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{ "abstract": "OBJECTIVE\nTo describe a case of Listeria monocytogenes rhombencephalitis in a patient receiving fingolimod.\n\n\nMETHODS\nThis is a case study.\n\n\nRESULTS\nOur patient developed acute rhombencephalitis with hydrocephalus induced with Listeria monocytogenes while on fingolimod. Shunt surgery was performed for the hydrocephalus and patient recovered partially after medical and surgical therapy.\n\n\nCONCLUSIONS\nWe describe the first probable case of fingolimod-associated Listeria monocytogenes rhombencephalitis in a patient with multiple sclerosis. Clinicians should be aware of listeriosis and implement measures for its prevention.", "affiliations": "Inonu University, School of Medicine, Department of Neurology, Malatya, Turkey.;Inonu University, School of Medicine, Department of Neurology, Malatya, Turkey. Electronic address: okamisli@yahoo.com.;Inonu University, School of Medicine, Department of Neurology, Malatya, Turkey.;Inonu University, School of Medicine, Department of Neurology, Malatya, Turkey.;Inonu University, School of Medicine, Department of Neurology, Malatya, Turkey.", "authors": "Tecellioglu\|Mehmet\|M\|;Kamisli\|Ozden\|O\|;Kamisli\|Suat\|S\|;Erdogmus\|Umut Adem\|UA\|;Özcan\|Cemal\|C\|", "chemical_list": "D007166:Immunosuppressive Agents; D000068876:Fingolimod Hydrochloride", "country": "Netherlands", "delete": false, "doi": "10.1016/j.msard.2018.11.025", "fulltext": null, "fulltext_license": null, "issn_linking": "2211-0348", "issue": "27()", "journal": "Multiple sclerosis and related disorders", "keywords": "Fingolimod; Listeria monocytogenes; Multiple sclerosis; Rhombencephalitis", "medline_ta": "Mult Scler Relat Disord", "mesh_terms": "D000328:Adult; D001921:Brain; D004660:Encephalitis; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents; D008089:Listeria monocytogenes; D008088:Listeriosis; D009103:Multiple Sclerosis", "nlm_unique_id": "101580247", "other_id": null, "pages": "409-411", "pmc": null, "pmid": "30530070", "pubdate": "2019-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Listeria monocytogenes rhombencephalitis in a patient with multiple sclerosis during fingolimod therapy.", "title_normalized": "listeria monocytogenes rhombencephalitis in a patient with multiple sclerosis during fingolimod therapy" }	[ { "companynumb": "TR-TEVA-2018-TR-993526", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FINGOLIMOD" }, "drugadditional": "3", ...
{ "abstract": "Pregnancy after kidney transplantation is becoming more common as more patients of childbearing age are undergoing successful transplantation. There is limited evidence on the safety and efficacy of mammalian target of rapamycin inhibitors during pregnancy, which are considered Category C. We will review the use of this class of medications in pregnancy, which is currently contraindicated due to risk of fetal complications. We will also present the case of a successful pregnancy and renal outcome in a 33-year-old kidney transplant recipient who was administered everolimus throughout pregnancy.", "affiliations": "Department of Nephrology, Washington Hospital Center, Washington, DC. Electronic address: hannahma@pcom.edu.;Department of OB/GYN, Georgetown University Hospital, Washington, DC.;Department of Nephrology, Washington Hospital Center, Washington, DC.;Department of Nephrology, Washington Hospital Center, Washington, DC.;Georgetown University Transplant Institute, Washington, DC.", "authors": "Margoles\|H R\|HR\|;Gomez-Lobo\|V\|V\|;Veis\|J H\|JH\|;Sherman\|M J\|MJ\|;Moore\|J\|J\|", "chemical_list": "D007166:Immunosuppressive Agents; D000068338:Everolimus; D020123:Sirolimus", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0041-1345", