HCV associated with clinical resistance to DAAs was infrequent, around 2%, and did not impair the SVR rate.\n\nThe observed high SVR rate is consistent with results of prior studies on smaller numbers of subjects from outside Brazil that employed the same therapeutic regimen.[40–43] Other studies, however, have associated the presence of HIV coinfection with a higher failure rate of anti-HCV DAA.[20,22–24] Berenguer et al[22] observed in a cohort of more than 2000 coinfected individuals that CD4+ T lymphocyte counts below 200/mm3 and a history of opportunistic disease were associated with therapeutic failure. In contrast, ARV therapy was successful in the majority of patients (98.9%) in our study and less than 5% had a CD4+ T cell count below 200/mm3. It is likely that this effective control of HIV infection contributed to the observed high positive rates of SVR and negated our ability to evaluate the possible impact of variables associated with immunodepression on success rates.\n\nOther factors, such as infection with HCV GT3, liver cirrhosis, or baseline RASs, have also been related to reduced SVR.[19,37,44–46] RBV use and the duration of therapy have also been reported to interfere with SVR rates in specific populations.[20,40,45] However, these variables were not associated with a lack of SVR in our cohort. In our study, patients who received a regimen of SOF+DVC 24 weeks (n = 9; 7 HCV GT1 and 2 HCV GT3) and SOF+pegIFN+RBV (n = 7; all HCV GT3; 50% with cirrhosis) had relatively low SVR rates (77.8% and 71.4%, respectively). We did not find a statistical difference in the SVR rates between HCV genotypes 1 and 3 or duration of treatment (12 versus 24 weeks). It is important to highlight that the number of patients receiving these 2 therapy regimens was small (n = 16) and according to national guidelines, the choice of concomitant administration of RBV and/or the treatment of HCV GT3 positive patients with IFN-based regimen was made at the discretion of the attending physician.\n\nIn our cohort, patients with liver cirrhosis had slightly lower SVR rates than those observed in the noncirrhotic population, but without statistical significance (P = .21 in ITT analysis and P = .44 in m-ITT analysis). When analyzing only cirrhotic patients (N = 238), those positive for HCV GT3 achieved the lowest SVR rate (74.1%), but this also was not statistically significant when compared with cirrhotic individuals with other HCV genotypes (P = .90).\n\nOur analysis identified that anticonvulsant medications predicted a reduction in the SVR rate (OR = 12.54 in m-ITT analysis). Nine patients (1.4%) were prescribed anticonvulsant medications to control chronic neurological or psychiatric disorders. Anticonvulsant medications are reported to be potent inducers of P-glycoprotein polypeptide and cytochrome P450-CYP3A4 enzymes capable of decreasing sofosbuvir and daclatasvir plasma concentrations, respectively, leading to reduced therapeutic effect of these antivirals.[47–50] It is important to emphasize that in our series, the use of anticonvulsant medications was associated with therapeutic failure in all analyses performed, whether in the multivariate analysis of the 643 patients (by IIT or m-ITT) or in the separate analysis of the 520 coinfected patients, for whom we had all the clinical information related to HIV immunosuppression.\n\nIn our study, female gender and age were also significantly associated with a reduction in the SVR (P = .04 and P = .04 with modified-ITT analysis). It is known that with IFN-based anti-HCV therapy, gender (specifically male), and advanced age are predictive of nonresponse to treatment.[51,52] With the advent of DAAs, these variables have become of less concern, as high rates of SVR have been achieved, and most studies have not reported their association with therapeutic failure.[16–19] In the few studies that identified an impact of gender and age on SVR in the DAAs era, the results have been conflicting. Berenguer et al found that males had a higher rate of virological failure in a Spanish HCV/HIV cohort, while Bischoff reported in a German cohort that males aged over 50 years had a higher SVR rate.[20,22] Our sample consisted predominantly of men (74.7%) and individuals over 40 years of age (89.9%). We found that the prevalence of comorbidities, psychiatric disorders, and the use of non-ARV medications were higher in females than in men in our cohort. These variables, either individually or in combination, may have contributed to the observed female association with therapeutic failure.\n\nThe impact of comorbidities on DAAs treatment outcomes has been described previously.[53–56] A recent Brazilian study with mono-infected patients showed that having a higher number of comorbidities was significantly associated with therapeutic failure using SOF-based regimens.[55] In the cohort of HCV/HIV coinfected patients described by Cachay et al,[56] the only factor identified as associated with a lower SVR was the presence of psychiatric disease. Considering the evidence that individuals with HIV infection have a higher prevalence and number of comorbidities, especially psychiatric disorders, it is essential in this population to evaluate all possible comorbidities, medication usage, known drug interactions, and patient adherence to achieve an optimal outcome with HCV therapy.[26,53,56,57]\n\nRegarding substitutions in the HCV genome associated with clinical resistance to DAAs, these were identified in less than 2% of our patients analyzed. The frequency of RASs in HCV NS5A genes in our study was lower than observed in other studies,[38,58–60] and their presence did not impair SVR rates in our population. An explanation for our results is that RASs, especially in the HCV NS5A gene, appear to impact the treatment response mainly in patients infected with HCV GT 1a and GT 3a.[37,38,58] In addition, we highlight that in the present study, RASs were not found at baseline in HCV GT3-positive patients (N = 32). This contrasts with results of other Brazilian studies where amino acid substitutions at positions 30 and 93 were identified.[61,62]\n\nLimitations in our study need to be acknowledged. Its retrospective nature did not allow us to obtain totally comprehensive data for all included patients nor was it possible to adequately assess adherence to treatment, relying only on data from medical records. In addition, the high SVR rates observed made it difficult to identify predictors of treatment failure, resulting in a reduction in the statistical power of these analyses. We acknowledge that, although the SOF-DCV regimen is not currently a first-line regimen in the Americas, Europe, and Brazil, it remains one of the preferred regimens according to WHO guidelines.[33] Despite these limitations, this is one of the largest series of subjects to be evaluated using SOF-DCV combination therapy in people living with HIV as well as possibly the largest case series of HCV/HIV coinfected patients in Latin America.\n\nConsidering the epidemiological setting and the impact of HCV/HIV coinfection and its outcomes on global public health, the results regarding the HCV treatment response in this population may contribute to the implementation of improved global strategies for HCV elimination. In addition, it is important to note that HCV treatment in this population goes beyond SVR. Management of the risk for reinfection and the need for hepatocarcinoma surveillance, especially in patients with advanced liver disease, are priorities in the clinical follow-up of this population. It is also necessary to mention that subgroups of coinfected patients continue to have specific barriers to effective care. Comorbidities, especially psychiatric issues, dependency on alcohol, and other drugs, difficulties to access health services and even situations of incarceration reduce access to HCV treatment.[26,28,63] Implementation of health programs involving multidisciplinary teams could improve the overall clinical management of this population.\n\nIn summary, the high cure rate of HCV/HIV coinfected individuals after SVR in our multicenter population confirms the efficacy and safety of this protocol and supports its universal distribution.\n\nAuthor contributions\nSMM and MCMC developed the original idea to conduct this study. They were responsible for the data analysis, wrote the first draft and final revision of the manuscript.\n\nAGV, AGL, ACMD, PRAF, DCJ, SBT, CEBM, MPG, FS, KDP, DVN: participated in the study design, in the patient cohort recruitment and data collection and revision of the manuscript.\n\nGLN and RSA were responsible for data analysis\n\nJRRP and FMM were responsible for laboratory analysis\n\nSSW was responsible for the study concept and revision of the article.\n\nAll authors assessed, reviewed, and edited the manuscript and approved the final version for publication.\n\nAbbreviations: AE = adverse event, DAAs = direct-action antivirals, DCV = daclatasvir, HCV = hepatitis C virus, ITT = intention to treat, SOF = sofosbuvir, SVR = sustained virological response.\n\nHow to cite this article: Machado SM, Vigani AG, Leite AG, Diaz AC, Ferreira PR, Carnaúba-Júnior D, Tenore SB, Brandão-Mello CE, Gonzalez MP, Siroma F, Prado KD, Nunes DV, Lisboa-Neto G, Pinho JR, Malta FM, Azevedo RS, Witkin SS, Mendes-Correa MC. Effectiveness of direct-acting antivirals for hepatitis C virus infection in hepatitis C/HIV co-infected individuals: A multicenter study. Medicine. 2020;99:30(e21270).\n\nLIM 52, Institute of Tropical Medicine, São Paulo.\n\nThe authors have no conflicts of interest to disclose.\n\nThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.\n==== Refs\nReferences\n[1] Global Hepatitis Report, 2017. Geneva: World Health Organization, 2017. Available at: https://www.who.int/hepatitis/publications/global-hepatitis-report2017/en/ .\n[2] Stepanova M Younossi ZM \nEconomic burden of hepatitis C infection\n. Clin Liver Dis \n2017 ;21 :579 –94\n.28689595 \n[3] Global AIDS Update, 2016. Geneva: United Nations Programme on HIV/AIDS (UNAIDS). Available at: http://www.unaids.org/sites/default/files/media_asset/global-AIDS-update-2016_en.pdf .\n[4] Alter MJ \nEpidemiology of viral hepatitis and HIV co-infection\n. 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"issue": "99(30)",
"journal": "Medicine",
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"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D060085:Coinfection; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000072230:Sustained Virologic Response",
"nlm_unique_id": "2985248R",
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"pages": "e21270",
"pmc": null,
"pmid": "32791706",
"pubdate": "2020-07-24",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Effectiveness of direct-acting antivirals for hepatitis C virus infection in hepatitis C/HIV coinfected individuals: A multicenter study.",
"title_normalized": "effectiveness of direct acting antivirals for hepatitis c virus infection in hepatitis c hiv coinfected individuals a multicenter study"
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{
"abstract": "To analyze the clinical differences between patients with primary intracerebral hemorrhage (ICH) with and without atrial fibrillation (AF) and assess whether the effect of the antithrombotic pretreatment on outcome is modified by the presence of AF.\n\n\n\nIn this prospective observational study, researchers from 2 university hospitals included 1,106 consecutive patients with ICH. Clinical characteristics were described and stratified by presence of AF. In-hospital and 3-month mortality and 3-month disability were analyzed, considering antithrombotic pretreatment (none, antiplatelets, or oral anticoagulants) and AF (yes/no).\n\n\n\nAF was present in 21.9% of primary ICH cases. Patients with AF-ICH were older, with more vascular risk factors, more antithrombotic pretreatment, higher clinical severity, higher hematoma volume, and higher in-hospital and 3-month mortality. Do-not-resuscitate orders were applied more frequently in AF-ICH cases. After 2 different adjustment models, mortality remained significantly higher in patients with AF-ICH. However, after introducing previous antithrombotic treatment in the model, the adjusted odds ratio for 3-month mortality was 1.45 (95% confidence interval 0.74-2.85, p = 0.284) for patients with AF-ICH compared with non-AF cases. AF modified the effect of antithrombotic pretreatment on in-hospital (p int = 0.077) and 3-month mortality (p int = 0.008). Among patients without AF, antithrombotic pretreatment increased mortality; no effect was observed in patients with AF-ICH.\n\n\n\nPatients with AF and ICH had increased mortality; however, AF had no independent effect on mortality after adjustment for antithrombotic pretreatment. Conversely, antithrombotic pretreatment had a deleterious effect on outcome in patients with ICH without AF, but no detectable effect in patients with AF with ICH.",
"affiliations": "From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain. jroquer@parcdesalutmar.cat.;From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain.;From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain.;From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain.;From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain.;From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain.;From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain.;From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain.;From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain.;From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain.;From the Servei de Neurologia (J.R., R.M.V.-H., E.C.-G., E.G.S., J.J.-C., A.R.-C., A.O.), IMIM-Hospital del Mar; Departament de Medicina (J.R., E.G.S., J.J.-C., A.R.-C., A.O.), Universitat Autònoma de Barcelona; Servei de Neurologia (L.L.P.-S., A.M.-D., D.G.-A.), Hospital de Sant Pau; and DCEXS (E.C.-G., J.M.-F.), Universitat Pompeu Fabra, Barcelona, Spain.",
"authors": "Roquer|Jaume|J|0000-0001-5992-2606;Vivanco-Hidalgo|Rosa Maria|RM|;Prats-Sánchez|Lluís L|LL|;Martínez-Domeño|Alejandro|A|;Guisado-Alonso|Daniel|D|;Cuadrado-Godia|Elisa|E|;Giralt Steinhauer|Eva|E|;Jiménez-Conde|Jordi|J|;Rodríguez-Campello|Ana|A|;Martí-Fàbregas|Joan|J|;Ois|Angel|A|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1212/WNL.0000000000008462",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "93(19)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D016022:Case-Control Studies; D002543:Cerebral Hemorrhage; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011379:Prognosis; D011446:Prospective Studies; D016414:Resuscitation Orders; D012720:Severity of Illness Index; D013030:Spain",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "e1820-e1829",
"pmc": null,
"pmid": "31597709",
"pubdate": "2019-11-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Interaction of atrial fibrillation and antithrombotics on outcome in intracerebral hemorrhage.",
"title_normalized": "interaction of atrial fibrillation and antithrombotics on outcome in intracerebral hemorrhage"
} | [
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"companynumb": "ES-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2020-BI-012744",
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"abstract": "BACKGROUND\nStreptococcus pyogenes is responsible for 5-15% and 20-30% of acute pharyngitis/tonsillitis in adults and children, respectively. It not only causes acute illness but also can give rise to local suppurative complications such as peritonsillar abscess as well as trigger the postinfectious syndromes of glomerulonephritis, acute rheumatic fever and poststreptococcal reactive arthritis. Here, we report a case of a young healthy adult in whom both peritonsillar abscess and poststreptococcal reactive arthritis developed as a complication of acute streptococcal tonsillitis. To the best of our knowledge, such a coincidence of poststreptococcal sequelae has not been reported previously.\n\n\nMETHODS\nA 32-year-old previously healthy woman was diagnosed with acute tonsillitis by her family doctor and treated empirically with amoxicillin/clavulanic acid (875/125 mg) twice daily for 5 days. Four days after completing antibiotic therapy, peritonsillar abscess of left tonsil developed. Needle aspiration followed by incision and drainage were performed by otolaryngologist at the Emergency Department. Next, the patient was discharged home on a 10-day course of cefuroxime and metronidazole. The symptoms of peritonsillar abscess were subsiding during treatment, however on the last day of antibiotic therapy, swelling and pain of the left ankle appeared. Five days later the patient was consulted by rheumatologist. Cultures of throat swabs and abscess aspirate collected 2 weeks before revealed the presence of Streptococcus pyogenes. Antistreptolysin O (ASO) titer was evaluated and proved to be 412 IU/ml (normal 0-200 IU/ml). The level of C-reactive protein was 13,0 mg/L (normal <5,0 mg/L). There was no known cardiac involvement. Poststreptococcal reactive arthritis was diagnosed. Left ankle arthralgia persisted for about 5-6 weeks. Six months after the presentation at the Emergency Department, the patient was well, with ASO titer reaching 262 IU/ml.\n\n\nCONCLUSIONS\nClinicians should be aware that appropriate choice of antibiotic, proper dose as well as duration of therapy of acute GAS pharyngitis/tonsillitis are crucial to prevent poststreptococcal sequelae.",
"affiliations": "Medical Microbiology Department, Medical University of Lublin, ul. Chodźki 1, 20-093, Lublin, Poland. elamazur@yahoo.com.;Department of Otolaryngology, Regional Specialist Hospital in Radom, ul. Aleksandrowicza 5, 26-617, Radom, Poland. edcz@op.pl.;Microbiological Laboratory at the Regional Specialist Hospital in Radom, ul. Aleksandrowicza 5, 26-617, Radom, Poland. aneta.grochowalska@op.pl.;Medical Microbiology Department, Medical University of Lublin, ul. Chodźki 1, 20-093, Lublin, Poland. koziolm@yahoo.com.",
"authors": "Mazur|Elżbieta|E|;Czerwińska|Ewa|E|;Grochowalska|Aneta|A|;Kozioł-Montewka|Maria|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12879-015-0780-8",
"fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 78010.1186/s12879-015-0780-8Case ReportConcurrent peritonsillar abscess and poststreptococcal reactive arthritis complicating acute streptococcal tonsillitis in a young healthy adult: a case report Mazur Elżbieta elamazur@yahoo.com Czerwińska Ewa edcz@op.pl Grochowalska Aneta aneta.grochowalska@op.pl Kozioł-Montewka Maria koziolm@yahoo.com Medical Microbiology Department, Medical University of Lublin, ul. Chodźki 1, 20-093 Lublin, Poland Department of Otolaryngology, Regional Specialist Hospital in Radom, ul. Aleksandrowicza 5, 26-617 Radom, Poland Microbiological Laboratory at the Regional Specialist Hospital in Radom, ul. Aleksandrowicza 5, 26-617 Radom, Poland 7 2 2015 7 2 2015 2015 15 5015 6 2014 23 1 2015 © Mazur et al.; licensee BioMed Central. 2015This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nStreptococcus pyogenes is responsible for 5-15% and 20-30% of acute pharyngitis/tonsillitis in adults and children, respectively. It not only causes acute illness but also can give rise to local suppurative complications such as peritonsillar abscess as well as trigger the postinfectious syndromes of glomerulonephritis, acute rheumatic fever and poststreptococcal reactive arthritis. Here, we report a case of a young healthy adult in whom both peritonsillar abscess and poststreptococcal reactive arthritis developed as a complication of acute streptococcal tonsillitis. To the best of our knowledge, such a coincidence of poststreptococcal sequelae has not been reported previously.\n\nCase presentation\nA 32-year-old previously healthy woman was diagnosed with acute tonsillitis by her family doctor and treated empirically with amoxicillin/clavulanic acid (875/125 mg) twice daily for 5 days. Four days after completing antibiotic therapy, peritonsillar abscess of left tonsil developed. Needle aspiration followed by incision and drainage were performed by otolaryngologist at the Emergency Department. Next, the patient was discharged home on a 10-day course of cefuroxime and metronidazole. The symptoms of peritonsillar abscess were subsiding during treatment, however on the last day of antibiotic therapy, swelling and pain of the left ankle appeared. Five days later the patient was consulted by rheumatologist. Cultures of throat swabs and abscess aspirate collected 2 weeks before revealed the presence of Streptococcus pyogenes. Antistreptolysin O (ASO) titer was evaluated and proved to be 412 IU/ml (normal 0–200 IU/ml). The level of C-reactive protein was 13,0 mg/L (normal <5,0 mg/L). There was no known cardiac involvement. Poststreptococcal reactive arthritis was diagnosed. Left ankle arthralgia persisted for about 5–6 weeks. Six months after the presentation at the Emergency Department, the patient was well, with ASO titer reaching 262 IU/ml.\n\nConclusions\nClinicians should be aware that appropriate choice of antibiotic, proper dose as well as duration of therapy of acute GAS pharyngitis/tonsillitis are crucial to prevent poststreptococcal sequelae.\n\nKeywords\nStreptococcus pyogenesTonsillitisPeritonsillar abscessPoststreptococcal reactive arthritisAntibiotic therapyissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nStreptococcus pyogenes (group A streptococcus, GAS) is responsible for 5 to 15% and 20 to 30% of acute pharyngitis/tonsillitis in adults and children, respectively. It not only causes acute illness but also can give rise to local suppurative complications such as peritonsillar abscess (PTA) as well as trigger the postinfectious syndromes of glomerulonephritis, acute rheumatic fever (ARF) and poststreptococcal reactive arthritis (PSRA) [1-3]. PTA, defined as a collection of pus located between the tonsillar capsule and the pharyngeal constrictor muscle, occurs mainly in young adults [4,5]. PSRA is defined as arthritis associated with proven streptococcal infection but not fulfilling the modified Jones criteria for the diagnosis of acute rheumatic fever [2,3]. Here, we report a case of a young healthy adult in whom both, PTA and PSRA, developed as a complication of acute streptococcal tonsillitis. To the best of our knowledge, such a coincidence of poststreptococcal sequelae has not been reported previously.\n\nCase presentation\nA 32-year-old woman was diagnosed with acute tonsillitis by her family doctor. Microbiological examination was not performed at that time. Amoxicillin/clavulanic acid 875/125 mg twice daily for 5 days was prescribed empirically. The symptoms of tonsillitis resolved within five-day treatment, however, four days after completing the course of antibiotic therapy, sore throat, more prominent on the left side, reappeared. Two days later the patient presented to the Emergency Department with a two-day history of worsening sore throat, painful swallowing and fever. The patient was previously well, with no history of chronic diseases, recurrent tonsillitis or previous peritonsillar abscess. Seven months previously she gave birth to her second child and was still breastfeeding the baby. She denied smoking. On physical examination her temperature was 38°C, pulse rate: 80 beats/min, respiratory rate: 22 breaths/min and blood pressure: 120/80 mm Hg. Examination of the oral cavity and oropharynx showed enlarged and inflamed left tonsil as well as congested and bulging soft palate on the left side with contralateral displacement of the uvula. Both tonsils were covered with whitish exudate. No dental caries was noted. There was also bilateral, moderately tender submandibular lymphadenopathy. The remainder of physical examination was unremarkable. Blood tests results are shown in Table 1. Separate swabs were obtained from the surfaces of both tonsils. Next, under local anesthesia, diagnostic needle aspiration of left tonsil was performed by otolaryngologist, during which scanty amount of pus was obtained. This initial procedure was followed by incision and drainage. Tonsil swabs and abscess aspirate were sent to laboratory for microbiological examination. The patient refused hospitalization at the Otolaryngology Department, thus was discharged home on a 10-day course of cefuroxime (500 mg twice daily) and metronidazole (500 mg 3 times daily) with recommendation to discontinue breastfeeding for the duration of the antibiotic therapy and to present at follow-up visit to Otolaryngology Clinic after completing antibiotic therapy. The symptoms of peritonsillar abscess as well as fever were subsiding steadily during treatment, however on the last day of antibiotic therapy, swelling and pain of the left ankle appeared, thus the patient presented to her family doctor. Upon presentation she was afebrile and had marked oedema and pain of her left ankle. Her heart rate was 72 beats/min, she did not have an appreciable cardiac murmur. Her chest was clear to auscultation. Antibiotic therapy with cefuroxime (500 mg once daily) for next 5 days was prescribed, as well as pain relief medication with paracetamol. After completing antibiotic therapy the patient presented at follow-up visit to Otolaryngology Clinic. She was afebrile, with normal vital signs. Examination of oropharynx showed resolution of both, congestion and oedema of left tonsil and soft palate. There was no exudate on the tonsils. Cultures of throat swabs and abscess aspirate collected 2 weeks before revealed the presence of Streptococcus pyogenes in all three materials. According to the patient report, left ankle swelling with which she presented to her family doctor, resolved within 4 days. Upon presentation the patient only had moderate pain in the joint. She was consulted by rheumatologist. Her heart rate was 70 beats/min. She did not have a regurgitant murmur. Her chest was clear to auscultation. Antistreptolysin O (ASO) titer was evaluated and proved to be 412 IU/ml (normal 0–200 IU/ml). The level of C-reactive protein was 13,0 mg/L. Control throat swabs were collected for culture, which revealed normal oropharynx flora. The patient was recommended to continue pain relief medication with paracetamol and present at follow-up visit to Rheumatology Clinic after 2 weeks. Her only complaint was persisting slight pain in left ankle joint. The results of physical examination were analogous to those observed at previous follow-up. ASO titer was 503 IU/ml. Control throat swabs were collected and culture yielded normal flora. The patient was recommended to present at follow-up visit at Rheumatology Clinic after 2 months. At that time, she was well. Ankle pain, according to the patient report, disappeared shortly after last visit. The results of physical examination were analogous to those observed previously. ASO titer was 396 IU/ml. Six months after the presentation at Emergency Department, the patient was well, with ASO titer reaching 262 IU/ml. Table 1 summarizes the chronology of clinical findings and blood tests results.Table 1 \nSummary of clinical findings and blood tests over time\n\n\n\nTimeline\n\t\nClinical findings\n\t\nBlood tests results\n\t\nDay 1: presentation to the family doctor\tAcute tonsillitis\tNot performed\t\nDay 11: presentation to the Emergency Department\tLeft side peritonsillar abscess\tLeukocytosis: 15 270/mm3 Granulocytes: 79.7%\t\nLymphocytes: 15.9%\t\nMonocytes: 2.8%\t\nHemoglobin: 13.0 g/dl Hematocrit: 38.9%\t\nPlatelet count: 329 000/mm3\n\t\nCRP: 131.0 mg/L (normal <5.0 mg/L)\t\nDay 20: 2nd presentation to the family doctor\tLeft ankle arthritis\tNot performed\t\nDay 25: follow-up visit to the Otolaryngology Department and the rheumatologist consultation\tLeft ankle arthralgia\tASO: 412 IU/ml (normal 0–200 IU/ml)\t\nCRP: 13.0 mg/L\t\nDay 40: 1st follow up to the rheumatologist\tLeft ankle arthralgia\tASO: 503 IU/ml\t\nDay 100: 2nd follow up to the rheumatologist\tHealthy\tASO: 396 IU/ml\t\nDay 180: 3rd follow up to the rheumatologist\tHealthy\tASO: 262 IU/ml\t\nCRP: C-reactive protein; ASO: antistreptolysin titer.\n\n\n\nBacteriology findings\nCultures of PTA aspirate revealed Streptococcus pyogenes as a predominant species as well as Prevotella oralis and Haemophilus parainfluenzae. Tonsil swabs, collected at the time the patient presented with PTA, yielded copious growth of Streptococcus pyogenes as well as normal throat flora, namely Streptococcus viridians, Neisseria spp, and Haemophilus parainfluenzae. Two control throat swabs revealed only normal oropharynx flora. Bacterial species were identified with the use of routine microbiological methods, drug susceptibility of S. pyogenes was assessed using Vitek 2 Compact (bioMérieux). Antimicrobial susceptibility results were interpreted according to the European Committee on Antimicrobial Susceptibility Testing recommendations (EUCAST 2013, version 3.1) [6]. Streptococcus pyogenes strains isolated from tonsil swabs and abscess aspirate demonstrated identical susceptibility patterns. They were resistant to erythromycin, clindamycin, tetracycline and fully susceptible to all other antibiotics tested. MLSi phenotype (inducible coresistance to macrolide, lincosamide and streptogramine) was detected with the use of double-disc diffusion testing [7].\n\nDiscussion\nGAS pharyngitis is a self-limiting disease in most cases, however, it can cause suppurative and nonsuppurative complications [1,2]. In our patient both, peritonsillar abscess and poststreptococcal reactive arthritis occurred as a complication of acute GAS tonsillitis. Although microbiological examination was not performed at the time the patient presented with tonsillitis, the reappearance of sore throat within 4 days after completing a 5-day antibiotic therapy with amoxicillin/clavulanic acid and the presence of GAS in throat swab cultures at the time she presented with PTA, strongly suggest GAS aetiology of antecedent tonsillitis. Moreover, the isolation of GAS strains with identical susceptibility patterns from both, throat swabs and abscess aspirate, leaves no doubt that GAS strain that caused tonsillitis participated in the development of PTA. From the majority of PTA aspirates polymicrobial mixture of aerobic and anaerobic bacteria is recovered, however, GAS along with Fusobacterium necrophorum are commonly regarded to be the primary pathogens [4,5]. In our patient three bacterial species were detected in abscess aspirate: GAS, Prevotella oralis, and H. parainfluenzae. There are no uniform recommendations regarding PTA antibiotic therapy, thus treatment options vary greatly between clinicians and are based mainly on their preferences [4,8,9]. In most cases antibiotics of choice include penicillin combined with metronidazole, amoxicillin with clavulanic acid, clindamycin, cefuroxime, or metronidazole [8-10]. In our department cefuroxime combined with metronidazole is administered as empiric antimicrobial therapy in most cases, our patient was treated with these drugs as well.\n\nPSRA is defined as arthritis associated with proven streptococcal infection but not fulfilling the modified Jones criteria for the diagnosis of acute rheumatic fever (ARF). It is still not clear whether this entity represents a distinct syndrome or is a manifestation of ARF [2,3]. ARF has now become rare in developed countries. Its incidence in Western Europe is currently less than 1 case per 100 000 population, whereas PSRA is relatively more frequent with the annual incidence of approximately 2 cases per 100 000 people [11]. There is a mean interval of 14 days between the onset of GAS pharyngitis symptoms and the occurrence of PSRA [3]. Age distribution appears to be bimodal, with two incidence peaks, at ages 8–14 and 21–37 years, respectively [3]. Joint involvement is typically non-migratory and affects large joints, particularly those of lower limbs. Knee and ankle joints are regularly involved, although small joints and axial involvement occurs as well. Mono-, oligo- and polyarthritis are equally represented. Unlike the self-limiting and exquisitely responsive to salicylates arthritis of ARF, PSRA responds relatively poorly to salicylates and nonsteroid anti-inflammatory drugs. Carditis is a rare event. The disease resolves within weeks [3,11,12]. Discrimination between ARF and PSRA is ambiguous due to the lack of generally accepted set of criteria for the diagnosis of PSRA [11]. In our patient non-migratory monoarthritis, localized in the left ankle, without fever or known cardiac involvement occurred approximately 20 days after the onset of tonsillitis while the patient was still on antibiotic therapy due to PTA. Although joint oedema resolved within 4 days, arthralgia, moderately responsive to nonsteroid anti-inflammatory drugs, persisted for about 5–6 weeks. Antecedent GAS throat infection was confirmed by cultures as well as serologically. However, the modified Jones criteria were not fulfilled, thus PSRA was diagnosed. Similarly to what was noted by Jansen et al. [13], clinical findings of PSRA in our patient had subsided before ASO titre reached its maximum value. At present, there are no evidence-based guidelines whether patients with PSRA, similarly to those with ARF, should receive long-term antibiotic prophylaxis [11]. Recent data indicate no increased risk of valvular heart disease in adults with PSRA [14]. Accordingly, our patient did not receive secondary antibiotic prophylaxis.\n\nSome European guidelines, among them British, Scottish, Dutch and Belgian, consider GAS pharyngitis to be a mild, self-limiting disease that does not require a specific diagnosis or antimicrobial treatment except in high-risk patients, such as those with a history of valvular heart disease or acute rheumatic fever, immunosuppressed or severely ill [15-18]. Recently issued recommendations of European Society of Clinical Microbiology and Infectious Diseases represent similar approach [19]. However, the remaining European and North American guidelines recommend that all cases of acute streptococcal pharyngitis/tonsillitis should be appropriately treated to prevent both, suppurative and nonsuppurative poststreptococcal complications [20]. According to Polish recommendations, phenoxymethyl penicillin, 2–3 million units twice daily for 10 days, is currently antibiotic therapy of choice for GAS pharyngitis. Second and third-line drugs include: first generation cephalosporin in patients with penicillin allergy who do not have immediate hypersensitivity to beta-lactam antibiotics or macrolides (erythromycin, azithromycin, clarithromycin) in those with hypersensitivity to beta-lactam antibiotics. Azithromycin is the only drug that is given in a 5-day course as opposed to a 10-day course for all the other antibiotics [21]. Currently, American Heart Association/American Academy of Pediatrics and Infectious Diseases Society of America recommend amoxicillin once or twice daily for 10 days as alternative first-line therapy, since in comparative clinical trials once-daily amoxicillin (50 mg/kg, to a maximum of 1000 mg) for 10 days has been shown to be effective for GAS pharyngitis [2,22]. However, the treatment of tonsillitis in our patient did not comply the recommendations, particularly with respect to the duration of therapy. Five-day treatment with amoxicillin/clavulanic acid resulted in the lack of GAS eradication, which in turn caused both PTA and PSRA.\n\nConclusion\nIn summary, to the best of the authors’ knowledge, this is the first published account of the coincidence of both PTA and PSRA, complicating acute GAS tonsillitis in a young healthy adult. Moreover, the occurrence of both complications might have an association with improper management of acute streptococcal tonsillitis. Clinicians should be aware that appropriate choice of antibiotic, proper dose as well as duration of therapy of acute GAS pharyngitis/tonsillitis are crucial to prevent poststreptococcal sequelae.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nEM conceived the idea of the case description and coordinated drafting the manuscript. EC was responsible for the patient’s management and collected all significant clinical information. AG, EM and MKM participated in the bacteriologic studies. All authors participated in drafting and revising the manuscript. All authors read and approved its final version.\n\nAuthors’ information\n\nEM, MKM: Medical Microbiology Department, Medical University of Lublin, Poland.\n\nEC: Department of Otolaryngology, Regional Specialist Hospital in Radom, Poland.\n\nAG: Microbiological Laboratory at the Regional Specialist Hospital in Radom, Poland.\n==== Refs\nReferences\n1. Wessels MR Clinical practice: streptococcal pharyngitis N Engl J Med 2011 364 648 655 10.1056/NEJMcp1009126 21323542 \n2. Gerber MA Baltimore RS Eaton CB Gewitz M Rowley AH Shulman ST Taubert KA Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics Circulation 2009 119 1541 1551 10.1161/CIRCULATIONAHA.109.191959 19246689 \n3. Mackie SL Keat A Poststreptococcal reactive arthritis: what is it and how do we know? Rheumatology (Oxford) 2004 43 8 949 954 10.1093/rheumatology/keh225 15150434 \n4. Powell EL Powell J Samuel JR Wilson JA A review of the pathogenesis of adult peritonsillar abscess: time for a re-evaluation J Antimicrob Chemother 2013 68 9 1941 1950 10.1093/jac/dkt128 23612569 \n5. Klug TE Incidence and microbiology of peritonsillar abscess: the influence of season, age, and gender Eur J Clin Microbiol Infect Dis 2014 33 7 1163 1167 10.1007/s10096-014-2052-8 24474247 \n6. The European Committee on Antimicrobial Susceptibility Testing. Breakpoints tables for interpretation of MICs and zone diameters. Version 3.1, 2013. [http://www.eucast.org/fileadmin/src/media/PDFs/EUCAST_files/Breakpoint_tables/Breakpoint_table_v_3.1.pdf]\n7. Żabicka D, Izdebski R, Hryniewicz W. Rekomendacje doboru testów do oznaczania wrażliwości bakterii na antybiotyki i chemioterapeutyki 2009. Oznaczanie wrażliwości ziarniaków Gram-dodatnich z rodzaju Streptococcus spp. [http://www.korld.edu.pl/pdf/03-Rek2009-Streptococcus_pneumoniae_i_Streptococcus..pdf]\n8. Powell J Wilson JA An evidence-based review of peritonsillar abscess Clin Otolaryngol 2012 37 2 136 145 10.1111/j.1749-4486.2012.02452.x 22321140 \n9. Wikstén J Blomgren K Eriksson T Guldfred L Bratt M Pitkäranta A Variations in treatment of peritonsillar abscess in four Nordic countries Acta Otolaryngol 2014 134 8 813 7 10.3109/00016489.2014.905702 24930914 \n10. Sowerby LJ Hussain Z Husein M The epidemiology, antibiotic resistance and post-discharge course of peritonsillar abscess in London, Ontario J Otolaryngol Head Neck Surg 2013 42 5 10.1186/1916-0216-42-5 23663820 \n11. van der Helm-van Mil AH Acute rheumatic fever and poststreptococcal reactive arthritis reconsidered Curr Opin Rheumatol 2010 22 4 437 42 10.1097/BOR.0b013e328337ba26 20150812 \n12. Shulman ST Ayoub EM Poststreptococcal reactive arthritis Curr Opin Rheumatol 2002 14 5 562 565 10.1097/00002281-200209000-00014 12192255 \n13. Jansen TL Janssen M de Jong AJ Jeurissen ME Post-streptococcal reactive arthritis: a clinical and serological description, revealing its distinction from acute rheumatic fever J Intern Med 1999 245 3 261 267 10.1046/j.1365-2796.1999.0438e.x 10205588 \n14. van Bemmel JM Delgado V Holman ER Allaart CF Huizinga TW Bax JJ van der Helm-van Mil AH No increased risk of valvular heart disease in adult poststreptococcal reactive arthritis Arthritis Rheum 2009 60 4 987 993 10.1002/art.24401 19333942 \n15. National Institute for Health and Clinical Excellence. Respiratory tract infections - antibiotic prescribing. Prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care. NICE clinical guideline 69. 2008. [http://www.nice.org.uk/nicemedia/pdf/CG69FullGuideline.pdf]\n16. Scottish Intercollegiate Guidelines Network. Management of sore throat and indication for tonsillectomy. A national clinical guideline 2010. [http://www.sign.ac.uk/pdf/sign117.pdf]\n17. Starreveld JS Zwart S Boukes FS Wiersma T Goudswaard AN Summary of the practice guideline “Sore throat” (second revision) from the Dutch College of General Practitioners Ned Tijdschr Geneeskd 2008 152 431 435 18361191 \n18. Chevalier P, De Sutter A. Guide belge des traitements anti-infectieux en pratique ambulatoire. Belgian Antimicrobial Policy Coordination Committee. 2008. [http://www.health.belgium.be/eportal/Myhealth/Care/Properuse/Antibiotics/Humanmedicine/Recommendations/index.htm]\n19. ESCMID Sore Throat Guideline Group Pelucchi C Grigoryan L Galeone C Esposito S Huovinen P Little P ESCMID guideline for the management of acute sore throat Clin Microbiol Infect 2012 18 Suppl. 1 1 28 22432746 \n20. Mazur E Management of acute streptococcal pharyngitis: still the subject of controversy Cent Eur J Med 2013 8 6 713 719 10.2478/s11536-013-0216-z \n21. Hryniewicz W, Ozorowski T, Radzikowski A, Zielonka TM, Albrecht P, Lukas W, et al. Rekomendacje postępowania w pozaszpitalnych zakażeniach układu oddechowego 2010. [http://www.antybiotyki.edu.pl/pdf/RekomendacjeA42009.pdf]\n22. Shulman ST Bisno AL Clegg HW Gerber MA Kaplan EL Lee G Martin JM Van Beneden C Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America Clin Infect Dis 2012 55 10 e86 102 10.1093/cid/cis629 22965026\n\n",
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"mesh_terms": "D000208:Acute Disease; D000328:Adult; D016918:Arthritis, Reactive; D005260:Female; D006801:Humans; D000039:Peritonsillar Abscess; D010612:Pharyngitis; D012541:Scarlet Fever; D013290:Streptococcal Infections; D013297:Streptococcus pyogenes",
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"title": "Concurrent peritonsillar abscess and poststreptococcal reactive arthritis complicating acute streptococcal tonsillitis in a young healthy adult: a case report.",
"title_normalized": "concurrent peritonsillar abscess and poststreptococcal reactive arthritis complicating acute streptococcal tonsillitis in a young healthy adult a case report"
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"abstract": "Bortezomib is a chemotherapeutic agent that acts via proteasome inhibition resulting in cellular apoptosis and inhibition of angiogenesis. Although widely accepted as treatment of multiple myeloma and non-Hodgkin's lymphoma, it has also been shown to be efficacious in a variety of solid tumours such as pancreatic and colonic. Posterior reversible encephalopathy syndrome (PRES) is a neuroradiological syndrome characterised by vasogenic oedema involving the postero-occipital cortical and subcortical white matter resulting in visual disturbances, seizures and altered mental status. Although in most cases PRES is reversible with removal of the provoking condition or drug, if not appropriately recognised and treated it may lead to permanent and life-threatening sequelae such as intracerebral haemorrhage and ischaemic infarction. We report a case of PRES associated with bortezomib therapy and contrast it with four other previously reported cases. Recognition of this potentially severe neurological complication is important with the increasingly widespread use of bortezomib.",
"affiliations": "Department of Internal Medicine, University of Calgary, Calgary, Alberta, Canada.;Department of Critical Care Medicine, University of Calgary, Calgary, Alberta, Canada.",
"authors": "Nixon|N A|NA|;Parhar|K|K|",
"chemical_list": "D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib",
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"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001897:Boronic Acids; D000069286:Bortezomib; D001921:Brain; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D009101:Multiple Myeloma; D059906:Neuroimaging; D054038:Posterior Leukoencephalopathy Syndrome; D011719:Pyrazines",
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"title": "Posterior reversible encephalopathy syndrome resulting from repeat bortezomib usage.",
"title_normalized": "posterior reversible encephalopathy syndrome resulting from repeat bortezomib usage"
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"abstract": "BACKGROUND\nAntidementia drugs, antidepressants and antipsychotics are among the most frequently prescribed medication in old and multimorbid patients. Due to side effects (e. g. prolonged QTc interval) in emergency medicine/intensive care unit or patients' wishes the question is often raised whether these drugs can be stopped and how this may be done.\nIf the cognition is stable under antidementia drugs or if the patient is in favour of the medication, it should be continued. After stopping antidementia drugs there may be a deterioration of cognitive function in the following 2-3 months. This should be discussed with the patient and the relatives/caregiver.\nIn case of only slight or reactive depressive mood antidepressants should be tapered. The dose should be reduced over a period of at least 4 weeks. A sudden stop may cause a withdrawal syndrome with flu-like symptoms, fatigue, tremor, insomnia, anxiety or confusion. In severe depressive episodes there is a high risk of relapse; therefore deprescribing should only be done after a stable remission of 4-9 months.\nAntipsychotics in dementia or nursing home patients as well as in cases of delirium should be tapered, whereby confusion may increase again. When antipsychotics were prescribed because of hallucinations or severe psychosis, they should not be reduced or only with great caution.",
"affiliations": "Zentrum für Medizin im Alter, DIAKOVERE Henriettenstift, Schwemannstraße 19, 30559, Hannover, Deutschland. klaus.hager@diakovere.de.;Klinik für Anästhesiologie und Intensivmedizin, Medizinische Hochschule Hannover, Hannover, Deutschland.;Zentrum für Medizin im Alter, DIAKOVERE Henriettenstift, Schwemannstraße 19, 30559, Hannover, Deutschland.",
"authors": "Hager|K|K|;Temps|T|T|;Krause|O|O|",
"chemical_list": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents",
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"doi": "10.1007/s00063-018-0451-9",
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"issue": "114(5)",
"journal": "Medizinische Klinik, Intensivmedizin und Notfallmedizin",
"keywords": "Antidepressants; Antipsychotics; Cholinesterase inhibitors; Deprescribing",
"medline_ta": "Med Klin Intensivmed Notfmed",
"mesh_terms": "D000368:Aged; D000375:Aging; D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D001007:Anxiety; D000075202:Contraindications; D003704:Dementia; D006801:Humans",
"nlm_unique_id": "101575086",
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"pages": "463-469",
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"pubdate": "2019-06",
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"title": "Tapering of antidementia drugs, antidepressants and antipsychotics in elderly patients : When possible, when not?",
"title_normalized": "tapering of antidementia drugs antidepressants and antipsychotics in elderly patients when possible when not"
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"abstract": "A single-institution series using a (neo)adjuvant chemotherapy and interdigitated hyperfractionated split-course radiation therapy (CRT) treatment protocol for soft tissue sarcoma was reviewed. Our specific aims were to study recurrence rates and long-term toxicity. Between 1998 and 2016, 89 patients with non-metastatic soft tissue sarcoma were treated with surgery combined with six courses of doxorubicin and ifosfamide and hyperfractionated radiation therapy (42-60 Gy/1.5 Gy twice daily). Patients were considered being at high risk if tumour malignancy grade was high and the tumour fulfilled at least two of the following criteria: size >8 cm, presence of necrosis or vascular invasion. The mean age of the patients was 50.7 years. With a median follow-up of 5.4 years for survivors, the local control rate was 81.4%. Six (7%) patients progressed during neoadjuvant CRT. Seven (8%) patients discontinued the treatment due to toxicity. Eighty-six patients were operated and three (3%) of these developed a long-term complication. The estimated metastasis-free survival was 47.6% and overall survival 53.0% at five years. The limb-salvage rate was 93%. The limb-salvage rate, local control and complication rates were good in these patients with high risk soft tissue sarcoma. Metastases-free survival and overall survival rates were less satisfactory, reflecting the aggressive nature of these tumours.",
"affiliations": "Comprehensive Cancer Center, Helsinki University Hospital (HUH), Helsinki, Finland.;University of Helsinki, Helsinki, Finland.;Comprehensive Cancer Center, Helsinki University Hospital (HUH), Helsinki, Finland.;Department of Pathology, University of Helsinki and HUSLAB, HUH, Helsinki, Finland.;Comprehensive Cancer Center, Helsinki University Hospital (HUH), Helsinki, Finland.;Department of Pathology, University of Helsinki and HUSLAB, HUH, Helsinki, Finland. mika.sampo@helsinki.fi.",
"authors": "Nevala|Riikka|R|;Tukiainen|Erkki|E|;Tarkkanen|Maija|M|;Böhling|Tom|T|;Blomqvist|Carl|C|;Sampo|Mika|M|",
"chemical_list": "D004317:Doxorubicin; D007069:Ifosfamide",
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"fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group UK London 4379410.1038/s41598-019-43794-3Article(Neo)adjuvant chemotherapy and interdigitated split-course hyperfractionated radiation in high risk soft tissue sarcoma – Results from a large single-institution series Nevala Riikka 12Tukiainen Erkki 23Tarkkanen Maija 12Böhling Tom 4Blomqvist Carl 125Sampo Mika mika.sampo@helsinki.fi 41 0000 0000 9950 5666grid.15485.3dComprehensive Cancer Center, Helsinki University Hospital (HUH), Helsinki, Finland 2 0000 0004 0410 2071grid.7737.4University of Helsinki, Helsinki, Finland 3 Department of Plastic Surgery, HUH, Helsinki, Finland 4 0000 0004 0410 2071grid.7737.4Department of Pathology, University of Helsinki and HUSLAB, HUH, Helsinki, Finland 5 0000 0001 0123 6208grid.412367.5Department of Oncology, Orebro University Hospital, Orebro, Sweden 13 5 2019 13 5 2019 2019 9 730417 10 2018 29 4 2019 © The Author(s) 2019Open 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/.A single-institution series using a (neo)adjuvant chemotherapy and interdigitated hyperfractionated split-course radiation therapy (CRT) treatment protocol for soft tissue sarcoma was reviewed. Our specific aims were to study recurrence rates and long-term toxicity. Between 1998 and 2016, 89 patients with non-metastatic soft tissue sarcoma were treated with surgery combined with six courses of doxorubicin and ifosfamide and hyperfractionated radiation therapy (42–60 Gy/1.5 Gy twice daily). Patients were considered being at high risk if tumour malignancy grade was high and the tumour fulfilled at least two of the following criteria: size >8 cm, presence of necrosis or vascular invasion. The mean age of the patients was 50.7 years. With a median follow-up of 5.4 years for survivors, the local control rate was 81.4%. Six (7%) patients progressed during neoadjuvant CRT. Seven (8%) patients discontinued the treatment due to toxicity. Eighty-six patients were operated and three (3%) of these developed a long-term complication. The estimated metastasis-free survival was 47.6% and overall survival 53.0% at five years. The limb-salvage rate was 93%. The limb-salvage rate, local control and complication rates were good in these patients with high risk soft tissue sarcoma. Metastases-free survival and overall survival rates were less satisfactory, reflecting the aggressive nature of these tumours.\n\nSubject terms\nSarcomaSurgical oncologyCompetitive Research Funding of Helsinki University Hospital Finnish Cancer Societyissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nTreatment of soft tissue sarcoma (STS) aims to ensure adequate local control (LC) without major disability and to prevent distant metastases. Radiation therapy (RT) combined with surgery improves LC and enables less mutilating surgery1. However, RT has no documented effect on metastases-free survival (MFS)1. Twenty to 30% of STS patients develop metastases and most of them die from the disease2.\n\nThe role of adjuvant systemic therapy in STS is still controversial. In a meta-analysis from 2008, the combination of doxorubicin and ifosfamide was associated with an overall survival (OS) benefit and an absolute risk reduction of 11%3. Many patients with STS at high risk of developing metastatic disease are also at risk of local recurrence (LR). Thus, these patients have indications for both RT and chemotherapy (CT). Delaying RT may expose the patient to an increased risk of LR. Delaying CT may expose the patient to growth of subclinical metastases during RT.\n\nThe behavior of high-grade STS can be aggressive. The growth rate of pulmonary metastases from sarcomas can be rapid, up to a volume doubling time of only 7–9 days4,5. Conventionally fractionated RT has a duration of 6–7 weeks. Theoretically during that time aggressively proliferating occult metastases can increase their volume 64–128-fold. Similarly, four to six CT cycles may enable local tumour growth of more than 100-fold, if the sarcoma does not respond to CT. Thus, a hyperfractionated split-course RT interdigitated between CT cycles (CRT) offers a theoretically interesting option to avoid these problems.\n\nIn the present study, we retrospectively reviewed all STS patients at high risk who received hyperfractionated split-course RT interdigitated between (neo)adjuvant doxorubicin and ifosfamide with special interest on outcome and treatment-related long-term complications.\n\nPatients and Methods\nEighty-nine high-risk patients were treated for local STS by the Soft Tissue Sarcoma Group at Helsinki University Hospital (HUH) during 1998–2016 with CRT. The study was approved by the HUH Ethics Committee and the Ministry of Social and Health Affairs. All methods were performed in accordance with the relevant guidelines and regulations. In Finland, National Institute for Health and Welfare can issue a permission to use patient data for retrospective studies and therefore informed patient consent was not gathered.\n\nOur treatment protocol for STS was set up in 1987. The treatment plan of all new STS patients is decided by multidisciplinary team (MDT) consisting of oncologists, plastic surgeons, radiologists and pathologists. Staging procedures include magnetic resonance imaging (MRI) or computed tomography or both of the primary tumour and an ultrasound-guided or computed tomography-guided core needle biopsy and fine needle aspiration. A computed tomography of the lungs is recommended for all patients. Surgery with wide margins is preferred when feasible. A wide margin is achieved if a cuff of healthy tissue is at least 2.5 cm or an uninvolved fascia surrounds the whole tumour periphery. RT is recommended if the surgical margin is less than 2.5 cm or if tumour cell contamination is suspected. Preoperative RT is recommended if the tumour is assessed to be inoperable.\n\nOur adjuvant CT treatment protocol was set up in 1998: patients with WHO performance status 0–1 are offered adjuvant CT if the tumour malignancy grade is high (3 in a three-tiered scale) and the tumour fulfills at least two of the following criteria: size >8 cm (in synovial sarcomas >5 cm), presence of necrosis or vascular invasion according to the guidelines of the Scandinavian Sarcoma Group (SSG)6. The recommended CT regimen is six cycles of doxorubicin and ifosfamide (IA) with 21-day intervals. Our protocol of interdigitated six CT courses and split-course hyperfractionated RT was derived from the SSG IX for Ewing’s sarcoma7. In this protocol, patients with inoperable tumours or with inadequate margins received split-course hyperfractionated RT (1.5 Gy twice daily) in two CT breaks to a total dose of 42–60 Gy (Fig. 1).Figure 1 Treatment protocol used by our multidisciplinary team (MDT). BID: twice daily; IA: doxorubicin-ifosfamide; PD: progressive disease; RT: radiation therapy.\n\n\n\nNeoadjuvant CT combined with interdigitated split-course hyperfractionated RT is preferred when the tumour is aggressive and growing fast and the margin in definite surgery is likely to be intralesional, marginal or an amputation seemed unavoidable. If the patient needs both CT and RT as adjuvant therapy, interdigitated hyperfractionated therapy is preferred instead of sequential CT and RT treatment. For abdominal or for other tumor localization, where acute toxicity of RT is to be expected, sequential therapy is preferred.\n\nCRT treatment starts with two cycles of CT, which consists of doxorubicin (50 mg/m2) and ifosfamide (5 g/m2) (IA) combination (q21) (Fig. 1). Granulocyte stimulating factor (G-CSF) is used, if the risk of infection is considered high or if the low white blood cell count is going to cause a delay of CT. After two CT cycles, hyperfractionated RT 30 Gy/1.5 Gy twice a day for ten days with an interfraction interval of at least 6 hours is delivered. After the first course of RT a further hyperfractionated RT 12 Gy/1.5 Gy twice a day is delivered during the interval between CT cycle 3 and 4. Before surgical treatment MRI of primary tumour and computed tomography of lungs are performed to evaluate the treatment response and to exclude disseminated disease.\n\nLimb-sparing surgery is planned whenever feasible. Postoperatively patients receive two cycles of IA depending on the evaluation of histologic response to preoperative treatment in MDT discussion. Patients with positive microscopic margins are re-operated and if this is not feasible or patient refuses of amputative surgery, a RT boost of 18 Gy (1.5 Gy twice daily) is delivered to a reduced target volume. Computed tomography-based treatment planning and individual fixation methods are used in RT. The target volume is defined as the involved muscle compartment in the transversal direction, with a margin of at least 5 cm longitudinally. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 is used to report adverse effects.\n\nThe equivalent dose of an accelerated hyperfractionated treatment scheme with 1.5-Gy fractions compared to a fractionation scheme with 2-Gy fractions is calculated by the linear quadrate (alfa/beta) formula modified by Thames and Hendry8 to account for incomplete repair of sublethal damage when fraction interval is less than 24 hours. The equivalent dose is calculated according to the formula: TE=N∗d(alfa/beta+d∗(1+hM)), where, TE = total effect, N = number of fractions, d = dose per fraction, alfa/beta = measure of the fractionation sensitivity of the tissue, and hM = the correction term for incomplete repair of sublethal damage, dependent of repair half time, interval between fractions and number of fractions per day9. An alfa/beta ratio of 10 Gy for acute, and 3 Gy for late effects and a repair half time of 1.2 h for acute and 3.5 h for late effects are used. With these assumptions an accelerated hyperfractionated RT scheme of 1.5 Gy twice daily should be equivalent to a schedule of 2 Gy × 1 for late effects, while the acute effects should be slightly less. Total doses are reduced 15% from 50 Gy to 42 Gy for microscopic and 70 Gy to 60 Gy for macroscopic disease to account for the radiosensitizating effect of doxorubicin and the improved effect of the shorter treatment time when compared to our dose recommendations of RT alone.\n\nTumour size is defined as the largest diameter of the tumour in the surgical specimen reported by the pathologist, or in the case of neoadjuvant treatment the largest measure in pretreatment MRI/computed tomography. Histological malignancy of the tumour is determined according to the French grading system10. After formalin fixation, the surfaces of specimens are painted and dissected. The margins are measured from histological slides. All diagnoses are verified by an experienced sarcoma pathologist.\n\nAll patients have a regular follow-up. Patients with high-grade sarcoma undergo a chest X-ray every two months during the first two years, and thereafter three times annually up to five years. Clinical control and a computed tomography or a MRI scan of the primary tumour region are planned six months postoperatively and thereafter once every six months up to two years and thereafter annually up to five years. However, the follow-up of synovial sarcomas is continued up to ten years.\n\nStatistical methods\nLC, MFS, OS and sarcoma-specific survival (SSS) were calculated according to the Kaplan-Meier method. IBM® SPSS® Statistics version 23 (SPSS, Chicago, Illinois, USA) was used for all analyses.\n\nResults\nThe present study includes 89 patients with a STS of the trunk wall (n = 9), lower (n = 59) or upper extremity (n = 9), head and neck (n = 1) or deep sites (n = 11) (Table 1). They received treatment with curative intention during 1998–2016. The mean age of the patients at diagnosis was 50.7 years. The three most common histological subtypes were undifferentiated pleomorphic sarcoma, liposarcoma, and synovial sarcoma. Median tumour size was 10.5 cm. All but one tumour were high grade, and all but one were deep-seated. The patient with the liposarcoma of intermediate grade received combination treatment to improve LC because of proximity of major nerves and vessels were expected to compromise surgical margins. In all, preoperative imaging showed that in 21 patients with limb-girdle and limb tumour the definite positive margin would be inevitable with limb-sparing surgery alone. Median follow-up for survivors was 5.4 years.Table 1 Description of tumour, patient and treatment characteristics of 89 patients with interdigitated hyperfractioned radiation therapy and chemotherapy.\n\nCharacteristics\tNo. of patients\t%\t\nSex\t\n Male\t53\t60\t\n Female\t36\t40\t\nAge at Diagnosis (years)\t\n Mean\t50.7\t\t\n Range\t16.3–75.4\t\t\nReferral status\t\n Virgin\t58\t65\t\n FNA\t9\t10\t\n CNB\t14\t16\t\n Open biopsy\t3\t3\t\n Intralesional surgery\t4\t4\t\n Marginal surgery\t1\t1\t\nSite\t\n Lower extremity\t59\t66\t\n Upper extremity\t9\t10\t\n Trunk\t9\t10\t\n Head&neck\t1\t1\t\n Other sites*\t11\t12\t\nGrade according to French system\t\n Intermediate\t1\t1\t\n High\t88\t99\t\nDepth (trunk wall and extremity tumours)\t\n Superficial†\t1\t1\t\n Deep‡\t77\t99\t\nTumour size (cm)§\t\n Median\t10.5\t\t\n Range\t1.5–41.0\t\t\nVascular invasion¶\t\n Present\t17\t41\t\n Absent\t24\t59\t\nNecrosis**\t\n Present\t37\t86\t\n Absent\t6\t14\t\nHistological subtype\t\n UPS\t39\t44\t\n Liposarcoma\t16\t18\t\n Synovial sarcoma\t11\t12\t\n Leiomyosarcoma\t8\t9\t\n MPNST\t4\t4\t\n Fibrosarcoma\t4\t4\t\n Neurofibrosarcoma\t1\t1\t\n Myxofibrosarcoma\t5\t6\t\n Epithelioid sarcoma\t1\t1\t\nMargin (in 86 operated patients)\t\n Intralesional\t16\t19\t\n Marginal\t59\t69\t\n Wide\t11\t13\t\nAbbreviations: CNB, core needle biopsy; FNA, fine needle aspiration; MPNST, malignant peripheral neural sheath tumour; UPS, undifferentiated pleomorphic sarcoma. *One in thorax cavity, one in vagina, two in prostate and one in retroperitoneum. †Subcutaneous tumours with or without cutaneous extention but without involvement of the deep fascia. ‡Tumours with involvement of the deep fascia or deep to it. §Size was not determined in three tumors. ¶Vascular invasion in 44 patients with no neoadjuvant treatment, three missing. **Necrosis in 44 patients with no neoadjuvant treatment, one missing.\n\n\n\nCRT was given preoperatively in 45 (51%) patients and postoperatively in 44 (49%) patients (Fig. 1). Treatment was stopped in 14 (16%) patients. Reasons for discontinuation were toxicity (7 patients, including myelotoxicity despite G-CSF use in two patients; fatigue in one patient; delayed wound healing in three patients and infection in one patient), progression during treatment (6 patients), and re-classification of tumour histology and grade (one patient). Postoperative CT was omitted from six (7%) patients because of poor histological response to neoadjuvant treatment.\n\nSixty-six patients were planned to receive 42 Gy/1.5 Gy twice daily and 23 patients were planned to receive 60 Gy/1.5 Gy twice daily. Sixty-three (95%) of 66 patients were treated to 42 Gy as planned whereas 21 (91%) of 23 were treated to 60 Gy as planned. Two patients received only 24 Gy due to progression. One patient planned to receive 42 Gy and two patients planned to receive 60 Gy had minor dose modifications due to acute skin reactions. Three patients received a boost with conventional fractionation.\n\nSixty (70%) patients received all six courses of IA. Six (7%) patients had dose reductions due to myelotoxicity. G-CSF was used in 57 (66%) patients and 22 (26%) patients received G-CSF after each IA course. Twenty-two (25%) patients were hospitalized because of neutropenic fever and one (1%) patient because of influenza A without neutropenia. Other reasons of IA dose or cycle modification were wound complication (two patients, 2%), central nervous toxicity from ifosfamide (one patient, 1%), oesophageal mucositis (one patient, 1%), deteriorated performance status (one patient, 1%) and re-classification of tumour grade and histology (one patient, 1%).\n\nThree (3%) patients could not be operated due to progression. Definite margin was intralesional, marginal and wide in 16 (19%), 59 (69%) and 11 (12%) out of 86 operated patients, respectively. Seven patients with limb and limb-girdle tumour refused of amputation and had a definite microscopically positive margin whereas nine patients out of 21 patients preoperatively evaluated to have definite positive margin with limb-sparing surgery alone had limb-sparing surgery with negative margin after neoadjuvant treatment. Sixty-two (72%) patients were operated with direct closure. Nine (10%) patients required a microvascular flap and eleven (13%) a pedicled flap. Vascular reconstruction was performed on four (5%) patients. Reoperation was necessary in eight (19%) patients out of 42 operated patients after neoadjuvant treatment due to wound necrosis (four patients), haemorrage (two patients), and infection (two patients). Reoperation was necessary in four (9%) patients out of 44 patients with adjuvant CRT due to wound necrosis (two patients), and infection (two patients). Three patients received a microvascular flap as part of reconstruction for complications.\n\nFive (7%) out of 68 patients with tumour of extremity or limb girdle had an amputation (one hemipelvectomy, two rotationplasties, two amputations) yielding a limb-salvage rate of 93%. Fourteen (16%) out of 86 operated patients developed LR yielding estimated LC of 81.4% at five years (Fig. 2). Two patients had a late LR at 5.5 years and at 12 years. The estimated MFS was 50.3% at three years, and 47.6% at five years (Fig. 3). SSS was 60.1% at three years and 56.2% at five years. OS was 58.2% at three years and 53.0% at five years (Fig. 4) for the whole study population.Figure 2 Local control by time in 86 operated patients.\n\nFigure 3 Metastases-free survival by time for the whole population.\n\nFigure 4 Overall survival by time for the whole population.\n\n\n\nThree patients (3%) developed moderate or severe long-term treatment-related toxicity. One (1%) patient had stiffness and severely limited flexion of the knee joint (Grade 3). One (1%) patient suffered from a chronic pain syndrome with allodynia (Grade 3) and one (1%) patient developed late rupture of the wound eight months after finishing treatment (Grade 3). No treatment-related deaths were recorded.\n\nDiscussion\nIn the present retrospective study 89 STS patients with high risk of developing both local recurrence and metastatic disease had LC rate of 81% and limb-salvage rate of 93% at 5 years after surgery and (neo)adjuvant CRT. The patients were highly selected, representing only 7% of the STS patients treated by our group during the same period.\n\nDisease-progression in six of our patients during (neo)adjuvant therapy underscores the fast growth rate of high-grade STS. The long-term survival remained also unsatisfactory with approximately 50% of patients dying from their disease despite the aggressive therapy. However, this can partly be anticipated as adjuvant CT has only a moderate effect on survival3.\n\nThe first neoadjuvant CRT protocol of STS was published by Eilber and colleagues in 198011. Patients were treated with preoperative intra-arterial doxorubicin and hypofractionated RT. An impressive LC rate of 97% and limb-salvage rate of 92% were reported11. However, significant morbidity was seen from intra-arterial doxorubicin used as chemosensitizer11–19. This included arterial thrombosis13,14,16,17, pain13,18, severe local skin reactions15 and catheter site infections13. Due to local complications intra-arterial infusion was later replaced by intravenous administration of CT13,14,16,17.\n\nA summary of the most important efficacy endpoints and toxicity in published studies of CRT in STS is shown in Table 2. Since the aim of most CRT protocols in sarcomas has been the achievement of a high LC without amputation, mostly patients with extremity or limb girdle tumours have been included. In the present study, nine patients out of 21 patients preoperatively evaluated to have definite positive margin with limb-sparing surgery alone had limb-sparing surgery with negative margin after neoadjuvant treatment. LC after CRT and surgery of extremity sarcomas has been good to excellent ranging from 71% to 100% with a variety of RT fractionation and CT regimens11–38. In a study by Gronchi et al. (2014) preoperative CRT has been used also for localized retroperitoneal sarcoma with LC rate 61% at five years, which has to be considered good for sarcomas at this site39. Long-term survival varies significantly among CRT studies (Table 2). Most patient series are small with variable chemotherapeutic agents and RT fractionations and patient characteristics vary significantly. Thus the comparison between the survival rate in our study and other published patient series is difficult, and no firm conclusions can be made on the effect of CRT on overall outcome.Table 2 Studies on chemoradiation therapy for STS reporting survival rates and complications.\n\nStudy\tStudy period\tn\tCT\tRT (Gy)\tCRT timing pre/post\tCRT C/S\tHigh grade tumors (%)\tLC% (at years of FU)\tDFS% (at years of FU)\tOS% (at years of FU)\tMajor complications (%)*\t\nEilber et al.11\t1972–1979\t65\tA 30 mg × 1 i.a. 3 days\t35/3.5\tpre\tS\t80\t97 (2.5)\tNA\t75 (5)\t28\t\nGoodnight et al.12\t1980–1984\t17\tA 25–30 mg i.a. 3 days\t35/3.5 or 40/2\tpre\tS\t76\t100 (2.5)\t59 (2.5)\t82 (2.5)\t35\t\nLevine et al.13\t1978–1991\t55\tA 10 mg/m2 i.a. 10 days\t25/2.5\tpre\tC\t58\t85 (5)\t51 (5)\t69 (5)\t25\t\nMason et al.14\t1983–1985\t13\tA 10–30 mg i.a. 3 days\t40–65/2\tpre\tNA\t85\t77 (4.5)\tNA\tNA\t69\t\nNijhuis et al.15\t1983–1987\t11\tA 20 mg/m2 i.a. 3 days\t35/3.5\tpre\tS\t100\t100 (7)\t55 (7)\t55 (7)\t45\t\nMack et al.16\t1984–1996\t75\tA 30 mg × 1 i.a. 3 days\t30/3\tpre\tS\t48\t95 (5)\tNA\t63 (5)\t8\t\nTemple et al.17\t1984–1994\t40\tA 30 mg × 1 i.a. 3 days\t30/3\tpre\tS\tNA\t97 (5)\tNA\t79 (5)\t13\t\nTemple et al.18\t1986–2002\t44\tA 30 mg × 1 3 days\t30/3 or 33/1.65 × 2\tpre\tS\t45\t96 (5)\t68 (5)\t73 (5)\t11\t\nDincbas et al.27\t1989–2007\t44\tIA × 6\t35/3.5 or 46–50/2\tpre\tS\tNA\t82 (5)\t47 (5)\t70 (5)\t30\t\nMantravadi et al.19\tNA\t32\tA 10 mg/m2 i.a. 10 days\t25/2.5\tpre\tC\t100\t97 (3)\t57 (3)\t70 (3)\tNA\t\nBrodowicz et al.31\t1992–NA\t31\tIFADIC × 4 + IFDIC × 2\t51/1.7 × 2\tpost\tNA\t81\t94 (3.5)\t77 (3.5)\t97 (3.5)\t10\t\nAguiar Jr et al.35\t1995–2004\t49\tA 20 mg/m2 × 3\t30/2.5\tpre\tC\t59\t82 (5)\t47 (5)\t58 (5)\t42\t\nGreto et al.21\t1998–2011\t32\tIE × 2\t50/2\tpre\tC\t100\tNA\t53 (4.9)\tNA\tNA\t\nMahmoud et al.16\t1999–2012\t49\tIA × 4–6\t63/1.8–2\tpost\tS\t92\t71 (5)\t43 (5)\t67 (5)\t10\t\nGronchi et al.22\t2002–2007\t135\tIE × 3–5\t50\tpre\tNA\t100\t96 (5)\t67 (5)\t70 (5)\tNA\t\nGronchi et al.39\t2003–2010\t83\tI 14 g/m2 × 3\t50.4/1.8\tpre\tC\t19\t63 (5)\t44 (5)\t59 (5)\t22\t\nKraybill et al.33\t1997–2000\t64\tMAID × 6\t44\tpre\tS\t80\t78 (5)\t56 (5)\t71 (5)\t13\t\nEdmonson et al.29\t1994–1997\t39\tIMAP* × 2 + MAP × 3\t45/1.8\tpre\tC\t95\t90 (5)\t75 (5)\t80 (5)\t5\t\nBrands et al.37\t1997–2004\t27\tIA × 4\t50.4/1.8–2\tpost\tS\t74\t85 (5)\t66 (5)\t80 (5)\t0\t\nNesseler et al.34\t1990–2012\t29\tA × 6 or MAID × 6\t50–56/2\tpost\tC or S\t69\t96 (5)\t58 (5)\t72 (5)\t21\t\nStubbe et al.30\t2000–2011\t53\tIA × 2\t60/1.5 × 2 or 50.4–60/1.8–2\tpre\tC\t55\t90 (5)\tNA\t83 (5)\t21\t\nMacDermed et al.25\t1995–2008\t34\tI 2.5 g/m2 5 days\t28/3.5\tpre\tC\t94\t89 (5)\t53 (5)\t42 (5)\t18\t\nRyan et al.28\t2002–2005\t25\tIE × 5 + I × 1\t28/3.5\tpre\tC\t88\t88 (2)\t62 (2)\t84 (2)\t24\t\nMullen et al.32\t1989–1999\t48\tMAID × 6\t44/2\tpre\tS\t49\t90 (7)\t65 (10)\t84 (5), 66 (10)\t46\t\nJebsen et al.20\t1998–2007\t76\tIA × 6\t36–45/1.8 × 2\tpost\tS\t100\t71–90 (5)\tNA\tNA\t2\t\nLehane et al.26\t1995–2012\t29\tA 30 mg × 1 3 days\t30/1.5 × 2\tpre\tS\t69\t88 (5)\tNA\t87 (5)\t14\t\nOkuno et al.23\t2001–2006\t38\tIMAP × 2 + MAP × 2\t45–50/1.8\tpre\tC\t100\tNA\t69 (3)\t82 (3)\tNA\t\nRaval et al.24\t1997–2010\t16\tMAID × 6\t44/2\tpre\tS\t100\t100 (3)\t63 (3)\t73 (3)\t0\t\nSchliemann et al.38\t1997–2014\t104\tIA × 4\t50.4/1.8–2\tpost\tC\t84\t89 (5)\t68 (5)\t76 (5)\t0\t\nPresent study\t1998–2016\t89\tIA × 6\t42–60/1.5 × 2\tpre or post\tS\t99\t81 (5)\t48 (5)\t53 (5)\t3\t\nAbbreviations: A, doxorubicin; C, concomitant (RT and CT in same day); CRT, chemoradiotherapy; CT, chemotherapy; DFS, disease-free survival; FU, follow-up; I, ifosfamide; i.a.; intra-arterial; IA, ifosfamide + doxorubicin; IE, ifosfamide + epirubicin; IFADIC, ifosfamide + doxorubicin + dacarbazine; IFDIC, ifosfamide + dacarbazine; IMAP, ifosfamide + mitomycin + doxorubicin + cisplatin; LC, local control; MAID, doxorubicin + ifosfamide + dacarbazine; MAP, mitomycin + doxorubicin + cisplatin; NA, not available; OS, overall survival; RT, radiation therapy; S, sequential (RT and CT in different days). *Toxicity is a sum of fatal complications, complications requiring reoperation or embolectomy and late complications affecting the quality of life.\n\n\n\nComplication rates in hyperfractionated RT regimens have been variable. In our study, 19% of patients in neoadjuvant and 9% of adjuvant CRT group needed a re-operation. In other neoadjuvant studies using hyperfractionated low fraction doses, wound complication rates varied between 6% and 14%26,30. In two postoperative hyperfractionation studies, no problems of wound healing were reported20,31. RT fraction size and preoperative treatment are probably important factors for the risk of developing local complications. In five neoadjuvant studies using hypofractionation (single dose >3 Gy) wound complications requiring intervention were frequent (11–29%)12,15,25,27,28. On the other hand, in three neoadjuvant trials with smaller than conventional RT fraction size (<2 Gy) wound complications were very rare23,29,39. Also the development of surgical techniques together with lower RT doses per fraction decrease the risk of local problems in recent series.\n\nDespite frequent use of G-CSF the risk of acute CT related toxicity was still relatively high as 26% of our patients were hospitalized due to infections. The Scandinavian Sarcoma Group CRT regimen was associated with a similar risk of acute complications, because one third of patients were hospitalized, received a blood transfusion or experienced fever20. Treatment compliance was excellent in the Scandinavian study because 92% of patients completed all six IA courses. Other CT regimens have been considerably more toxic. For example, 97% of patients receiving the MAID regimen experienced grade three or higher toxicities, although these were mostly acute and transitory33. Only 59–83% of patients could receive all six chemotherapy cycles32,33.\n\nLong-term toxicity was rare (3%) in our series but may have been underestimated due to the short survival of many patients. In other CRT studies, bone fractures (3–7%)11,30,32, chronic pain disorders (2–15%)32,33, decreased joint movement (3%)33, significant motion limitations (6%)32 and late sequelae (2%)20 have been described. A few treatment related deaths due to secondary myelodysplasia33, acute myelogenous leukemias32, severe nephrotoxicity20 and hypokinetic heart failure34 has been reported. No treatment-related deaths occurred in our study.\n\nHyperfractionated RT interdigitated between CT cycles has been used in only five studies in addition to the present18,20,26,30,31, while most other CRT protocols have used once daily fractionation. A recent Scandinavian prospective study had a similar design to our protocol using sequential IA cycles with hyperfractionated RT20. The outcomes were similar or better with five-year LR, MFS and OS rates of 12%, 59% and 68%, respectively20.\n\nExperience of interdigitated doxorubicin-based CT and hyperfractionated RT in Ewing’s sarcoma has also verified the feasibility of this approach7,40. Patients were randomized into conventional RT fractionation with a break for CT or hyperfractionated RT simultaneously with the CT40. Five-year OS was similar with hyperfractionated and conventional fractionationated RT (63% and 65%) but LC was slightly, but not significantly better with the hyperfractionated RT. Radiation-related long-term complications were rare without difference between the two arms40. A reliable estimation of the efficacy and toxicity of hyperfractionated RT and interdigitated CT compared to sequential treatment in non-Ewing STS would require a similar randomized study. Comparison between the results in Ewing’s sarcoma and our results should be made with caution because patients with Ewing’s sarcoma were significantly younger (25 years or less) than patients in our study (mean age 50.7 years). Furthermore, Ewing’s sarcoma is more sensitive to both radiation therapy and chemotherapy than sarcoma of other histology.\n\nIn summary, our protocol with interdigitated CT courses and hyperfractionated split-course RT yielded a satisfactory local control and low long-term complication rate. Our results and previous studies indicate that interdigitated hyperfractionated RT and CT is a feasible method of delivering both treatment modalities in patients with highly aggressive STS, where treatment delays may be detrimental.\n\nPublisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThis study was supported by the Competitive Research Funding of Helsinki University Hospital and the Finnish Cancer Society. They had no role in the study design, data interpretation or article writing. Henri Mynttinen is thanked for invaluable comments on the manuscript.\n\nAuthor Contributions\nR.N., C.B. and M.S. designed the study; R.N., E.T., T.B. and M.S. collected the data; R.N., M.T., T.B., C.B. and M.S. interpreted the results; R.N., E.T., M.T., T.B., C.B. and M.S. prepared the manuscript; All authors approved the final version of the manuscript.\n\nCompeting Interests\nThe authors declare no competing interests.\n==== Refs\nReferences\n1. Yang JC Randomized prospective study of the benefit of adjuvant radiation therapy in the treatment of soft tissue sarcomas of the extremity J. Clin. Oncol. 1998 16 197 203 10.1200/JCO.1998.16.1.197 9440743 \n2. Gronchi A Primary extremity soft tissue sarcomas: outcome improvement over time at a single institution Ann. Oncol. 2011 22 1675 1681 10.1093/annonc/mdq643 21242585 \n3. 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Edmonson JH Chemotherapy, irradiation, and surgery for function-preserving therapy of primary extremity soft tissue sarcomas: initial treatment with ifosfamide, mitomycin, doxorubicin, and cisplatin plus granulocyte macrophage-colony-stimulating factor Cancer 2002 94 786 792 10.1002/cncr.10259 11857314 \n30. Stubbe F Effective local control of advanced soft tissue sarcoma with neoadjuvant chemoradiotherapy and surgery: A single institutional experience Cancer Radiother. 2016 20 6 13 10.1016/j.canrad.2015.05.032 26700874 \n31. Brodowicz T Intensified Adjuvant IFADIC Chemotherapy for Adult Soft Tissue Sarcoma: A Prospective Randomized Feasibility Trial Sarcoma 2000 4 151 160 10.1155/2000/126837 18521295 \n32. Mullen JT Long-term follow-up of patients treated with neoadjuvant chemotherapy and radiotherapy for large, extremity soft tissue sarcomas Cancer 2012 118 3758 3765 10.1002/cncr.26696 22180344 \n33. Kraybill WG Long-term results of a phase 2 study of neoadjuvant chemotherapy and radiotherapy in the management of high-risk, high-grade, soft tissue sarcomas of the extremities and body wall: Radiation Therapy Oncology Group Trial 9514 Cancer 2010 116 4613 4621 10.1002/cncr.25350 20572040 \n34. Nesseler JP A retrospective cohort study to assess adjuvant concurrent chemoradiation (CCRT) compared to adjuvant radiation therapy (RT) in the treatment of grade 2 and 3 extremity soft tissue sarcomas Radiother. Oncol. 2017 125 160 167 10.1016/j.radonc.2017.08.037 28951009 \n35. Aguiar Junior S Neoadjuvant chemoradiation therapy for soft tissue sarcomas of the extremities Clinics (Sao Paulo) 2009 64 1059 1064 10.1590/S1807-59322009001100005 19936179 \n36. Mahmoud O The Impact of Perioperative Chemotherapy Timing in Conjunction With Postoperative External-Beam Radiation Therapy on Extremity Soft-Tissue Sarcomas Outcome Am. J. Clin. Oncol. 2016 39 528 534 10.1097/COC.0000000000000087 24879472 \n37. Brandts CH Adjuvant therapy for resectable high-risk soft tissue sarcoma: feasibility and efficacy of a sandwich chemoradiotherapy strategy Cancer Chemother. Pharmacol. 2012 69 613 620 10.1007/s00280-011-1731-8 21947168 \n38. Schliemann C Adjuvant chemotherapy-Radiotherapy-Chemotherapy sandwich protocol in resectable soft tissue sarcoma: An updated single-center analysis of 104 cases PLoS One 2018 13 e0197315 10.1371/journal.pone.0197315 29787570 \n39. Gronchi A Preoperative chemo-radiation therapy for localised retroperitoneal sarcoma: a phase I-II study from the Italian Sarcoma Group Eur. J. Cancer 2014 50 784 792 10.1016/j.ejca.2013.11.021 24316063 \n40. Dunst J Radiation therapy in Ewing’s sarcoma: an update of the CESS 86 trial Int. J. Radiat. Oncol. Biol. Phys. 1995 32 919 930 10.1016/0360-3016(95)00016-R 7607966\n\n",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000671:Amputation; D000971:Antineoplastic Combined Chemotherapy Protocols; D059186:Chemoradiotherapy, Adjuvant; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D005387:Finland; D005500:Follow-Up Studies; D006801:Humans; D007069:Ifosfamide; D023821:Limb Salvage; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D012189:Retrospective Studies; D012509:Sarcoma; D015996:Survival Rate; D055815:Young Adult",
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"pubdate": "2019-05-13",
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"title": "(Neo)adjuvant chemotherapy and interdigitated split-course hyperfractionated radiation in high risk soft tissue sarcoma - Results from a large single-institution series.",
"title_normalized": "neo adjuvant chemotherapy and interdigitated split course hyperfractionated radiation in high risk soft tissue sarcoma results from a large single institution series"
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"abstract": "A boy with central nervous system relapse of Burkitt leukemia developed fever and neurologic symptoms and cognitive impairment. He had received multi-drug chemotherapy including rituximab. Enterovirus (EV) was detected in cerebrospinal fluid by polymerase chain reaction, and magnetic resonance imaging findings were consistent with viral infection. The patient was treated with intravenous immunoglobulin and within 1 month cleared his EV. Rituximab can cause a profound B-cell deficiency predisposing patients to infections including EV encephalitis. This is the first report of enteroviral encephalitis in a child undergoing treatment for lymphoma with rituximab and suggests the need to watch for this complication of therapy.",
"affiliations": "Birmingham Children's Hospital, Steelhouse Lane, Birmingham, United Kingdom.",
"authors": "Shaheen|Najma|N|;Mussai|Francis|F|",
"chemical_list": "D000069283:Rituximab",
"country": "United States",
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"doi": "10.1097/MPH.0000000000001077",
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"issn_linking": "1077-4114",
"issue": "41(1)",
"journal": "Journal of pediatric hematology/oncology",
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"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D002051:Burkitt Lymphoma; D016543:Central Nervous System Neoplasms; D002675:Child, Preschool; D018792:Encephalitis, Viral; D004770:Enterovirus; D004769:Enterovirus Infections; D006801:Humans; D008297:Male; D000069283:Rituximab",
"nlm_unique_id": "9505928",
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"pages": "e27-e29",
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"pmid": "29315142",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Enteroviral Encephalitis in a Child With CNS Relapse of Burkitt Leukemia Treated With Rituximab.",
"title_normalized": "enteroviral encephalitis in a child with cns relapse of burkitt leukemia treated with rituximab"
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"abstract": "Acute graft-versus-host disease (aGvHD) reduces the efficiency and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In recent years, attempts have been made to transplant fecal microbiota from healthy donors to treat intestinal GvHD. This study presented two cases of patients undergoing allo-HSCT who were later selected for fecal microbiota transplantation (FMT). In the first patient, FMT resulted in the complete resolution of symptoms, whereas therapeutic efficacy was not achieved in the second patient. FMT eliminated drug-resistant pathogens, namely very drug-resistant Enterococcus spp., but not multidrug-resistant Acinetobacter baumannii or Candida spp. Further research is needed, particularly on the safety of FMT in patients with intestinal steroid-resistant GvHD and on the distant impact of transplanted microflora on the outcomes of allo-HSCT. FMT appears promising for the treatment of patients with steroid-resistant GvHD.",
"affiliations": "Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.;Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.;Department and Clinic of Internal and Occupational Diseases and Hypertension, Wroclaw Medical University, Wroclaw, Poland.;Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.;Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.;Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland.",
"authors": "Biernat|Monika Maria|MM|https://orcid.org/0000-0003-3161-3398;Urbaniak-Kujda|Donata|D|;Dybko|Jarosław|J|;Kapelko-Słowik|Katarzyna|K|;Prajs|Iwona|I|;Wróbel|Tomasz|T|",
"chemical_list": "D005938:Glucocorticoids",
"country": "England",
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"doi": "10.1177/0300060520925693",
"fulltext": "\n==== Front\nJ Int Med Res\nJ. Int. Med. Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605 1473-2300 SAGE Publications Sage UK: London, England \n\n10.1177/0300060520925693\n10.1177_0300060520925693\nCase Report\nFecal microbiota transplantation in the treatment of intestinal steroid-resistant graft-versus-host disease: two case reports and a review of the literature\nhttps://orcid.org/0000-0003-3161-3398Biernat Monika Maria 1 Urbaniak-Kujda Donata 1 Dybko Jarosław 2 Kapelko-Słowik Katarzyna 1 Prajs Iwona 1 Wróbel Tomasz 1 \n1 Department and Clinic of Haematology, Blood Neoplasms, and Bone Marrow Transplantation, Wroclaw Medical University, Wroclaw, Poland\n\n2 Department and Clinic of Internal and Occupational Diseases and Hypertension, Wroclaw Medical University, Wroclaw, Poland\nMonika Biernat, Department and Clinic of Haematology, Blood Neoplasms and Bone Marrow Transplantation, Wroclaw Medical University, Pasteura Street 4, 50-367, Wroclaw, Poland. Email: mobiernat@gmail.com\n12 6 2020 \n6 2020 \n48 6 03000605209256936 10 2019 17 4 2020 © The Author(s) 20202020SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This 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).Acute graft-versus-host disease (aGvHD) reduces the efficiency and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT). In recent years, attempts have been made to transplant fecal microbiota from healthy donors to treat intestinal GvHD. This study presented two cases of patients undergoing allo-HSCT who were later selected for fecal microbiota transplantation (FMT). In the first patient, FMT resulted in the complete resolution of symptoms, whereas therapeutic efficacy was not achieved in the second patient. FMT eliminated drug-resistant pathogens, namely very drug-resistant Enterococcus spp., but not multidrug-resistant Acinetobacter baumannii or Candida spp. Further research is needed, particularly on the safety of FMT in patients with intestinal steroid-resistant GvHD and on the distant impact of transplanted microflora on the outcomes of allo-HSCT. FMT appears promising for the treatment of patients with steroid-resistant GvHD.\n\nIntestinal microfloraallogeneic hematopoietic stem cell transplantationacute graft-versus-host diseasetreatmentmultidrug resistancemultiorgan failureantibioticsedited-statecorrected-prooftypesetterts2\n==== Body\nIntroduction\nAcute graft-versus-host disease (aGvHD) reduces the efficiency and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The condition is usually severe, and it carries a high mortality rate. GvHD may manifest with skin, intestinal, and liver involvement.1 Intestinal localization is one of the most severe forms of the disease. Disturbance of the mechanisms responsible for homeostasis of the immune system in the intestine and excessive responses of the donor’s cytotoxic lymphocytes play crucial roles in the development of this form of GvHD. In the course of aGvHD, the mucosal barrier in the intestine is disturbed by conditioning treatment, resulting in the release of bacterial lipopolysaccharides and pro-inflammatory cytokines and the subsequent activation of immune response receptors and the cytokine storm.2 In addition, earlier treatment with broad-spectrum antibiotics and colonization with multidrug-resistant (MDR) bacteria before transplantation may also be important in the pathogenesis of aGvHD and may influence its course.3,4 Corticosteroids and immunosuppressive drugs are used routinely as the initial therapies. However, the effectiveness of these treatments is unsatisfactory, and there are no drugs with proven effectiveness against steroid-resistant GvHD. Because of the lack of effective treatment options for intestinal GvHD, it is necessary to identify new methods for preventing and treating this complication after allo-HSCT.\n\nIn recent years, the importance of intestinal microflora in maintaining gastrointestinal homeostasis has been increasingly described.5 On the basis of mouse models and research studies in patients with gastrointestinal tract diseases, it has been proven that the quantitative and qualitative composition of the gastrointestinal microflora plays an important role in the pathogenesis of many human diseases, such as inflammatory bowel diseases, metabolic diseases, autoimmune diseases, allergies, and infectious diseases.1,3,6 Understanding the importance of the gastrointestinal microflora in the course of GvHD may contribute to the development of new therapeutic strategies.7,8 In recent years, attempts have been made to transplant intestinal microflora from healthy donors as a treatment for intestinal GvHD. Therefore, this study presented two cases of patients undergoing allo-HSCT who were selected for fecal microbiota transplantation (FMT).\n\nCase 1 presentation\nThe first case concerned a 25-year-old male patient with acute myeloid leukemia that was diagnosed in September 2016. The bone marrow examination identified 97% of the cells as various myeloid dendritic cells, which immunophenotypically were classified as CD11c+, CD56+, CD123+/−, and CD4−. On the basis of cytogenetic and molecular studies, the patient was diagnosed with 9; 11(p22; q23) translocation with MLL and NPM1 (+) rearrangement, i.e., intermediate cytogenetic risk II. The treatment was based on an induction regimen using the DAC protocol (daunorubicin, cytarabine, cladribine). After the patient achieved complete remission with minimal residual disease, treatment was continued with a consolidation regimen using the high-dose cytarabine (HiDAC) protocol. The patient qualified for allo-HSCT using cells donated by his brother. The Cy-Bu regimen was used as the conditioning regimen, and prophylaxis for GvHD consisted of cyclosporine and methotrexate. In the transplant, the patient received 8.38 × 106 CD34+ cells/kg recipient body weight. The evidence for hematological restoration (engraftment) was as follows: granulocytes >500/μL on day 16 after transplantation and platelets >20.0 G/L on day 17 after transplantation. The patient received ciprofloxacin, fluconazole, and acyclovir as routine anti-infective prophylaxis according to the local protocol. No infection or GvHD was observed in the early post-transplantation period. The post-transplant chimerism test result revealed 100% donor T-cell chimerism. On day 34 after transplantation, the patient was readmitted to the Department of Hematology because of diarrhea (10–12 bowel movements/day, approximately 2 L/day) and abdominal pain. Laboratory tests revealed anemia, elevated concentrations of CRP, fibrinogen, and lactate dehydrogenase (LDH), and decreased total protein and serum albumin levels. An infectious cause of diarrhea, including parasitic or viral infection and bloodstream infection, was excluded. The patient, who was afebrile, underwent rectosigmoidoscopy, and an analysis of biopsy samples confirmed the diagnosis of grade II aGvHD. Cytomegalovirus-induced enteritis was excluded. The intestinal form of aGvHD (grade IV) was also detected. Initially, methylprednisolone was administered at a dose of 2 mg/kg/day. A stool culture was performed, revealing the presence of Enterococcus faecalis, Escherichia coli extended-spectrum beta-lactamase-positive (ESBL+), Candida albicans, and Klebsiella pneumoniae ESBL+. Additionally, the patient was diagnosed with neutropenic fever, followed by pneumonia. For treatment, broad-spectrum antibiotics, initially including meropenem and vancomycin, were used, followed by meropenem and linezolid, which were co-administered with anti-fungal agents (voriconazole). Because the patient’s diarrhea did not improve after approximately 3 weeks of treatment, immunosuppressive therapy (infliximab and budesonide, followed by methotrexate and then cyclophosphamide) was intensified. To treat severe abdominal pain, morphine was added to the regimen. Additionally, immunoglobulin was administered. Because of the persistence of diarrhea and progressive cachexia, it was decided to include parenteral nutrition. The presence of BK virus DNA in urine and plasma without dysuria was found in viral tests. After 3 months, because of the ineffectiveness of the therapy, FMT was performed as a rescue therapy with the prior written consent of the patient and the consent of the Bioethical Commission of Wroclaw Medical University. Fecal suspensions used for transplantation were obtained from healthy donors of Caucasian race (age, 20–40 years) as previously described.9 Briefly, active bacterial, viral, fungal, and parasitic infections were excluded in the donors, especially HAV, HBV, HCV, HIV, CMV, EBV, syphilis, intestinal parasites, Clostridium difficile, and enteropathogenic flora. Donors were not treated with antibiotics for 3 months before sampling, they were in good overall health, they had normal BMIs, and they followed a regular diet. Each product was derived from 100 g of feces. Fecal suspensions were prepared at the Center for Research and Transplantation of Intestinal Microbiota, Center for Preventive Medicine and Rehabilitation in Warsaw according to a previously described protocol and immediately transported to the Wroclaw Transplant Center within 5 hours.9 FMT was performed as follows. Patients were fasted on the day of transplantation, and no medications were administered. In the morning and 30 minutes before the procedure, pantoprazole was administered at a dose of 40 mg intravenously, and approximately 150 to 250 mL of fecal samples suspended in physiological salt were administered through an intranasal probe previously installed by a physician, after which the probe was removed. An easily digestible diet was applied, and a control examination of feces was performed 7 days after the procedure. The second procedure was performed no sooner than 7 to 10 days after the first procedure. Antibiotics were temporarily stopped prior to each FMT administration.\n\nThe patient underwent FMT three times without complications. Fecal culture was performed 7 days after each transplantation (Table 1). A gradual improvement of gastrointestinal symptoms, mainly a decrease in the amount of diarrheal stools, was observed after the second FMT, and the symptoms were completely resolved a couple of days after the third FMT, occurring in the sixth month of hospitalization. The patient was discharged in good general condition. After 1 month, he was readmitted to the Department of Hematology because of malaise, weakness, and vomiting. There was no history of diarrhea since the prior discharge. Laboratory analyses uncovered pancytopenia, elevation of transaminases to 4× the upper limit of normal, and a total bilirubin level exceeding 12 mg/dL, whereas CMV or EBV reactivation was excluded. The patient was diagnosed with liver GvHD. Methylprednisolone was readministered at a dose of 2 mg/kg/day. Additionally, because of deterioration of the patient status and further increases of his bilirubin level, extracorporeal photopheresis (ECP) was performed. On the fifth day of hospitalization, the patient developed a bloodstream infection caused by MDR Acinetobacter baumannii related to the indwelling catheter, and he died in the intensive care unit of multiorgan failure.\n\nTable 1. Results of the analysis of stool specimens from patients.\n\n\tPatient 1\tPatient 2\t\nPre-transplant\tClostridium difficile-negative\nCandida albicans\nEnterococcus faecalis (S)\tClostridium difficile-negative \nEnterococcus faecium (S) \nEnterococcus faecalis HLGR\t\nPost-transplant GvHD\tClostridium difficile-negative\nCandida albicans (S) \nKlebsiella pneumoniae (ESBL+)\nEnterococcus faecalis (S) \nEscherichia coli ESBL+\tC. difficile-negative \nEnterobacter cloacae ESBL+ \nKlebsiella pneumoniae (S) \nCandida albicans (S), \nCandida parapsilosis (S-voriconazole, R-fluconazole, anidulafungin)\t\nPost 1st FMT\tEscherichia coli (S) \nKlebsiella pneumoniae MDR\nCandida albicans\tEnterococcus faecium HLGR \nCandida albicans (S) \nCandida parapsilosis\n\n(S – voriconazole, R – fluconazole, anidulafungin) \nStenotrophomonas maltophilia\n\n(S – trimethoprim/\nsulfamethoxazole), \nKlebsiella pneumoniae (S)\t\nPost 2nd FMT\tEnterococcus faecium GRE*** \nKlebsiella pneumoniae PDR**** \nAcinetobacter baumannii MDR***** \nCandida albicans\tStenotrophomonas maltophilia\n\n(S- trimethoprim/\nsulfamethoxazole) \nEnterococcus faecium VRE\nCandida albicans\t\nPost 3rd FMT\tKlebsiella pneumoniae (S) \nCandida albicans (S) \nAcinetobacter baumannii MDR*****\tEscherichia coli ESBL+\nEnterococcus faecium VRE\nCandida albicans\t\nPost 4th FMT\tNot done\tEscherichia coli (S)\nCitrobacter freundii (S)\t\nFMT, fecal microbiota transplantation; S, susceptible to all tested antibiotics; R, resistant to at least one of the tested drugs; GvHD, graft-versus host disease, ESBL+, extended-spectrum beta-lactamase positive; MDR, multidrug-resistant; PDR, pan-drug-resistant; HLGR, high-level aminoglycoside-resistant\n\nE. coli ESBL+ *(S – netilmicin, meropenem, ertapenem, piperacillin/tazobactam, gentamicin, amikacin; R – ciprofloxacin, cefuroxime, ceftazidime, ampicillin/sulbactam, levofloxacin, trimethoprim/sulfamethoxazole), Klebsiella pneumoniae MDR** – all, S – colistin, imipenem, tigecycline), Enterococcus faecium GRE*** (R – ampicillin, imipenem, vancomycin, teicoplanin, gentamicin, S – linezolid), Klebsiella pneumoniae PDR* (R – all, S – colistin), Enterococcus faecium HLGR (S – vancomycin, teicoplanin, linezolid, R – ampicillin, imipenem, gentamicin), Acinetobacter baumannii MDR***** – all, S – colistin, tobramycin), Enterobacter cloacae ESBL+ (R – all, S – meropenem, ertapenem, imipenem, colistin).\n\nCase 2 presentation\nThe second case concerned a man with cerebral palsy who was admitted to the Department of Hematology at an age of 32 years. The patient was diagnosed with osteomyelofibrosis at an age of 31 years and categorized as intermediate risk 1 according to the DIPSS plus scale. The patient was scheduled for allo-HSCT using cells obtained from an unrelated donor. The diagnosis of osteomyelofibrosis was made in the regional hematological ward on the basis of trepanobiopsy (presence of fibrosis [collagen fibers], MF1/2 approximately 80%), and the presence of the V617F mutation in the JAK2 gene. On admission, the patient was in a good condition. The morphological examination revealed severe normocytic and normochromic anemia, mild leukopenia according to the World Health Organization classification, and elevated LDH levels. For condition, the patient was treated according to the Cy-Bu protocol. On day 0, stem cells were administered at 7.43 × 106 CD34+ cells/kg recipient body weight. The patient received ciprofloxacin, fluconazole, and acyclovir as routine anti-infective prophylaxis according to the local protocol. The evidence of hematological restoration (engraftment) was as follows: granulocytes >500/μL on day 21 after transplantation and platelets >20.0 G/L on day 19 after transplantation. The post-transplant chimerism test result revealed 100% donor T-cell chimerism. On day 17 after transplantation, dysuria with hematuria was observed, and the virological examination uncovered the presence of BK virus with viral loads of 1465 copies/mL in plasma and 1.3078 ×107 copies/ml in urine). Intensive fluid therapy was administered, resulting in the resolution of symptoms and reduced viral loads in urine and plasma. On day 42 after transplantation, diarrhea occurred (up to 15 stools/day, approximately 2.5 L/day). The patient was afebrile, and infectious parameters (e.g., C-reactive protein, procalcitonin) were negative. The patient underwent ultrasonography and CT, which revealed thickening of the intestinal wall in the ileum. The patient was disqualified from endoscopy because of the severe clinical condition and the increased risk of perforation. The diagnosis was the intestinal form of aGvHD (grade IV). Fecal culture revealed positivity for E. coli ESBL (+), Enterococcus faecium GRE, Candida albicans, C. parapsilosis, K. pneumoniae, Stenotrophomonas maltophilia, and C. difficile GDH antigens, whereas C. difficile toxins A and B were not detected. Corticosteroids (methylprednisolone 2 mg/kg/d IV) were administered for 2 weeks, followed by calcineurin inhibitors and infliximab (anti-TNF-α) at a dose of 10 mg/kg recipient body weight. Moreover, because of pneumonia and neutropenic fever, empiric antibiotic therapy (ceftazidime and vancomycin followed by imipenem-cilastatin and linezolid) and antifungal drugs (voriconazole) were administered. CMV DNAemia in the early stage of replication was detected on day 51 after transplantation. Intravenous ganciclovir (5 mg/kg every 12 hours) was administered, and after 14 days, the treatment was changed to maintenance therapy. Control CMV quantitative PCR was negative. Because of the lack of clinical improvement and persistence of diarrhea, the patient underwent FMT as a rescue therapy based on the prior written consent of the patient and the consent of the Bioethical Commission of Wroclaw Medical University. FMT was repeated four times with a minimum interval of 7 days. Fecal culture was performed after each transplantation (Table 1). After the third and fourth rounds of FMT, a temporary reduction in symptoms, i.e., pain and the amount of stool, was observed (approximately 1/day). E. coli and Citrobacter freundii were detected in stool samples after administration of the fourth round of FMT without resistance mechanisms. Because of the recurrence of diarrhea within 1 week and the presence of liver dysfunction characterized by elevated liver enzymes above 3× the upper limit of normal and total bilirubin levels exceeding 15 mg/dL, the patient qualified to undergo ECP. No episode of CMV or EBV reactivation was detected. He required parenteral nutrition, blood, platelets, and plasma substitution. Only temporary improvement of the patient’s condition was achieved with the applied treatment. Death occurred on day 128 after transplantation with symptoms of multiorgan failure.\n\nDiscussion\nIn recent years, the role of the microbiome and its evolution in patients who underwent allotransplanation have been reported.10,11 It was demonstrated that a conditioning chemotherapy regimen and total-body irradiation lead to changes in the quantitative and qualitative composition of the intestinal flora. Chemotherapeutic agents used in conditioning regimens decrease the counts of species, mainly Clostridium and Bifidobacterium spp., and increase those of bacteria in the genus Enterococcus.1,12 The reduction in the diversity of the intestinal microflora appears to be an independent factor influencing mortality in the course of GvHD.13–15 Patients undergoing allo-HSCT develop long-term dysbiosis, which plays an essential role in GvHD pathogenesis.11,12,16 Of importance, dysbiosis leads to the prevalence of one type of bacterium or fungus and acute inflammation.14 In addition, it was demonstrated that the early use of broad-spectrum antibiotics, especially carbapenems and piperacillin/tazobactam, in the treatment of infections after allo-HSCT increased mortality associated with intestinal GvHD.17–19 The use of FMT to restore the normal microbiome can be an attractive option in the treatment of intestinal GvHD. To date, there have been few reports on this subject. FMT was used in auto-HSCT and allo-HSCT recipients to treat C. difficile infection.20 Bilinski et al.9 used FMT in eight allo-HSCT recipients who developed infections caused by MDR bacteria. These researchers observed that these bacteria were eradicated in 75% of the patients within 1 month.9 The use of FMT in patients with steroid-resistant intestinal GvHD was discussed in single-institution studies and in one pilot study.21–23 The authors observed an almost complete resolution of symptoms and few adverse effects of the treatment in most patients. In our center, FMT was applied in two patients as described previously. In both cases, patients underwent all-HSCT, and post-transplantation chimerism analysis revealed 100% donor T-cell chimerism. Both patients were diagnosed with severe intestinal aGvHD and treated with standard therapy, which was ineffective. CMV reactivation was identified in one patient, whereas BK virus-associated viremia was detected in both patients. The frequency of BK virus infection in the post-transplant period is estimated to be approximately 7% to 70%, whereas CMV reactivation develops in more than 60% of seropositive recipients.24–27 CMV reactivation may exacerbate GvHD and increase transplant-related mortality.28–30 In the first patient, three rounds of FMT resulted in complete symptom resolution, and the death of the patient was not related to the FMT procedure. However, according to the culture analysis, the patient developed a catheter-related bloodstream infection by A. baumannii with the same phenotype as the strain previously isolated from the patient’s feces. It appears that the patient was permanently colonized by this Acinetobacter strain, but the occurrence of a new infection cannot be excluded. The aspect of the eradication of MDR microorganisms, especially of the genus Enterococcus VRE and MDR rods of the Enterobacteriaceae family, using FMT has resulted in conflicting results.31–34 Moreover, the impact of FMT administration on the eradication of Acinetobacter and other non-fermenting rods is unknown. In the second patient, the therapeutic effect was mediocre, but FMT eliminated drug-resistant pathogens and temporarily improved the patient’s symptoms. No adverse events were observed after FMT in either patient. However, both patients ultimately died. As demonstrated by the culture results, previously detected bacteria such as K. pneumoniae and MDR Enterococcus species were not isolated after the second and third rounds of FMT, confirming the reports of other authors on the elimination of MDR bacteria by this procedure. However, it should be noted that FMT carries some risks for adverse infectious events, which was demonstrated by DeFlilipp et al.35 The authors described two patients who developed bacteremia caused by ESBL-producing E. coli after FMT from the same stool donor. The effect of FMT on the mycobiome is unknown, and few relevant reports have been published.36–38 The observations in our patients indicate the constant presence of Candida fungi in patients’ feces independent of FMT. Invasive mycoses are common and extremely serious complications in the post-transplant period, and prophylactic fluconazole reduces the frequency of these infections as well as the severity of GvHD. Van der Velden et al.39 found that dysfunction of dectin-1, an innate receptor for fungi, was associated with increased colonization by Candida species in human recipients and the aggravation of aGvHD. Moreover, studies using mouse models reported that the injection of fungal mannan and heat-killed C. albicans exacerbated GvHD in the lungs.37 The effect of colonization with non-fermenting rods and Candida fungi on the course of GvHD requires further research. Another aspect is the use of ECP in patients with steroid-refractory GvHD and its interaction with FMT. We used ECP in our patients, mainly because of the worsening of the condition of both patients. The utility of ECP in the treatment of GvHD has not yet been established. Although the exact mechanism of action is unknown, reports on small groups of patients are promising, especially concerning the treatment of cutaneous and intestinal GvHD.40–42\n\nThe present report had some limitations. We presented only two cases, both of which were fatal despite the use of all available treatment methods, illustrating the difficulty in treating GvHD. We were unable to perform metagenomic analyses, which would be useful for analyzing material from donors and tracking changes in the microflora after subsequent transplantations. Recent studies revealed that metagenomic analysis targeting the 16S rRNA of intestinal bacterial flora permit the analysis of the molecular mechanisms by which the microbiota affect the clinical outcomes of patients and assessments of changes in the composition and fluctuations of microbiota after transplantation, which cannot be achieved using standard culture methods.43 In particular, classical culture methods do not allow analyses of the composition of particular bacterial genera because many of these microorganisms do not grow on standard culture media. Furthermore, reports have found that using next-generation sequencing analysis that it is possible to demonstrate the prognostic significance of each intestinal bacterial genus in patients who underwent allo-HSCT. It has been demonstrated that increased abundance of the genus Enterococcus as detected using 16S rRNA sequencing, but not using stool culture techniques, was associated with poor survival in patients who underwent -allo-HSCT.44 Little is known regarding the relationship between FMT and CMV reactivation and the impact of FMT on the intestinal mycobiome.\n\nConclusion\nIn the future, FMT may emerge as a supportive treatment for GvHD, but additional research is needed to assess its safety and efficacy in patients with intestinal steroid-resistant GvHD. Future research should also be conduct to improve donor selection and remotely monitor recipients. It appears that monitoring of the occurrence of the main groups of microorganisms responsible for maintaining intestinal homeostasis in patients undergoing HSCT during the post-transplantation period may be one of the elements that will clarify the relationship between the intestinal microbiome and infections in the post-transplantation period, especially in the course of GvHD.\n\nAcknowledgments\nWe thank Richard Ashcroft for the correction of the manuscript. Dr Pawel Grzesiowski and Bożena Rychwalska were involved in donor selection and fecal microbiota preparation procedure.\n\nDeclaration of conflicting interest\nThe authors declare that there is no conflict of interest.\n\nEthics and consent to publish\nThe study protocol was approved by Bioethical Commission of Wroclaw Medical University. The patients participating in the study provided verbal informed consent for publication.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nORCID iD\nMonika Maria Biernat https://orcid.org/0000-0003-3161-3398\n==== Refs\nReferences\n1 Staffas A Burgos Da Silva M Van Den Brink MR. \nThe intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease.\n\nBlood \n2017 ; \n129 : 927 –933\n.27940475 \n2 Whangbo J Ritz J A Bhatt A. \nAntibiotic-mediated modification of the intestinal microbiome in allogeneic hematopoietic stem cell transplantation.\n\nBone Marrow Transplant \n2017 ; \n52 : 183 –190\n.27526283 \n3 Andermann TM Rezvani A Bhatt AS. \nMicrobiota manipulation with prebiotics and probiotics in patients undergoing stem cell transplantation.\n\nCurr Hematol Malig Rep \n2016 ; \n11 : 19 –28\n.26780719 \n4 Becattini S Taur Y Pamer EG. \nAntibiotic-induced changes in the intestinal microbiota and disease.\n\nTrends Mol Med \n2016 ; \n22 : 458 –478\n.27178527 \n5 Teshima T Reddy P Zeiser R. \nAcute Graft-versus-host disease: novel biological insights.\n\nBiol Blood Marrow Transplant \n2016 ; \n22 : 11 –16\n.26453971 \n6 Myles IA. \nFast food fever: reviewing the impacts of the Western diet on immunity.\n\nNutrition Journal \n2014 ; \n13 : 61 .24939238 \n7 Kaysen A Heintz-Buschart A Muller EEL , et al\nIntegrated meta-omic analyses of the gastrointestinal tract microbiome in patients undergoing allogeneic hematopoietic stem cell transplantation.\n\nTransl Res \n2017 ; \n186 : 79 –94\n.28686852 \n8 Kumari R Palaniyandi S Hildebrandt GC. \nMicrobiome: an emerging new frontier in graft-versus-host disease.\n\nDig Dis Sci \n2019 ; \n64 : 669 –677\n.30523482 \n9 Bilinski J Grzesiowski P Sorensen N , et al\nFecal microbiota transplantation in patients with blood disorders inhibits gut colonization with antibiotic-resistant bacteria: results of a prospective, single-center study\n. Clin Infect Dis \n2017 ; \n65 : 364 –370\n.28369341 \n10 Raghunathan VM Sheng I Lim SH. \nIntestinal dysbiosis and allogeneic hematopoietic progenitor cell transplantation.\n\nJ Transl Med \n2016 ; \n14 : 335 .27912759 \n11 Zama D Biagi E Masetti R , et al\nGut microbiota and hematopoietic stem cell transplantation: where do we stand?\n\nBone Marrow Transplantation \n2017 ; \n52 : 7 –14\n.27348539 \n12 Shallis RM Terry CM Lim SH. \nChanges in intestinal microbiota and their effects on allogeneic stem cell transplantation.\n\nAm J Hematol \n2018 ; \n93 : 122 –128\n.28842931 \n13 Holler E Butxhammer P Schmid K , et al\nMetagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease.\n\nBiol Blood Marrow Transplant \n2014 ; \n20 : 640 –645\n.24492144 \n14 Taur Y. \nIntestinal microbiome changes and stem cell transplantation: lessons learned\n. Virulence \n2016 ; \n8 : 930 –938\n.\n15 Koh AY. \nThe microbiome in hematopoietic stem cell transplant recipients and cancer patients: opportunities for clinical advances that reduce infection\n. PLoS Pathog \n2017 ; \n13 : e1006342 . DOI: 10.1371/journal.ppat.100634228662165 \n16 Golob J Pergam SA. \nStool microbiota at neutrophil recovery is predictive for severe acute graft vs host disease after hematopoietic cell transplantation.\n\nClin Infect Dis \n2017 ; \n65 : 1984 –1991\n.29020185 \n17 Shono Y Docampo MD Peled JU , et al\nIncreased GVHD-related mortality with broad-spectrum antibiotic use after allogeneic hematopoietic stem cell transplantation in human patients and mice\n. Sci Transl Med \n2016 ; \n18 : 339ra71 .\n18 Weber D Jenq RR Peled JU , et al\nMicrobiota disruption induced by early use of broad-spectrum antibiotics is an independent risk factor of outcome after allogeneic stem cell transplantation\n. Biol Blood Marrow Transplant \n2017 ; \n23 : 845 –852\n.28232086 \n19 Noor F Kaysen A Wilmes P , andSchneider JG. \nThe Gut Microbiota and Hematopoietic Stem Cell Transplantation: Challenges and Potentials\n. J Innate Immun \n2019 ; \n11 : 405 –415\n.30286447 \n20 Andermann T Peled JU Ho C , et al\nThe microbiome and hematopoietic cell transplantation: past, present, and future.\n\nBiol Blood Marrow Transplan \n2018 ; \n24 : 1322 –1340\n.\n21 Spindelboeck W Schulz E Uhl B , et al\nRepeated fecal microbiota transplantations attenuate diarrhea and lead to sustained changes in the fecal microbiota in acute, refractory gastrointestinal graft-versus-host-disease.\n\nHaematologica \n2017 ; \n102 : e210 –e213\n.28154090 \n22 Kakihana K Fujioka Y Suda W , et al\nFecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut.\n\nBlood \n2016 ; \n128 : 2083 –2088\n.27461930 \n23 Qi X Li X Zhao Y , et al\nTreating steroid refractory intestinal acute graft-vs.-host disease with fecal microbiota transplantation: a pilot study\n. Front Immunol \n2018 ; \n25 : 2195 .\n24 Philippe M Ranchon F Gilis L , et al\nCidofovir in the treatment of BK virus associated hemorrhagic cystitis after allogeneic hematopoietic stem cell transplantation\n. Biol Blood Marrow Transplant \n2016 ; \n22 : 723 –730\n.26718666 \n25 Stern L Withers B Avdic S , et al\nHuman cytomegalovirus latency and reactivation in allogeneic hematopoietic stem cell transplant recipients\n. Front Microbiol \n2019 ; \n10 : 1186 .31191499 \n26 Dzieciatkowski T Tomaszewska A Przybylski M , et al\nAnalysis of the shedding of three β-herpesviruses DNA in Polish patients subjected to allogeneic hematopoietic stem cell transplantation: six-year follow up.\n\nJ Clin Virol \n2016 ; \n76 : 30 –35\n.26809130 \n27 Ando T Suzuki T Ishiyama Y , et al\nImpact of cytomegalovirus reactivation and natural killer reconstitution on outcomes after allogeneic hematopoietic stem cell transplantation: a single center analysis\n. Biol Blood Marrow Transplant \n2019 ; \n26 : S1083-8791(19)30639-1.\n28 Sun BL Jain R Patel C , et al\nGraft-versus-host disease with early cytomegalovirus infection in gastrointestinal tract biopsies.\n\nInt J Surg Pathol \n2018 ; \n26 : 347 –352\n.29207904 \n29 Okubo H Nagata N Uemura N. \nFulminant gastrointestinal graft-versus-host disease concomitant with cytomegalovirus infection: case report and literature review.\n\nWorld J Gastroenterol \n2013 ; \n19 : 597 –603\n.23382644 \n30 Cho BS Yahng SA Kim JH , et al\nImpact of cytomegalovirus gastrointestinal disease on the clinical outcomes in patients with gastrointestinal graft-versus-host disease in the era of preemptive therapy.\n\nAnn Hematol \n2013 ; \n92 : 497 –504\n.23180439 \n31 Dinh A Fessi H Duran C , et al\nClearance of Carbapenem-resistant Enterobacteriaceae versus Vancomycin-resistant enterococci carriage after fecal microbiota transplant: a prospective comparative study\n. J Hosp Infect \n2018 ; \n99 : 481 –486\n. DOI: 10.1016/j.jhin.2018.02.018.29477634 \n32 Davido B Batista R Dinh A , et al\nFifty shades of graft: how to improve the efficacy of faecal microbiota transplantation for decolonization of antibiotic-resistant bacteria.\n\nInt J Antimicrob Agents \n2019 ; \n53 : 553 –556\n.30880228 \n33 Singh R de Groot PF Geerlings SE , et al\nFecal microbiota transplantation against intestinal colonization by extended spectrum beta-lactamase producing Enterobacteriaceae: a proof of principle study.\n\nBMC Res Notes \n2018 ; \n11 : 190 .29566738 \n34 Tavoukjian V. \nFaecal microbiota transplantation for the decolonization of antibiotic-resistant bacteria in the gut: a systematic review and meta-analysis.\n\nJ Hosp Infect \n2019 ; \n102 : 174 –188\n.30926290 \n35 DeFilipp Z Bloom PP Torres Soto M , et al\nDrug-resistant E. coli bacteremia transmitted by fecal microbiota transplant.\n\nN Engl J Med \n2019 ; \n381 : 2043 –2050\n.31665575 \n36 Fiedorová K Radvanský M Němcová E , et al\nThe impact of DNA extraction methods on stool bacterial and fungal microbiota community recovery\n. Front Microbiol \n2019 ; \n10 : 821 .31057522 \n37 Uryu H Hashimoto D Kato K , et al\nα-Mannan induces Th17-mediated pulmonary graft-versus-host disease in mice.\n\nBlood \n2015 ; \n125 : 3014 –3023\n.25740827 \n38 Van Der Velden WJ Netea MG De Haan AF , et al\nRole of the mycobiome in human acute graft-versus-host disease.\n\nBiol Blood Marrow Transplant \n2013 ; \n19 : 329 –332\n.23160005 \n39 Van Der Velden WJ Plantinga TS Feuth T , et al\nThe incidence of acute graft-versus-host disease increases with Candida colonization depending the dectin-1 gene status.\n\nClin Immunol \n2010 ; \n136 : 302 –306\n.20452827 \n40 Zhang H Chen R Cheng J , et al\nSystematic review and meta-analysis of prospective studies for ECP treatment in patients with steroid-refractory acute GVHD\n. Patient Prefer Adherence \n2015 ; \n9 : 105 –111\n.25653504 \n41 Cho A Jantschitsch C Knobler R. \nExtracorporeal photopheresis-an overview.\n\nFront Med (Lausanne) \n2018 ; \n5 : 236 .30211164 \n42 Abu-Dalle I Reljic T Nishihori T , et al\nExtracorporeal photopheresis in steroid-refractory acute or chronic graft-versus-host disease: results of a systematic review of prospective studies.\n\nBiol Blood Marrow Transplant \n2014 ; \n20 : 1677 –1686\n.24867779 \n43 Kusakabe S Fukushima K Maeda T , et al\nPre- and post-serial metagenomic analysis of gut microbiota as a prognostic factor in patients undergoing haematopoietic stem cell transplantation.\n\nBr J Haematol \n2020 ; \n188 : 438 –449\n.31566729 \n44 Kusakabe S Fukushima K Yokota T , et al\nEnterococcus: a predictor of ravaged microbiota and poor prognosis after allogeneic hematopoietic stem cell transplantation\n. Biol Blood Marrow Transplant \n2020 ; \n26 : 1028 –1033\n. DOI: 10.1016/j.bbmt.2020.01.019.32018061\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0300-0605",
"issue": "48(6)",
"journal": "The Journal of international medical research",
"keywords": "Intestinal microflora; acute graft-versus-host disease; allogeneic hematopoietic stem cell transplantation; antibiotics; multidrug resistance; multiorgan failure; treatment",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D004351:Drug Resistance; D064806:Dysbiosis; D017809:Fatal Outcome; D000069467:Fecal Microbiota Transplantation; D000069196:Gastrointestinal Microbiome; D005938:Glucocorticoids; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007413:Intestinal Mucosa; D015470:Leukemia, Myeloid, Acute; D008297:Male; D055728:Primary Myelofibrosis; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "0346411",
"other_id": null,
"pages": "300060520925693",
"pmc": null,
"pmid": "32527171",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "28662165;30286447;27461930;31057522;27940475;28686852;27526283;28154090;28232086;31563574;29477634;30523482;28842931;20452827;30880228;30319644;26453971;27178527;30926290;25740827;28369341;27912759;27805463;23180439;29566738;32018061;31566729;29207904;23382644;30211164;26780719;26809130;29471034;27194729;23160005;24939238;27348539;31665575;24492144;31191499;26718666;25653504;29020185;24867779",
"title": "Fecal microbiota transplantation in the treatment of intestinal steroid-resistant graft-versus-host disease: two case reports and a review of the literature.",
"title_normalized": "fecal microbiota transplantation in the treatment of intestinal steroid resistant graft versus host disease two case reports and a review of the literature"
} | [
{
"companynumb": "PL-TEVA-2020-PL-1805854",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to evaluate engraftment and adverse events with a conditioning and prophylactic regimen intended to achieve high rates of engraftment with minimal graft-versus-host disease (GVHD) in allogeneic transplantation for chronic granulomatous disease in a single center.\n\n\nMETHODS\nForty patients, 37 male, with chronic granulomatous disease were transplanted. Transplant products were matched sibling peripheral blood stem cells (PBSCs) in four and matched unrelated donor (MUD) bone marrow in three, and one patient received mismatched unrelated PBSCs. Thirty-two patients received MUD PBSCs. All patients received a conditioning regimen of busulfan/alemtuzumab (with low-dose total body irradiation for MUD recipients) with sirolimus graft-versus-host disease prophylaxis.\n\n\nRESULTS\nEngraftment occured in 38/40 recipients (95%). Acute or chronic GVHD occurred in 18 (45%) and 5 (12.5%), respectively, with 6 episodes of grades III-IV and/or steroid refractory GVHD. Overall survival was 33/40 (82.5%) and event-free survival was 30/40 (80%). Successful engraftment was associated with myeloid and NK cell, but not CD3+ chimerism. Myeloid engraftment was greater than 70% in 30/32 recipients at mean follow-up of 3.4 years. Evidence of persistent immunodeficiency was not seen in successful transplants. Attempts to rescue failed or poorly functioning grafts were associated with unacceptable morbidity and mortality.\n\n\nCONCLUSIONS\nA reduced-intensity allogeneic transplant protocol based on alemtuzumab and busulfan with sirolimus GVHD prophylaxis produced high rates of successful engraftment and minimal regimen-related toxicity. Prolonged clinical follow-up has confirmed its efficacy in ameliorating CGD-related disease. Outcomes were not acceptable with donor cell infusion rescue of cause with poor graft function.",
"affiliations": "Clinical Research Directorate, Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Frederick, Maryland, 21702, USA. mark.parta@nih.gov.;Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA.;Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA.;Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA.;Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA.;Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, USA.;Applied Developmental Research Directorate, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, 21702, USA.;Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA.;Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA.;Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA.;Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, USA.",
"authors": "Parta|Mark|M|http://orcid.org/0000-0003-0534-6759;Kelly|Corin|C|;Kwatemaa|Nana|N|;Theobald|Narda|N|;Hilligoss|Diane|D|;Qin|Jing|J|;Kuhns|Douglas B|DB|;Zerbe|Christa|C|;Holland|Steven M|SM|;Malech|Harry|H|;Kang|Elizabeth M|EM|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10875-017-0422-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0271-9142",
"issue": "37(6)",
"journal": "Journal of clinical immunology",
"keywords": "Chronic granulomatous disease; hematopoietic stem cell transplantation; reduced-intensity conditioning",
"medline_ta": "J Clin Immunol",
"mesh_terms": "D046528:Chimerism; D005260:Female; D006086:Graft vs Host Disease; D006105:Granulomatous Disease, Chronic; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007166:Immunosuppressive Agents; D008297:Male; D011446:Prospective Studies; D035781:Siblings; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "8102137",
"other_id": null,
"pages": "548-558",
"pmc": null,
"pmid": "28752258",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": "21926962;16371922;21736681;20946467;20587785;27216217;23937637;25175046;20007560;20483732;21763253;24419524;20488796;21190454;17393167;11259721;24161820;22326631;22078471;18505782;12393596;21384251;19222467;24035782;11981422;23870668;25845644",
"title": "Allogeneic Reduced-Intensity Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease: a Single-Center Prospective Trial.",
"title_normalized": "allogeneic reduced intensity hematopoietic stem cell transplantation for chronic granulomatous disease a single center prospective trial"
} | [
{
"companynumb": "US-OTSUKA-2017_018021",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Simultaneous infection with histoplasmosis and miliary tuberculosis is rare and mainly affects people with severe immunosuppression, they can present very diverse clinical forms, similar to other infectious and neoplastic pathologies. We present the case of a 27-year-old woman diagnosed with HIV infection for 08 years who refuses to receive antiretroviral treatment (ART) and conceals her diagnosis, comes to the Hospital for pain, abdominal distension and ulcer in the oral cavity. The patient was diagnosed with likely cancer by presenting irregular intestinal thickening with homogeneous gray pattern in colon tomography and signs of intestinal obstruction, that after hemicolectomy was evidenced histoplasmosis in the pathological study, during the treatment with amphotericin B deoxycholate and improvement of the oral ulcer, the patient presented dyspnea, micronodular pattern on the chest radiograph that had not previously existed and the lipoarabinomanan antigen in the urine was positive for tuberculosis. In immunosuppressed patients, intestinal histoplasma infection may have clinical and tomographic characteristics similar to colon cáncer.",
"affiliations": "Facultad de Medicina, Universidad Nacional del Centro del Perú, Avenue Mariscal Castilla 3909, 1206, Huancayo, Perú. otivo3@hotmail.com.;Facultad de Medicina, Universidad Nacional del Centro del Perú, Avenue Mariscal Castilla 3909, 1206, Huancayo, Perú.;Servicio de Patología, Hospital Daniel Alcides Carrión, Huancayo, Perú.;Facultad de Medicina, Universidad Nacional del Centro del Perú, Avenue Mariscal Castilla 3909, 1206, Huancayo, Perú.",
"authors": "Montalvo|Raúl|R|http://orcid.org/0000-0003-0227-8850;Pomalaza|Gisel|G|;Sandoval|Magaly|M|;Quispe|Jocelyn|J|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11046-020-00437-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0301-486X",
"issue": "185(3)",
"journal": "Mycopathologia",
"keywords": "HIV; Histoplasma capsulatum; Histoplasmosis; Immunocompromised; Miliary tuberculosis",
"medline_ta": "Mycopathologia",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D003110:Colonic Neoplasms; D003717:Denial, Psychological; D003937:Diagnosis, Differential; D005260:Female; D015658:HIV Infections; D006660:Histoplasmosis; D006801:Humans; D016867:Immunocompromised Host; D019226:Oral Ulcer; D016312:Treatment Refusal; D014391:Tuberculosis, Miliary",
"nlm_unique_id": "7505689",
"other_id": null,
"pages": "583-586",
"pmc": null,
"pmid": "32385592",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated Histoplasmosis and Miliary Tuberculosis Imitating Colon Cancer in Patient with HIV Who Refuses to Antirretroviral Treatment.",
"title_normalized": "disseminated histoplasmosis and miliary tuberculosis imitating colon cancer in patient with hiv who refuses to antirretroviral treatment"
} | [
{
"companynumb": "PE-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-305353",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"d... |
{
"abstract": "Acute myeloid leukemia (AML) is a rare disease in children, with only 50% to 60% event-free survival. Among patients with AML, 10% do not respond to first-line chemotherapy. There is no recommendation concerning second-line treatments. Gemtuzumab ozogamicin (GO) is a monoclonal antibody targeting CD33, linked to calicheamicin. We report the efficacy and tolerance of a salvage regimen of fludarabin, cytarabine, and GO (FLA-GO) in patients refractory to first-line treatment.\n\n\n\nEight patients (median age 14.5 years), who had more than 2% minimal residual disease (MRD) by flow cytometry (MRD flow), received gemtuzumab 3 mg/m² on days 1, 4, 7, associated with cytarabine 2000 mg/m² and fludarabin 30 mg/m² on days 1 to 5.\n\n\n\nSix patients achieved complete remission (CR) (blast count morphology ≤5 × 10-2 , CR-MRD flow <1 × 10-3 for four patients). Five patients received a second course. We observed 11 episodes of febrile neutropenia, including 6 septicemias without complication. There was no fungal infection or toxic death. Two patients received granulocyte colony stimulating factor. One patient had partial platelet recovery; one, prolonged pancytopenia. All patients received hematopoietic stem cell transplantation (HSCT). We observed five mild-to-severe sinusoidal obstruction syndromes during HSCT procedures, particularly in patients who did not receive defibrotide prophylaxis. At the date of last contact (median follow-up: 58 months; range: 22-78), six patients were in continuous CR with negative MRD. Two patients died of post-HSCT relapse.\n\n\n\nFLA-GO is a good salvage regimen for pediatric refractory AML, with significant but acceptable toxicity. HSCT is mandatory to achieve sustained CR in these patients.",
"affiliations": "Institute of Pediatric Hematology and Oncology, Hospices Civils de Lyon, Lyon, France.;Laboratory of Hematology, Lyon Sud Hospital, Hospices Civils de Lyon, Lyon, France.;Laboratory of Hematology, Center of Biology and Pathology East, Hospices Civils de Lyon, Lyon, France.;Laboratory of Hematology, CHU Lille, Lille, France.;Institute of Pediatric Hematology and Oncology, Hospices Civils de Lyon, Lyon, France.;Institute of Pediatric Hematology and Oncology, Hospices Civils de Lyon, Lyon, France.",
"authors": "Penel-Page|Mathilde|M|0000-0002-7271-4833;Plesa|Adriana|A|;Girard|Sandrine|S|;Marceau-Renaut|Alice|A|;Renard|Cécile|C|;Bertrand|Yves|Y|",
"chemical_list": "D003561:Cytarabine; D000079982:Gemtuzumab; D014740:Vidarabine; C024352:fludarabine",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28305",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(6)",
"journal": "Pediatric blood & cancer",
"keywords": "AML: molecular diagnosis and therapy; gemtuzumab; minimal residual disease; pediatric hematology/oncology; refractory AML; salvage therapy",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D003131:Combined Modality Therapy; D003561:Cytarabine; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D000079982:Gemtuzumab; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D012189:Retrospective Studies; D016879:Salvage Therapy; D015996:Survival Rate; D014740:Vidarabine",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28305",
"pmc": null,
"pmid": "32307866",
"pubdate": "2020-06",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Association of fludarabin, cytarabine, and fractioned gemtuzumab followed by hematopoietic stem cell transplantation for first-line refractory acute myeloid leukemia in children: A single-center experience.",
"title_normalized": "association of fludarabin cytarabine and fractioned gemtuzumab followed by hematopoietic stem cell transplantation for first line refractory acute myeloid leukemia in children a single center experience"
} | [
{
"companynumb": "FR-PFIZER INC-2020195154",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "3... |
{
"abstract": "The administration of fluconazole is commonly used in both inpatient and outpatient settings for the management of candidiasis infection. Although it is associated with a relatively safe side effect profile, some patients experience adverse effects associated with increased morbidity. We describe 1 such patient, a 42-year-old woman with a history of severe eczema who developed fluconazole-induced type 1 Kounis syndrome. Review of literature indicates that this as the first case reported of fluconazole-induced type 1 Kounis syndrome.",
"affiliations": "University of British Columbia, Vancouver, Canada.",
"authors": "Singh Mahal|Hardeep|H|",
"chemical_list": "D000935:Antifungal Agents; D015725:Fluconazole",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0000000000000113",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "23(3)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D054058:Acute Coronary Syndrome; D000328:Adult; D000787:Angina Pectoris; D000935:Antifungal Agents; D004342:Drug Hypersensitivity; D004485:Eczema; D005260:Female; D015725:Fluconazole; D006801:Humans; D013577:Syndrome",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e961-2",
"pmc": null,
"pmid": "26938747",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fluconazole-Induced Type 1 Kounis Syndrome.",
"title_normalized": "fluconazole induced type 1 kounis syndrome"
} | [
{
"companynumb": "CA-MYLANLABS-2016M1025199",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Whether prolonged survival with current chemotherapy using molecular target agents has changed the rate of primary tumor-related complications in patients with unresectable stage IV colorectal cancer is unclear.\n\n\n\nThis study aimed to investigate the rate of primary tumor-related complications among patients receiving targeted therapy as compared with patients receiving chemotherapy without molecular target agents.\n\n\n\nThis was a retrospective review of data from a prospectively maintained database.\n\n\n\nThe study was conducted at a high-volume multidisciplinary tertiary cancer center in Japan.\n\n\n\nSubjects were 352 consecutive patients with unresectable stage IV colorectal cancer who received systemic chemotherapy without primary tumor resection from 2001 to 2015. Patients were categorized into nontargeted and targeted groups according to the use of molecular target agents.\n\n\n\nComplication rates attributed to primary tumors were measured.\n\n\n\nOf the 352 patients, 159 were categorized into the nontargeted group and 193 patients into the targeted group. Competing risk-adjusted univariate analysis revealed that the primary tumor-related complication rates in the nontargeted group were 6.9% (95% CI, 3.8%-11.9%) at 1 year and 8.2% (95% CI, 4.8%-13.8%) at 2 years, whereas the targeted group had complication rates of 11.5% (95% CI, 7.5%-16.6%) at 1 year and 16.7% (95% CI, 12.4%-23.3%) at 2 years. Multivariate analysis revealed that the targeted group was ≈2 times more likely to have primary tumor-related complications (subdistribution HR = 2.04 (95% CI, 1.12-4.01); p = 0.020). Median survival time was 12.0 months in the nontargeted group and 24.1 months in the targeted group (p < 0.001).\n\n\n\nThis study was limited by the retrospective design.\n\n\n\nTargeted therapy was associated with a significantly increased risk of primary tumor-related complications during chemotherapy. However, targeted therapy also improved overall survival, making it a tolerable therapy. See Video Abstract at http://links.lww.com/DCR/B536.\n\n\n\nANTECEDENTES:No está claro si la supervivencia prolongada con la quimioterapia actual utilizando agentes moleculares dirigidos ha cambiado la tasa de complicaciones relacionadas con el tumor primario en pacientes con cáncer colorrectal en estadio IV irresecable.OBJETIVO:Este estudio tuvo como objetivo investigar la tasa de complicaciones relacionadas con el tumor primario entre los pacientes que reciben terapia dirigida, en comparación con pacientes que reciben quimioterapia sin agentes moleculares dirigidos.DISEÑO:Revisión retrospectiva de datos de una base de datos mantenida prospectivamente.ESCENARIO CLINICO:Centro oncológico de tercer nivel multidisciplinario de alto volumen en Japón.PACIENTES:352 pacientes consecutivos con cáncer colorrectal en estadio IV irresecable que recibieron quimioterapia sistémica sin resección del tumor primario entre 2001 y 2015. Los pacientes se clasificaron en grupos dirigidos y no dirigidos según el uso de agentes moleculares dirigidos.PRINCIPALES MEDIDAS DE VALORACION:Tasas de complicaciones debidas a tumores primarios.RESULTADOS:De los 352 pacientes, 159 se clasificaron en el grupo no dirigido y 193 pacientes en el grupo dirigido. El análisis univariado ajustado al riesgo competitivo reveló que las tasas de complicaciones primarias relacionadas con el tumor en el grupo no dirigido fueron del 6,9% (intervalo de confianza (IC) del 95%, 3,8 - 11,9%) al año y del 8,2% (IC del 95%, 4,8%). - 13,8%) a los dos años, mientras que el grupo dirigido tuvo tasas de complicaciones del 11,5% (IC del 95%, 7,5 - 16,6%) al año y del 16,7% (IC del 95%, 12,4 - 23,3%) a los dos años. El análisis multivariado reveló que el grupo dirigido tenía aproximadamente dos veces más probabilidades de tener complicaciones relacionadas con el tumor primario (razón de riesgo de subdistribución, 2,04; IC del 95%, 1,12 a 4,01; p = 0,020). La mediana del tiempo de supervivencia fue de 12,0 meses en el grupo no dirigido y de 24,1 meses en el grupo dirigido (p <0,001).LIMITACIONES:Este estudio estuvo limitado por el diseño retrospectivo.CONCLUSIONES:La terapia dirigida se asoció con un riesgo significativamente mayor de complicaciones relacionadas con el tumor primario durante la quimioterapia. Sin embargo, la terapia dirigida también mejoró la SG, convirtiéndola en una terapia tolerable. Consulte Video Resumen en http://links.lww.com/DCR/B536.",
"affiliations": "Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.;Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.;Division of Frontier Surgery, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.;Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.;Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.;Division of Frontier Surgery, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.;Department of Colorectal Surgery, National Cancer Center Hospital, Tokyo, Japan.",
"authors": "Tanabe|Taro|T|;Shida|Dai|D|;Boku|Narikazu|N|;Yoshida|Takefumi|T|;Tsukamoto|Shunsuke|S|;Takashima|Atsuo|A|;Kanemitsu|Yukihide|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/DCR.0000000000002010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-3706",
"issue": "64(9)",
"journal": "Diseases of the colon and rectum",
"keywords": null,
"medline_ta": "Dis Colon Rectum",
"mesh_terms": null,
"nlm_unique_id": "0372764",
"other_id": null,
"pages": "1074-1082",
"pmc": null,
"pmid": "34397558",
"pubdate": "2021-09-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Primary Tumor-Related Complications Among Patients With Unresectable Stage IV Colorectal Cancer in the Era of Targeted Therapy: A Competing Risk Regression Analysis.",
"title_normalized": "primary tumor related complications among patients with unresectable stage iv colorectal cancer in the era of targeted therapy a competing risk regression analysis"
} | [
{
"companynumb": "JP-ROCHE-2995051",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "OBJECTIVE\nAn episode of acute hypokalemic paralysis associated with the use of inhaled albuterol is described.\n\n\nCONCLUSIONS\nA 34-year-old woman admitted to the emergency department reported the development of pain and diffuse paralysis of the extremities and torso shortly after using an albuterol inhaler. At age 18, she had been diagnosed with hyokalemic periodic paralysis (HPP), a disorder of muscle membrane excitability caused by serum potassium depletion that can lead to life-threatening neuromuscular and cardiovascular complications. After a 15-year period of episodically recurring HPP symptoms despite long-term acetazolamide use, she was switched to spironolactone therapy and had experienced no HPP exacerbations for about 1 year. On her arrival in the emergency department, the patient's serum potassium concentration was 1.8 meq/L and she was mildly tachycardic (heart rate of 125 beats/min). After careful supplementation to gradually increase the serum potassium concentration to 5.4 meq/L, the patient slowly regained movement and strength in her extremities. Application of the adverse drug reaction probability scale of Naranjo et al. to this case yielded a score of 3, indicating that albuterol was possibly the cause of the patient's HPP exacerbation. Beta-2-adrenergic agonists and several other medications can affect serum potassium levels; although the potential risks posed by the use of such drugs in patients with a history of HPP are unclear, cautious use in the context of known HPP is advised.\n\n\nCONCLUSIONS\nA patient previously diagnosed with HPP experienced an exacerbation of HPP possibly induced by inhaled albuterol treatment.",
"affiliations": "Critical Care, St. Vincent's Medical Center, Jacksonville, FL, USA. calvin.tucker@jaxhealth.com",
"authors": "Tucker|Calvin|C|;Villanueva|Lyn|L|",
"chemical_list": "D000318:Adrenergic beta-Agonists; D002257:Carbonic Anhydrase Inhibitors; D000086:Acetazolamide; D000420:Albuterol; D011188:Potassium",
"country": "England",
"delete": false,
"doi": "10.2146/ajhp130086",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-2082",
"issue": "70(18)",
"journal": "American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists",
"keywords": null,
"medline_ta": "Am J Health Syst Pharm",
"mesh_terms": "D000086:Acetazolamide; D000208:Acute Disease; D000280:Administration, Inhalation; D000318:Adrenergic beta-Agonists; D000328:Adult; D000420:Albuterol; D002257:Carbonic Anhydrase Inhibitors; D003866:Depressive Disorder; D004632:Emergency Medical Services; D005260:Female; D006801:Humans; D020514:Hypokalemic Periodic Paralysis; D009330:Nebulizers and Vaporizers; D011014:Pneumonia; D011188:Potassium; D013610:Tachycardia",
"nlm_unique_id": "9503023",
"other_id": null,
"pages": "1588-91",
"pmc": null,
"pmid": "23988599",
"pubdate": "2013-09-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute hypokalemic periodic paralysis possibly precipitated by albuterol.",
"title_normalized": "acute hypokalemic periodic paralysis possibly precipitated by albuterol"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2014GSK011265",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALBUTEROL"
},
"drugadditional": null... |
{
"abstract": "Codeine containing analgesics are commonly taken in overdose, but the frequency of respiratory depression is unknown. We investigated whether paracetamol-codeine combination overdoses caused respiratory depression more than paracetamol alone.\n\n\n\nWe reviewed deliberate self-poisoning admissions with paracetamol (>2 g) and paracetamol-codeine combinations presenting to a tertiary toxicology unit (1987-2013). Demographic information, clinical effects, treatment (naloxone, length of stay [LOS], mechanical ventilation) were extracted from a prospective database. Primary outcome was naloxone requirement or ventilation for respiratory depression.\n\n\n\nFrom 4488 presentations, 1376 admissions were included with paracetamol alone (929), paracetamol-codeine combinations (346) or paracetamol-codeine-doxylamine combinations (101) without co-ingestants. Median age was 23 years (12-89 years); 1002 (73%) were female. Median dose was 12 g (interquartile range [IQR]: 7.5-20 g). Median LOS was 16 h (IQR: 6.5-27 h) and 564 (41%) were given acetylcysteine. Significantly larger paracetamol doses were ingested and more acetylcysteine given in paracetamol alone versus paracetamol combination overdoses. Seven out of 1376 patients were intubated or received naloxone (0.5%; 95% CI: 0.2-1.1%), three intubated, three given naloxone and one both. Three out of 929 patients ingesting paracetamol alone (0.3%; 95% CI: 0.1-1%) required intubation or naloxone, compared to two out of 346 ingesting paracetamol-codeine combinations (0.6%; 95% CI: 0.1-2.3%; absolute difference, 0.26%; 95% CI: -0.7-1.2%; P = 0.62). Two out of 101 patients ingesting paracetamol-codeine-doxylamine combinations (2%; 95% CI: 0.3-8%) required intubation or naloxone. Four patients were intubated for reasons other than respiratory depression: hepatotoxicity (2), retrieval (1), no data (1). Two out of 929 (0.2%) paracetamol alone overdoses had a Glasgow coma score < 9 compared to three out of 346 (0.9%) in the paracetamol-codeine group.\n\n\n\nParacetamol-codeine combination overdoses are rarely associated with severe respiratory depression, with only two given naloxone and none intubated for respiratory depression.",
"affiliations": "Department of Clinical Toxicology, Calvary Mater Newcastle, New South Wales, Australia.;Department of Clinical Toxicology, Calvary Mater Newcastle, New South Wales, Australia.",
"authors": "Heppell|Simon P E|SPE|;Isbister|Geoffrey K|GK|0000-0003-1519-7419",
"chemical_list": "D000931:Antidotes; D004338:Drug Combinations; D009292:Narcotic Antagonists; C526278:acetaminophen, codeine drug combination; D000082:Acetaminophen; D009270:Naloxone; D003061:Codeine; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13224",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "83(6)",
"journal": "British journal of clinical pharmacology",
"keywords": "codeine; naloxone; overdose; paracetamol; poisoning; respiratory depression",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000931:Antidotes; D002648:Child; D003061:Codeine; D003422:Critical Care; D004338:Drug Combinations; D062787:Drug Overdose; D005260:Female; D015600:Glasgow Coma Scale; D006801:Humans; D007902:Length of Stay; D008297:Male; D008875:Middle Aged; D009270:Naloxone; D009292:Narcotic Antagonists; D012121:Respiration, Artificial; D012131:Respiratory Insufficiency; D012189:Retrospective Studies; D013406:Suicide, Attempted; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "1273-1278",
"pmc": null,
"pmid": "28035699",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "23248093;28035699;26650439;6412809;8845855;25929508;23964853;24458010;22569351;9196648;23614474;25670515;25585351;26464438;16243090;7833757;24747667;19692698;17719135;23748253;26624241;12453926",
"title": "Lack of respiratory depression in paracetamol-codeine combination overdoses.",
"title_normalized": "lack of respiratory depression in paracetamol codeine combination overdoses"
} | [
{
"companynumb": "AU-FRESENIUS KABI-FK201705559",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null... |
{
"abstract": "There has been much newspaper and online news coverage of in-flight obstetric births on commercial aircraft over several decades. This case series reviews several cases of in-flight birth and immediate maternal and neonatal outcomes from air medical retrievals in the Northern Territory of Australia over a 4-year [corrected] period.\n\n\n\nThis is a retrospective written case note and electronic medical retrieval record analysis of 4 patients undergoing in-flight, at altitude, obstetric birth.\n\n\n\nFour premature births are recorded by CareFlight Operations over a 4-year period from January 2011 to January 2015. All patients involved were preterm; term ranged from 22 weeks to 36 weeks. Tocolysis was implemented on all 4 patients according to local obstetric guidelines. Maternal complications included 1 patient suffering antepartum hemorrhage and 2 patients suffering postpartum hemorrhage. Three neonates born at altitude needed neonatal resuscitation including positive-pressure ventilation. One neonate, 22 weeks' gestation, died approximately 2 hours after delivery. Maternal follow-up showed no morbidity or mortality at 1 to 6 days after birth.\n\n\n\nIn-flight deliveries are rare events in air medical medicine. This case series includes patients of variable preterm gestation and correlates poor outcomes to prematurity of neonates. Close communication between remote clinics, obstetric centers, and air medical teams plus up-to-date early labor guidelines are essential for safe practice and to limit the risk of in-flight births.",
"affiliations": "CareFlight, Northern Territory, Australia. Electronic address: toby.shipway@gmail.com.;CareFlight, Northern Territory, Australia.;CareFlight, Northern Territory, Australia.;CareFlight, Northern Territory, Australia.;CareFlight, Northern Territory, Australia.",
"authors": "Shipway|Toby|T|;Johnson|Elaine|E|;Bell|Sheridan|S|;Martin|Jodie|J|;Clark|Peter|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1067-991X",
"issue": "35(5)",
"journal": "Air medical journal",
"keywords": null,
"medline_ta": "Air Med J",
"mesh_terms": "D000328:Adult; D017732:Air Ambulances; D005260:Female; D005865:Gestational Age; D006801:Humans; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D007234:Infant, Premature; D015876:Northern Territory; D011175:Positive-Pressure Respiration; D006473:Postpartum Hemorrhage; D011247:Pregnancy; D011248:Pregnancy Complications; D047928:Premature Birth; D012151:Resuscitation; D012189:Retrospective Studies; D015145:Tocolysis; D014187:Transportation of Patients; D014592:Uterine Hemorrhage",
"nlm_unique_id": "9312325",
"other_id": null,
"pages": "317-20",
"pmc": null,
"pmid": "27637445",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case Review: In-Flight Births Over a 4-Year Period in the Northern Territory, Australia.",
"title_normalized": "a case review in flight births over a 4 year period in the northern territory australia"
} | [
{
"companynumb": "AU-ALEMBIC PHARMACUETICALS LIMITED-2016SCAL000899",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"dr... |
{
"abstract": "Finding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line 'JVE404' derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient's treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining signal intensities of a half and a third of control, respectively, with crizotinib. The patient had a 6-month lasting stable disease on crizotinib, but progressive disease occurred, including the finding of cerebral metastases, at 8 months. With lorlatinib, partial response, including clinical cerebral activity, was already achieved at 11 weeks' use and ongoing partial response at 7 months. To our best knowledge, this is the first reported case describing a patient-specific targeted treatment with lorlatinib based on an EML4-ALK gene fusion v3 in a thyroid cancer patient, and own cancer cell line. Tumor-agnostic targeted therapy may provide valuable treatment options in personalized medicine.",
"affiliations": "Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands.;Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.",
"authors": "Aydemirli|Mehtap Derya|MD|0000-0003-2891-7059;van Eendenburg|Jaap D H|JDH|;van Wezel|Tom|T|;Oosting|Jan|J|;Corver|Willem E|WE|;Kapiteijn|Ellen|E|;Morreau|Hans|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nEndocr Relat Cancer\nEndocr Relat Cancer\nERC\nEndocrine-Related Cancer\n1351-0088\n1479-6821\nBioscientifica Ltd Bristol\n\n33878728\n10.1530/ERC-20-0436\nERC-20-0436\nResearch\nTargeting EML4-ALK gene fusion variant 3 in thyroid cancer\nM D Aydemirli et al.\nTargeting EML4-ALK v3 in thyroid cancer\nhttp://orcid.org/0000-0003-2891-7059\nAydemirli Mehtap Derya 12\nvan Eendenburg Jaap D H 1\nvan Wezel Tom 1\nOosting Jan 1\nCorver Willem E 1\nKapiteijn Ellen 2*\nMorreau Hans 1*\n1 Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands\n2 Department of Medical Oncology, Leiden University Medical Center, Leiden, The Netherlands\nCorrespondence should be addressed to H Morreau: J.Morreau@lumc.nl\n*(E Kapiteijn and H Morreau contributed equally as last authors)\n\n20 4 2021\n01 6 2021\n28 6 377389\n22 3 2021\n20 4 2021\n© The authors\n2021\nThe authors\nhttps://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License.\n\nFinding targetable gene fusions can expand the limited treatment options in radioactive iodine-refractory (RAI-r) thyroid cancer. To that end, we established a novel cell line ‘JVE404’ derived from an advanced RAI-r papillary thyroid cancer (PTC) patient, harboring an EML4-ALK gene fusion variant 3 (v3). Different EML4-ALK gene fusions can have different clinical repercussions. JVE404 cells were evaluated for cell viability and cell signaling in response to ALK inhibitors crizotinib, ceritinib and lorlatinib, in parallel to the patient’s treatment. He received, after first-line lenvatinib, crizotinib (Drug Rediscovery Protocol (DRUP) trial), and lorlatinib (compassionate use). In vitro treatment with crizotinib or ceritinib decreased viability in JVE404, but most potently and significantly only with lorlatinib. Western blot analysis showed a near total decrease of 99% and 89%, respectively, in pALK and pERK expression levels in JVE404 cells with lorlatinib, in contrast to remaining signal intensities of a half and a third of control, respectively, with crizotinib. The patient had a 6-month lasting stable disease on crizotinib, but progressive disease occurred, including the finding of cerebral metastases, at 8 months. With lorlatinib, partial response, including clinical cerebral activity, was already achieved at 11 weeks’ use and ongoing partial response at 7 months. To our best knowledge, this is the first reported case describing a patient-specific targeted treatment with lorlatinib based on an EML4-ALK gene fusion v3 in a thyroid cancer patient, and own cancer cell line. Tumor-agnostic targeted therapy may provide valuable treatment options in personalized medicine.\n\nKeywords\n\nthyroid cancer\nEML4-ALK gene fusion\ncrizotinib\nceritinib\nlorlatinib\ntargeted therapy\npersonalized medicine\nhumans\ncancer cell line\ncell signaling\nALK\nAKT\nERK\nSTAT\n==== Body\nIntroduction\n\nThyroid cancer is the most common endocrine malignancy and its incidence is on the rise (Siegel et al. 2019). Non-medullary thyroid cancer (NMTC) includes differentiated thyroid cancer (DTC), accounting for ~95% of thyroid cancers, with main histologic subtypes papillary (PTC), follicular thyroid carcinoma (FTC) and Hürthle cell carcinoma (HCC). Usually, prognosis is favorable in differentiated thyroid cancer cases with standard therapy including thyroidectomy combined with RAI therapy (Haugen et al. 2016). However, a subset may be in or progress to RAI-refractory status which implies a very poor 10-year survival of <10% (Schlumberger et al. 2015).\n\nTreatment options in RAI-refractory differentiated thyroid cancer (RAI-rDTC or RRDTC) are limited and include local treatments or registered first-line drugs lenvatinib and sorafenib. When these treatment options have been exhausted, inclusion in trials may sometimes be warranted (Haugen et al. 2016). Yet, over the last few years, advanced diagnostics are evolving and their role becomes more pivotal in directing the most suitable patient management choices. The application of therapeutic options across cancer types of various affected organs based on their molecular profiling (a tumor-agnostic approach), facilitates tailored therapy in precision medicine and several basket trials have been initiated and are ongoing for this purpose (ClinicalTrials.gov) (van der Velden et al. 2019). However, unique molecular profiles in one type of cancer may potentially render (in)sensitivities to certain drugs that have otherwise proven to be effective in another cancer type. For instance, favorable results with vemurafenib in BRAF mutated melanoma vs limited effect in colon cancer (Flaherty et al. 2010, Kopetz et al. 2015), or panitumumab (EGFR inhibitor) in RAS WT colon cancer vs Hürthle cell cancer of the thyroid (Aydemirli et al. 2019, Battaglin et al. 2019).\n\nEchinoderm microtubule-associated protein-like 4 – anaplastic lymphoma kinase (EML4-ALK) gene fusions are prevalent in lung cancer and treatment with ALK inhibitors is a part of conventional care (Recondo et al. 2018). This set of targetable gene fusions may also present in thyroid cancer (Cancer Genome Atlas Research Network 2014, Demeure et al. 2014, Kelly et al. 2014, Chou et al. 2015, Landa et al. 2016, Panebianco et al. 2019, van der Tuin et al. 2019). EML4-ALK gene fusions (by the EML4 coiled-coil domain that mediates constitutive dimerization) result in constitutive ALK kinase activation (Soda et al. 2007, Mano 2008, 2015) and thereby lead to oncogenic signaling via several pathways including phosphatidylinositol 3-kinase (PI3K)/AKT, RAS/extracellular signal-regulated kinase (ERK), Janus kinase/signal transducer and activator of transcription protein (JAK/STAT) (Hallberg & Palmer 2016, Sabir et al. 2017). Depending on varying gene fusion points of EML4, different EML4-ALK fusion variants, of varying lengths, may arise (Sabir et al. 2017). For instance, EML4-ALK fusion variants 3 and 5 are ‘shorter’ and lack the tandem atypical beta-propeller (TAPE) domain that is present in v1 or v2 (Bayliss et al. 2016). Their respective susceptibility to various ALK inhibitors is reported to vary (Heuckmann et al. 2012, Sabir et al. 2017).\n\nCrizotinib and ceritinib are the first- and a second-generation ALK TKI, respectively, approved for the treatment of patients with ALK-positive advanced non-small cell lung cancer (NSCLC), and lorlatinib is a third-generation ALK TKI approved for previously treated ALK-positive metastatic NSCLC (Recondo et al. 2018) (also see https://www.drugs.com/history/xalkori.html, https://www.drugs.com/history/zykadia.html and https://www.drugs.com/history/lorbrena.html). With lorlatinib treatment, the NSCLC patients who harbored EML4-ALK v3 have been reported to show a longer progression-free survival (PFS) than those harboring EML4-ALK v1 (Lin et al. 2018). With crizotinib, for those with EML4-ALK fusion variants 1/2/others (i.e. non-v3) longer PFS have been reported than for EML4-ALK v3 among treated patients (Seo et al. 2017, Woo et al. 2017, Christopoulos et al. 2018). Further studies with crizotinib reported longer PFS for v1 (Yoshida et al. 2016), longer PFS for v2 (Li et al. 2018), and lower PFS and overall survival (OS) for v3 or v5 than other fusion variants (Su et al. 2019). However, several other studies reported no differences in PFS with crizotinib based on the EML4-ALK fusion variant (Cha et al. 2016, Lei et al. 2016, Lin et al. 2018, 2019, Mitiushkina et al. 2018).\n\nAll in all, the standard of care regarding ALK TKIs for ALK rearranged NSCLC is rapidly evolving with the elucidation of the complexity, for example, resistance mechanisms, efficacy, CNS-penetrance of various ALK TKIs. In ALK rearranged NSCLC in general, standard first-line treatment is now shifting from crizotinib to second-generation ALK TKIS ceritinib and alectinib (McCusker et al. 2019). With crizotinib, its poor CNS-penetrance may account for the fact that CNS metastasis is common among the 70% of patients who failed on this first-generation ALK TKI (Costa et al. 2015, McCusker et al. 2019). Second- or third-generation ALK TKIs have a higher intracranial activity and may constitute more appropriate ALK TKIs in case of CNS involvement (Zhang et al. 2015, McCusker et al. 2019).\n\nThyroid cancer has its own general molecular profile (Pozdeyev et al. 2018, van der Tuin et al. 2019) with PI3K/AKT and RAS/ERK constituting major signaling pathways involved in thyroid tumorigenesis (Ricarte-Filho et al. 2009, Nikiforov 2011, Brehar et al. 2013, Xing 2013, Penna et al. 2016, Yarchoan et al. 2016). Conversely, as various mutations or variants of the EML4-ALK gene fusion may be present (Sabir et al. 2017, Recondo et al. 2018), it would be informative to investigate the patient’s treatment response and put real-life outcome into perspective in parallel to a surrogate in vitro findings.\n\nAt our institution, a patient presented with refractory papillary thyroid cancer (PTC) wherein an EML4-ALK gene fusion was detected. Hence, after lenvatinib treatment, the patient was included in the Drug Rediscovery Protocol (DRUP) basket trial (NCT02925234) as a candidate for treatment with the ALK tyrosine kinase inhibitor (TKI) crizotinib. From the patient’s papillary thyroid cancer (lymph node metastasis) we derived a primary cell line harboring an EML4-ALK gene fusion v3. As they share the same essential growth driver due to constitutively activated ALK, we investigated the applicability of ALK inhibitors, such as in conventional therapy of lung cancer harboring EML4-ALK, to thyroid cancer.\n\nMaterials and methods\n\nPatient\n\nLenvatinib was used as standard therapy. Crizotinib was made available within the DRUP trial (ethical approval central committee Dutch Cancer Institute 19 April 2016; Clinical Trials registration October 5, 2016, NCT02925234) (van der Velden et al. 2019). Lorlatinib was used within the context of compassionate use. Overall lesion response was evaluated using RECIST 1.1 (Eisenhauer et al. 2009). Specimens were handled in compliance with the Code of Conduct for Proper Secondary Use of Human Tissue according to the Federation of Dutch Medical Scientific Societies (Federa) (https://www.federa.org/codes-conduct). The patient was informed about the secondary use of coded residual material for research and had no objections (opt-out policy, exempt from institutional review board approval). Additional informed consent for the publication of anonymized information on clinical data and research on the cancer cell line was obtained from the patient.\n\nGene fusion and somatic gene variant screening\n\nGene fusion and DNA variant analyses were extensively described previously (van der Tuin et al. 2019). A fully automated procedure for nucleic acid isolation was used (van Eijk et al. 2013). Isolated nucleic acids (DNA and RNA) from resected formalin-fixed paraffin-embedded (FFPE) tumor material were analyzed for the detection of fusion genes using next generation sequencing (NGS) with the Archer® FusionPlex CTL panel (ArcherDX Inc., Boulder, CO, USA). Somatic mutation analysis was performed using NGS with a custom AmpliSeq™ Cancer Hotspot Panel v6 (Thermo Fisher Scientific). Additionally, copy number analysis was performed. Additional TERT-promoter mutation analysis was done using Sanger sequencing, at Macrogen (Amsterdam, the Netherlands). Detected class 5 (pathogenic) and class 4 (likely pathogenic) DNA variations were reported. Within the context of the DRUP trial, metastatic tissue biopsied from the lymph node was analyzed using whole genome sequencing (WGS) (Illumina X10 setup, https://emea.illumina.com/company.html#) at the Hartwig Medical Foundation as described previously by Priestley et al. (2019), along with a control blood sample (peripheral blood leukocytes).\n\nImmunohistochemistry\n\nImmunohistochemistry was performed as previously described (Hermsen et al. 2013), with the use of primary antibody: ALK rabbit mAb, 1:100 (Cell Signaling Technology (CST), #3633).\n\nCompounds\n\nFor laboratory assessment, the compounds crizotinib (PF-02341066, Cat. No. S1068, Selleck Chemicals LLC, Houston, TX, USA), ceritinib (LDK378, Cat. No. S7083, Selleck Chemicals LLC, Houston, TX, USA) and lorlatinib (PF-6463922, Cat. No. S7536, Selleck Chemicals LLC, Houston, TX, USA) were prepared as stock solutions of 5 mM in DMSO (J.T. Baker, Avantor Performance Materials Poland S.A., Gliwice, Poland).\n\nCell line establishment, DNA/RNA isolation, cell line authentication, cell culture, cell count\n\nCell line establishment was performed as previously described (Boot et al. 2016). Cancer cell line DNA isolation was performed using the NucleoSpin® DNA purification kit (Macherey–Nagel GmbH & Co. KG, Düren, Germany) according to the manufacturer’s instruction. Cancer cell line RNA isolation was performed using the NucleoSpin® RNA purification kit (Macherey–Nagel GmbH & Co. KG) according to the manufacturer’s instruction. DNA and RNA concentrations were measured using Nanodrop 1000 (Isogen, De Meern, the Netherlands). The cancer cell lines (Table 1) were authenticated by short tandem repeat (STR) profiles (GenePrint® 10 system, Promega). STR profile of the novel cancer cell line JVE404 is as follows: AM: X,Y; CSF1PO: 11,12; D13S317: 9; D16S539: 11,13; D21S11: 31.2,33.2; D5S818: 11,12; D7S820: 10,11; TH01: 9.3; TPOX: 8,1; VWA: 15,17. Table 1 Cancer cell line characteristics.\n\nCell Line\tSex\tAge\tOrigin\tLocalization\tGene fusion\tRef.\t\nJVE404\tm\t61\tPTC\tLN metas.\tEML4-ALK v3\t*\t\nNCI-H2228\tf\tuk\tNSCLC\tprimary\tEML4-ALK v3 (Koivunen et al. 2008), ALK-PTPN3 (Jung et al. 2012)**\t(Phelps et al. 1996)\t\nKarpas-299\tm\t25\tTCNHL\tprimary\tNPM1-ALK (Krumbholz et al. 2018)\t(Fischer et al. 1988)\t\nBHP 2-7\tf\tuk\tPTC\tprimary\tRET/PTC1 (Melillo et al. 2005, Schweppe et al. 2008)\t(Ohta et al. 1997)\t\n*First described in the present study. **Non-pathogenic gene fusion.\n\nf, female; LN, lymph node; m, male; metas., metastasis; NSCLC, non-small cell lung cancer; PTC, papillary thyroid carcinoma; Ref., references; TCNHL, T cell non-Hodgkin lymphoma; uk, unknown.\n\nCells were cultured under standard conditions in a humidified atmosphere (5% CO2, 95% air, 37°C). Cells of the cell lines JVE404, NCI-H2228 and BHP 2-7 were cultured in DMEM/F-12 medium (Cat. No 11330032, Gibco, Life Technologies) and cells of Karpas-299 in RPMI medium 1640 (Cat. No 52400025, Gibco, Life Technologies). The media were supplemented with penicillin (50 U/mL), streptomycin (50 µg/mL) (Cat. No 15140122, Gibco, Life Technologies) and 10% heat-inactivated fetal bovine serum (Cat. No 758093, Greiner bio-one, Longwood, FL, USA).The cancer cells were tested for mycoplasma using a mycoplasma-specific PCR (van Kuppeveld et al. 1993).\n\nCells were harvested using Hank’s balanced salt solution (HBSS, Sigma–Aldrich) containing 0.125% trypsin (Gibco, Life Technologies) and 0.25 mM EDTA at 37°C for cell passaging.\n\nCells were counted using a 1:20 dilution of AO-DAPI (solution 18, Cat. No 9103018, Chemometec, Allerød, Denmark), loaded in quadruplicate onto the NC-Slide A8 (Chemometec) and subsequently read out using the automated cell analyzer nucleoCounter NC-250 (Chemometec) with NucleoView NC-250 software (Chemometec).\n\nQuantitative multiplexed near-infrared fluorescent Western blotting\n\nFor the preparation of protein lysates for Western blotting, the cells were cultured until 70 to 80% confluency and treated with DMSO (0.006%), crizotinib (30, 100, 300 nM) or lorlatinib (30, 100, 300 nM) for 2 hours, followed by washing with ice-cold PBS and lysed with Hot-SDS buffer containing PhosSTOP™ (Cat. No 04906837001, Roche Diagnostics) and cOmplete™ (Cat. No 11697498001, Roche Diagnostics). Quantitative multiplexed near-infrared fluorescent Western blotting was performed as previously described (Aydemirli et al. 2019). The Bio-Rad DC™ protein assay was used for the determination of protein concentrations, according to the manufacturer’s instructions (Bio-Rad Laboratories, Inc.). For each sample, 20 µg of lysate was mixed with 4× Laemmli sample buffer (Cat. No 1610747, Bio-Rad Laboratories, Inc.) containing βME, heated for 5 min at 100°C and loaded onto a 1.5 mm 10% acrylamide gel in addition to molecular weight markers (92840000 310014776 LI-COR, Lincoln, NE, USA). Electrophoresis was performed at 50 V throughout the gel. The Bio-Rad semi-dry Trans-Blot Turbo Transfer System was used for blotting (Limit 25V, constant 2.5A, 15 min). Blots were washed in 1× TBS, blocked for 1 h in Odyssey blocking buffer (TBS) (Cat. No 92750000, LI-COR, Lincoln, NE) 1:1 with 1× TBS, washed in 1× TBS, incubated overnight at 4°C with primary antibodies in 1× TBS/0.1% Tween-20/5% BSA (Sigma-A9647, Sigma–Aldrich). Blots were washed in 1× TBS/0.1% Tween-20, then incubated for 1 h with secondary antibodies in 1× TBS/0,1% Tween-20/5% BSA protected from light, then washed with 1× TBS. Western blotting experiments were repeated three times. The blots were imaged at high-resolution using the Odyssey infrared imaging system (LI-COR, Lincoln, NE). Image Studio Lite Ver 5.2 software package (LI-COR, Lincoln, NE) was used for image analysis. Signal intensity values were corrected to the loading control (α-Tubulin), followed by percentual calculations against DMSO control, then plotted in bar charts, along with two-way ANOVA followed by Tukey’s post-hoc test (statistical significance was considered at P < 0.05), using GraphPad Prism (version 8.0.1 (244) for Windows, GraphPad Software, www.graphpad.com).\n\nAntibodies\n\nPrimary antibodies: anti-α tubulin mouse, 1:50,000 (clone: DM1A, Cat. No. 14450282, eBioscience, San Diego, CA, USA); ALK rabbit mAb, 1:2000 (CST #3633); pALK (Tyr1507) rabbit mAb (CST #14678); Akt mouse mAb, 1:2000 (CST #2920); pAkt (Ser473) rabbit mAb, 1:1000 (CST #9277); Erk 1/2 mouse mAb, 1:1000 (CST #4696); pErk 1/2 (Thr202/Tyr204) rabbit mAb, 1:2000 (CST #4370); STAT3 mouse mAb, 1:1000 (CST #9139); pSTAT3 (Tyr705) mouse mAb, 1:2000 (CST #4113). Secondary antibodies: green-fluorescent goat anti-rabbit IRDye 800CW, 1:10,000 (92632211 LI-COR, Lincoln, NE). Red-fluorescent goat anti-mouse IRDye 680LT, 1:10,000 (92668020 LI-COR, Lincoln, NE).\n\nToxicity profiling\n\nCells were seeded in 96 well cell culture microplates (655090, Greiner Bio-One GmbH, Frickenhausen, Germany) at 10,000 cells per well. Twenty-four hours after seeding, the compounds crizotinib, ceritinib, lorlatinib or DMSO were added to the wells. After 72 h of incubation with the compounds, PrestoBlue™ cell viability reagent (invitrogen by Thermo Fisher Scientific, Life Technologies Corporation) was added to the wells and viability was measured according to the manufacturer’s instructions. The cell viability assessments were performed in quadruplicate and reproduced in two independent experiments. Dose-response curves (expressed as mean values with standard deviation), IC50 values and comparison between compounds (RM one-way ANOVA test followed by Tukey’s post-hoc test) were determined using GraphPad Prism (version 8.0.1 (244) for Windows, GraphPad Software, www.graphpad.com). Statistical significance was considered at P < 0.05.\n\nResults\n\nPatient\n\nA 60-year-old man without past medical history presented with a palpable thyroid nodule and a swollen lymph node in the neck, suspicious of metastasis. The lymph node was excised and corresponded on histologic examination to a poorly differentiated follicular variant of papillary thyroid carcinoma (FVPTC). Thyroidectomy with lymph node dissection was performed for the T4N1M0-staged partly poorly differentiated papillary thyroid carcinoma with subsequent I-131 therapy, also see Supplementary Fig. 1 (see section on supplementary materials given at the end of this article). Over the next 4 years after initial diagnosis, the I-131 was iterated multiple times to a cumulative dose of 27.7 GBq of RAI (Fig. 1).\n\nA year after the surgery, a re-excision of lymph node metastases in the neck (paratracheal and caudal to the sternocleidomastoid muscle) was performed, corresponding to PTC, partly poorly differentiated. Molecular analysis of tumor tissue showed an EML4-ALK gene fusion. EML4 exon 6, NM_019063.3: ALK exon 20, NM_004304.4. Copy number analysis showed homozygous deletion of CDKN2A (P16) gene. Also, a TERT promoter c.-124C>T (C228T; COSM1716558) variant was detected. No other class 4 or 5 pathogenic variants were detected. Congruently, immunohistochemical analysis of the tumor metastasis in the lymph node showed ALK overexpression in the tumor cells, indicative of the functional nature of this fusion gene. Both the EML4-ALK gene fusion and the promoter TERT variant were confirmed in the primary tumor.\n\nDespite these therapies, thyroglobulin levels were on the rise and his disease had progressed to radioiodine refractory status. In retrospect, the last RAI dose proved to be unjustified. The patient showed a progression of lymph node metastases (mediastinum, neck, supraclavicular) and pulmonary metastases. No osseous lesions were seen. Recurrent tumor tissue was causing local mechanic compression with focal vascular invasion into the left subclavian vein, which manifested in s.c. edema of the left arm. For decompression, the re-excision of recurrent thyroid tissue along with excision of lymph node metastasis in the neck was performed.\n\nThe patient was treated with lenvatinib (the conventional daily dosage of 24 mg) according to local practice with TKI treatment registered for RR-DTC. The patient used lenvatinib for two-and-a-half months till adverse events of acute cholecystitis (due to existent gallbladder stones) and intra-abdominal abscess formation, possibly due to intestinal perforation, emerged, of which relatedness to lenvatinib could not be excluded. Hereupon, lenvatinib was ceased. Due to the relatively short treatment course, response evaluation according to RECIST had not been performed during therapy. However, as a subjective and, in fact, the ostensive measure of clinical benefit, the edema in the patient’s arm had diminished within 2 weeks of lenvatinib therapy, suggestive of response to lenvatinib. When lenvatinib was ceased, partial response was noted on the following CT scan 2 weeks later. However, clinical progression was suspected based on swollenness of the arm and progressive disease (PD) was noted, based on a CT scan according to RECIST 6 weeks later.\n\nBecause the somatic EML4-ALK v3 rearrangement was affirmatively identified in newly acquired biopsy material from a lymph node metastasis using whole genome sequencing, the patient was considered a potential candidate for inclusion in the DRUP trial with ALK as a therapeutic target. Other genetic alterations detected in the biopsy material using WGS were a somatic variant (MUC6 c. 793G>A, p.(Gly265Ser)). Inactivation of the CDKN2A gene encoding for p16 was confirmed. Within the context of the DRUP trial, the first-generation ALK TKI crizotinib was made available to the patient. Two-and- a-half months after the prior lenvatinib regimen, the 66-year-old patient commenced crizotinib treatment with a daily dosage of 2× 250 mg. The first RECIST evaluation showed SD after 2 months use, as well as after 4 and 6 months and no treatment-emergent adverse events had occurred.\n\nAfter 8 months of crizotinib use, the radiologic evaluation revealed progressive disease on the CT scan of neck/thorax and abdomen and on a CT brain which was made after traumatic injury to the head, multiple cerebral lesions were seen. It is unknown whether these lesions were already present. Hereupon, crizotinib was ceased and lenvatinib was restarted. With lenvatinib use, clinical benefit was noted by the patient with reduced swollenness of palpable lymph nodes and decreasing levels of thyroglobulin. Gastrointestinal adverse events of nausea, vomiting and abdominal pain ensued because of elevation of the left diaphragm, requiring hospital admission but was manageable with analgesics and supportive measures. The first RECIST evaluation showed SD after 2 months of lenvatinib treatment. However, the evaluation after four-and-a-half months showed PD on the CT scan of the neck/thorax and abdomen and the progression of multiple cerebral metastases, whereupon lenvatinib was stopped.\n\nTwo weeks later, within the context of compassionate use and on basis of the tumor cell line experiments described below, the patient started with the third-generation ALK TKI lorlatinib (100 mg per day). Within 2 weeks, thyroglobulin levels dropped by about 75%. After 11 weeks of lorlatinib therapy, the CT scan showed partial response (PR), with a 37% decrease in the sum of the target lesions. Also after 7 months of initiation with lorlatinib treatment, an ongoing PR was determined with a 38% decrease in the sum of the target lesions as compared with the previous CT scan (61% decrease from baseline), also see Figs 1 and 2. Two of three cerebral foci also decreased in maximum diameter (from 9 to 6 mm, and 10 mm to indiscernible, respectively), while one focus showed growth (from 8 to 12 mm). No toxicity was reported with lorlatinib. The patient is currently alive, he has been scheduled for stereotactic radiotherapy for the cerebral lesions and treatment with lorlatinib is ongoing.Figure 1 Timeline showing the disease course of our patient since his thyroidectomy, along with thyroglobulin plasma levels (upper line graph) and RECIST evaluations with the sum of the target lesions (lower line graph) during the targeted therapies. The patient received first lenvatinib for two and a half months, then the ALK inhibitor crizotinib within the DRUP trial for 8 months, followed by lenvatinib for four and a half months, and then (until now) the ALK inhibitor lorlatinib for about 7 months as part of compassionate use. MD, molecular diagnostics; LN, lymph node; WGS, whole genome sequencing; LEN, lenvatinib; CRI, crizotinib; LOR, lorlatinib; B, baseline; PR, partial response; SD, stable disease; PD, progressive disease. ‘LN+’, ‘Lung+’, ‘Brain+’, indicates new metastatic spread.\n\nFigure 2 CT scan impressions of the (ongoing) partial response (according to RECIST) on 7 months of lorlatinib treatment. The sum of four target lesions has decreased from 192 mm at baseline to 75 mm; two of these target lesions are shown in the figure. A subcarinal lymph node metastasis reduced from 64 mm at baseline (A) to 28 mm after 7 months lorlatinib (B) in diameter. A pretracheal lymph node metastasis showed a reduced diameter from 29 mm at baseline (C) to 8 mm after 7 months lorlatinib treatment (D).\n\nMatching novel thyroid cancer cell line\n\nJVE404 (Supplementary Fig. 2), the PTC-derived cell line harboring the EML4-ALK gene fusion variant 3 has been established from the patient’s lymph node at age 61 that was resected 1 year after thyroidectomy. Localization of the known papillary thyroid cancer was present in the lymph node but with poorly differentiated parts and frequent mitotic figures. STR profiles of the novel cancer cell line JVE404 matched with the original metastatic material localized in the lymph node. Immunohistochemical analyses of the cancer cell line (passage number 23) also showed ALK expression (ALK-positive) and confirmed thyroidal origin (TTF1 positive, PAX8 positive, thyroglobulin negative) (Baloch et al. 2018). The absence of thyroglobulin staining may comply with poorly differentiated thyroid cancer (PDTC) (Baloch et al. 2018) or with loss of thyroglobulin expression in cell culture in absence of TSH (Bravo et al. 2013).\n\nToxicity profiling\n\nAs the specific variants of the EML4-ALK gene fusion may be associated with higher sensitivity or resistance to certain types of ALK inhibitors, additional clinically used 2nd and 3rd generation ALK TKIs (ceritinib and lorlatinib, respectively) were tested in comparison to crizotinib (1st generation ALK TKI) that was administered to the patient.\n\nTreatment with crizotinib, ceritinib or lorlatinib led to decreased viability in JVE404, H2228 and Karpas-299 (Fig. 3 and Table 2). As shown in the dose-response curves, the cancer cell lines had a higher sensitivity to lorlatinib as compared to crizotinib. In JVE404, the inhibitory effect of only lorlatinib was significantly superior compared to control (P = 0.0022), while crizotinib (P = 0.239) or ceritinib (P = 0.0624) were not. Further, in JVE404, the inhibitory effect of lorlatinib was significantly higher compared to crizotinib (P = 0.0097) and of ceritinib compared to crizotinib (P = 0.0153). In NCI-H2228, the inhibitory effect of lorlatinib (P = 0.0006) and of ceritinib (P = 0.015), respectively, was significantly superior compared to control, while crizotinib (P = 0.1217) was not. In NCI-H2228, both lorlatinib and ceritinib, respectively, were significantly superior compared to crizotinib. In Karpas-299, only lorlatinib showed significantly superior inhibition compared to control (P = 0.0247). The DMSO control appeared to exert no substantial toxicity. BHP 2-7, the negative control cell line harboring no ALK target, showed no substantial change in response to the compounds on cell viability.Figure 3 Dose–response curves. In the graphs, the mean relative viability of JVE404, NCI-H2228, Karpas-299 and BHP 2-7 cancer cells are shown for increasing concentrations of DMSO control (grey dot line) and treatment with three ALK TKIs (black lines): crizotinib (solid line), ceritinib (dash line), lorlatinib (dot line).\n\nTable 2 IC50 values, with 95% CI, for the ALK TKIs in the cancer cell lines.\n\n\tJVE404\tNCI-H2228\tKarpas-299\t\nCrizotinib\t196.4 nM, 95% CI: 113.8–350.2\t86.8 nM, 95% CI: 56.1–134.7\t131.3 nM, 95% CI: 77.4–228.7\t\nCeritinib\t58.1 nM, 95% CI: 34.7–97.0\t21.6 nM, 95% CI: 12.3–37.4\t59.9 nM, 95% CI: 36.1–99.9\t\nLorlatinib\t0.718 nM, 95% CI: 0.483–1.069\t0.322 nM, 95% CI: 0.159–0.672\t2.399 nM, 95% CI: 1.104–5.310\t\nIC50, half maximal inhibitory concentration.\n\nWestern blot analysis\n\nWestern blot analysis (Fig. 4) showed a gradual decrease in pALK and pERK expression upon 30, 100, 300 nM crizotinib on the EML-ALK v3 harboring JVE404 cells (pALK +2, −8, −49%, respectively, and pERK −35, −63, −68%, respectively), but less pronounced than on NCI-H2228 (lung cancer cell line, also characterized by EML4-ALK v3) (pALK −35, −59, −80%, respectively, and pERK −58, −89, −96%, respectively) (also see Supplementary Figs 3 and 4). Comparatively, the impact on protein expression levels of phosphorylated ALK and downstream effectors was higher with lorlatinib (JVE404: pALK −93, −97, −98%, respectively, and pERK −79, −89, −88%, respectively; NCI-H2228: pALK −94, −98, −99%, respectively, and pERK −97, −97, −98%, respectively).Figure 4 Quantitative, multiplexed near-infrared fluorescent Western blotting. In the Western blot, the expression of proteins and phosphorylated proteins ((p)ALK as the fusion protein of EML4 or NPM1 with conformable molecular sizes, (p)STAT, (p)AKT, (p)ERK and household protein control α-Tubulin) for the cancer cell lines JVE404, NCI-H2228, BHP 2-7 and Karpas-299 are shown in the treated conditions of DMSO control, crizotinib (30, 100, 300 nM) and lorlatinib (30, 100, 300 nM), respectively. αTub, α-Tubulin; CR, crizotinib; LO, lorlatinib.\n\nInterestingly, despite these significantly reduced expression levels in JVE404 of pALK, up to −49 (P = 0.004) and -98% (P < 0.0001), upon increasing crizotinib dose or lorlatinib treatment, respectively, the treatment did not show a strong change in expression levels of pAKT (about −30 and −22%, respectively, not significant) in JVE404. The latter holds true also in contrast to pAKT in NCI-H2228 cells that showed significantly reduced expression (up to −73 and −79% with crizotinib and lorlatinib, respectively, P < 0.0001) levels upon treatment. However, compared to JVE404, the baseline expression level of pAKT was ~20% higher in NCI-H2228 and highest (>16×) in BHP 2-7 cells (Fig. 4, also see Supplementary Figs 5 and 6). NCI-H2228 cells seemed to express pSTAT, albeit at low levels, but nevertheless ~3× more than JVE404 (pSTAT expression not reliably distinguishable) (also see Supplementary Fig. 3C).\n\nIn the control cells Karpas-299 (harboring NPM1-ALK) ALK was relatively overexpressed and pALK and pSTAT expression levels showed a decrease (up to −84 and −86%, respectively, P < 0.0001) upon crizotinib and even more upon lorlatinib (up to −98 and −94%, respectively, P < 0.0001). In Karpas-299, expression levels of pAKT and pERK were not reliably distinguishable. In the control cells BHP 2-7 (harboring RET/PTC1) ALK was not present indeed, STAT was present, but pSTAT expression was not distinguishable. In BHP 2-7, the levels of pAKT fluctuated for the various treatment conditions with DMSO and ALK TKIs, while remaining overexpressed. The levels of pERK decreased upon treatment in BHP 2-7 cells, however, still overexpressed, unlike JVE404 or NCI-H2228.\n\nDiscussion\n\nWe present a patient with metastatic refractory thyroid cancer harboring EML4-ALK gene fusion variant 3. This patient was treated with the ALK inhibitor lorlatinib after matching tumor cell line data showed that lorlatinib was a more potent drug than the already administered crizotinib. Apart from inhibiting EML-ALK v3 better than crizotinib, lorlatinib also exhibited CNS-activity.\n\nThe novel and unique patient’s cancer cell line JVE404 showed response, in terms of viability and reduction in cell signaling effectors, to ALK inhibitors in vitro. Moreover, the in vitro impact of targeting constitutively activated ALK in the context of a variant 3 of the EML4-ALK gene fusion was more pronounced with lorlatinib (highly significant compared to control and lowest IC50 value) than for crizotinib (not significant compared to control) or ceritinib (significance and half-maximal inhibitory value inferior to lorlatinib; not significant compared to control in JVE404, but significant in NCI-H2228). The latter corroborates previous studies in lung cancer (Zou et al. 2015, Seo et al. 2017, Woo et al. 2017, Lin et al. 2018).\n\nThe presented approach of investigating single cases and cell lines may serve as a rationale to substantiate the use of tested drugs in thyroid cancer by evaluating cell signaling mechanisms combined with analysis of cell viability. Although valuable, this is a very exceptional approach as even only the establishment of a cancer cell line takes a large amount of time and effort and is rarely successful. Demeure et al. also described a papillary thyroid cancer patient carrying an EML4-ALK v1 gene fusion with stable disease on 6 months’ crizotinib treatment (Demeure et al. 2014). To the best of our knowledge, our report presents the first case of an advanced thyroid cancer patient carrying an EML4-ALK gene fusion v3 who was treated with lorlatinib. The present study also demonstrates the applicability of a tumor-agnostic approach, whilst carefully taking note of various considerations. Although, this is not yet approved common practice for every druggable mutation that is clinically confirmed in another cancer type.\n\nWith tissue-agnostic targeted therapy approaches, such as in the context of basket trials or in the context of compassionate use, it is interesting to investigate the intended impact against the targeted tumor’s own background.\n\nPresumably, the differences in expression levels of the phosphorylated proteins as shown in the Western blot analysis may be indicative of relative insensitivity to the compound, as shown by varying IC50 values. It may also be a reflection of general cell signaling characteristics inherent to the cell line with its specific gene fusions or gene variants or to the organ it was derived from. For instance, our patient’s PTC-derived cell line showed pAKT protein expression that remained relatively unaffected (decreased signal intensity of ~20%, not significant), in contrast to a near total 98–88% decrease of pALK and pERK expression, and in contrast to the lung cancer-derived cell line NCI-H2228 (also harboring EML4-ALK v3) that showed a decrease of ~80%. Major signaling pathways involved in thyroid tumorigenesis include the MAPK and the PI3K/AKT signaling pathways (Nikiforov 2011, Xing 2013). Moreover, in PTC, pAKT is upregulated (Miyakawa et al. 2003, Vasko 2004, Faustino et al. 2012, Matson et al. 2017) and its nuclear expression has been associated with metastases (Tavares et al. 2018). Therefore, in general, AKT seems an interesting target of therapy. On the other hand, it has been shown by a previous study that depletion of EML4-ALK v1 or v3 suppressed pERK and pSTAT3, but not pAKT in non-transformed mouse fibroblast cells and in the lung cancer cell line H3122 (harboring EML4-ALK v1); therefore suggesting activation of ERK and STAT3 signaling by such gene fusions but not of the PI3K-AKT pathway (Takezawa et al. 2011). Moreover, in comparison to two other thyroid cancer cell lines with known constitutively activated AKT (Aydemirli et al. 2019) (being XTC.UC1 cells derived from Hürthle cell cancer and BHP 2-7 cells derived from PTC harboring RET/PTC1), baseline pAKT expression levels in JVE404 were ~94% lower (as shown in Supplementary Figs 5 and 6). Also baseline levels of pSTAT in JVE404 were about a third of the expression in NCI-H2228 and subtly discernible, and in these two cell lines, about 97% lower compared to Karpas-299. However, STAT3 activation has been shown to be strongly implicated in lymphomagenesis mediated by NPM-ALK (Chiarle et al. 2005). These considerations, taken altogether, suggest that in JVE404 predominantly the MAPK pathway is upregulated by the EML4-ALK gene fusion v3, as reflected by highly activated ERK that could be brought down concurrently with pALK, upon treatment with ALK inhibitors. This appears to be in line with previous findings of dependence on MAPK in lung adenocarcinoma harboring EML4-ALK (Takezawa et al. 2011, Hrustanovic et al. 2015).\n\nIn terms of effectiveness and toxicity, targeted therapy might potentially be more advantageous when an essential growth driver is aimed over a multi-targeted therapy approach (Mano 2015). Kohler et al. showed that constitutively activated ALK induced metastatic, poorly differentiated thyroid cancer (PDTC) in mice; therefore, it appears to be a driver of thyroid carcinogenesis (Kohler et al. 2019). Moreover, ALK-driven thyroid cancers seem to be associated with solid/trabecular architecture and an increased mitotic rate in PDTC or anaplastic thyroid carcinoma (ATC) (Hamatani et al. 2012, Godbert et al. 2015, Kohler et al. 2019). Detailed characterization of ALK-driven thyroid cancer has recently been described elsewhere, with infiltrative (FV)PTC as the most typical morphology (Panebianco et al. 2019). For instance, in the ATC case study by Godbert and colleagues (Godbert et al. 2015), a patient is reported with an ALK rearrangement in both its well-differentiated part as well as anaplastic part of the tumor. Also, the presence of the ALK rearrangement in both components would favor it to constitute an early carcinogenic driver event, in addition to the excellent response to crizotinib in their patient (Godbert et al. 2015). The histologic examination concerning our patient case had revealed FVPTC in a lymph node metastasis, partly poorly differentiated PTC in the primary tumor (also see Supplementary Fig. 1), and metastases with poorly differentiated areas. This seems to fit the range of previously observed morphologies in ALK-driven thyroid cancer.\n\nFurthermore, the impact of effectively targeting essential growth drivers might probably prove to be even more relevant in RAI-rDTC in particular, regarding the potential of possibly inducing redifferentiation and contingent regain of iodine uptake (Buffet et al. 2020). The latter, in case it would supervene from the treatment with the drug, may facilitate radioactive-iodine therapy in the patient, and thereby, potentially raising the chances for a cure rather than a prolongation of the progression-free interval (Buffet et al. 2020). However, due to practical reasons, we could not investigate this.\n\nAnother interesting point of discussion is that a CDK4/6 inhibitor, currently available in the DRUP study (van der Velden et al. 2019), constitutes an additional (future) option for targeted therapy aiming for the homozygous CDKN2A deletion in our patient. Moreover, even in the absence of this deletion, a synergistic in vitro activity of the combination of an ALK inhibitor with a CDK inhibitor in neuroblastoma was reported in the literature (Wood et al. 2017). However, this dual therapy was not tested in our experiments or clinically applicable.\n\nRegarding the general toxicity profile; that of available multi-targeted TKIs registered for RAI-rDTC, lenvatinib or sorafenib (Yu et al. 2019), may differ from that of lorlatinib (Bauer et al. 2019) or crizotinib (Hou et al. 2019), as is also illustrated by the patient. Also, the patient described in the current study developed CNS metastasis after treatment with crizotinib failed, as may be seen in a subset of patients who failed on crizotinib treatment due to its poor CNS-penetrance (Costa et al. 2015, McCusker et al. 2019). In that regard, higher generation ALK TKIs, such as lorlatinib, may be considered in case of CNS metastasis (McCusker et al. 2019).\n\nConclusion\n\nIn this study, ALK targeted therapy with crizotinib and lorlatinib in a thyroid cancer patient harboring an EML4-ALK gene fusion v3, is illustrated. Additionally, analyses of cell viability and cell-signaling protein molecules have been performed on the novel papillary thyroid cancer cell line harboring an EML4-ALK v3 derived from the patient’s tumor. Our findings corroborate that also in thyroid cancer with EML4-ALK v3, targeting ALK appears feasible. We observed clinical activity and in vitro impact on viability and downstream signaling in response to the 1st generation ALK TKI crizotinib, although stable disease lasted 6 months and progressive disease included the finding of cerebral metastases at 8 months, but higher sensitivity and clinical partial response with CNS activity to the 3rd generation ALK TKI lorlatinib. With the increasing application of techniques as NGS in daily clinical practice, it seems valuable to recognize molecularly targetable drivers, when treatment options are limited, and even more so in refractory thyroid cancer.\n\nSupplementary Material\n\nSupplemental Figure S1\n\nSupplemental Figure S2\n\nSupplemental Figure S3\n\nSupplemental Figure S4\n\nSupplemental Figure S5\n\nSupplemental Figure S6\n\nDeclaration of interest\n\nE K is in Advisory boards BMS, Novartis, Roche, Merck, Amgen, Pierre-Fabre, EISAI, Bayer, Genzyme-Sanofi and has received research grants from Novartis and BMS. H M is an advisor in GenomeScan, Leiden, The Netherlands. The other authors declare no conflict of interest.\n\nFunding\n\nThis work did not receive any specific grant from any funding agency in the public, commercial, or not-for-profit sector.\n\nAuthor contribution statement\n\nM D A was involved in setting up, performing laboratory experiments and analysis (toxicity profiling, Western blotting, DNA/RNA isolation; cell culturing and cell counting involved), drafting the manuscript, preparation figures, tables and supplementary. J v E was involved in the establishment of cancer cell line JVE404, cell culture. T v W is a registered molecular scientist in pathology and was involved in setting up gene fusion analysis, critical evaluation of the manuscript. J O advised on statistical analysis. W E C was involved in supervising the design of toxicity profiling, supervising Western blot analysis, critical evaluation of the manuscript. E K is an attending medical oncologist in charge of the recurrent endocrine cancer patient care and a contact person for DRUP trial and compassionate use program pharmaceutical company(ies), critical evaluation of the manuscript. H M is an attending pathologist and registered molecular scientist in pathology and was involved in study concept and rationale, supervising data analysis, drafting the manuscript and final evaluation of the manuscript. Ellen Kapiteijn and Hans Morreau were the shared last authors.\n\nAcknowledgments\n\nThis publication and the underlying study have been made possible partly due to the molecular analyses by Clinical Molecular Biologists in Pathology, Dina Ruano for the bioinformatics involved and the analytic personnel of the laboratory for Molecular Diagnostics of the Department of Pathology, Leiden University Medical Center, the Netherlands. 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(10.3390/cancers9090118)\nSchlumberger M Tahara M Wirth LJ Robinson B Brose MS Elisei R Habra MA Newbold K Shah MH Hoff AO 2015 Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. New England Journal of Medicine 372 621–630. (10.1056/NEJMoa1406470)\nSchweppe RE Klopper JP Korch C Pugazhenthi U Benezra M Knauf JA Fagin JA Marlow LA Copland JA Smallridge RC 2008 Deoxyribonucleic acid profiling analysis of 40 human thyroid cancer cell lines reveals cross-contamination resulting in cell line redundancy and misidentification. Journal of Clinical Endocrinology and Metabolism 93 4331–4341. (10.1210/jc.2008-1102)18713817\nSeo S Woo CG Lee DH Choi J 2017 The clinical impact of an EML4-ALK variant on survival following crizotinib treatment in patients with advanced ALK-rearranged non-small-cell lung cancer. Annals of Oncology 28 1667–1668. (10.1093/annonc/mdx185)28407036\nSiegel RL Miller KD Jemal A 2019 Cancer statistics, 2019. CA: A Cancer Journal for Clinicians 69 7–34. 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(10.1136/jmg.2003.015339)14985374\nWoo CG Seo S Kim SW Jang SJ Park KS Song JY Lee B Richards MW Bayliss R Lee DH 2017 Differential protein stability and clinical responses of EML4-ALK fusion variants to various ALK inhibitors in advanced ALK-rearranged non-small cell lung cancer. Annals of Oncology 28 791–797. (10.1093/annonc/mdw693)28039177\nWood AC Krytska K Ryles HT Infarinato NR Sano R Hansel TD Hart LS King FJ Smith TR Ainscow E 2017 Dual ALK and CDK4/6 inhibition demonstrates synergy against neuroblastoma. Clinical Cancer Research 23 2856–2868. (10.1158/1078-0432.CCR-16-1114)27986745\nXing M 2013 Molecular pathogenesis and mechanisms of thyroid cancer. Nature Reviews: Cancer 13 184–199. (10.1038/nrc3431)23429735\nYarchoan M Ma C Troxel AB Stopenski SJ Tang W Cohen AB Pappas-Paxinos M Johnson BA Chen EY Feldman MD 2016 pAKT expression and response to sorafenib in differentiated thyroid cancer. Hormones and Cancer 7 188–195. (10.1007/s12672-016-0253-6)26994002\nYoshida T Oya Y Tanaka K Shimizu J Horio Y Kuroda H Sakao Y Hida T Yatabe Y 2016 Differential crizotinib response duration Among ALK fusion variants in ALK-positive non-small-cell lung cancer. Journal of Clinical Oncology 34 3383–3389. (10.1200/JCO.2015.65.8732)27354483\nYu ST Ge JN Luo JY Wei ZG Sun BH Lei ST 2019 Treatment-related adverse effects with TKIs in patients with advanced or radioiodine refractory differentiated thyroid carcinoma: a systematic review and meta-analysis. Cancer Management and Research 11 1525–1532. (10.2147/CMAR.S191499)30863162\nZhang I Zaorsky NG Palmer JD Mehra R Lu B 2015 Targeting brain metastases in ALK-rearranged non-small-cell lung cancer. Lancet: Oncology 16 e510–e521. (10.1016/S1470-2045(15)00013-3)26433824\nZou HY Friboulet L Kodack DP Engstrom LD Li Q West M Tang RW Wang H Tsaparikos K Wang J 2015 PF-06463922, an ALK/ROS1 inhibitor, overcomes resistance to first and second generation ALK inhibitors in preclinical models. Cancer Cell 28 70–81. (10.1016/j.ccell.2015.05.010)26144315\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1351-0088",
"issue": "28(6)",
"journal": "Endocrine-related cancer",
"keywords": "AKT; ALK; EML4-ALK gene fusion; ERK; STAT; cancer cell line; cell signaling; ceritinib; crizotinib; humans; lorlatinib; personalized medicine; targeted therapy; thyroid cancer",
"medline_ta": "Endocr Relat Cancer",
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"pages": "377-389",
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"pmid": "33878728",
"pubdate": "2021-05-11",
"publication_types": "D016428:Journal Article",
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"title": "Targeting EML4-ALK gene fusion variant 3 in thyroid cancer.",
"title_normalized": "targeting eml4 alk gene fusion variant 3 in thyroid cancer"
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"abstract": "Rifampin-induced acute kidney injury is very rare. Most cases of acute renal injury from rifampin use are related to acute tubular necrosis and acute interstitial nephritis. In this case report, we detail a unique presentation of rifampin-associated acute intravascular hemolysis and subsequent tubular injury in a tuberculosis patient. The patient had presented to the hospital with acute kidney injury and oliguria from intravascular volume depletion secondary to intractable vomiting. The patient had stopped taking his antituberculosis medications two weeks before hospitalization. At the time of hospital admission, his antituberculosis regimen of rifampin and isoniazid was reinstituted. Within four days of initiation of rifampin, he developed acute hemolytic anemia. His kidney biopsy revealed hemoglobin pigment deposition in the kidney tubules. Rifampin was discontinued, and he received a total of eight hemodialysis treatments spanning over 17 days. Subsequently, after discontinuing rifampin, his anemia and oliguria resolved with renal function markedly improved to near normal baseline levels. This case report also offers a review of known mechanisms of rifampin-induced acute hemolysis and acute renal failure, along with a discussion of contemporary literature.",
"affiliations": "Internal Medicine, Corpus Christi Medical Center, Corpus Christi, USA.;Internal Medicine, Corpus Christi Medical Center, Corpus Christi, USA.;Internal Medicine, Corpus Christi Medical Center, Corpus Christi, USA.;Pathology, Corpus Christi Medical Center, Corpus Christi, USA.",
"authors": "Sanwal|Chandra|C|;Kaldas|Amber|A|;Surani|Salim|S|;Bailey|Michael|M|",
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"doi": "10.7759/cureus.9120",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.9120\nHematology\nRifampin-Induced Acute Intravascular Hemolysis Leading to Heme Pigment-Related Kidney Injury\nMuacevic Alexander Adler John R Sanwal Chandra 1 Kaldas Amber 1 Surani Salim 12 Bailey Michael 3 \n1 \nInternal Medicine, Corpus Christi Medical Center, Corpus Christi, USA \n\n2 \nInternal Medicine, University of North Texas, Dallas, USA \n\n3 \nPathology, Corpus Christi Medical Center, Corpus Christi, USA \n\nChandra Sanwal chandra_prakash@hotmail.com\n10 7 2020 \n7 2020 \n12 7 e91201 7 2020 10 7 2020 Copyright © 2020, Sanwal et al.2020Sanwal et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/36701-rifampin-induced-acute-intravascular-hemolysis-leading-to-heme-pigment-related-kidney-injuryRifampin-induced acute kidney injury is very rare. Most cases of acute renal injury from rifampin use are related to acute tubular necrosis and acute interstitial nephritis. In this case report, we detail a unique presentation of rifampin-associated acute intravascular hemolysis and subsequent tubular injury in a tuberculosis patient. The patient had presented to the hospital with acute kidney injury and oliguria from intravascular volume depletion secondary to intractable vomiting. The patient had stopped taking his antituberculosis medications two weeks before hospitalization. At the time of hospital admission, his antituberculosis regimen of rifampin and isoniazid was reinstituted. Within four days of initiation of rifampin, he developed acute hemolytic anemia. His kidney biopsy revealed hemoglobin pigment deposition in the kidney tubules. Rifampin was discontinued, and he received a total of eight hemodialysis treatments spanning over 17 days. Subsequently, after discontinuing rifampin, his anemia and oliguria resolved with renal function markedly improved to near normal baseline levels. This case report also offers a review of known mechanisms of rifampin-induced acute hemolysis and acute renal failure, along with a discussion of contemporary literature.\n\nacute tubular necrosisacute interstitial nephritisimmune hemolytic anemiarifampinhemolysisdrug-induced acute renal failureThe 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\nDrugs were first suspected as a cause of immune-hemolytic anemia (IHA) in 1953 [1]. Drug-induced thrombocytopenia is more common than drug-induced immune-hemolytic anemia (DIIHA). There is good data for the incidence of drug-induced thrombocytopenia (10-18 cases per million) and neutropenia (2-15 cases per million) but only crude estimates for DIIHA of about one per million of the population. Compared to DIIHA, autoimmune hemolytic anemia (AIHA) prevalence is higher and is reportedly one per hundred thousand of the population. The number of drugs causing DIIHA has increased from 15 known drugs in 1967 to a modest number of 125 in 2010. DIIHA is caused by IgM or IgG antibodies and seems to have no relationship to other allergic reactions (e.g., anaphylaxis), which are usually associated with IgE antibodies [1]. In a study by Mayer et al., among 73 patients with drug-induced hemolytic anemia, the most common single drugs identified were diclofenac, piperacillin, ceftriaxone, and oxaliplatin [2].\n\nRifampin is widely used in multidrug regimens for the treatment of tuberculosis (TB) and nontuberculous mycobacterial infections, and is also considered an effective antistaphylococcal agent. Hepatitis, thrombocytopenia, cutaneous syndrome, flu syndrome, abdominal syndrome, respiratory syndrome, orange-colored urine, and even disseminated intravascular coagulation (DIC) are some of the known side effects of rifampin [3-5]. Rifampin-associated acute renal failure (RARF) is a complication of anti-TB treatment occurring in less than 0.1% of patients with TB [6].\n\nRifampin treatment regimens are classified as ‘‘continuous,’’ with a daily intake of a rifampin dose; ‘‘intermittent,’’ with ingestion of a dose one, two, three, or five times weekly; and ‘‘interrupted,’’ when therapy is resumed after a course of daily or intermittent treatment and a subsequent drug-free interval [7]. In any case, it is widely accepted that the vast majority of RARF events are due to intermittent or interrupted rifampin use, for instance, in patients with previous drug exposure or poor compliers [6-8]. However, cases of RARF after continuous use of rifampin have been also reported [6,7]. There are multiple mechanisms of RARF: acute tubular necrosis (ATN), acute interstitial nephritis (AIN), rapidly progressive glomerulonephritis (RPGN), and light chain proteinuria. ATN from rifampin use can happen from heme pigment deposition due to intravascular hemolysis alone or from direct renal tubular damage [7,9]. Our case report is a rare presentation of RARF due to rifampin use in the interrupted manner, due to heme pigment deposition in renal tubules from intravascular hemolysis.\n\nCase presentation\nThe patient is a 49-year-old Vietnamese male with a past medical history of latent TB and non-insulin-dependent diabetes mellitus type 2. He presented with nausea, vomiting, and progressively decreasing urine output for one week. The patient described his urine color dark brown like “Coca-Cola”. He had associated symptoms of generalized weakness and lower back pain. About two months before the current presentation, he was admitted to the hospital for pneumonia and diagnosed with latent TB. Chest CT at that time revealed multifocal pulmonary nodules or nodular consolidations widely distributed throughout each lung area. The consolidations were largest in the perihilar portion of the right lung and throughout the dependent portion of the left lung base that contained numerous internal air bronchograms (Figure 1).\n\nFigure 1 Chest CT of the patient at the time of tuberculosis diagnosis with air bronchograms (yellow arrows) and pulmonary nodules (orange arrows).\nCT-guided biopsy of a right pulmonary nodule was negative for malignancy or granuloma without any evidence of focal necrosis. Due to his country of origin in Southeast Asia, TB was suspected. Both sputum and bronchoalveolar lavage samples taken from broncoscopy were negative for acid-fast bacilli (AFB) stain or cultures. His purified protein derivative test revealed an induration of 31 mm, and the QuantiFERON®-TB Gold test was positive. He did not have any active TB symptoms of fevers, cough, weight loss, or night sweats, etc. He was then diagnosed with latent TB and discharged with supervised TB treatment with rifampin 300 mg weekly and isoniazid 900 mg weekly with a local health department.\n\nAbout two weeks before the current presentation, he missed taking rifampin and isoniazid due to the unavailability of a home health nurse. On the day of his current presentation, he had mild leukocytosis with white blood cell (WBC) count of 11.6 x 109/L, hemoglobin 13.4 g/dL, hematocrit 26.4%, platelet count 132 x 109 /L, blood urea nitrogen (BUN) 133 mmol/L, creatinine 16.1 mg/dL, glomerular filtration rate (GFR) 3 mL/min/1.73 m2 (compared to baseline creatinine 0.7 mg/dL, GFR 95 mL/min/1.73 m2 two months ago), normal transaminases (total bilirubin 0.5 µmol/L, aspartate aminotransferase [AST] 13 units/L, alanine aminotransferase [ALT] 12 units/L), sodium 132 mEq/L, potassium 4.9 mmol/L, chloride 97 mEq/L, bicarbonate 18 mEq/L, glucose 208 mg/dL, and a fractional excretion of sodium (FENa) less than 1%. His renal ultrasound was unremarkable with normal-sized bilateral kidneys and the absence of hydronephrosis. CT chest findings in present admission were mostly unchanged from CT chest done in the previous admission two months ago. He did not report any symptoms of active TB comprising of fevers, cough, weight loss, or night sweats. On the day of admission, his home rifampin 300 mg weekly dose was re-administered after a drug-free interval of two weeks. During the first two days of admission, he received aggressive fluid hydration to address hypovolemia from vomiting. He started to exhibit clinical symptoms of volume overload without significant improvement in his renal function. He continued to remain oliguric, and hemodialysis was commenced. Over first four days after rifampin resumption, his hemoglobin-hematocrit continued to decline from 13.4 g/dL-26.4% to 8.5 g/dL-24%, respectively. His total bilirubin increased to 2.4 µmol/L with a direct component of the bilirubin value of 0.5 µmol/L. On day 4, since admission, his urine analysis revealed a pH of 7.5, urine protein 1+, urine occult blood 3+, and trace red blood cells (RBCs). The urinalysis was suspicious for hemoglobin or myoglobin pigment-related kidney injury due to the marked presence of urine occult blood while lacking a significant number of RBCs. His serum creatinine kinase (CK) was mildly elevated at 300 units/L that ruled out myoglobin-induced acute renal failure (ARF), i.e., rhabdomyolysis. Coombs test was positive, and lactic acid dehydrogenase (LDH) was 450 units/L. Based on published reports of RARF and convincing laboratory data, it was concluded that his acute renal injury was worsened by intravascular hemolysis triggered by the re-introduction of rifampin. Due to limited resources, we were not able to check the anti-rifampin antibodies in his serum. On the sixth day post rifampin administration, despite receiving three hemodialysis sessions, his renal function did not improve, and a renal biopsy was performed. His renal biopsy revealed acute tubular injury with intratubular hemoglobin casts, concerning of intravascular hemolysis and hemoglobinuria (Figures 2-4).\n\nFigure 2 Immunoperoxidase stain showing hemoglobin containing brown casts inside three tubules (yellow arrows).\nFigure 3 Hematoxylin and eosin stain of renal tubules containing pink red blood cell (RBC) casts (green arrows).\nFigure 4 Red cell casts in tubules with damaged tubular epithelium (green arrow).\nRifampin was discontinued. Subsequently, after five more hemodialysis sessions, his renal function exhibited steady improvement with a decrease in serum creatinine and an increase in GFR. When his urine output increased over 50 cc/hour with concomitant near normalization of creatinine and GFR, his hemodialysis was discontinued. He was discharged home, and rifampin was permanently removed from the discharge medication list. His latent TB treatment from the previous admission comprising of dual therapy with rifampin and isoniazid was substituted for monotherapy with isoniazid for a total of six months. In subsequent outpatient follow-ups of over 10 months to date, his renal function has remained within normal limits.\n\nDiscussion\nVarious mechanisms of DIIHA have been proposed: “immune complex” (e.g., quinine and quinidine), “drug adsorption” (e.g., penicillin and cefotetan), true RBC autoantibodies causing AIHA (e.g., methyldopa), and “membrane modification” (e.g., cephalothin) [1]. The first immune complex mechanism is where drug-antidrug antibody complexes attach to the surface membrane of RBCs and cause lysis by complement activation. The second drug adsorption mechanism is where drug coats the surface of the cell membranes and drug-specific IgG antibodies attach to the drug, leading to extravascular hemolysis where macrophages destroy the RBCs that are coated with IgG antibodies. The third autoantibody mechanism is where drugs trigger the production of true RBC autoantibodies. The fourth mechanism of membrane modification is where the RBC membrane structure can become affected by the nonimmunological association of the drug to their membranes.\n\nThe IgM and IgG antibodies involved in DIIHA are of two main types: the first type is drug-dependent, i.e., will only react with RBCs in vitro in the presence of the drug [1]. The second type of antibody is drug-independent, i.e., will react with RBCs in vitro without the presence of the offending drug. Such antibodies appear to be as RBC autoantibodies rather than antibodies to the drug [1]. A case study reports immune hemolysis in three patients exhibiting the simultaneous development of both drug-independent autoantibody and drug-dependent antibody in response to rifampicin treatment [10].\n\nThe most common cause of acute kidney injury triggered by rifampin has tubular damage manifesting as AIN, ATN, and light-chain proteinuria [4,7,11,12]. One less common cause noted for AKI is diffuse proliferative crescentic glomerulonephritis [11]. ATN is mainly immune-mediated and is related to the formation of rifampin IgG and IgM antibodies in previous exposure to the drug [7]. The rifampin-dependent antibodies interact with I-antigen expressed on the surface of RBCs and form immune complexes leading to complement-mediated hemolysis of RBCs [7,9]. The I-antigen is also expressed in renal tubular cells. Hence, ATN could be triggered by two independent mechanisms, through anti-rifampin antibodies targeting the I-antigen on RBCs causing intravascular hemolysis, or anti-rifampin antibodies targeting I-antigen on renal tubular cells directly causing their destruction. Intravascular hemolysis indirectly causes ATN through the release of heme pigment that is nephrotoxic to renal tubules [7].\n\nRifampin-related IgG or IgM antibodies, which lead to acute RBC lysis, renal tubular cell damage, platelet lysis, or worse, even DIC leading to death, are commonly referred to as “immunoallergic” events [5]. These immunoallergic events are mainly observed with the intermittent or interrupted use of rifampin. The anti-rifampin antibodies can be detected in the serum of up to 30% of patients after three to four doses of monthly intermittent therapy with rifampin. Among all the immunoallergic reactions noted with sporadic rifampin use, 75% of reactions were observed after five or fewer doses. Infrequent dosing of rifampin on either intermittent or interrupted schedules can result in sensitization with a rapid increase in antibody titer after repeat drug exposure [5,6]. In contrast, the daily administration of rifampin is believed to confer immunologic tolerance against these reactions due to continuous clearance of anti-rifampin antibody complexes [5]. An observational study recording RARF events due to discontinuous rifampin use noted that the drug-free interval ranged from 10 days to six years [12]. One case reports RARF occurred after an 18-year interval since last rifampin use [4].\n\nIn a case series of 25 patients diagnosed with RARF over 10 years, RARF cases constituted 2.5% of all cases of ARF [12]. Another case study reports 60 cases of RARF over a period of eight years, and it was found there was one death (1.66%) among the 60 patients, compared to a 20% mortality rate of all ARF cases hospitalized in the same period (P < 0.05) [13]. Frequently reported clinical symptoms associated with RARF include nausea and vomiting (72%), fever (45%), chills (43%), abdominal pain (40%), diarrhea (26%), jaundice (19%), lumbar pain (17%), and anemia (96%) [14]. The severity of RARF can be quantified with the length of the anuric phase [13]. The duration of anuric phase had a positive correlation between the number of hemodialysis sessions, creatinine levels at 30 days, and the degree of hypergammaglobulinemia. Patients with hypergammaglobulinemia had a significantly longer anuric phase (15.5 ± 4.2 days vs. 10.4 ± 7.7 days, respectively, P = 0.05). The duration of the anuric phase, on average, was 11.4 days ± 7 days, and an average of 4.8 ± 4.6 hemodialysis sessions were required [13,14]. The mortality was very low, and renal function recovery was complete among 40% of patients in 30 days from the onset, and among 96.6% of patients in 90 days from the start [13]. In RARF cases, due to ATN alone, steroid therapy is not warranted [14].\n\nConclusions\nAcute hematologic dyscrasias with or without ARF associated with interrupted and intermittent use of rifampin can be potentially life-threatening. Before prescribing rifampin, a careful prior history of its dosing schedule is warranted. The reinstitution of rifampin after a prior interrupted interval should ideally be avoided or at least carefully monitored. If the patient has any clinical or laboratory evidence of acute hemolysis, thrombocytopenia, ARF, DIC, or any immunologic reaction to post-rifampin administration, the drug should be promptly discontinued and substituted with an alternative drug regimen.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n\nThe authors thank Dr. Antonio Guzman for proofreading the article.\n==== Refs\nReferences\n1 Immune hemolytic anemia associated with drug therapy Blood Rev Garratty G 143 150 24 2010 20650555 \n2 Variability of findings in drug-induced immune haemolytic anaemia: experience over 20 years in a single centre Transfus Med Hemother Mayer B Bartolmäs T Yürek S Salama A 333 339 42 2015 26696803 \n3 Rifampicin induced immune hemolytic anemia: a case report Int Pul Med Ommurugan B Saravu K 5 7 1 2019 https://www.gratisoa.org/journals/index.php/IPUM/article/view/1522 \n4 Acute hemolysis and oligoanuric acute renal failure caused by interrupted Internet J Nephrol Yanardag H Caner M Gunes Y Uygun S 1 3 2 2004 http://ispub.com/IJNE/2/1/4967 \n5 Recurrent disseminated intravascular coagulation caused by intermittent dosing of rifampin Am J Trop Med Hyg Havey TC Cserti-Gazdewich C Sholzberg M Keystone JS Gold WL 264 267 86 2012 22302861 \n6 Rifampicin-associated acute renal failure and hemolysis: a rather uncommon but severe complication Ren Fail Manika K Tasiopoulou K Vlogiaris L Lada M Papaemmanouil S Zarogoulidis K Kioumis I 1179 1181 35 2013 23883374 \n7 Rifampicin-associated acute renal failure: pathophysiologic, immunologic, and clinical features Am J Kidney Dis De Vriese AS Robbrecht DL Vanholder RC Vogelaers DP Lameire NH 108 115 31 1998 9428460 \n8 Intravascular hemolysis and acute renal failure following intermittent rifampin therapy Int J Lepr Other Mycobact Dis Gupta A Sakhuja V Gupta KL Chugh KS 185 188 60 1992 https://pubmed.ncbi.nlm.nih.gov/1522360/ 1522360 \n9 Immune hemolytic anemia and renal failure associated with rifampicin-dependent antibodies with anti-I specificity Ann Hematol Pereira A Sanz C Cervantes F Castillo R 56 58 63 1991 1878425 \n10 Belated diagnosis in three patients with rifampicin-induced immune hemolytic anaemia Br J Haematol Ahrens N Genth R Salama A 441 443 117 2002 11972531 \n11 Rifampicin-induced nephrotoxicity in a tuberculosis patient J Clin Tuberc Other Mycobact Dis Beebe A Seaworth B Patil N 13 15 1 2015 31723676 \n12 Acute renal failure due to rifampicin: a study of 25 patients Am J Kidney Dis Muthukumar T Jayakumar M Fernando EM Muthusethupathi MA 690 696 40 2002 12324902 \n13 Rifampicin-induced acute renal failure: a series of 60 patients Nephrol Dial Transplant Covic A Goldsmith DJ Segall L Stoicescu C Lungu S Volovat C Covic M 924 929 13 1998 9568851 \n14 Rifampicin in nontuberculous mycobacterial infections: acute kidney injury with hemoglobin casts Case Rep Nephrol Kora R Brodsky SV Nadasdy T Agra D Satoskar AA 9321621 2018 2018 29850312\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(7)",
"journal": "Cureus",
"keywords": "acute interstitial nephritis; acute tubular necrosis; drug-induced acute renal failure; hemolysis; immune hemolytic anemia; rifampin",
"medline_ta": "Cureus",
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"title": "Rifampin-Induced Acute Intravascular Hemolysis Leading to Heme Pigment-Related Kidney Injury.",
"title_normalized": "rifampin induced acute intravascular hemolysis leading to heme pigment related kidney injury"
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"abstract": "Simultaneous kidney-pancreas transplantation can successfully restore fertility in women with type 1 diabetes mellitus and kidney failure. There have been few cases of pregnancy after simultaneous kidney-pancreas transplantation, and a second pregnancy is rare. We report a case of two live births in rapid succession in a simultaneous kidney-pancreas transplantation recipient, complicated by pre-eclampsia but with excellent fetal and graft outcomes. The first pregnancy was achieved with IVF, while the second was achieved naturally. Simultaneous kidney-pancreas transplantation with stable pre-pregnancy graft function enabled this patient to achieve successful pregnancy. However, both pregnancies were complicated by transient renal graft dysfunction and pre-eclampsia precipitating pre-term birth.",
"affiliations": "Central and Northern Adelaide Renal and Transplantation Services (CNARTS), Royal Adelaide Hospital, Adelaide, South Australia.;Central and Northern Adelaide Renal and Transplantation Services (CNARTS), Royal Adelaide Hospital, Adelaide, South Australia.;Women's and Babies Division, Women's and Children's Hospital, Adelaide, Australia.;Central and Northern Adelaide Renal and Transplantation Services (CNARTS), Royal Adelaide Hospital, Adelaide, South Australia.",
"authors": "Mohammadi|Fadak|F|;McDonald|Stephen|S|;Clark|Erin|E|;Jesudason|Shilpanjali|S|",
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"issue": "13(2)",
"journal": "Obstetric medicine",
"keywords": "High-risk pregnancy; kidney; pancreas; pre-eclampsia; transplantation",
"medline_ta": "Obstet Med",
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"nlm_unique_id": "101464191",
"other_id": null,
"pages": "92-95",
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"title": "Two pregnancies after simultaneous pancreas-kidney transplantation: A case report.",
"title_normalized": "two pregnancies after simultaneous pancreas kidney transplantation a case report"
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"abstract": "About 10-20% of systemic lupus erythematosus cases occur in children, often with more severe features at onset and more active disease over time compared with adults. Cardiovascular complications are common in this population but thoracic aortic aneurysms rarely occur. Although the pathophysiology of this complication remains unclear, vasculitis seems to play an important role, leading to degeneration and fibrosis of the media and formation of the aneurysm. We report the case of a 9-year-old systemic lupus erythematosus patient with important renal involvement, who underwent aortic replacement surgery for the treatment of an aortic aneurysm. This case highlights the importance of monitoring the thoracic aorta in children with systemic lupus erythematosus and the need for the development of appropriate early management strategies for this serious complication.",
"affiliations": "Division of Pediatric Cardiology, CHU Sainte-Justine, University of Montreal, Canada.;Division of Pediatric Cardiology, CHU Sainte-Justine, University of Montreal, Canada.;Department of Pathology, CHU Sainte-Justine, University of Montreal, Canada.;Division of Pediatric Rheumatology, CHU Sainte-Justine, University of Montreal, Canada.",
"authors": "Rached-d'Astous|Soha|S|;Dahdah|Nagib|N|;Brochu|Pierre|P|;Saint-Cyr|Claire|C|",
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"mesh_terms": "D001013:Aorta, Thoracic; D017545:Aortic Aneurysm, Thoracic; D002648:Child; D006801:Humans; D008180:Lupus Erythematosus, Systemic; D008279:Magnetic Resonance Imaging; D008297:Male",
"nlm_unique_id": "101526291",
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"pubdate": "2014-06-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Rapidly progressive aortic aneurysmal dilation in a child with systemic lupus erythematosus: too early too severe.",
"title_normalized": "rapidly progressive aortic aneurysmal dilation in a child with systemic lupus erythematosus too early too severe"
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"companynumb": "CA-ROXANE LABORATORIES, INC.-2014-BI-44136GD",
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"abstract": "A 34-year-old woman visited our hospital because she had had abdominal bloating for 2 months. She had been diagnosed with invasive thymoma (WHO pathological type B2), for which she had undergone chemotherapy and total thymectomy 10 years previously. Six years previously, pleural dissemination was diagnosed and she had undergone right extra-pleural pneumonectomy. On presentation to our hospital, abdominal computed tomography and ultrasound scans revealed abundant ascites and a huge liver lesion, likely a metastasis from her thymoma, obstructing the inferior vena cava. The serum-ascites albumin gradient was high at 1.4 g/dL, which indicated portal hypertension. We diagnosed Budd-Chiari syndrome caused by liver metastasis from a previous thymoma. Steroid therapy resulted in shrinkage of her liver tumor and a marked decrease in her ascites. Although rare, Budd-Chiari syndrome caused by liver metastasis from a thymoma is a possible serious complication of advanced invasive thymoma.",
"affiliations": "Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.;Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.",
"authors": "Horiguchi|Tomoya|T|;Toyama|Yoko|Y|;Sakakibara|Yosuke|Y|;Ikeda|Aki|A|;Kako|Hisashi|H|;Ina|Takuma|T|;Okamura|Takuya|T|;Uozu|Sakurako|S|;Goto|Yasuhiro|Y|;Yokoi|Kohei|K|;Imaizumi|Kazuyoshi|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2021.101492",
"fulltext": "\n==== Front\nRespir Med Case Rep\nRespir Med Case Rep\nRespiratory Medicine Case Reports\n2213-0071\nElsevier\n\nS2213-0071(21)00154-4\n10.1016/j.rmcr.2021.101492\n101492\nCase Report\nBudd–Chiari syndrome caused by latent hepatic metastasis from a thymoma\nHoriguchi Tomoya\nToyama Yoko\nSakakibara Yosuke\nIkeda Aki\nKako Hisashi\nIna Takuma\nOkamura Takuya\nUozu Sakurako\nGoto Yasuhiro\nDepartment of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan\nYokoi Kohei\nDepartment of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan\nImaizumi Kazuyoshi jeanluc@fujita-hu.ac.jp\n∗\nDepartment of Respiratory Medicine, Fujita Health University School of Medicine, Toyoake, Aichi, Japan\n∗ Corresponding author. Department of Respiratory Medicine, Fujita Health University School of Medicine, 1-98 Dengakugakubo, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan. jeanluc@fujita-hu.ac.jp\n03 8 2021\n2021\n03 8 2021\n34 10149211 5 2021\n9 7 2021\n2 8 2021\n© 2021 The Authors. Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nA 34-year-old woman visited our hospital because she had had abdominal bloating for 2 months. She had been diagnosed with invasive thymoma (WHO pathological type B2), for which she had undergone chemotherapy and total thymectomy 10 years previously. Six years previously, pleural dissemination was diagnosed and she had undergone right extra-pleural pneumonectomy. On presentation to our hospital, abdominal computed tomography and ultrasound scans revealed abundant ascites and a huge liver lesion, likely a metastasis from her thymoma, obstructing the inferior vena cava. The serum–ascites albumin gradient was high at 1.4 g/dL, which indicated portal hypertension. We diagnosed Budd–Chiari syndrome caused by liver metastasis from a previous thymoma. Steroid therapy resulted in shrinkage of her liver tumor and a marked decrease in her ascites. Although rare, Budd–Chiari syndrome caused by liver metastasis from a thymoma is a possible serious complication of advanced invasive thymoma.\n\nKeywords\n\nThymoma\nLiver metastasis\nBudd-Chiari syndrome\nAscites\nAbbreviations\n\nBCS, Budd–Chiari syndrome\nCAMP, cisplatin, doxorubicin, and methylprednisolone\nIVC, inferior vena cava\nSAAG, serum-ascites albumin gradient\n==== Body\n1 Introduction\n\nBudd–Chiari syndrome (BCS) is characterized by portal hypertension caused by obstruction or stenosis of the hepatic vein or inferior vena cava (IVC) [1]. Primary BCS is typically caused by thrombosis of the IVC as a result of coagulation abnormalities or membrane-like obstruction. Secondary BCS develops because of extrinsic compression or direct invasion of these veins by primary or metastatic liver cancer [2]. Imaging tests such as abdominal ultrasound are useful for diagnosis. We herein present a case of BCS caused by obstruction of the IVC by a huge liver metastasis from a previously treated thymoma.\n\n2 Case presentation\n\nA 34-year-old non-smoking woman visited our hospital because of worsening abdominal bloating over 2 months. Ten years previously, she was diagnosed with invasive thymoma type B2 (Fig. 1), for which she underwent CAMP therapy (cisplatin, doxorubicin, and methylprednisolone) followed by total thymectomy [3]. Four years previously (6 years after the thymectomy), she was treated with CAMP again, followed by extra-pleural pneumonectomy, for right pleural dissemination. Two years previously (8 years after the thymectomy), she was found to have a recurrence in the right pleural cavity as well as liver metastasis, but then elected to stop attending the hospital because she was concerned about the potential side effects of further treatment.Fig. 1 Chest CT image on initial presentation (10 years before the onset of Budd–Chiari syndrome) showing an anterior mediastinal tumor mass with a low-density area. The pathological diagnosis was invasive thymoma (type B2). She underwent systemic chemotherapy (CAMP therapy) followed by total thymectomy at that time. CT, computed tomography.\n\nFig. 1\n\nPhysical examination on admission revealed marked abdominal distension and bilateral leg edema. She did not show caput medusae nor splenomegaly. Her performance status on admission was Eastern Cooperative Oncology Group (ECOG) grade 3. Laboratory studies revealed a white blood cell count of 14,400/μL, 38.5% hematocrit, a platelet count of 269,000/μL, mild hepatic impairment (total bilirubin 1.1 mg/dL, aspartate aminotransferase 35 IU/L, alanine aminotransferase 20 IU/L, lactate dehydrogenase 342 IU/L, alkaline phosphatase 574 IUL/L, gamma-glutamyl transpeptidase 63 IU/L, leucyl aminopeptidase 107 IU/L), and normal renal function (creatinine 0.63mg/dL, estimated glomerular filtration rate 86.4 mL/min/1.73 m2). An abdominal ultrasound and a non-enhanced computed tomography scan of the chest and abdomen showed a large amount of ascites and massive lesions with irregular borders in the S2 segment of the liver, peritoneum, and right pleural cavity (Fig. 2). Ascites cytology was negative for malignancy. A culture of the ascitic fluid was also negative. The ascites albumin concentration was 1.9 g/dL and the serum–ascites albumin gradient (SAAG) was 1.4 g/dL (>1.1 g/dL), which suggested portal hypertension. An abdominal ultrasound clearly showed marked compression of the IVC and blood flow limitation by a large tumor (Fig. 3). She had no thymoma-associated paraneoplastic disease such as myasthenia gravis, pure red cell aplasia, nor agammaglobulinemia.Fig. 2 Abdominal CT image on the first visit to our hospital showing a large right hepatic mass of irregular density with indistinct borders. Abundant ascites was also detected.\n\nFig. 2\n\nFig. 3 Abdominal ultrasonography findings. (A) A large mass is compressing the inferior vena cava (white arrow). * inferior vena cava, abdominal aorta. (B) A color doppler image showed congestion of blood flow in the inferior vena cava. . (For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 3\n\nTaking these findings together, we diagnosed BCS caused by a huge thymoma metastasis in the liver. We performed ascites drainage twice (1600 ml each) during her hospitalization, but her symptoms of abdominal bloating did not improve. Administration of steroid pulse therapy (methylprednisolone 1 g for 3 days) followed by prednisolone 25 mg for 7 days resulted in significant symptomatic improvement, and abdominal CT showed shrinkage of the liver metastasis and a reduction in the ascites. Her body weight (70 kg before commencing steroid treatment) fell to 60.8 kg after two cycles of steroid pulse therapy. She was discharged from the hospital on tapering doses of steroids.\n\n3 Discussion\n\nSecondary BCS is mainly caused by tumor invasion accompanied by compression of the IVC and/or hepatic vein [4]. Many abdominal tumors, including primary liver cancer and metastatic renal cancer, can cause BCS. However, there have only been a few reports of BCS caused by liver metastases from thoracic tumors, including lung cancer [2]. In particular, to the best of our knowledge, there are no published reports of secondary BCS caused by thymoma metastasis in the liver. Because the patient refused to receive any invasive procedures including liver biopsy, we could not obtain pathological confirmation of the liver mass. Although our initial differential diagnosis discussion included hepatoma or lymphoma, we concluded from her medical history of repeated recurrence of thymoma that the liver mass was metastasis of invasive thymoma.\n\nThymic tumors, especially thymic carcinoma and high-risk thymoma (B2, B3 WHO classification), sometimes metastasize to distant sites post-operatively. The pleura is the most common site of thymoma metastasis, followed by the thoracic lymph nodes [5]. Extra-thoracic metastases of thymic tumors are rare; the liver is the second most common extra-thoracic metastatic site [6]. Notably, thymoma relapses can be diagnosed years after resection of the primary tumor [7]. In our case, liver metastasis was first detected 8 years after thymectomy. Thus, latent metastases from thymomas can present in unexpected ways.\n\nWe initially suspected that our patient's ascites was attributable to peritoneal dissemination of the thymoma. However, her high SAAG (1.4 g/dL) led us to suspect portal hypertension, which in turn led to the diagnosis of BCS, this being confirmed by imaging. A high SAAG (>1.1 g/dL) is a useful indicator of portal hypertension [8], and was critical to the diagnosis in this case.\n\nWe discussed several options for reducing our patient's IVC obstruction. The possibilities included chemotherapy, interventional radiology, radiation therapy, or resection of the liver tumor. Because her liver metastasis was large and she also had thymoma metastases in the thorax, her general condition was poor. We therefore considered that systemic chemotherapy, radiation, or surgery were inadvisable. Given that steroid monotherapy can reportedly be effective against metastatic thymoma [9], we initiated steroid pulse therapy. This resulted in a remarkable decrease in the ascites and a moderate reduction in the liver tumor diameter, from 78.9 mm to 60.6 mm. We speculate that release of IVC decompression caused by tumor shrinkage resulted in an improvement in the venous return and renal fluid clearance.\n\n4 Conclusions\n\nInvasive thymoma is sometimes refractory to multimodal therapy. Rarely, latent metastases from thymomas cause serious complications such as BCS.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nDeclaration of competing interest\n\nThe authors have no conflicts of interest or financial ties to disclose with respect to publication of this article.\n\nAcknowledgements\n\nWe thank Ms. Naomi Maeda and Ms. Kaori Totani for their excellent secretarial support, and Ms. Chieko Oka and Ms. Noriko Hiramatsu for their technical support. We also thank Trish Reynolds, MBBS, FRACP, and H. Nikki March, PhD, from Edanz Group (https://jp.edanz.com/ac) for editing a draft of this manuscript.\n==== Refs\nReferences\n\n1 Grus T. Lambert L. Grusova G. Banerjee R. Burgetova A. Budd-chiari syndrome Prague Med. Rep. 118 2–3 2017 69 80\n2 Iliescu L. Toma L. Mercan-Stanciu A. Grumeza M. Dodot M. Isac T. Budd-Chiari syndrome - various etiologies and imagistic findings. A pictorial review Med Ultrason 21 3 2019 344 348 31476215\n3 Nakamura S. Kawaguchi K. Fukui T. Hakiri S. Ozeki N. Mori S. Multimodality therapy for thymoma patients with pleural dissemination Gen Thorac Cardiovasc Surg 67 6 2019 524 529 30725276\n4 Li Y. De Stefano V. Li H. Zheng K. Bai Z. Guo X. Epidemiology of Budd-Chiari syndrome: a systematic review and meta-analysis Clin Res Hepatol Gastroenterol 43 4 2019 468 474 30528513\n5 Khandelwal A. Sholl L.M. Araki T. Ramaiya N.H. Hatabu H. Nishino M. Patterns of metastasis and recurrence in thymic epithelial tumours: longitudinal imaging review in correlation with histological subtypes Clin. Radiol. 71 10 2016 1010 1017 27267746\n6 Passuello N. Pozza G. Blandamura S. Valmasoni M. Sperti C. Thymoma metastatic to liver and pancreas: case report and review of the literature J. Int. Med. Res. 45 2 2017 868 874 28415940\n7 Vladislav T. Jain R.K. Alvarez R. Mehta R.J. Gokmen-Polar Y. Kesler K.A. Extrathoracic metastases of thymic origin: a review of 35 cases Mod. Pathol. 25 3 2012 370 377 22080058\n8 Runyon B.A. Montano A.A. Akriviadis E.A. Antillon M.R. Irving M.A. McHutchison J.G. The serum-ascites albumin gradient is superior to the exudate-transudate concept in the differential diagnosis of ascites Ann. Intern. Med. 117 3 1992 215 220 1616215\n9 Kobayashi Y. Fujii Y. Yano M. Sasaki H. Yukiue H. Haneda H. Preoperative steroid pulse therapy for invasive thymoma: clinical experience and mechanism of action Cancer 106 9 2006 1901 1907 16598701\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2213-0071",
"issue": "34()",
"journal": "Respiratory medicine case reports",
"keywords": "Ascites; BCS, Budd–Chiari syndrome; Budd-Chiari syndrome; CAMP, cisplatin, doxorubicin, and methylprednisolone; IVC, inferior vena cava; Liver metastasis; SAAG, serum-ascites albumin gradient; Thymoma",
"medline_ta": "Respir Med Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101604463",
"other_id": null,
"pages": "101492",
"pmc": null,
"pmid": "34401316",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
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"title": "Budd-Chiari syndrome caused by latent hepatic metastasis from a thymoma.",
"title_normalized": "budd chiari syndrome caused by latent hepatic metastasis from a thymoma"
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"abstract": "OBJECTIVE\nTo evaluate whether rates of serious infection with anti-tumor necrosis factor (anti-TNF) therapy in rheumatoid arthritis (RA) patients differ in magnitude by specific drugs and patient characteristics.\n\n\nMETHODS\nAmong new nonbiologic disease-modifying antirheumatic drug users enrolled in Medicare and Medicaid or a large US commercial health plan, we created and validated a person-specific infection risk score based on age, demographics, insurance type, glucocorticoid dose, and comorbidities to identify patients at high risk for hospitalized infections. We then applied this risk score to new users of infliximab, etanercept, and adalimumab and compared the observed 1-year rates of infection to one another and to the predicted infection risk score estimated in the absence of anti-TNF exposure.\n\n\nRESULTS\nAmong 11,657 RA patients initiating anti-TNF therapy, the observed 1-year rate of infection was 14.2 infections per 100 person-years in older patients (age ≥65 years) and 4.8 in younger patients (age <65 years). There was a relatively constant rate difference of ~1-4 infections per 100 person-years associated with anti-TNF therapy across the range of the infection risk score. Infliximab had a significantly greater adjusted rate of infection compared to etanercept and adalimumab in both high- and lower-risk RA patients.\n\n\nCONCLUSIONS\nThe rate of serious infections for anti-TNF agents was incrementally increased by a fixed absolute difference irrespective of age, comorbidities, and other factors that contributed to infections. Older patients and those with high comorbidity burdens should be reassured that the magnitude of their incremental risk with anti-TNF agents is not greater than for lower-risk patients.",
"affiliations": "University of Alabama at Birmingham, Birmingham, AL, USA. jcurtis@uab.edu",
"authors": "Curtis|Jeffrey R|JR|;Xie|Fenglong|F|;Chen|Lang|L|;Muntner|Paul|P|;Grijalva|Carlos G|CG|;Spettell|Claire|C|;Fernandes|Joaquim|J|;McMahan|Raechele M|RM|;Baddley|John W|JW|;Saag|Kenneth G|KG|;Beukelman|Timothy|T|;Delzell|Elizabeth|E|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept",
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"keywords": null,
"medline_ta": "Arthritis Care Res (Hoboken)",
"mesh_terms": "D000068879:Adalimumab; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D000068800:Etanercept; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007074:Immunoglobulin G; D007239:Infections; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor; D012306:Risk; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101518086",
"other_id": null,
"pages": "1480-9",
"pmc": null,
"pmid": "22833479",
"pubdate": "2012-10",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "16845707;15353188;11409123;16291813;12911182;20447953;21548401;22012868;17665462;22256806;21345216;18302495;21285425;20637072;10944644;16052570",
"title": "Use of a disease risk score to compare serious infections associated with anti-tumor necrosis factor therapy among high- versus lower-risk rheumatoid arthritis patients.",
"title_normalized": "use of a disease risk score to compare serious infections associated with anti tumor necrosis factor therapy among high versus lower risk rheumatoid arthritis patients"
} | [
{
"companynumb": "US-JNJFOC-20121007376",
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... |
{
"abstract": "A 33-year-old primigravida presented with severe sepsis, severe pre-eclampsia, peripartum cardiomyopathy and the haemolysis, elevated liver enzymes and low platelets syndrome manifesting over the course of 24 h causing a diagnostic conundrum and a difficult sequence of physiological problems to overcome. We describe a previously unreported sequence of events involving a pre-eclamptic, septic parturient to improve anaesthetic and intensive care physician awareness of confounding factors that complicate assessment and management of these patients.",
"affiliations": "Department of Anaethesia and Intensive Care, Lister Hospital, London, UK.;Department of Anaethesia and Intensive Care, Lister Hospital, London, UK.;Department of Anaethesia and Intensive Care, Lister Hospital, London, UK.",
"authors": "Hoy|Michael|M|;Flavin|Kate|K|;Prasad|Venkat|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1751143717700910",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1751-1437",
"issue": "18(3)",
"journal": "Journal of the Intensive Care Society",
"keywords": "Peripartum cardiomyopathy; obstetrics; pre-eclampsia; sepsis",
"medline_ta": "J Intensive Care Soc",
"mesh_terms": null,
"nlm_unique_id": "101538668",
"other_id": null,
"pages": "239-243",
"pmc": null,
"pmid": "29118838",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports",
"references": "23300351;15065193;16098869;25879992;20883932;19786252;12402414;23995132;16765131;21860287;20657009;19455566;15932821;17631087",
"title": "A complex obstetric case.",
"title_normalized": "a complex obstetric case"
} | [
{
"companynumb": "GB-PFIZER INC-2017339571",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROCURONIUM BROMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "We describe an 82-year-old male farmer who had diabetes mellitus with no history of ocular trauma by soil or plants and who developed a corneal infection due to a fungus. The organism was identified as Roussoella solani based on both the morphological characteristics and phylogenetic analysis using LSU and ITS nrDNA sequences. The sexual stage of R. solani is described and illustrated for the first time. The patient was treated successfully with a combination of topical and systemic voriconazole and micafungin. This case is the first report of keratomycosis caused by R. solani.",
"affiliations": "Department of Ophthalmology, Gifu University, Graduate School of Medicine, Gifu, Japan. Electronic address: mochi-gif@umin.ac.jp.;Department of Ophthalmology, Gifu University, Graduate School of Medicine, Gifu, Japan.;Department of Ophthalmology, Gifu University, Graduate School of Medicine, Gifu, Japan.;Department of Ophthalmology, Gifu University, Graduate School of Medicine, Gifu, Japan; Department of Ophthalmology, Toho University, Ohashi Medical Center, Tokyo, Japan.;Department of Medical Technology, Osaka University Hospital, Osaka, Japan.;Department of Medical Technology, Osaka University Hospital, Osaka, Japan.;Department of Microbiology, Tokyo Medical University, Graduate School of Medicine, Tokyo, Japan.;Faculty of Agriculture and Life Science, Hirosaki University, Aomori, Japan.",
"authors": "Mochizuki|Kiyofumi|K|;Nishida|Takashi|T|;Murata|Kazuhiro|K|;Ishida|Kyoko|K|;Sunada|Atsuko|A|;Asari|Seishi|S|;Ohkusu|Kiyofumi|K|;Tanaka|Kazuaki|K|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D065819:Voriconazole; D000077551:Micafungin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2017.03.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "23(9)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Keratomycosis; Micafungin; Phylogeny; Roussoella solani; Taxonomy",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000369:Aged, 80 and over; D000935:Antifungal Agents; D001203:Ascomycota; D054714:Echinocandins; D015821:Eye Infections, Fungal; D000067565:Farmers; D006801:Humans; D007634:Keratitis; D055666:Lipopeptides; D008297:Male; D000077551:Micafungin; D065819:Voriconazole",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "651-654",
"pmc": null,
"pmid": "28389166",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Roussoella solani causing keratomycosis, with an observed both sexual and asexual morphs.",
"title_normalized": "roussoella solani causing keratomycosis with an observed both sexual and asexual morphs"
} | [
{
"companynumb": "JP-ACCORD-058073",
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"occurcountry": "JP",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "ITRACONAZOLE"
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{
"abstract": "Cytomegalovirus (CMV) is one of the most common opportunistic infections after transplantation. To prevent CMV infections, universal prophylaxis and pre-emptive therapy with ganciclovir or its prodrug valganciclovir is applied. However, prolonged antiviral therapy may result in drug-resistance emergence. We describe a case of a 43-year-old CMV-seronegative patient who underwent kidney transplantation from a CMV-seropositive donor and developed CMV disease despite valganciclovir prophylaxis. CMV viral load increased even though valgangiclovir dose was augmented and immunosuppressive therapy reduced. CMV genotyping revealed mutations in the viral UL97 protein kinase, explaining ganciclovir-resistant CMV infection. The viral load failed to respond to foscavir, cidofovir and CMV-neutralizing immunoglobulins. Kidney allograft dysfunction developed 3 months post-transplantation with a histopathologic diagnosis of CMV nephropathy and potentially concomitant T-cell mediated rejection. A transplantectomy was performed on day 164 post-transplantation since the patient had uncontrollable CMV disease associated with a circulating multidrug-resistant DNA polymerase-mutant virus. Detailed monitoring in this patient demonstrated hallmarks of complicated CMV disease: (i) relatively rapid evolution of drug-resistant CMV mutants in the setting of persistent high blood viral loads, (ii) emergence of viral drug-resistance linked to acute graft rejection, (iii) transient and, thereafter, lack of response to various anti-CMV treatments, (iv) compartmentalization and heterogeneity of CMV viral populations, (v) possible differential ability of viral mutants to cause disease in the graft, and (vi) detection of minor viral variants by next generation sequencing. Translational research platforms that provide rapid molecular genotyping for detection of CMV drug-resistance are essential in guiding CMV disease management in high-risk transplant recipients.",
"affiliations": "Rega Institute for Medical Research, KU Leuven, Belgium. Electronic address: graciela.andrei@kuleuven.be.;Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium.;Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium.;Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium.;Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium.;Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium.;Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium.;Rega Institute for Medical Research, KU Leuven, Belgium.;Rega Institute for Medical Research, KU Leuven, Belgium.;Rega Institute for Medical Research, KU Leuven, Belgium.;Laboratory of Clinical Bacteriology and Mycology University Hospitals Leuven, Leuven, Belgium.;Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium.;Rega Institute for Medical Research, KU Leuven, Belgium.;Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Belgium.",
"authors": "Andrei|Graciela|G|;Van Loon|Elisabet|E|;Lerut|Evelyne|E|;Victoor|Jasper|J|;Meijers|Björn|B|;Bammens|Bert|B|;Sprangers|Ben|B|;Gillemot|Sarah|S|;Fiten|Pierre|P|;Opdenakker|Ghislain|G|;Lagrou|Katrien|K|;Kuypers|Dirk|D|;Snoeck|Robert|R|;Naesens|Maarten|M|",
"chemical_list": "D000998:Antiviral Agents; D007166:Immunosuppressive Agents; D014764:Viral Proteins",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.antiviral.2019.06.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0166-3542",
"issue": "168()",
"journal": "Antiviral research",
"keywords": "Cytomegalovirus; Kidney transplantation; Multi drug-resistance; Viral compartmentalization",
"medline_ta": "Antiviral Res",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D024921:Drug Resistance, Multiple, Viral; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007668:Kidney; D016030:Kidney Transplantation; D017211:Treatment Failure; D019562:Viral Load; D014764:Viral Proteins",
"nlm_unique_id": "8109699",
"other_id": null,
"pages": "203-209",
"pmc": null,
"pmid": "31212020",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Persistent primary cytomegalovirus infection in a kidney transplant recipient: Multi-drug resistant and compartmentalized infection leading to graft loss.",
"title_normalized": "persistent primary cytomegalovirus infection in a kidney transplant recipient multi drug resistant and compartmentalized infection leading to graft loss"
} | [
{
"companynumb": "BE-EMA-DD-20210326-KUMARVN_P-150236",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugaddi... |
{
"abstract": "We report a rare case of type 2M von Willebrand disease diagnosed in an elderly multiple myeloma patient who had no personal and family bleeding history. This case report emphasis the importance to not systematically exclude a congenital vWD in adult patients when coagulation screening tests indicate toward a vWD.",
"affiliations": "Laboratory of Haematology Laboratoire Hospitalier Universitaire de Bruxelles Institut Jules Bordet and Saint Pierre University Université Libre de Bruxelles Brussels Belgium.;Laboratory of Haematology Laboratoire Hospitalier Universitaire de Bruxelles Institut Jules Bordet and Saint Pierre University Université Libre de Bruxelles Brussels Belgium.;Laboratory of Haematology Laboratoire Hospitalier Universitaire de Bruxelles Institut Jules Bordet and Saint Pierre University Université Libre de Bruxelles Brussels Belgium.;Department of Haematology Jules Bordet Institute Brussels Belgium.;Laboratory of Haematology Laboratoire Hospitalier Universitaire de Bruxelles Institut Jules Bordet and Saint Pierre University Université Libre de Bruxelles Brussels Belgium.",
"authors": "El Ouaaliti|Malika|M|;Li|Rong|R|;Gobin|Delphine|D|;Bron|Dominique|D|;Cantinieaux|Brigitte|B|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.603",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.603CCR3603Case ReportCase ReportsDiagnosis of congenital von Willebrand disease during a preoperative assessment in a multiple myeloma patient without bleeding history M. El Ouaaliti et al.El Ouaaliti Malika \n1\nLi Rong \n1\nGobin Delphine \n1\nBron Dominique \n2\nCantinieaux Brigitte \n1\n1 Laboratory of HaematologyLaboratoire Hospitalier Universitaire de BruxellesInstitut Jules Bordet and Saint Pierre UniversityUniversité Libre de BruxellesBrusselsBelgium2 Department of HaematologyJules Bordet InstituteBrusselsBelgium* Correspondence\n\nMalika El Ouaaliti, Undergoing a Master in Clinical Biology at Laboratoire Hospitalier Universitaire de Bruxelles. CHU Saint‐Pierre and Institut Jules Bordet, ULB, Laboratory of Haematology, Rue Haute, 322. Brussels, BE 1000, Belgium. Tel: +3224352159; Fax: 003224352079; E‐mail: elouaaliti.malika@hotmail.com\n13 6 2016 7 2016 4 7 10.1111/ccr3.2016.4.issue-7703 706 03 2 2016 11 5 2016 23 5 2016 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nWe report a rare case of type 2M von Willebrand disease diagnosed in an elderly multiple myeloma patient who had no personal and family bleeding history. This case report emphasis the importance to not systematically exclude a congenital vWD in adult patients when coagulation screening tests indicate toward a vWD.\n\n1‐desamino‐8‐d‐arginine vasopressincongenital von Willebrand diseasemultiple myelomapreoperative screeningprolonged apTTvon Willebrand factor source-schema-version-number2.0component-idccr3603cover-dateJuly 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:06.07.2016\n\nClinical Case Reports \n2016 ; 4 (7 ): 703 –706\n==== Body\nCase Presentation\nThe case we present concerns a 77‐year‐old man who was diagnosed in 2008 with an IgA‐Κappa MM (10.3 g/L; normal values: 0.7–4 g/L) at a stage III 1. He was treated with melphalan, corticoids and thalidomide. The patient responded well to the treatment and IgA level decreased to 1.8 g/L. Due to the neurotoxicity side effects of thalidomide, the treatment was changed to dinatrii pamidronas. In 2009, the patient started to develop an osteonecrosis of the jaw, medullar plasma cells were 5%, and IgA levels remained at about 5 g/L for another 3 years. In April 2012, serum IgA went up to 10 g/L and medullar plasma cells rose up to 10%. The patient was further treated with corticosteroids and lenalidomide. IgA level decreased and remained low for another year and a half (2.6 g/L). In October 2013, IgA level was high at 11 g/L and the patient was treated again with lenalidomide in association with corticoids. The treatment lowered IgA level to 4.5 g/L. In April 2014, the patient was admitted to our hospital as he needed surgery for osteonecrosis of the jaw.\n\nIn the preoperative coagulation screening tests, an isolated prolonged activated partial thromboplastin time (aPTT) (Synthasil®, Instrumentation Laboratory Company, Bedford, USA) was found with normal platelet count, normal prothrombin time (PT%, Innovin, Siemens Healthcare, Germany), normal thrombin time (TT, Thrombin Reagente, Siemens Healthcare, Germany), and a normal fibrinogen level (Table 1). With no known family and personal histories of bleeding but with a MM‐associated hemorrhagic risk, a second analysis and complementary tests were undertaken.\n\nTable 1 Assessment tests were performed prior to the patient surgery for osteonecrosis of the jaw. First, aPTT, PT, and fibrinogen measurements were done (1st)\n\nAssessment results\t1st\t2nd\tMonths after surgery\tNormal range\t\nPLT (* 103/μL)\t233 * 103\n\t\t192 * 103\n\t150–440\t\nPT (%)\t103.6\t101.4\t33\t>70\t\nINR\t0.98\t0.98\t1.97\t0.95–1.31\t\nFibrinogen (mg/dL)\t434\t445\t\t200–400\t\naPTT (s)\t34.6\t34.1\t46.2\t21.7–33.9\t\nTT (s)\t18.0\t\t16.1\t16.2–20.7\t\nActin® FS (s)\tProlonged\t\t\t21.3–31.1\t\nMixing (s)\tNormal\t\t\t21.7–33.9\t\nFVIII (%)\t43.6\t48.5\t67.1\t50–200\t\nvWF:Ag (%)\t19\t20\t29\t50–200\t\nvWF:RCo (%)\t11\t13\t17.7\t50–200\t\nvWF:RCo/vWF:Ag\t0.58\t0.65\t0.61\t0.7\t\nFVIII/vWF:Ag\t2.29\t2.43\t2.31\t1.0\t\nRIPA (Ristocetin 0.3 ml ml−1) (%)\t<10\t\t\t<10\t\nCollagen‐binding Assay (I and III) (%)\t39\t\t\t50–160\t\nvWF:CB/vWF:Ag\t2.05\t\t\t0.7\t\nMultimer analysis\tNormal\t\t\tDetection of a triple structure\t\nMolecular analysis (PCR)\tHeterozygous mutation p.R1315C/c.3943C>T in exon 28 of the vWF gene (A1 domain)\t\t\tNo mutation\t\nAs aPTT results were perturbed, TT, Actin® FS and mixing analyses were undertaken. Consequent to a prolonged Actin® FS result and corrected mixing study, FVIII, vWF:Ag, and vWF:RCo were evaluated. As the later values obtained were low, vWD was suspected and supplementary tests were done. Samples were sent to UZAntwerpen laboratory for collagen‐binding assay, multimer, and molecular analysis. Three days later, low levels of FVIII, vWF:Ag, and vWF:RCo were confirmed on a second sample (2nd). Eight months later, when IgA‐Kappa level was confirmed as stable, aPTT, FVIII, vWF:Ag, and vWF:RCo were evaluated to confirm the initial results obtained during the preoperative assessment tests. aPTT (Synthasil, IL), PT (Innovin, Siemens), fibrinogen, TT, Actin® FS (rich is PL), FVIII, vWF:Ag, and vWF:RCo dosage were performed using CS5000 or CS2100 (Sysmex). Finally, RIPA was also performed using Chrono‐log Aggregometer.\n\nPlatelets (PLT); prothrombin time (PT); activated partial thromboplastin time (aPTT); thrombin time (TT); vWF antigen (vWF:Ag); ristocetin cofactor activity (vWF:RCo); ristocetin‐induced platelet aggregation (RIPA).\n\nJohn Wiley & Sons, LtdResults suggested an intrinsic coagulation factor deficiency as aPTT was still prolonged using Actin® FS (Siemens Healthcare, Germany), another reagent which is more sensitive to coagulation factors and less to lupus anticoagulant, and as the prolonged aPTT observed in the screening coagulation tests was corrected by the mixing aPTT study. Further investigations demonstrated decreased levels of FVIII (43.6%) (FACTOR VIII DEFICIENT, Siemens Healthcare, Germany), of vWF antigen (vWF:Ag, Siemens Healthcare, Germany) (19%), and of ristocetin cofactor activity (vWF:RCo, INNOVANCE vWF Ac, Siemens Healthcare, Germany) (11%) (Table 1). The patient's blood group was determined as O positive. The ratios of vWF:RCo/vWF:Ag and FVIII/vWF:Ag were of 0.58 and of 2.29. Finally, the low level in these factors was confirmed 3 days later on a new sample suggesting a vWD.\n\nNo inhibitors of FVIII and vWF:Ag could be detected by the Bethesda method suggesting that the decrease in level of these factors were not secondary to auto‐antibodies. Electrophoresis of vWF multimer showed a normal triple structure of the protein while collagen (I and III) binding assay was slightly reduced (Table 1). Finally, genetic analysis by PCR was performed and showed a heterozygous mutation p.R1315C/c.3943C>T in exon 28 of the vWF gene which is situated in the domain A1 of vWF protein.\n\nBased on these results and absence of increased platelet aggregation at low ristocetin concentration (RIPA), the DDAVP (1‐desamino‐8‐d‐arginine vasopressin) test was evaluated (Fig. 1). FVIII, vWF:Ag, and vWF:RCo were measured 0 min before, 30 and 90 min after, DDAVP injection. The answer was determined as insufficient and led to the administration of recombinant vWF prior to surgery, and of tranexamic acid after his intervention. No bleeding event was recorded.\n\nFigure 1 Left side of the graph: FVIII, vWF:Ag, and vWF:Rco were evaluated prior to (t = 0 min) and 30, 90 min after DDAVP administration. As the patient did not respond sufficiently, recombinant vWF was administrated prior to surgery. Right side of the graph: FVIII, vWF:Ag, and vWF:Rco were evaluated prior to recombinant vWF administration and prior surgery (t = 0'), post recombinant vWF administration and prior surgery (prior surgery), and post recombinant vWF administration and postsurgery (post surgery). There was no hemorrhagic incidence during peri‐ and postoperation with tranexamic acid. vWF:Ag and vWF:Rco values are situated above the graph. activated partial thromboplastin time (aPTT); vWF antigen (vWF:Ag); ristocetin cofactor activity (vWF:RCo), recombinant vWF (rvWF).\n\nEight months after surgery (IgA: 5.3 g/L), the patient was admitted again in our hospital for pyrexia. During his hospitalization, atrial fibrillation was detected and acenocoumarol was administrated. After medication, coagulation tests showed an INR of 1.97 and an aPTT of 46.2 s, probably due to low level of FIX. FVIII level was normal while vWD:Ag and vWD:RCo levels remained low and the vWD:RCo/vWD:Ag ratio was of 0.61 (Table 1). Confirmation of these results several months after surgery, in addition to the absence of response to DDAVP, further supports the importance of conducting complete VWF studies in MM patients even if an acquired vWD is suspected in order to avoid hemorrhagic events.\n\nDiscussion\nvWD is the most commonly inherited bleeding disorder. vWD is either congenital, or more rarely, acquired. Acquired vWD is most frequently observed in MM and it results from the synthesis of new auto‐antibodies acting against vWF. The worst case outcome for these patients is hemorrhage during surgery and the clinical picture is usually similar to type II or type I vWD 2.\n\nThree types of congenital vWD have been described and their classification is based on a qualitative or a quantitative default 2. Type III vWD classification is used for patients with virtually no vWF (<3%) and type I vWD represents patients with an equivalent mild to moderately severe reduction of vWF:Ag and vWF:RCo in the plasma. Type II regroups, all different types of qualitative default in vWF, within which there are four principle subgroups: 2A, 2N, 2M, and 2B 2, 3.\n\nIn this case report, we present a patient diagnosed with vWD during a preoperative assessment with a history of MM which was diagnosed 6 years earlier. vWD diagnosis was based on a prolonged aPTT and low levels of FVIII, vWF:Ag, and vWF:RCo. As no auto‐antibodies were detected, the hypothesis of an acquired vWD secondary to MM was rejected and the possibility of a congenital vWD was considered.\n\nPatients with an O blood group usually have 25–30% lower levels of vWF than non‐O blood group patients and this modestly low vWF level does not predict significant bleeding 4. In this case report, the patient's blood group was therefore not sufficient to explain a first vWF:Ag value of 19% and a vWF:RCo of 11%. Further tests were then pursued to determine the subtype of vWD in order to avoid any hemorrhagic events during and postsurgery. Indeed, this is important as the treatment of patients with vWD varies with vWD subtypes 3, 5.\n\nThe value of the ratio between vWF:RCo and vWF:Ag was not indicative as it defines a gray area which cannot help in discriminating between type I and type II vWD 3. Collagen‐binding protein assay and a ratio vWF:CB/vWF:Ag of 2.05 suggests that the collagen‐binding function was not altered. Furthermore, a high FVIII/vWF:Ag ratio (2.3) and the results obtained months after surgery which showed normal levels of FVIII while vWF:Ag remained low, both suggest that vWF synthesis is probably reduced. Of note, while the prolonged aPTT values obtained in the two samples prior surgery were secondary to low FVIII level, the one obtained 8 months after surgery, when FVIII level was back to normal, could be explained by low levels of FIX secondary to acenocoumarol treatment administrated for paroxysmal atrial fibrillation.\n\nNo structural default of the protein was revealed and type 2A vWD, which results from a loss of intermediate‐ and high‐molecular weight multimers, was ruled out. As a result of absence of platelet aggregation in response to low concentration of ristocetin (enhanced RIPA) and normal platelet count, type 2B vWD could also be excluded. Finally, as type 2N vWD mutations result in an increased clearance of the factor which is in opposition to the high FVIII/vWF:Ag ratio observed for this patient, this subtype was excluded 5.\n\nThe two diagnoses which remain are either a type 1 or a type 2M vWD. Mutation in the A1 domain has previously been reported in type 2M vWD 3. The distinction is of crucial therapeutic use as most type 2M patients do not benefit from DDAVP treatment due to their loss‐of‐function phenotype 3, 5.\n\nThe heterozygous mutation p.R1315C/c.3943C>T in exon 28 is situated within the A1 domain of vWF monomer which binds to both collagen and platelet GPIb 3, 6. With a ratio of vWF:CB/vWF:Ag of 2.05, the missense mutation in the A1 domain suggests that it is the binding of vWF to GPIb, rather than to collagen, which is affected by the p.R1315C/c.3943C>T mutation. Even though a reduced production of vWF is suggested by vWF:CB/vWF:Ag and FVIII/vWF:Ag ratio values, the absence of effect of DDAVP on vWF:RCo support that the vWD detected in this case report is a type 2M vWD 6, 7.\n\nOverall, the diagnosis of this patient is probably a type 2M vWD which results from impaired binding of vWF to the platelet GPIb due to missense substitutions in the A1 domain. This could explain the absence of optimal response to DDAVP, ratio vWF:RCo/vWF:Ag < 0.7, normal multimers presence, normal RIPA test, increased ratio FVIII/vWF:Ag > 1.0, and a ratio vWF:CB/vWF:Ag > 0.6. Moreover, type 2M VWD is classically associated with a milder bleeding phenotype than other types of vWD with A1 domain mutation 6.\n\nIn conclusion, diagnosis of congenital vWD should always be considered and ruled out prior to surgery, even for an elderly patient diagnosed with MM who presents no personal or family bleeding history. A complete investigation will impact the choice of treatment to avoid perioperative bleeding.\n\nConflict of Interest\nNone declared.\n==== Refs\nReferences\n1 \n\nDurie , B. G. M. \n, and \nS. E. \nSalmon \n. 1975 \nA clinical staging system for multiple myeloma . Cancer \n36 :842 –854 .1182674 \n2 \n\nCastaman , G. \n, \nR. R. \nMontgomery \n, \nS. S. \nMeschengieser \n, \nS. L. \nHaberichter \n, \nA. I. \nWoods \n, and \nM. A. \nLazzari \n. 2010 \nvon Willebrand's disease diagnosis and laboratory issues . Haemophilia \n16 :67 –73 .20590859 \n3 \n\nJames , P. D. \n, and \nD. \nLillicrap \n. 2013 \nThe molecular characterization of von Willebrand disease: good in parts . Br. J. Haematol. \n161 :166 –176 .23406206 \n4 \n\nMiller , C. H. \n, \nE. \nHaff \n, \nS. J. \nPlatt \n, \nP. \nRawlins \n, \nC. D. \nDrews \n, \nA. B. \nDilley \n, et al. 2003 \nMeasurement of von Willebrand factor activity: relative effects of ABO blood type and race . J. Thromb. Haemost. \n1 :2191 –2197 .14521604 \n5 \n\nCastaman , G. \n, \nA. \nGoodeve \n, and \nJ. \nEikenboom \n. 2013 \nPrinciples of care for the diagnosis and treatment of von Willebrand disease . Haematologica \n98 :667 –674 .23633542 \n6 \n\nGadisseur , A. \n, \nC. \nHermans \n, \nZ. \nBerneman \n, \nW. \nSchroyens \n, \nH. \nDeckmyn \n, and \nJ. J. \nMichiels \n. 2009 \nLaboratory diagnosis and molecular classification of von Willebrand disease . Acta Haematol. \n121 :71 –84 .19506352 \n7 \n\nSadler , J. E. \n, \nU. \nBudde \n, \nJ. C. \nEikenboom \n, \nE. J. \nFavaloro \n, \nF. G. \nHill \n, \nL. \nHolmberg \n, et al. 2006 \nUpdate on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor . J. Thromb. Haemost. \n4 :2103 –2114 .16889557\n\n",
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"issue": "4(7)",
"journal": "Clinical case reports",
"keywords": "1‐desamino‐8‐d‐arginine vasopressin; congenital von Willebrand disease; multiple myeloma; preoperative screening; prolonged apTT; von Willebrand factor",
"medline_ta": "Clin Case Rep",
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"title": "Diagnosis of congenital von Willebrand disease during a preoperative assessment in a multiple myeloma patient without bleeding history.",
"title_normalized": "diagnosis of congenital von willebrand disease during a preoperative assessment in a multiple myeloma patient without bleeding history"
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"abstract": "BACKGROUND\nBenign epilepsy with centrotemporal spikes (BECTS) is one of the most common forms of childhood epilepsy, which is expected to resolve before 16 years of age, with mild effects on the cognitive or behavioral functions in adulthood. This study aims to report the first propofol-induced refractory status epilepticus (SE) in patients with BECTS after 16 years of age, and to review SE in BECTS or induced by propofol.\nA 16-year-old Chinese girl, who was diagnosed with BECTS at the age of 2 years, developed refractory SE induced by propofol administered during the maintenance stage of general anesthesia during a plastic surgery procedure.\nConsidering her medical history, EEG, and magnetic resonance images, and brain computed tomography, a diagnosis of refractory SE in BECTS was confirmed.\n\n\nMETHODS\nThe patient had been seizure-free for 3 years from treatment with 2 anti-epileptic drugs (AEDs) valproate acid (VPA) and oxcarbazepine (OXC), and had started monotherapy with OXC for 3 months before the seizure incidence. She had undergone blepharoplasty under local anesthesia prior to receiving general anesthesia. During the maintenance state she developed convulsive SE, which was uncontrolled seizure and lasted for 14 hours. The treatment for which included midazolam, diazepam, propofol, VPA, OXC, and levetiracetam (LEV).\n\n\nRESULTS\nThe prolonged seizure was controlled by diazepam (4 mg/h), propofol (6 mg/kg/h), VPA (2400 mg/d intravenous injection). Subsequently, she was administered VPA (800 mg/d po), OXC (600 mg/d po), and LEV (1000 mg/d po). Finally, on the 17th day she was discharged, and did not have any seizure recurrence and EEG results were normal as noted during the 3-month follow-up.\n\n\nCONCLUSIONS\nThis was the first report of an SE in BECTS patient past the remission age. This report implied that interventions of sedation or analgesia in a patient after remission age of BECTS might still be at risk of refractory SE and therefore, should be carefully evaluated and monitored during such procedures, especially when an AED medication has been withdrawn or altered.",
"affiliations": "Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.",
"authors": "Lu|Lu|L|;Xiong|Weixi|W|;Zhang|Yingying|Y|;Xiao|Yingfeng|Y|;Zhou|Dong|D|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31277145MD-D-19-0026810.1097/MD.0000000000016257162575300Research ArticleClinical Case ReportPropofol-induced refractory status epilepticus at remission age in benign epilepsy with centrotemporal spikes A case report and literature reviewLu Lu MDXiong Weixi MDZhang Yingying MDXiao Yingfeng MDZhou Dong MD, PhD∗NA. Department of Neurology, West China Hospital, Sichuan University, Chengdu, China.∗ Correspondence: Dong Zhou, Departments of Neurology, West China Hospital, Sichuan University, No. 37 GuoXue Alley, Chengdu 610041, China (e-mail: zhoudong66@yahoo.de).7 2019 05 7 2019 98 27 e1625712 1 2019 30 4 2019 7 6 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nBenign epilepsy with centrotemporal spikes (BECTS) is one of the most common forms of childhood epilepsy, which is expected to resolve before 16 years of age, with mild effects on the cognitive or behavioral functions in adulthood. This study aims to report the first propofol-induced refractory status epilepticus (SE) in patients with BECTS after 16 years of age, and to review SE in BECTS or induced by propofol.\n\nPatient concern:\nA 16-year-old Chinese girl, who was diagnosed with BECTS at the age of 2 years, developed refractory SE induced by propofol administered during the maintenance stage of general anesthesia during a plastic surgery procedure.\n\nDiagnoses:\nConsidering her medical history, EEG, and magnetic resonance images, and brain computed tomography, a diagnosis of refractory SE in BECTS was confirmed.\n\nInterventions:\nThe patient had been seizure-free for 3 years from treatment with 2 anti-epileptic drugs (AEDs) valproate acid (VPA) and oxcarbazepine (OXC), and had started monotherapy with OXC for 3 months before the seizure incidence. She had undergone blepharoplasty under local anesthesia prior to receiving general anesthesia. During the maintenance state she developed convulsive SE, which was uncontrolled seizure and lasted for 14 hours. The treatment for which included midazolam, diazepam, propofol, VPA, OXC, and levetiracetam (LEV).\n\nOutcomes:\nThe prolonged seizure was controlled by diazepam (4 mg/h), propofol (6 mg/kg/h), VPA (2400 mg/d intravenous injection). Subsequently, she was administered VPA (800 mg/d po), OXC (600 mg/d po), and LEV (1000 mg/d po). Finally, on the 17th day she was discharged, and did not have any seizure recurrence and EEG results were normal as noted during the 3-month follow-up.\n\nLessons:\nThis was the first report of an SE in BECTS patient past the remission age. This report implied that interventions of sedation or analgesia in a patient after remission age of BECTS might still be at risk of refractory SE and therefore, should be carefully evaluated and monitored during such procedures, especially when an AED medication has been withdrawn or altered.\n\nKeywords\nanesthesiabenign epilepsy with centrotemporal spikesneurocritical carepropofolreviewstatus epilepticusOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nBenign epilepsy with centrotemporal spikes (BECTS), also known as rolandic epilepsy, is one of the most common form of childhood epilepsy syndromes.[1] The seizure onset is usually between 3 and 10 years of age. Children can expect terminal remission by the age of 16 years.[2,3] Although some BECTS patients with atypical evolutions have been reported during the past few decades including atypical benign focal epilepsy of childhood (ABFEC), status epilepticus (SE) of BECTS, Landau Kleffner syndrome (LKS), and continuous spike-and-waves during slow sleep (CSWS) syndrome, which may be parts of a continuum related to BECTS, the age-dependent remission is unexceptional.[4] The cognitive or behavioral deficits in patients with BECTS have been repeatedly discussed.[5–7] Impairment can last in patients who have been symptom-free of seizure for years.[8] Thus, whether there is an underestimated risk of epileptic incidence after remission has been unclear. Until now, no reports have shown the recurrence of an epileptic incidence in BECTS patients after 16 years of age. Herein, we present the case of a 16-year-old girl with typical BECTS clinical features who suffered a prolonged seizure during a plastic surgery procedure under general anesthesia after being seizure-free for 3 years.\n\n2 Methods\n2.1 Ethical approval and consent for publication\nThe ethics committee of West China Hospital has approved this study. Written informed consent was obtained from the patient and her guardians.\n\n2.2 Collection of the data\nWe identified a Han Chinese female patient as diagnosed with BECTS at our center 13 years ago. The patient's previous medical records, medical history, and electronic medical records during the course of the SE were collected and considered for this report.\n\n2.3 Review of the literature\nWe have searched the literatures for BECTS with recurrence after 16 years of age, SE in BECTS, and propofol-induced SE in PubMed. We have included studies that reported of SE or recurrence in BECTS patients or studies that followed more than 50 BECTS patients, by reading the full content. Additionally, we have also reviewed literatures that reported SE induced by propofol.\n\n3 Case report\nThe patient was a 16-year-old girl who had her first unprovoked seizure at 2 years of age. Within half hour of sleep, she had awakened with bilateral numbness of legs and arms, which developed to be generalized tonic-clonic seizure (GTCS) that lasted for around 3 to 5 minutes. Symptoms including hemifacial clonic manifestations and sialorrhea were reported by the parents. She used to experience a seizure attacks monthly prior to medical treatment. A 3T magnetic resonance imaging (MRI) investigation showed no remarkable disorders (Shown in Fig. 1A). EEG showed typical features of BECTS. There was no remarkable history before seizure onset. No developmental deficits were found during the entire course. The patient experienced seizure yearly during treatment with anti-epilepsy drugs (AEDs) until treatment with valproate (VPA, 1000 mg/d) and oxcarbazepine (OXC, 750 mg/d) was initiated at the age of 13 years. The EEG results were negative during the same period. VPA dosage was gradually reduced during the seizure-free 3 years. Eventually, monotherapy with daily 600 mg OXC was continued for 4 months until the incidence of SE.\n\nFigure 1 A: Magnetic resonance imaging (MRI), in T1 Flair at age 12; B: Computed tomography (CT) scan on the 7th day, showed severe hydrocephalus, C: CT scan on the 15th day, D: MRI scan in T1 Flair at the discharge.\n\nThis patient was presented to the Emergency room (ER) with uncontrolled tonic-clonic convulsions lasting for at least 4 hours. Prior to SE, she had undergone blepharoplasty under local anesthesia with no complications. Thereafter, when she was undergoing an augmentation rhinoplasty, she developed convulsive SE under general anesthesia induced by propofol (1.5 mg/kg). The local anesthetics were made of 2% lidocaine, 0.5% bupivacaine, 1/1000 of adrenaline, and saline. The infusion of propofol was 4 mg/kg. A prolonged trembling symptom was noted at first which was not treated by the operator until it developed to a convulsive SE. At first it was controlled with repeated midazolam injections (40 mg), but recurred after the withdrawal of the endotracheal intubation. Treatments including midazolam (extra 20 mg) and diazepam (20 mg), propofol (4 mg/kg/h), VPA (2400 mg/d intravenous injection) were used in the ER, and the seizure episode continued for over 14 hours before ceasing. The prolonged seizures were controlled by diazepam (4 mg/h), propofol (6 mg/kg/h), VPA (2400 mg/d i.v.), and the oral AEDs used were VPA (800 mg/d), OXC (600 mg/d), and LEV (1000 mg/d). The emergency Computed tomography (CT) showed diffuse cerebral edema. The consciousness could not be evaluated under narcotism. The machinery applied were ventilator, peripherally inserted central catheter (PICC), and circulation supporting treatment in intensive care unit (ICU) 5 hours after the onset. Her vital signs were stable under the ICU care, the blood pressure was varied around 80–120/60–90 mmHg and the SpO2 was between 98% and 100%. The blood PH was around 7.46–7.44, and was within the normal limit after the withdrawal of propofol.\n\nShe was treated with sedative and AEDs for the following 12 days. Her consciousness had not returned to the baseline, while repeated convulsive seizures were stopped. She had recurrences of 2 GTCSs on the 3rd and the 10th day during the withdrawal of IV diazepam and VPA. The EEG recording showed continual slow waves in all leads with little spikes in the F3, T3, T5 leads (shown in Fig. 2). She had the tracheal intubation removed on the 11th day. Dexmedetomidine and propofol were stopped 2 days after. On the 13th day time point, cognition functions test, calculation and orientation, showed slightly impaired memory. Defective perception was noted during this transient period. CT scan showed hydrocephalus on the 7th and 15th day after the attack (shown in Fig. 1B and C). She was given 3 types of oral AEDs including VPA, OXC, and LEV until the 15th day of the onset. Then a dual therapy of OXC (600 mg/d po) and VPA (1000 mg/d po) was prescribed. She was discharged on the 17th day, the MRI result is shown in Fig. 1D).\n\nFigure 2 A: Video electroencephalogram (VEEG) recording of the 7th day, showed the continuous slow wave and spikes in T3, T5, F3 leads; B: VEEG recording 3 months after status epilepticus showed normal background.\n\nA follow-up was performed 3 months after the discharge and no seizure recurrence with normal EEG were reported under the same dual therapy (shown in Fig. 2).\n\n4 Discussion\nWe report a BECTS patient aged sixteen who developed refractory SE after being seizure-free for 3 years. To the best of our knowledge, this case is the first report of a refractory SE after remission age in patients with BECTS, presenting the risk of epileptic incidence in a more severe form in patients with BECTS after “terminally resolved.”\n\nSE has been recognized as an atypical form of benign rolandic epilepsy since the report in 1987 [9]; most of the SE phenomenon was describe as a prolonged focal onset seizure, which is typical in BECTS patients including intermittent drooling and oromotor dyspraxia or other motor symptoms of the face.[10–12] Secondary GTCS in SE was only seen in one case in previous reports.[13] Most of the cases were found at the beginning of the course or during the first 5 years of seizure onset. Awareness was reported in only few cases. No SE events were reported in patients with BECT older than 13 years old, nor did the study report of any refractory SE. No SE was reported after anesthesia. In recent population studies in BECTS patients, the incidence rate of SE has dramatically decreased, in most of them, no SE event had occurred.[14–16] The population studies and case reports are shown in Table 1.\n\nTable 1 Previous study of SE reports in typical or atypical BECTS population.\n\nThe recurrence rate of seizure in BECTS patients was relatively low compared to other childhood epilepsy syndromes, the recurrence risk after drug withdrawal ranged from 6% to 24%.[19–21] Seizure recurrence was mostly seen at 6 to 8 years old. Evident improvement was usually seen by the age of 12. At puberty, most patients with BECTS would be seizure-free with few cases reporting to have focal onset motor symptoms during this period. No study reported SE as a recurring incidence among all the studied population.\n\nThe primary reasons for relapse after 2-year remission in children with epilepsy was considered to be the tapering off of medication, including the tapering initiated before a child achieved a 2-year remission.[20] There are no recommendation to follow or treat young adults with BECTS for any epilepsy-related social or medical issues.[22] Our case indicated the possibility of an epileptic incidence in adolescent patient during the tapering or withdrawal of AEDs, cautioning the neurologists or psychiatrists of the management of these patients adapting to relative circumstances including anesthesia.\n\nThe prognosis of BECTS patients has been excellent, and adults who had recovered from BECTS did not have general negative outcomes in the field of development, education, employment, and social adaptation.[14] The recent studies have questioned the highly prevalent cognitive and behavioral limitations of BECTS patients after a long-lasting seizure-free period. While the mechanism behind the post-epileptic effect was under investigation, we did see this patient with early seizure onset and long duration develop unfavorable outcome during the seizure-free period, whether it underlines a possible change in susceptibility in anesthesia-induced epilepsy would require more population for confirmation.\n\nAnesthesia-induced SE has been commonly studied during the past few decades with respect to a few anesthetics. If anesthesia is necessary in patients with epilepsy, anesthetics with higher seizure-inducing properties should be avoided, such as ketamine, sevoflurane, desflurane etc. Propofol was recommended in patients with epilepsy as an anesthetic.[23] Thus, only a few cases of propofol-induced SE have been published. The very first case report of a patient with epilepsy was reported in 1987 in which the patient suffered a partial SE for 40 mins during recovery state following propofol (3.02 mg/kg).[24] Similar reports were also seen in the 1990s, reports from Finland demonstrated a patient that developed symmetric tonic-clonic seizure, and was hardly managed after 3 days.[25] In a systematic review, 4 patients with epilepsy developed SE after propofol, with no exceptions beyond recovery stage. A report from Japan stated that prolonged GTCS was initiated 10 minutes after propofol infusion after brachial plexus block.[26] Although the prognoses of these seizures were not clear, persistent seizures and SE were likely to lead to postoperative dysfunction in patients.[27]\n\nThe effect of propofol is dose-dependent, low dose propofol is epileptogenic.[28] Study among mechanisms suggest the involvement of 4-aminopyridine pathway, protein kinase C (PKC) pathway and glycine-antagonist mechanism. A high dose of propofol is antiepileptic and has been recommended as third line in SE rescue[29,30] and the first line treatment in refractory SE related to anesthesia.[31] The relationship between anesthesia and epilepsy is complicated and requires further research. Studies should not only consider the types of anesthetics, but also hypercapnia and hypoventilation that occur during anesthesia[32] cause seizures and prolong the duration of it.\n\nThe management of patient with epilepsy was a huge challenge for the anesthesiologist during the preoperative period. Anesthesia in epilepsy surgery for more precise location of the seizure onset zone has been frequently discussed.[33] It is now common to evaluate patients with epilepsy in non-epilepsy surgery. Safe administration of anesthesia requires a high attention to detail. The preoperative investigations and preanesthetic evaluations were recommended. Patients in these non-epilepsy surgeries requiring general anesthesia, induction was suggested to be done with propofol or thiopentone, and blood levels of antiepileptics should be obtained to adjust the doses accordingly.[34] Although the patients with poorly controlled seizures in perioperative period were under higher risk of anesthesia-induced SE, our case represents a rare case in a well-managed patient. If convulsions persist over 5 minutes, it requires a precise recognition and treatment initiation that offers to lower both morbidity and mortality.[35]\n\n5 Conclusion\nIn this case report, we presented a patient with BECTS at the terminal remission age who developed refractory SE under anesthesia. We suggested that anesthesia or other sedation and analgesia involving treatments in patients past the remission age of BECTS have a risk of refractory SE and should be carefully evaluated and monitored during such procedures, especially when treatment with AEDs have been withdrawn or changed.\n\nAuthor contributions\nData curation: Yingfeng Xiao.\n\nFunding acquisition: Weixi Xiong, Dong Zhou.\n\nInvestigation: Lu Lu, Weixi Xiong, Yingfeng Xiao.\n\nMethodology: Lu Lu, Weixi Xiong, Yingying Zhang.\n\nProject administration: Dong Zhou.\n\nWriting – original draft: Lu Lu.\n\nWriting – review & editing: Weixi Xiong, Yingying Zhang, Dong Zhou.\n\nDong Zhou orcid: 0000-0001-7101-4125.\n\nAbbreviations: ABFEC = atypical benign focal epilepsy of childhood, AEDs = anti-epileptic drugs, BECTS = benign epilepsy with centrotemporal spikes, CSWSS = continuous spike-and- waves during slow sleep, CT = computed tomography, ER = Emergency room, GTCS = generalized tonic-clonic seizure, i.v. = intravenous injection, ICU = intensive care unit, LEV = Levetiracetam, LKS = Landau-Kleffner syndrome, MRI = magnetic resonance imaging, OXC = oxcarbazepine, PICC = peripherally inserted central catheter, SE = status epilepticus, VPA = valproate.\n\nThe patient and the guardians have provided informed consent for publication of the case.\n\nThis work was supported by grants from the National Foundation of Natural Science of China (Grant Nos. 81801294, 81420108014, No. 81871017), grants from China Postdoctoral Science Foundation (Grant No. 2017M620427) and from Postdoctoral Research Foundation of Sichuan University (Grant No. 2018SCU12038).\n\nThe authors report no conflicts of interest in relation to this work.\n==== Refs\nReferences\n[1] Fisher RS Acevedo C Arzimanoglou A \nILAE official report: a practical clinical definition of epilepsy . Epilepsia \n2014 ;55 :475–82 .24730690 \n[2] Guerrini R Pellacani S \nBenign childhood focal epilepsies . Epilepsia \n2012 ;53 Suppl 4 :9–18 .\n[3] Panayiotopoulos CP Michael M Sanders S \nBenign childhood focal epilepsies: assessment of established and newly recognized syndromes . Brain \n2008 ;131 (Pt 9) :2264–86 .18718967 \n[4] 2010 ;Fejerman NJE \nAtypical rolandic epilepsy . 50 (s7) :9–12 .\n[5] Wickens S Bowden SC D'Souza WJE \nCognitive functioning in children with self-limited epilepsy with centrotemporal spikes: a systematic review and meta-analysis . Epilepsia \n2017 ;58 :1673.28801973 \n[6] Eliel T Hadassa GS Bruria BZ \nThe prevalence of atypical presentations and comorbidities of benign childhood epilepsy with centrotemporal spikes . Epilepsia \n2011 ;52 :1483–8 .21692792 \n[7] Aldenkamp A Besag F Gobbi G \nPsychiatric and behavioral disorders in children with epilepsy (ILAE Task Force Report): adverse cognitive and behavioral effects of antiepileptic drugs in children . Epileptic Disord \n2016 ;18 (s1) :S55–67 .\n[8] Tristano I Nicita F Garone G \nCould Rolandic spikes be a prognostic factor of the neurocognitive outcome of children with BECTS? \nEpilepsy Behav \n2018 ;86 :157–62 .30031676 \n[9] Fejerman N Di BAJE \nStatus epilepticus of benign partial epilepsies in children: report of two cases . Epilepsia \n1987 ;28 :351–5 .3113924 \n[10] Gregory DL Kevin F Wong PKH \nPartial status epilepticus in benign childhood epilepsy with centrotemporal spikes: are independent right and left seizures a risk factor? \nEpilepsia \n2010 ;43 :936–40 .\n[11] Fejerman N Caraballo R Tenembaum SN \nAtypical evolutions of benign localization-related epilepsies in children: are they predictable? \nEpilepsia \n2000 ;41 :380–90 .10756401 \n[12] Wirrell EC Camfield PR Gordon KE \nBenign rolandic epilepsy: atypical features are very common . J Child Neurol \n1995 ;10 :455.8576555 \n[13] Peters JM Camfield CS Camfield PR \nPopulation study of benign rolandic epilepsy: is treatment needed? \nNeurology \n2001 ;57 :537.11502931 \n[14] Carol SC Peter RCJN \nRolandic epilepsy has little effect on adult life 30 years later: a population-based study . Neurology \n2014 ;82 :1162.24562059 \n[15] Tovia E Goldberg-Stern H Ben Zeev B \nThe prevalence of atypical presentations and comorbidities of benign childhood epilepsy with centrotemporal spikes . Epilepsia \n2011 ;52 :1483–8 .21692792 \n[16] Callenbach PMC Bouma PAD Geerts AT \nLong term outcome of benign childhood epilepsy with centrotemporal spikes: Dutch study of epilepsy in childhood . Seizure \n2010 ;19 :501–6 .20688544 \n[17] Anita D D Barry SJPN \nBenign epilepsy of childhood with rolandic spikes: typical and atypical variants . Pediatr Neurol \n2007 ;36 :141–5 .17352945 \n[18] Ma CKL Chan KYJB \nDevelopment Benign childhood epilepsy with centrotemporal spikes: a study of 50 Chinese children . Brain Dev \n2003 ;25 :390–5 .12907271 \n[19] Ramos-Lizana J Aguirre-Rodríguez J Aguilera-López P \nRecurrence risk after withdrawal of antiepileptic drugs in children with epilepsy: a prospective study . Eur J Paediatr Neurol \n2010 ;14 :116–24 .19541516 \n[20] Berg AT Shlomo S Levy SR \nTwo-year remission and subsequent relapse in children with newly diagnosed epilepsy . Epilepsia \n2001 .\n[21] Arhan E Serdaroglu A Ozturk Z \nSerial changes in the paroxysmal discharges in rolandic epilepsy may predict seizure recurrence: a retrospective 3-year follow-up study . Epilepsy Behav \n2018 ;82 :150–4 .29625366 \n[22] Camfield CS Berg A Stephani U \nTransition issues for benign epilepsy with centrotemporal spikes, nonlesional focal epilepsy in otherwise normal children, childhood absence epilepsy, and juvenile myoclonic epilepsy . Epilepsia \n2014 ;55 Supplement s3 :16–20 .\n[23] Wang X \nSpecial cases of refractory status epilepticus \n2017 .\n[24] Cameron AE \nOpisthotonos again . Anaesthesia \n1987 ;42 :1124.3120616 \n[25] Makela JP Iivanainen M Pieninkeroinen IP \nSeizures associated with propofol anesthesia . Epilepsia \n1993 ;34 :832–5 .8404733 \n[26] Yanaru T Sugi Y Higa K \nPropofol-induced generalized tonic-clonic seizure: a case report . Masui \n2010 ;59 :1036–8 .20715536 \n[27] Voss LJ Sleigh JW Barnard JPM \nThe howling cortex: seizures and general anesthetic drugs . Anesth Analg \n2008 ;107 :1689–703 .18931234 \n[28] 2014 ;Xiaojuan Z Xuefeng WJERoN \nAnesthesia-induced epilepsy: causes and treatment . 14 :1099–113 .\n[29] 2012 ;Brophy GM Rodney B Jan C \nGuidelines for the evaluation and management of status epilepticus . 17 :3–23 .\n[30] Glauser T Shinnar S Gloss D \nEvidence-based guideline: treatment of convulsive status epilepticus in children and adults: report of the guideline committee of the American epilepsy society . Epilepsy Curr \n2016 ;16 :48.26900382 \n[31] 2012 ;Monica F Simon SJBAJoN \nThe outcome of therapies in refractory and super-refractory convulsive status epilepticus and recommendations for therapy . 135 (Pt 8) :2314.\n[32] Kim MJ Lim DG Yeo JS \nRefractory status epilepticus occurred at the end of sevoflurane anesthesia in patient with epilepsy . Korean J Anesthesiol \n2013 ;65 :93–4 .23904950 \n[33] Shetty A Pardeshi S Shah VM \nAnesthesia considerations in epilepsy surgery . Int J Surg (London, England) \n2016 ;36 (Pt B) :454–9 .\n[34] Bajwa SJ Jindal R \nEpilepsy and nonepilepsy surgery: Recent advancements in anesthesia management . Anesth Essays Res \n2013 ;7 :10–7 .25885713 \n[35] Maranhao MV Gomes EA de Carvalho PE \nEpilepsy and anesthesia . Rev Bras Anestesiol \n2011 ;61 :232–41 . 242-254, 124-236 .21474031\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "98(27)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000293:Adolescent; D004569:Electroencephalography; D019305:Epilepsy, Rolandic; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D008279:Magnetic Resonance Imaging; D015742:Propofol; D013226:Status Epilepticus; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e16257",
"pmc": null,
"pmid": "31277145",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Propofol-induced refractory status epilepticus at remission age in benign epilepsy with centrotemporal spikes: A case report and literature review.",
"title_normalized": "propofol induced refractory status epilepticus at remission age in benign epilepsy with centrotemporal spikes a case report and literature review"
} | [
{
"companynumb": "CN-FRESENIUS KABI-FK201908463",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": "1",
... |
{
"abstract": "Varicella zoster virus (VZV) reactivates more frequently in immunocompromised patients than immunocompetent subjects and is a significant cause of morbidity and mortality. Acyclovir is frequently used for treatment against VZV reactivation. However, long-term use of acyclovir can result in the emergence of VZV strain resistant to acyclovir. Here, we report a 67-year-old man with adult T-cell leukemia who suffered from herpes zoster with acyclovir-resistant VZV after long-term prophylaxis. The isolated viruses from his skin lesions were a mixture of acyclovir-resistant and acyclovir-susceptible strains. Sequence analysis showed the presence of thymidine kinase (TK) mutations in the resistant clones. Interestingly, oral administration of famciclovir, a prodrug form of penciclovir, resulted in resolution of his herpes zoster, although most acyclovir-resistant strains of VZV were reported to be resistant to penciclovir. This implied that a certain amount of susceptible VZV with wild-type viral TK gene was present in vivo, and that famciclovir could be phosphorylated intracellularly by the intact viral kinases. As famciclovir is more potent and longer-acting than acyclovir, the susceptible strains might have suppressed the generation and proliferation of the resistant in vivo. Even when VZV is developing resistance to acyclovir, famciclovir might be effective at least in the early resistant phase.",
"affiliations": "Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Hematology, Kansai Electrical Power Hospital, Osaka, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Department of Hematology, Kyoto-Katsura Hospital, Kyoto, Japan. Electronic address: hishiza@kuhp.kyoto-u.ac.jp.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Senri Kinran University, Osaka, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.",
"authors": "Oka|Tomomi|T|;Hishizawa|Masakatsu|M|;Yamashita|Kouhei|K|;Shiraki|Kimiyasu|K|;Takaori-Kondo|Akifumi|A|",
"chemical_list": "D000998:Antiviral Agents; D000077595:Famciclovir; D000212:Acyclovir",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2020.12.013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "27(5)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Acyclovir; Famciclovir; Mutation; Thymidine kinase (TK); Varicella zoster virus (VZV)",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000212:Acyclovir; D000368:Aged; D000998:Antiviral Agents; D000077595:Famciclovir; D006562:Herpes Zoster; D014645:Herpesvirus 3, Human; D006801:Humans; D008297:Male",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "755-758",
"pmc": null,
"pmid": "33358593",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Successful treatment with famciclovir for varicella zoster virus infection resistant to acyclovir.",
"title_normalized": "successful treatment with famciclovir for varicella zoster virus infection resistant to acyclovir"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1874537",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "A 61-year-old woman with a left main lesion and coronary spastic angina was scheduled for off-pump coronary artery bypass grafting (OPCAB). She had been orally receiving selective serotonin reuptake inhibitor( SSRI) for the treatment of depression. OPCAB to left anterior discending artery( LAD) and left circumflex branch (LCX) was performed using the bilateral internal thoracic arteries assisted by intra-aortic balloon pumping. When the sternotomy was going to be closed, ST elevation of electrocardiogram (ECG) occurred and was followed by complete atrio-ventricular (AV) block. After returning to intensive care unit (ICU), the patient showed rapid elevation of the body temperature, excessive sweating, progressive metabolic acidosis, and abnormal high levels in white blood cell count and creatine phosphokinase. On suspicion of neuroleptic malignant syndrome(NMS) onset, dantrolene sodium hydrate was administered, resulting in marked improvement of the symptoms. We have concluded that this case was an NMS combined with coronary artery spasm during OPCAB treated successfully with dantrolene sodium hydrate.",
"affiliations": "Department of Cardiovascular Surgery, Sendai Open Hospital, Sendai, Japan.",
"authors": "Mori|Akiko|A|;Yamaya|Kazuhiro|K|;Nitta|Yoshio|Y|;Yoshida|Seijiro|S|",
"chemical_list": "D009125:Muscle Relaxants, Central; D003620:Dantrolene",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-5252",
"issue": "67(3)",
"journal": "Kyobu geka. The Japanese journal of thoracic surgery",
"keywords": null,
"medline_ta": "Kyobu Geka",
"mesh_terms": "D047549:Coronary Artery Bypass, Off-Pump; D003329:Coronary Vasospasm; D003620:Dantrolene; D005260:Female; D006801:Humans; D008875:Middle Aged; D009125:Muscle Relaxants, Central; D009459:Neuroleptic Malignant Syndrome",
"nlm_unique_id": "0413533",
"other_id": null,
"pages": "247-50",
"pmc": null,
"pmid": "24743539",
"pubdate": "2014-03",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Coronary artery spasm induced by neuroleptic malignant syndrome during off-pump coronary artery bypass grafting; report of a case.",
"title_normalized": "coronary artery spasm induced by neuroleptic malignant syndrome during off pump coronary artery bypass grafting report of a case"
} | [
{
"companynumb": "PHHY2015JP089667",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISOSORBIDE DINITRATE"
},
"drugadditional": null,
... |
{
"abstract": "Hereditary hyperferritinemia-cataract syndrome (HHCS) is an autosomal dominant disorder manifesting with high serum ferritin levels and the formation of early-onset cataracts, with numerous small opacities, predominantly in the lens cortex. HHCS is caused by mutations in the iron-responsive element of the FTL gene. The aim of this study was to establish a molecular diagnosis in three Czech probands with suspected HHCS.\n\n\n\nA complex ocular and systemic evaluation, including ferritin and iron measurements, was performed. The 5' untranslated region of FTL was directly sequenced in all available family members, followed by paternity testing in one family.\n\n\n\nThree different FLT pathogenic variants (c.-161C>T, c.-167C>T, and c.-168G>C) present in the heterozygous state were detected in each of the 3 probands. Two segregated with the disease phenotype within the families, but c.-167C>T occurred de novo (confirmed by paternity testing). Prior to establishing molecular diagnosis, two probands were misdiagnosed with hemochromatosis. One individual, aged 43 years, underwent phlebotomy; another, aged 8.5 years, was treated with the iron chelator deferasirox, leading to life-threatening acute hyperammonemia, without severe liver injury.\n\n\n\nLack of family history does not exclude HHCS, because the pathogenic variant can arise de novo. Noncoding regions are often omitted from diagnostic gene panels, thus evading detection. Careful clinical evaluations and targeted genetic screening are important for avoiding potentially harmful treatments.",
"affiliations": "Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.;Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic.;Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.;Department of Pediatric Hematology and Oncology, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.;Department of Biology and Medical Genetics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic.;Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.;Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic; Department of Ophthalmology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.;Research Unit for Rare Diseases, Department of Paediatrics and Inherited Metabolic Disorders, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic. Electronic address: lubica.dudakova@lf1.cuni.cz.",
"authors": "Moravikova|Jana|J|;Honzik|Tomas|T|;Jadvidzakova|Eva|E|;Zdrahalova|Katerina|K|;Kremlikova Pourova|Radka|R|;Korbasova|Marta|M|;Liskova|Petra|P|;Dudakova|Lubica|L|",
"chemical_list": "D001052:Apoferritins",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaapos.2020.07.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1091-8531",
"issue": "24(6)",
"journal": "Journal of AAPOS : the official publication of the American Association for Pediatric Ophthalmology and Strabismus",
"keywords": null,
"medline_ta": "J AAPOS",
"mesh_terms": "D001052:Apoferritins; D002386:Cataract; D018153:Czech Republic; D006801:Humans; D000085583:Hyperferritinemia; D008967:Molecular Biology; D009154:Mutation; D010375:Pedigree",
"nlm_unique_id": "9710011",
"other_id": null,
"pages": "352.e1-352.e5",
"pmc": null,
"pmid": "33221470",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hereditary hyperferritinemia-cataract syndrome in three Czech families: molecular genetic testing and clinical implications.",
"title_normalized": "hereditary hyperferritinemia cataract syndrome in three czech families molecular genetic testing and clinical implications"
} | [
{
"companynumb": "CZ-BION-009280",
"fulfillexpeditecriteria": "1",
"occurcountry": "CZ",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEFERASIROX"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "The use of methylene blue for vasoplegia in cardiac cases with cardiopulmonary bypass, septic shock, and acute liver failure is well documented. Use of MB for liver transplantation has been largely limited to case reports. We describe three separate liver transplantation patients with significant hypotension following reperfusion. Administration of methylene blue to each patient resulted in a significant decrease in vasopressor medication and two patients weaned completely. We argue that the use of MB should be considered as a treatment option for refractory hypotension.",
"affiliations": "University of Nebraska Medical Center-College of Medicine, Nebraska Medical Center, Omaha 68198-5520, NE, USA.;University of Nebraska Medical Center-Department of Anesthesiology, Nebraska Medical Center, Omaha 68198-7541, NE, USA.;University of Nebraska Medical Center-Department of Anesthesiology, Nebraska Medical Center, Omaha 68198-7541, NE, USA.",
"authors": "Harding|Paul|P|;Nicholas|Thomas|T|https://orcid.org/0000-0001-7060-6786;Kassel|Cale|C|https://orcid.org/0000-0003-2742-4674",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/6610754",
"fulltext": "\n==== Front\nCase Rep Anesthesiol\nCase Rep Anesthesiol\nCRIA\nCase Reports in Anesthesiology\n2090-6382\n2090-6390\nHindawi\n\n10.1155/2021/6610754\nCase Report\nThe Use of Methylene Blue during Liver Transplantation for Vasoplegia\nHarding Paul 1\nhttps://orcid.org/0000-0001-7060-6786\nNicholas Thomas 2\nhttps://orcid.org/0000-0003-2742-4674\nKassel Cale cale.kassel@unmc.edu\n2\n1University of Nebraska Medical Center—College of Medicine, Nebraska Medical Center, Omaha 68198-5520, NE, USA\n2University of Nebraska Medical Center—Department of Anesthesiology, Nebraska Medical Center, Omaha 68198-7541, NE, USA\nAcademic Editor: Sylvia Bele\n\n2021\n23 6 2021\n2021 661075412 1 2021\n3 6 2021\n14 6 2021\nCopyright © 2021 Paul Harding et al.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nThe use of methylene blue for vasoplegia in cardiac cases with cardiopulmonary bypass, septic shock, and acute liver failure is well documented. Use of MB for liver transplantation has been largely limited to case reports. We describe three separate liver transplantation patients with significant hypotension following reperfusion. Administration of methylene blue to each patient resulted in a significant decrease in vasopressor medication and two patients weaned completely. We argue that the use of MB should be considered as a treatment option for refractory hypotension.\n==== Body\n1. Introduction\n\nTraditionally used in the treatment of methemoglobinemia, methylene blue (MB) use for refractory hypotension was first described in sepsis and cardiac surgery [1, 2]. In liver transplantation (LT), the consequences of postreperfusion syndrome (PRS) and ischemia-reperfusion injury can be challenging to manage for anesthesiologists. The use of MB in LT can be a useful medication in management refractory hypotension and vasoplegia. We present three cases of the use of MB in LT as a potential therapy and suggest a simple stepwise approach to vasoplegia in LT.\n\n2. Case Series\n\n2.1. Case One\n\nA 63-year-old female presented for a LT from a donation after brain death (DBD) donor. Her first LT was in 1997 for primary sclerosing cholangitis. Since that time, she developed worsening hepatic encephalopathy, refractory ascites, portal hypertension, and hepatorenal syndrome (not requiring dialysis). Her MELD score at the time of her transplant was 36. She also was found to have a left ventricular outflow tract (LVOT) gradient on dobutamine stress echocardiography (DSE). Given her previous LT and DSE findings, we elected to utilize veno-venous bypass with a portal shunt for her LT.\n\nFollowing induction, she was started on phenylephrine infusion at 50 mcg/min and norepinephrine infusion at 2 mcg/min was added for blood pressure support. The phenylephrine was increased to 100 mcg/min and norepinephrine to 4 mcg/min with incremental boluses during dissection.\n\nThe duration of anhepatic phase was 50 minutes. She tolerated initiation of veno-venous bypass as well as total caval occlusion without significant changes in hemodynamics. Upon reperfusion, there was marked hypotension secondary to combined hypovolemia and low SVR (283 Dynes/sec/cm5) Left ventricular ejection fraction of 65–70% was confirmed by transesophageal echocardiography. Although the patient had a preoperative diagnosis of LVOT obstruction, it was felt that the patient did not have clinically significant obstruction after interrogation with 2D and color flow Doppler. Though blood loss was significant throughout the case (>6 L estimated), she was resuscitated adequately as assessed by TEE. Her worsening hypotension required continued phenylephrine at 50 mcg/min, norepinephrine up to 20 mcg/min, and vasopressin at 0.04 units/min. As we were unable to maintain our goal mean arterial pressure (MAP) of 65 mmHg, the decision was made to administer methylene blue (1 mg/kg). As seen in Figure 1, her hemodynamics improved and no longer required escalating doses of vasoactive medications. Figure 2shows that though she remained on vasopressin (0.04 units/min) and norepinephrine (8 mcg/min) when transferred to the ICU, her clinical picture improved. Her pH before arriving in the ICU was 7.41 (from 7.26) and lactic acid decreased from 7.8 to 5.5 within 1 hour of giving methylene blue.\n\n2.2. Case Two\n\nA 49-year-old female with a history of nonalcoholic steatohepatitis (NASH) cirrhosis, type II diabetes mellitus, hypertension, and chronic obstructive pulmonary disease underwent LT. Her Model for End-Stage Liver Disease (MELD) score was 25 before transplant. She received a donation after cardiac death (DCD) organ for her LT. During the preanhepatic phase, she required intermittent bolus doses of phenylephrine (500 mcg total). Seven minutes before IVC clamping, she was started on epinephrine infusion at 3 mcg/min and phenylephrine infusion at 20 mcg/min for hypotension. During the anhepatic phase (74 minutes), she required similar doses of epinephrine and phenylephrine. After reperfusion, the epinephrine infusion was increased to 10 mcg/min and phenylephrine dose was increased to 150 mcg/min. Vasopressin infusion was also added 45 minutes after reperfusion at 0.04 units/min. The patient remained tachycardic and hypotensive despite these efforts. Transesophageal echocardiography (TEE) revealed a hyperdynamic state with a low SVR (416 dynes/sec/cm5). Additionally, normal cardiac filling volumes were present, indicating adequate resuscitation even with a MAP less than 65 mmHg. At this time, we elected to administer methylene blue (MB) for refractory hypotension. She was given a total of 100 mg over 20 minutes. Figures 3 and 4 show the effects of MB on her blood pressure and we were able to rapidly wean down her vasopressor requirements. Upon transfer to the ICU, she required no vasoactive medications.\n\n2.3. Case Three\n\nThe final case involved a 65-year-old male with hepatocellular carcinoma presenting for LT. Past medical history included hypertension, hyperlipidemia, insulin-dependent type 2 diabetes mellitus, and hypothyroidism. From induction to the anhepatic phase, he remained remarkably stable. However, during the anhepatic phase, the patient became hypotensive with underfilled ventricles requiring norepinephrine infusion up to 16 mcg/min. Initially, the patient was stable after, but became increasingly hypotensive despite volume resuscitation. Systemic vascular resistance was low (653 Dynes/sec/cm5) and vasopressin was then added at 0.04 units/min in addition to norepinephrine at 16 mcg/min. Blood loss was significant (>7 L was estimated), but the patient received a significant amount of blood products that included 22 units of plasma, 8 units of red blood cells, and 5.7 L of crystalloid. His volume status was watched throughout the procedure utilizing TEE. Given that he received a donation after cardiac death (DCD) organ and was requiring significant vasoactive medication to support a MAP of 65 mmHg, the decision was made to administer MB (50 mg). This improved his hemodynamics quickly as noted in Figure 5. Figure 6shows that 22 minutes after administration of MB, the norepinephrine infusion was discontinued. Vasopressin was discontinued 32 minutes after MB administration.\n\n3. Discussion\n\nThe use of MB for refractory hypotension continues to be an area of interest during liver transplantation. Based on evidence from sepsis, cardiac surgery, and acute liver failure, successful use of MB in LT has been described over the years in various case reports [3–5]. Though limited to case reports, a growing body of evidence suggests MB can be useful for hypotension refractory to standard therapies during LT.\n\nPostreperfusion syndrome (PRS) was first described in 1987 as a “transient, profound cardiovascular collapse” following reperfusion of the new liver [6]. This included decreases in mean arterial pressure (MAP) and systemic vascular resistance (SVR) with increased pulmonary artery pressure (PAP) and pulmonary capillary wedge pressure (PCWP). Hilmi expanded on the definition classifying PRS as either mild or significant [7]. A hallmark of significant PRS is the need for vasopressor infusion intraoperatively. The incidence of PRS varies widely from as low as 8% to rates as high as 77% [8, 9].\n\nWhile PRS has a distinct set conditions immediately following graft reperfusion, vasoplegia is often harder to describe. A key element of vasoplegia is low SVR, often in the setting of normal or increased cardiac output (CO) [10]. Commonly associated with cardiac surgery, it can be seen in noncardiac surgery, sepsis, and perioperative use of angiotensin-converting enzyme inhibitors (ACE-I) [11]. The incidence of vasoplegia in LT is hard discerned owing to the lack of universally accepted criteria and overlap with PRS. Release of nitric oxide, carbon monoxide, and hydrogen sulfide all contribute to vasodilation as well as a deficiency of vasopressin [12].\n\nA heterocyclic aromatic dye, MB, can be used as a treatment of methemoglobin or as an indicator dye. More recently, understanding how MB inhibits nitric oxide synthase and reduces the production of nitric oxide (NO) created new opportunities for MB use in perioperative care of LT patients.\n\nOne of the first published reports of MB use in LT was by Koelzow et al. [13] in 2002. In their study, they described the hemodynamic effects of PRS described above and postulated the use of MB could be used to improve specific hemodynamic parameters after reperfusion. After randomizing 36 patients to receive MB or normal saline before graft reperfusion, they compared MAP, cardiac index (CI), and systemic vascular resistance (SVR). There was not a significant difference in SVR between the two groups. Serum lactate was also significantly lower in the MB group at 1 hour compared to the control group. Graft function and length of stay were not statistically different between the MB group and control group. Even with the small number of patients, this study offered insight into how MB could be a valuable tool in PRS.\n\nFukazawa and Pretto retrospectively reviewed 715 LT patients and the propensity score matched those who received MB to those who did not [14]. A total of 105 patients received MB and were largely similar to the control group, except for the MB group being older (55.5 ± 0.9 vs. 53.1 ± 0.8 years, p = 0.026). The rate of PRS was similar between the two groups (55.7% vs. 55.8%, p = 0.993). Overall, there were no significant differences in percent changes in MAP after reperfusion, use of vasopressors within 30 minutes of reperfusion, or postreperfusion vasopressor use. Transfusion requirements were not significantly different either.\n\nOther case reports on the use of MB in LT are limited, but have shown success in improving vasoplegia. Cao et al. reported the use of MB for vasoplegia following reperfusion of the liver. The patient required increasing doses of norepinephrine and despite this their SVR remained low (369 dynes/s/cm2). A single dose of 0.5 mg/kg of MB was administered with improvement in blood pressure and SVR. Ultimately, norepinephrine was weaned off within three hours of arriving in the ICU [5]. Another case report from Levin et al. described a similar use of MB in a LT [2]. Despite the use of three different vasopressor medications, TEE showed an elevated CO and low SVR. A dose of MB at 2 mg/kg (over 30 minutes) followed by an infusion at 0.5 mg/kg/h improved the patient's hemodynamics improved promptly and they were able to wean two of the three vasopressor medications. Finally, Daemen-Gubbels et al. described three patients who received MB during LT at various stages in the procedure [1]. Two of the three patients received 100 mg doses of MB and the third was given 1.5 mg/kg all with good response and improvement in hemodynamics.\n\nAll three of our patients described had low SVR based on TEE findings, consistent with some degree of vasoplegia. In fact, most of the challenges of hypotension in these patients were during the neohepatic period after the period when PRS would be the concern. Wagener et al. noted that routine use of MB in LT did not prevent postreperfusion hypotension, decrease transfusion requirements, or decrease vasopressor use. However, those that received MB were at the provider's discretion and typically given before reperfusion, not after reperfusion [12]. Most case reports including ours report administration of MB after reperfusion. Perhaps, as Cao and Tao noted in an editorial response, MB is better suited for the treatment of VS not PRS [15]. Specifically, VS and the association with increased NO may explain why MB works better when administered following reperfusion [16]. As many of the other case reports noted, initial reperfusion was challenging but the hypotension and vasopressor requirements continued past the initial 5 minutes. This differs from the conclusion of the Koelzow et al.'s study which was “a single bolus of MB has limited capacity to prevent hypotension immediately following portal revascularization and reperfusion” [13]. Indeed, we would not argue for the routine use of MB in LT patients. Evidence to date does not support routine use of MB, and further studies to identify patients in which MB would be beneficial are needed [17].\n\nHow best then should anesthesiologists utilize MB during LT? We argue for a stepwise approach to vasoplegia in LT patients to rule out common causes of hypotension before utilizing MB. Review of laboratory findings to should focus on ensuring appropriate hemoglobin and calcium levels. Utilization of a thromboelastogram (TEG) to guide transfusion and assess coagulation status is also useful [18]. Use of TEE can be helpful to guide assessment volume, rule out pulmonary embolism, evaluate ventricular function, and assess SVR [19]. As described in our cases, we recognized that volume status (as measured by CO) was adequate, yet SVR remained low despite multiple vasopressors. Vasopressors such as norepinephrine, epinephrine, or phenylephrine remain the standard treatment for VS, but some cases remain refractory to treatment. The choice of vasoactive medication should be based on clinical findings, but vasopressin may be useful as a first line agent given the relative deficiency in ESLD [12]. After review of laboratory and TEG findings and TEE assessment, if the use of vasoactive medications continues to increase or fail to improve hemodynamic parameters, MB should be considered if there are no contraindications.\n\nThe use of MB remains a useful option in vasoplegia and PRS for transplant anesthesiologists. We argue in favor of establishing protocols for their use during LT. By standardizing the approach to the use of MB, other causes of hypotension can be ruled out before administration. Despite the benefits described in case studies, there remains a lack of randomized controlled trials describing their use in LT.\n\nData Availability\n\nThe data used to support the findings of this study are included within the article.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Vital signs from IVC clamp until 90 minutes following MB administration. IVC, inferior vena cava; PV, portal vein; PR, postreperfusion; MB, methylene blue.\n\nFigure 2 Vasoactive medication use during case #1.\n\nFigure 3 Vital signs from IVC clamp until 90 minutes following MB administration.\n\nFigure 4 Vasoactive medication use during case #2.\n\nFigure 5 Vital signs from IVC clamp until 90 minutes following MB administration.\n\nFigure 6 Vasoactive medication use during case #3.\n==== Refs\n1 Daemen-Gubbels C. R. Groeneveld P. H. Groeneveld A. B. van Kamp G. J. Bronsveld W. Thijs L. G. Methylene blue increases myocardial function in septic shock Critical Care Medicine 1995 23 8 1363 1370 10.1097/00003246-199508000-00009 2-s2.0-0029085244 7634806\n2 Levin R. L. Degrange M. A. Bruno G. F. Methylene blue reduces mortality and morbidity in vasoplegic patients after cardiac surgery The Annals of Thoracic Surgery 2004 77 2 496 499 10.1016/s0003-4975(03)01510-8 2-s2.0-0442292295 14759425\n3 Cheng S. S. Berman G. W. Merritt G. R. The response to methylene blue in patients with severe hypotension during liver transplantation Journal of Clinical Anesthesia 2012 24 4 324 328 10.1016/j.jclinane.2011.10.010 2-s2.0-84861176827 22608589\n4 Fischer G. W. Bengtsson Y. Scarola S. Cohen E. Methylene blue for vasopressor-resistant vasoplegia syndrome during liver transplantation Journal of Cardiothoracic and Vascular Anesthesia 2010 24 3 463 466 10.1053/j.jvca.2008.07.015 2-s2.0-77952585421 18835528\n5 Cao Z. Gao Y. Tao G. Vasoplegic syndrome during liver transplantation Anesthesia & Analgesia 2009 108 6 1941 1943 10.1213/ane.0b013e3181a286fc 2-s2.0-66349117699 19448226\n6 Aggarwal S. Kang Y. Freeman J. A. Fortunato F. L. Pinsky M. R. Postreperfusion syndrome: cardiovascular collapse following hepatic reperfusion during liver transplantation Transplantation Proceedings 1987 19 4 Suppl 3 54 55\n7 Hilmi I. Horton C. N. Planinsic R. M. The impact of postreperfusion syndrome on short-term patient and liver allograft outcome in patients undergoing orthotopic liver transplantation Liver Transplantation 2008 14 4 504 508 10.1002/lt.21381 2-s2.0-42149179173 18383079\n8 Manning M. W. Kumar P. A. Maheshwari K. Arora H. Post-reperfusion syndrome in liver transplantation-an overview Journal of Cardiothoracic and Vascular Anesthesia 2020 34 2 501 511 10.1053/j.jvca.2019.02.050 2-s2.0-85065439177 31084991\n9 Chung I. S. Jee H. S. Han S. Effect of prereperfusion ephedrine on postreperfusion syndrome and graft function in living donor liver transplantation Transplantation Proceedings 2017 49 8 1815 1819 10.1016/j.transproceed.2017.05.009 2-s2.0-85031734102 28923631\n10 Lambden S. Creagh-Brown B. C. Hunt J. Summers C. Forni L. G. Definitions and pathophysiology of vasoplegic shock Critical Care 2018 22 1 p. 174 10.1186/s13054-018-2102-1 2-s2.0-85049629337\n11 Webb A. J. Seisa M. O. Nayfeh T. Wieruszewski P. M. Nei S. D. Smischney N. J. Vasopressin in vasoplegic shock: a systematic review World Journal of Critical Care Medicine 2020 9 5 88 98 10.5492/wjccm.v9.i5.88 33384951\n12 Wagener G. Kovalevskaya G. Minhaz M. Mattis F. Emond J. C. Landry D. W. Vasopressin deficiency and vasodilatory state in end-stage liver disease Journal of Cardiothoracic and Vascular Anesthesia 2011 25 4 665 670 10.1053/j.jvca.2010.09.018 2-s2.0-80052751028 21126886\n13 Koelzow H. Gedney J. A. Baumann J. Snook N. J. Bellamy M. C. The effect of methylene blue on the hemodynamic changes during ischemia reperfusion injury in orthotopic liver transplantation Anesthesia & Analgesia 2002 94 4 824 829 10.1097/00000539-200204000-00009 2-s2.0-0036210418 11916779\n14 Fukazawa K. Pretto E. A. The effect of methylene blue during orthotopic liver transplantation on post reperfusion syndrome and postoperative graft function Journal of Hepato-Biliary-Pancreatic Sciences 2011 18 3 406 413 10.1007/s00534-010-0344-7 2-s2.0-79958272044 21104279\n15 Cao Z. Tao G. Is it possible to distinguish between vasoplegic syndrome and postreperfusion syndrome during liver graft reperfusion? Anesthesia & Analgesia 2010 110 3 10.1213/ane.0b013e3181c9982c 2-s2.0-77949310548\n16 Shanmugam G. Vasoplegic syndrome-the role of methylene blue European Journal of Cardio-Thoracic Surgery 2005 28 5 705 710 10.1016/j.ejcts.2005.07.011 2-s2.0-27544434008 16143539\n17 Andritsos M. J. Con: methylene blue should not be used routinely for vasoplegia perioperatively Journal of Cardiothoracic and Vascular Anesthesia 2011 25 4 739 743 10.1053/j.jvca.2011.04.007 2-s2.0-80052769792 21684763\n18 Hawkins R. B. Raymond S. L. Hartjes T. Review: the perioperative use of thromboelastography for liver transplant patients Transplantation Proceedings 2018 50 10 3552 3558 10.1016/j.transproceed.2018.07.032 2-s2.0-85058561603 30577236\n19 Gold A. K. Patel P. A. Lane-Fall M. Cardiovascular collapse during liver transplantation-echocardiographic-guided hemodynamic rescue and perioperative management Journal of Cardiothoracic and Vascular Anesthesia 2018 32 5 2409 2416 10.1053/j.jvca.2018.01.050 2-s2.0-85042907108 29525193\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6390",
"issue": "2021()",
"journal": "Case reports in anesthesiology",
"keywords": null,
"medline_ta": "Case Rep Anesthesiol",
"mesh_terms": null,
"nlm_unique_id": "101581025",
"other_id": null,
"pages": "6610754",
"pmc": null,
"pmid": "34258070",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "21126886;22608589;28923631;29980217;7634806;30577236;31084991;18383079;18835528;11916779;21684763;29525193;3303534;33384951;14759425;19448226;16143539;20185672;21104279",
"title": "The Use of Methylene Blue during Liver Transplantation for Vasoplegia.",
"title_normalized": "the use of methylene blue during liver transplantation for vasoplegia"
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"abstract": "Standard treatment for placental site trophoblastic tumor is hysterectomy. This may be unacceptable to women desiring fertility. Cells aberrant in placental site trophoblastic tumor display an ability to invade normal tissue while evading the immune system.\n\n\n\nWe present a case of a 23-year-old woman with stage I placental site trophoblastic tumor who declined hysterectomy. Tumor assay for program cell death-ligand 1 staining was performed and suggestive of an immune-responsive tumor. The patient initiated intravenous pembrolizumab 200 mg every 2 weeks, and by cycle 3 her β-hCG level fell to undetectable. She subsequently conceived and went on to have an uncomplicated term vaginal birth after cesarean. At 6 weeks postpartum, she remained without evidence of disease.\n\n\n\nImmunotherapy can eliminate early program cell death-ligand 1-positive placental site trophoblastic tumor with subsequent normal pregnancy.",
"affiliations": "Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Washington University in St. Louis School of Medicine, Saint Louis, Missouri.",
"authors": "Polnaszek|Brock|B|;Mullen|Mary|M|;Bligard|Katherine|K|;Raghuraman|Nandini|N|;Massad|L Stewart|LS|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab",
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0000000000004434",
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"issn_linking": "0029-7844",
"issue": "138(1)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D005260:Female; D006801:Humans; D007167:Immunotherapy; D011247:Pregnancy; D047929:Term Birth; D018245:Trophoblastic Tumor, Placental Site; D014594:Uterine Neoplasms; D055815:Young Adult",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "115-118",
"pmc": null,
"pmid": "34259474",
"pubdate": "2021-07-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Term Pregnancy After Complete Response of Placental Site Trophoblastic Tumor to Immunotherapy.",
"title_normalized": "term pregnancy after complete response of placental site trophoblastic tumor to immunotherapy"
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"companynumb": "US-009507513-2108USA003917",
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"abstract": "BACKGROUND\nSystemic diseases and their treatment influence aggressive posterior retinopathy of prematurity.\nA premature infant with aggressive posterior retinopathy of prematurity underwent laser treatment with a favourable outcome. She was started on oral sidenafil citrate for pulmonary hypertension. Ten days later she developed neovascularization within the lasered retina.\nConsidering the possible role of sildenafil in this unusual development, the drug was withdrawn resulting in regression of the neovascularization.\nThe clinician should be aware of this retinal adverse effect of sildanefil in neonates with aggressive posterior retinopathy of prematurity.",
"affiliations": "Departments of Pediatric Retina, Narayana Nethralaya Institute ; and #Neonatology, Columbia Asia Referral Hospital, Bangalore, India. Correspondence to: Dr Anand Vinekar, Department of Pediatric Retina, Narayana Nethralaya Eye Institute, 121C, 1st R Block, Rajajinagar, Bangalore 560010, India. anandvinekar@yahoo.com.",
"authors": "Jayadev|Chaitra|C|;Ramasastry|Phanibhushan|P|;Gul|Alia|A|;Vinekar|Anand|A|",
"chemical_list": "D014665:Vasodilator Agents; D000068677:Sildenafil Citrate",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0019-6061",
"issue": "53 Suppl 2()",
"journal": "Indian pediatrics",
"keywords": null,
"medline_ta": "Indian Pediatr",
"mesh_terms": "D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008028:Light Coagulation; D028022:Low-Level Light Therapy; D012178:Retinopathy of Prematurity; D000068677:Sildenafil Citrate; D014665:Vasodilator Agents",
"nlm_unique_id": "2985062R",
"other_id": null,
"pages": "S155-S156",
"pmc": null,
"pmid": "27915325",
"pubdate": "2016-11-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Possible Role of Sildenafil Citrate in the Recurrence of Neovascularization in Laser-regressed Aggressive Posterior ROP.",
"title_normalized": "possible role of sildenafil citrate in the recurrence of neovascularization in laser regressed aggressive posterior rop"
} | [
{
"companynumb": "IN-PFIZER INC-2016570881",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SILDENAFIL CITRATE"
},
"drugadditional": "1",
... |
{
"abstract": "Background Malignant brain tumors are unpredictable and incurable, with 5-year survival rates less than 30%. The poor prognosis combined with intensive treatment necessitates the inclusion of complementary and supportive therapies that optimize quality of life and reduce treatment-related declines in health. Exercise therapy has been shown to be beneficial in other cancer populations, but no evidence is available for brain cancer survivors. Therefore, we report results from 2 preliminary cases. Methods Two female patients diagnosed with glioblastoma multiforme and oligodendroglioma participated in a structured and supervised 12-week exercise program. The program consisted of two 1-hour resistance and aerobic exercise sessions per week and additional self-managed aerobic sessions. Outcome measures of strength, cardiovascular fitness, and several psychological indicators (depression, anxiety, and quality of life) were recorded at baseline, after 6 weeks and at the conclusion of the intervention. Results Exercise was well tolerated; both participants completed all 24 sessions and the home-based component with no adverse effects. Objective outcome measures displayed positive responses relating to reduced morbidity. Similar positive responses were found for psychological outcomes. Scores on the Hospital Anxiety and Depression Scale showed clinically meaningful improvements in depression and total distress. Conclusion These findings provide initial evidence that, despite the difficulties associated with brain cancer treatment and survivorship, exercise may be safe and beneficial and should be considered in the overall management of patients with brain cancer.",
"affiliations": "University of Calgary, AB, Canada Edith Cowan University, Perth, WA, Australia gregory.levin@ucalgary.ca.;Edith Cowan University, Perth, WA, Australia Capital Medical University, Beijing, PRC.;Edith Cowan University, Perth, WA, Australia.;St John of God Hospital, Subiaco, WA, Australia.;Edith Cowan University, Perth, WA, Australia.",
"authors": "Levin|Gregory T|GT|;Greenwood|Kenneth M|KM|;Singh|Favil|F|;Tsoi|Daphne|D|;Newton|Robert U|RU|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1534735415600068",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1534-7354",
"issue": "15(2)",
"journal": "Integrative cancer therapies",
"keywords": "anxiety; comprehensive cancer care; depression; exercise oncology; neuro-oncology",
"medline_ta": "Integr Cancer Ther",
"mesh_terms": "D001007:Anxiety; D001932:Brain Neoplasms; D003863:Depression; D015444:Exercise; D005081:Exercise Therapy; D005260:Female; D006801:Humans; D008603:Mental Health; D008875:Middle Aged; D011788:Quality of Life; D011795:Surveys and Questionnaires; D017741:Survivors",
"nlm_unique_id": "101128834",
"other_id": null,
"pages": "190-6",
"pmc": null,
"pmid": "26276806",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16367493;22539238;25768333;24694745;21694556;24042308;25905043;8315439;16444764;19949016;4053261;8055007;17671237;21690470;6880820;16420209;24424484;16709014;22786489;9555993;19016830;11180574;21972328;22658206;18830672;11832252;17635953;24399786;21664123;21339383;25768331;2748771;20559064;19548070",
"title": "Exercise Improves Physical Function and Mental Health of Brain Cancer Survivors: Two Exploratory Case Studies.",
"title_normalized": "exercise improves physical function and mental health of brain cancer survivors two exploratory case studies"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-311896",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TEMOZOLOMIDE"
},
"dr... |
{
"abstract": "Six patients are presented who developed pulmonary infiltrates of undetermined origin while being treated for severe ventricular arrhythmias with amiodarone hydrochloride. Biopsy material was available in four patients and revealed interstitial or alveolar fibrosis and pneumonitis. Four patients recovered and two died of severe cardiopulmonary decompensation; all of the patients who recovered received corticosteroid therapy. Pulmonary fibrosis is a previously unreported complication of amiodarone therapy.",
"affiliations": null,
"authors": "Sobol|S M|SM|;Rakita|L|L|",
"chemical_list": "D001572:Benzofurans; D000638:Amiodarone",
"country": "United States",
"delete": false,
"doi": "10.1161/01.cir.65.4.819",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-7322",
"issue": "65(4)",
"journal": "Circulation",
"keywords": null,
"medline_ta": "Circulation",
"mesh_terms": "D000328:Adult; D000368:Aged; D000638:Amiodarone; D001145:Arrhythmias, Cardiac; D001572:Benzofurans; D003327:Coronary Disease; D005260:Female; D006333:Heart Failure; D006801:Humans; D008168:Lung; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D011014:Pneumonia; D011658:Pulmonary Fibrosis",
"nlm_unique_id": "0147763",
"other_id": null,
"pages": "819-24",
"pmc": null,
"pmid": "7060263",
"pubdate": "1982-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pneumonitis and pulmonary fibrosis associated with amiodarone treatment: a possible complication of a new antiarrhythmic drug.",
"title_normalized": "pneumonitis and pulmonary fibrosis associated with amiodarone treatment a possible complication of a new antiarrhythmic drug"
} | [
{
"companynumb": "US-PFIZER INC-2017033473",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMIODARONE HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "OBJECTIVE\nWhile 6- to 12-month courses of isoniazid for tuberculosis prevention are considered safe in pregnant women, the effects of longer-term isoniazid prophylaxis or isoniazid in combination with antiretroviral therapy (ART) are not established in human-immunodeficiency-virus-(HIV-) infected women who experience pregnancy during the course of therapy.\n\n\nMETHODS\nNested study of pregnancy outcomes among HIV-infected women participating in a placebo-controlled, TB-prevention trial using 36 months daily isoniazid. Pregnancy outcomes were collected by interview and record review.\n\n\nRESULTS\nAmong 196 pregnant women, 103 (52.6%) were exposed to isoniazid during pregnancy; all were exposed to antiretroviral drugs. Prior to pregnancy they had received a median of 341 days (range 1-1095) of isoniazid. We observed no isoniazid-associated hepatitis or other severe isoniazid-associated adverse events in the 103 women. Pregnancy outcomes were 132 term live births, 42 premature births, 11 stillbirths, 8 low birth weight, 6 spontaneous abortions, 4 neonatal deaths, and 1 congenital abnormality. In a multivariable model, neither isoniazid nor ART exposure during pregnancy was significantly associated with adverse pregnancy outcome (adjusted odds ratios 0.6, 95% CI: 0.3-1.1 and 1.8, 95% CI 0.9-3.6, resp.).\n\n\nCONCLUSIONS\nLong-term isoniazid prophylaxis was not associated with adverse pregnancy outcomes, such as preterm delivery, even in the context of ART exposure.",
"affiliations": "Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention (CDC), National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, 1600 Clifton Road, NE MS E-45, Atlanta, GA 30333, USA. ataylor2@cdc.gov",
"authors": "Taylor|Allan W|AW|;Mosimaneotsile|Barudi|B|;Mathebula|Unami|U|;Mathoma|Anikie|A|;Moathlodi|Ritah|R|;Theebetsile|Irene|I|;Samandari|Taraz|T|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
"country": "Egypt",
"delete": false,
"doi": "10.1155/2013/195637",
"fulltext": "\n==== Front\nInfect Dis Obstet GynecolInfect Dis Obstet GynecolIDOGInfectious Diseases in Obstetrics and Gynecology1064-74491098-0997Hindawi Publishing Corporation 10.1155/2013/195637Research ArticlePregnancy Outcomes in HIV-Infected Women Receiving Long-Term Isoniazid Prophylaxis for Tuberculosis and Antiretroviral Therapy Taylor Allan W. \n1\n*Mosimaneotsile Barudi \n2\nMathebula Unami \n2\nMathoma Anikie \n2\nMoathlodi Ritah \n2\nTheebetsile Irene \n2\nSamandari Taraz \n2\n\n3\n1Division of HIV/AIDS Prevention, Centers for Disease Control and Prevention (CDC), National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, 1600 Clifton Road, NE MS E-45, Atlanta, GA 30333, USA2BOTUSA, CDA Gaborone and Francistown, Plot 14818 Lebatlane Road, Phase One, Gaborone, Botswana3Division of Tuberculosis Elimination, CDC, 1600 Clifton Road NE, Mailstop E-45, Atlanta, GA 30333, USA*Allan W. Taylor: ataylor2@cdc.govAcademic Editor: Gregory T. Spear\n\n2013 7 3 2013 2013 1956378 11 2012 28 1 2013 Copyright © 2013 Allan W. Taylor et al.2013This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nObjective. While 6- to 12-month courses of isoniazid for tuberculosis prevention are considered safe in pregnant women, the effects of longer-term isoniazid prophylaxis or isoniazid in combination with antiretroviral therapy (ART) are not established in human-immunodeficiency-virus-(HIV-) infected women who experience pregnancy during the course of therapy. Design. Nested study of pregnancy outcomes among HIV-infected women participating in a placebo-controlled, TB-prevention trial using 36 months daily isoniazid. Pregnancy outcomes were collected by interview and record review. Results. Among 196 pregnant women, 103 (52.6%) were exposed to isoniazid during pregnancy; all were exposed to antiretroviral drugs. Prior to pregnancy they had received a median of 341 days (range 1–1095) of isoniazid. We observed no isoniazid-associated hepatitis or other severe isoniazid-associated adverse events in the 103 women. Pregnancy outcomes were 132 term live births, 42 premature births, 11 stillbirths, 8 low birth weight, 6 spontaneous abortions, 4 neonatal deaths, and 1 congenital abnormality. In a multivariable model, neither isoniazid nor ART exposure during pregnancy was significantly associated with adverse pregnancy outcome (adjusted odds ratios 0.6, 95% CI: 0.3–1.1 and 1.8, 95% CI 0.9–3.6, resp.). Conclusions. Long-term isoniazid prophylaxis was not associated with adverse pregnancy outcomes, such as preterm delivery, even in the context of ART exposure.\n==== Body\n1. Introduction \nTuberculosis (TB) is a major cause of morbidity and mortality for HIV-infected persons [1]. A clinical trial was recently completed in Botswana, in which a 36-month course of isoniazid prophylaxis against TB (IPT) was highly efficacious in reducing the risk of TB in tuberculin-skin-test-positive adults [2] when compared with a shorter-term regimen. Based upon this and other evidence [3], the World Health Organization recommended that in countries with high TB transmission, national health programs consider providing 36-month isoniazid prophylaxis for persons living with HIV [4]. The HIV epidemic disproportionately affects women in developing countries [5]. As availability of antiretroviral medications for therapy (ART) and for prevention of mother-to-child HIV transmission (PMTCT) has been rapidly scaled up [6], and with increasing health, pregnancy is common. While 6- to 12-month courses of isoniazid are considered safe in pregnancy [7], our objective was to describe the effects of longer-term isoniazid prophylaxis or simultaneous isoniazid and ART in pregnant HIV-infected women.\n\n2. Methods \n2.1. Study Population\nA cohort of 1995 HIV-infected adults was enrolled at eight clinics located in Francistown and Gaborone, Botswana, from 2004 to 2006. Details of enrolment are provided elsewhere [8]. This double-blind, randomized, placebo-controlled trial gave participants 6 months of isoniazid (300–400 mg/day) plus vitamin B6 (25 mg/day), after which either isoniazid or placebo (1 : 1) was provided for 30 months longer. Participants returned monthly for medication refills. Per national policy at the time, if a woman became pregnant and was not already receiving ART, she was referred to an antenatal clinic for free short-course zidovudine (AZT) prophylaxis from week 34 of gestation (if her CD4+ T-cell count was >200/mm3) or ART if her CD4+ T-cell count was <200/mm3. Pregnancy outcome data were collected by maternal interview and from antenatal clinic records.\n\n2.2. Definitions\nSevere hepatitis was defined as elevation of liver enzymes to >5 times the upper limit of normal. Severe rash was defined as generalized erythroderma, eruption, or desquamation covering ≥50% of body surface area. Adverse events were determined by a blinded, independent committee to be possibly, probably, definitely, or not associated with the study medication. We defined adverse pregnancy outcome (AO) as any of the following: preterm delivery (estimated gestational age (EGA) ≤37 weeks at birth), low birth weight (<2500 g), stillbirth (delivery of an infant with no signs of life at ≥28 weeks EGA), spontaneous abortion (spontaneous termination of pregnancy <24 weeks EGA), neonatal mortality (death of term infant within 28 days of delivery), or any noted congenital abnormality. We defined ART as therapy with ≥3 antiretroviral drugs from ≥2 classes provided for treatment of HIV disease. The pregnancy outcomes analysis included only the first-born infant of the first pregnancy experienced by women during the trial pregnancies completed by February 19, 2009, and only included women who registered for PMTCT.\n\n2.3. Statistical Methods\nWe performed univariate, bivariate, and multivariable analysis to investigate associations between AO, isoniazid exposure, and ART exposure in pregnancy. Continuous variables were compared using t-tests or nonparametric tests. We computed bivariate odds ratios to test crude associations of a priori interest. Multivariable logistic regression models were employed to explore associations of interest while controlling for potential confounders, including maternal CD4+ T-cell count nearest the last normal menstrual period (LNMP), maternal body mass index (BMI < 18.5), and age. Analyses were conducted using SAS v9.3 (SAS Institute Inc., Cary, NC, USA).\n\n2.4. Ethical Considerations\nAll participants provided informed consent. The protocol was approved by Botswana and Centers for Disease Control and Prevention (CDC) ethics committees. The trial was registered at http://www.clinicaltrials.gov/, NCT00164281.\n\n3. Results\nSeventy-two percent of the 1995 enrollees were female; their median age was 32 years; their median CD4+ count was 297 cells/mm3, and 47% initiated ART during the 36-month period of observation. Of the 1436 women in the study, 721 (50.2%) were randomized to 6 months of IPT; 715 women (49.8%) were randomized to 36 months of IPT. A total of 268 pregnancies were observed during the trial. We excluded 29 women who were still pregnant at the time the dataset was closed or who exited the trial prior to the end of pregnancy, 23 repeat pregnancies, and 20 women without PMCT regimen data, leaving a total of 196 pregnancies in the analysis dataset (98 per arm). Some participants received placebo after 6 months of IPT or stopped taking isoniazid while remaining under observation in the trial, resulting in some women not receiving isoniazid while pregnant. Of women in the 6-month isoniazid arm, 20 were exposed to isoniazid during pregnancy, and 39 were exposed to ART. Of women in the 36-month isoniazid arm, 83 were exposed to isoniazid in pregnancy, and 34 were exposed to ART.\n\nOverall, 103/196 (52.6%) women were exposed to isoniazid during some part of pregnancy, with 102 beginning in the first trimester, and 68% of these women had continuing exposure throughout pregnancy (Table 1). None of the women receiving isoniazid had severe hepatitis or rash either during pregnancy or in the postpartum period. Among these 103 women, 94 had begun isoniazid before pregnancy; the median duration of isoniazid receipt before the last menstrual period for these women was 341 days (range 1–1095 days).\n\nAll women were exposed to antiretroviral drugs during pregnancy: 73 (37%) received ART, and the remainder received either short-course zidovudine (121) or zidovudine/lamivudine (AZT/3TC) (2). Of 73 women receiving ART during pregnancy, the most (64/73, 88%) received AZT/3TC and nevirapine; 3 received lopinavir/ritonavir-based regimens; 6 received other combinations. Women taking ART had significantly lower CD4+ T-cell counts than those taking short-course prophylaxis (median CD4+ count 239 versus 452, Wilcoxon rank-sum P < 0.0001). Of the 73 women receiving ART, 62% did so during all 3 trimesters. For the 47 women who began taking ART before pregnancy, the median duration of ART before pregnancy was 347 days (range 21–2221 days). Twenty-six initiated ART during pregnancy.\n\nTwo pregnant women developed TB symptoms during their pregnancies. One started anti-TB treatment 3 months after having a live birth, and the other initiated anti-TB treatment a month after her LNMP and sustained a stillbirth 7 months later. Both successfully completed standard 6-month anti-TB treatment.\n\nFinal outcomes of the 196 pregnancies were 124 (63%) term live births; 42 (21.4%) premature deliveries, 8 (4%) low-birth-weight term infants, 11 (6%) stillbirths, 6 spontaneous abortions (3%), 4 neonatal deaths (2%), and 1 congenital abnormality (talipes equinovarus, Table 1).\n\nIn bivariate analysis (Table 2), ART receipt during pregnancy was associated with AO (unadjusted odds ratio (uOR) 2.0, 95% confidence interval (CI) 1.1–3.5), as was increasing maternal age (uOR 1.1 per year, 95%CI 1.0–1.1). Isoniazid exposure during pregnancy was not associated with increased odds of AO. Length of exposure to INH prior to pregnancy was also not associated with increased odds of AO when analyzed either as a continuous or categorical variable (data not shown).\n\nIn a multivariable model including all variables in Table 2, none was significantly associated with increased odds of AO except maternal age. Addition of a dichotomous variable representing maternal CD4 count <200 near delivery did not significantly change any model parameter, and this variable was not retained. A separate but otherwise identical model showed no association between any variable (including ART exposure) and the outcome of preterm delivery (not shown). Similarly, another separate analysis with the same covariates but with the antiretroviral drug exposure variable dichotomized as exposure prior to pregnancy or in the first trimester versus all others demonstrated no significant association with preterm delivery (not shown). \n\n4. Discussion\nWe observed no isoniazid-associated hepatitis or other severe isoniazid-associated adverse events in 103 women receiving isoniazid during pregnancy and/or immediately postpartum. Generally, isoniazid hepatitis occurs in the first months of treatment, as it did in the Botswana clinical trial [2]; pregnant women in this study had received isoniazid for a median of 341 days before pregnancy. In the earlier literature there was inconclusive evidence of potentially increased risk of isoniazid-associated hepatitis and death in pregnant or post-partum women [9, 10]. As they have a high risk of developing active TB, the CDC and American Thoracic Society recommend that IPT be initiated in HIV-infected women even during the first trimester (with routine monitoring of hepatic enzymes) [7]. Botswana policy is that, while women known to be pregnant should not initiate IPT, if they do become pregnant they should continue their course of therapy without monitoring hepatic enzymes. The overall risk of isoniazid-associated death observed in this trial—occurring in two nonpregnant women among 1995 persons who initiated isoniazid prophylaxis [2]—was no higher than the established estimated rate of hepatic death and hepatitis requiring liver transplantation of approximately 1/1000 in the United States [11].\n\nExtensive use of isoniazid during pregnancy has indicated that although it readily crosses the placental barrier, the drug is not teratogenic even when given during the first trimester [12, 13]. We report one congenital abnormality (talipes equinovarus) in a child born to a woman who was taking isoniazid near conception. The background rate for this abnormality is unknown in Botswana; in the United States this rate has been estimated at approximately 1/1000 live births [14–16]. To date a prospective registry has found no apparent increase in the frequency of this condition among infants exposed prenatally to antiretroviral medications [17].\n\nIn this study we did not observe increased odds of adverse pregnancy outcomes among women receiving ART in pregnancy compared to women receiving short-course antiretroviral regimens. Previous studies offered mixed evidence of such an association. Studies from Europe found an association between ART (especially with protease inhibitor-based ART) exposure in pregnancy and preterm delivery [18, 19]. Similarly, a study in Botswana found increased odds of small-for-gestational-age infants among women taking ART [20]. A separate study of 71 antiretroviral drug-exposed pregnancies in Botswana found no difference in rates of early pregnancy loss or stillbirths between efavirenz- and nonefavirenz-exposed pregnancies; only one congenital abnormality was observed (unrelated to efavirenz exposure) [21]. Studies from the United States have not generally observed such an association [22, 23], except possibly for women starting ART before pregnancy or during the first trimester, compared to later initiation [24]. Given the known association between advanced HIV disease and preterm delivery [25, 26], it is possible that the borderline association between ART use and adverse birth outcome observed in the unadjusted analysis of the present study was due to confounding by maternal health status. This interpretation is supported by the disappearance of the association after controlling for maternal CD4+ count. \n\nThis study provided a unique opportunity to examine pregnancy in the context of long-term INH exposure. Chief among its limitations was the small sample size, which limited the power of the study. Also, as antiretroviral medication use was not randomized, we were unable to rule out the existence of unmeasured confounders in our analysis of antiretroviral use and AO.\n\nIn summary, long-term prophylaxis with IPT appeared to be safe in this small secondary analysis, even when pregnancy was experienced by HIV-infected women during therapy and was not associated with adverse pregnancy outcomes.\n\nDisclosure\nThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.\n\nTable 1 Selected characteristics of subjects experiencing pregnancy during the Isoniazid Preventive Therapy Trial, Botswana, 2005–2008 (n = 196).\n\n \t\nNo.\t% or range\t\nCharacteristic (n = 196)\t \t \t\n Age (median, range)\t28\t19–39\t\n CD4+ lymphocyte count nearest LNMP (median, range) in cells/mm3\n\t368\t41–1231\t\n CD4+ lymphocyte count near LNMP <200 cells/mm3\n\t31\t16%\t\n Maternal BMI (median, range)\t22.9\t15.6–36.2\t\n Maternal BMI <18.5 near LNMP\t17\t19%\t\n Pregnancy outcome date range\t \tNov 26 2005 to Feb 19 2009\t\n Antiretroviral regimen in Pregnancy\t \t \t\n Antiretroviral therapy (≥3 drugs from ≥2 classes)\t73\t37%\t\n AZT or AZT/3TC only\t123\t63%\t\n\n\n\t\nAntiretroviral therapy exposure (n = 196)\t \t \t\n Number of women on ART prior to pregnancy\t47\t \t\n Time on ART before pregnancy (median, range) in days*\t347\t21–2221\t\n Timing of ART exposure during pregnancy\t \t \t\n First, second, and third trimesters\t45\t \t\n First and second trimesters only\t7\t \t\n Second and third trimesters only\t8\t \t\n Third trimester only\t8\t \t\n Timing unknown\t5\t \t\n\n\n\t\nIsoniazid exposure (n = 103)\t \t \t\n Time on isoniazid before pregnancy (median, range) in days\t341\t1–1095\t\n Exposed to isoniazid in pregnancy\t \t \t\n First trimester only\t11\t11%\t\n First and second, trimesters only\t21\t20%\t\n First, second, and third trimesters\t70\t68%\t\n Second trimester only\t1\t1%\t\n Any trimester (total)\t103\t100%\t\n\n\n\t\nPregnancy outcome (n = 196)\t \t \t\n Live birth\t124\t63%\t\n Stillbirth\t11\t6%\t\n Spontaneous (“inevitable”) abortion\t6\t3%\t\n Neonatal death\t4\t2%\t\n Premature\t42\t21%\t\n Term low birth weight\t8\t4%\t\n Congenital abnormality\t1\t1%\t\n Maternal death\t0\t0%\t\n3TC: lamivudine; ART: antiretroviral therapy; AZT: zidovudine; BMI: body mass index; IPT: isoniazid preventive therapy; LNMP: last normal menstrual period.\n\n*Among women with ART start date prior to LNMP (n = 47).\n\nTable 2 Association between adverse pregnancy outcomes and isoniazid and/or antiretroviral therapy during pregnancy in HIV-infected women, Isoniazid Preventive Therapy Trial, Botswana, 2005–2008 (n = 196).\n\nCharacteristic\tAdverse outcome\nno. (%)\tNo adverse outcome\nno. (%)\tuOR\t95% CI\taOR\t95% CI\t\nIsoniazid exposure in pregnancy\t \t \t \t \t \t \t\n Yes\t32 (31.1)\t71 (68.9)\t0.6\t0.3–1.1\t0.6\t0.3–1.1\t\n No\t40 (43.1)\t53 (57.0)\t1.0\t \t1.0\t \t\nAntiretroviral therapy regimen in pregnancy\t \t \t \t \t \t \t\n Antiretroviral therapy (≥3 drugs from ≥2 classes)\t34 (46.6)\t39 (53.4)\t2.0\t1.1–3.5\t1.8\t0.9–3.6\t\n Zidovudine or zidovudine/lamivudine only\t38 (31.0)\t85 (69.1)\t1.0\t \t1.0\t \t\nMaternal CD4+ lymphocyte count nearest LNMP\t \t \t \t \t \t \t\n <200 cells/mm3\n\t13 (41.9)\t18 (58.1)\t1.3\t0.6–2.8\t1.0\t0.4–2.5\t\n ≥200 cells/mm3\n\t59 (35.8)\t106 (64.2)\t1.0\t \t1.0\t \t\nMaternal BMI near LNMP\t \t \t \t \t \t \t\n Underweight <18.5\t9 (52.9)\t8 (47.1)\t2.0\t0.7–5.5\t2.4\t0.8–7.1\t\n Not underweight ≥18.5\t63 (35.8)\t113 (64.2)\t1.0\t \t1.0\t \t\nMaternal age (years)\t—\t—\t1.1\t1.0–1.1\t1.1\t1.0–1.2\t\nBMI: body mass index; aOR: adjusted odds ratio (adjusted for all variables shown); CI: confidence interval; uOR: unadjusted odds ratio; LNMP: last normal menstrual period.\n==== Refs\n1 Reid A Scano F Getahun H Towards universal access to HIV prevention, treatment, care, and support: the role of tuberculosis/HIV collaboration The Lancet Infectious Diseases 2006 6 8 483 495 2-s2.0-33746326775 16870527 \n2 Samandari T Agizew TB Nyirenda S 6-month versus 36-month isoniazid preventive treatment for tuberculosis in adults with HIV infection in Botswana: a randomised, double-blind, placebo-controlled trial The Lancet 2011 377 9777 1588 1598 2-s2.0-79955694277 \n3 Martinson N Barnes G Msandiwa R Moulton L Gray G McIntyre J Novel regimens for treating latent TB in HIV-infected adults in South Africa: a randomized clinical trial Proceedings of the 16th Conference on Retroviruses and Opportunistic Infections 2009 Montreal, Canada abstract #36bLB \n4 World Health Organization Guidelines for Intensified Tuberculosis Case Finding and Isoniazid Preventive Therapy for People Living with HIV in Resource Constrained Settings 2011 Geneva, Switzerland World Health Organization \n5 UNAIDS AIDS epidemic update, November 2009 \n6 Ojikutu B Makadzange AT Gaolathe T Scaling up ART treatment capacity: lessons learned from South Africa, Zimbabwe, and Botswana Current HIV/AIDS Reports 2008 5 2 94 98 2-s2.0-43249093378 18510895 \n7 American Thoracic Society Targeted tuberculin testing and treatment of latent tuberculosis infection MMWR Recommendations and Reports 2000 49 RR06 1 54 \n8 Mosimaneotsile B Mathoma A Chengeta B Isoniazid tuberculosis preventive therapy in HIV-infected adults accessing antiretroviral therapy: a botswana experience, 2004–2006 Journal of Acquired Immune Deficiency Syndromes 2010 54 1 71 77 2-s2.0-77951697611 19934764 \n9 Snider DE Jr. Caras GJ Isoniazid-associated hepatitis deaths: a review of available information The American Review of Respiratory Disease 1992 145 2 494 497 2-s2.0-0026570896 1736764 \n10 Franks AL Binkin NJ Snider DE Jr. Rokaw WM Becker S Isoniazid hepatitis among pregnant and postpartum Hispanic patients Public Health Reports 1989 104 2 151 155 2-s2.0-0024403618 2495549 \n11 Severe isoniazid-associated liver injuries among persons being treated for latent tuberculosis infection—United States, 2004–2008 Morbidity and Mortality Weekly Report 59 8 224 229 \n12 Wilson EA Thelin TJ Dilts PV Jr. Tuberculosis complicated by pregnancy The American Journal of Obstetrics and Gynecology 1973 115 4 526 529 2-s2.0-0015923850 4685503 \n13 Scheinhorn DJ Angelillo VA Antituberculous therapy in pregnancy. Risks to the fetus Western Journal of Medicine 1977 127 3 195 198 2-s2.0-0017717819 906455 \n14 Kancherla V Romitti PA Caspers KM Puzhankara S Morcuende JA Epidemiology of congenital idiopathic talipes equinovarus in Iowa, 1997–2005 The American Journal of Medical Genetics A 2010 152 7 1695 1700 2-s2.0-77954134923 \n15 Moorthi RN Hashmi SS Langois P Canfield M Waller DK Hecht JT Idiopathic talipes equinovarus (ITEV) (Clubfeet) in Texas The American Journal of Medical Genetics 2005 132 4 376 380 2-s2.0-12944273482 \n16 Chung CS Nemechek RW Larsen IJ Ching GH Genetic and epidemiological studies of clubfoot in Hawaii. General and medical considerations Human Heredity 1969 19 4 321 342 2-s2.0-0014621539 5391957 \n17 Antiretroviral Pregnancy Registry Steering Committee Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 Through 31 July 2009 2009 Wilmington, NC, USA Registry Coordinating Center \n18 European Collaborative Study Combination antiretroviral therapy and duration of pregnancy AIDS 2000 14 18 2913 2920 11398741 \n19 Thorne C Patel D Newell ML Increased risk of adverse pregnancy outcomes in HIV-infected women treated with highly active antiretroviral therapy in Europe AIDS 2004 18 17 2337 2339 2-s2.0-10244236453 15577551 \n20 Parekh N Ribaudo H Souda S Risk factors for very preterm delivery and delivery of very-small-for-gestational-age infants among HIV-exposed and HIV-unexposed infants in Botswana International Journal of Gynecology and Obstetrics 2011 115 1 20 25 21767835 \n21 Bussmann H Wester CW Wester CN Pregnancy rates and birth outcomes among women on efavirenz-containing highly active antiretroviral therapy in Botswana Journal of Acquired Immune Deficiency Syndromes 2007 45 3 269 273 2-s2.0-34347348169 17450102 \n22 Tuomala RE Watts H Li D Improved obstetric outcomes and few maternal toxicities are associated with antiretroviral therapy, including highly active antiretroviral therapy during pregnancy Journal of Acquired Immune Deficiency Syndromes 2005 38 4 449 473 2-s2.0-15044363712 15764963 \n23 Tuomala RE Shapiro DE Mofenson LM Antiretroviral therapy during pregnancy and the risk of an adverse outcome The New England Journal of Medicine 2002 346 24 1863 1870 2-s2.0-0037071791 12063370 \n24 Kourtis AP Schmid CH Jamieson DJ Lau J Use of antiretroviral therapy in pregnant HIV-infected women and the risk of premature delivery: a meta-analysis AIDS 2007 21 5 607 615 2-s2.0-33847238368 17314523 \n25 Stratton P Tuomala RE Abboud R Obstetric and newborn outcomes in a cohort of HIV-infected pregnant women: a report of the women and infants transmission study Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology 1999 20 2 179 186 2-s2.0-0033081272 10048906 \n26 Newell ML Dunn DT Peckham CS Semprini AE Pardi G Vertical transmission of HIV-1: maternal immune status and obstetric factors. The European collaborative study AIDS 1996 10 14 1675 1681 2-s2.0-0029951260 8970688\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1064-7449",
"issue": "2013()",
"journal": "Infectious diseases in obstetrics and gynecology",
"keywords": null,
"medline_ta": "Infect Dis Obstet Gynecol",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D000704:Analysis of Variance; D019072:Antibiotic Prophylaxis; D000995:Antitubercular Agents; D015331:Cohort Studies; D004311:Double-Blind Method; D005260:Female; D015658:HIV Infections; D006801:Humans; D007538:Isoniazid; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D014376:Tuberculosis; D055815:Young Adult",
"nlm_unique_id": "9318481",
"other_id": null,
"pages": "195637",
"pmc": null,
"pmid": "23533318",
"pubdate": "2013",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "8970688;906455;12063370;10881762;15764963;1736764;17314523;20203555;15577551;15633175;11398741;19934764;17450102;18510895;2495549;20583169;10048906;5391957;4685503;21492926;16870527;21767835",
"title": "Pregnancy outcomes in HIV-infected women receiving long-term isoniazid prophylaxis for tuberculosis and antiretroviral therapy.",
"title_normalized": "pregnancy outcomes in hiv infected women receiving long term isoniazid prophylaxis for tuberculosis and antiretroviral therapy"
} | [
{
"companynumb": "US-MYLANLABS-2017M1013391",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PYRIDOXINE"
},
"drugadditional": null,
... |
{
"abstract": "Histoplasmosis is a rare disease in nonendemic areas. We report a case of a 23-year-old male patient who presented with fever of unknown origin, cytopenias, organomegaly, and allograft dysfunction 4 months after renal transplant with father as donor. Bone marrow examination showed intracellular budding yeast cells, which was confirmed as histoplasmosis by culture of bone marrow biopsy sample. The patient was treated with intravenous liposomal amphotericin and responded well.",
"affiliations": "From the Department of Nephrology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.",
"authors": "Sethi|Jasmine|J|;Gupta|Krishnan L|KL|;Mohanty|Tirthankar|T|;Gupta|Shefali|S|;Ahluwalia|Jasmina|J|;Kohli|Harbir Singh|HS|",
"chemical_list": "D000935:Antifungal Agents; D015415:Biomarkers; C068538:liposomal amphotericin B; D000666:Amphotericin B; D007770:L-Lactate Dehydrogenase",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2018.0380",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "18(3)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D061605:Administration, Intravenous; D000666:Amphotericin B; D000935:Antifungal Agents; D015415:Biomarkers; D005335:Fever of Unknown Origin; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D016030:Kidney Transplantation; D007770:L-Lactate Dehydrogenase; D008297:Male; D011237:Predictive Value of Tests; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "390-391",
"pmc": null,
"pmid": "31050612",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fever of Unknown Origin in a Renal Transplant Recipient: Lactate Dehydrogenase as an Important Clue to Diagnosis.",
"title_normalized": "fever of unknown origin in a renal transplant recipient lactate dehydrogenase as an important clue to diagnosis"
} | [
{
"companynumb": "IN-FRESENIUS KABI-FK202007196",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": ... |
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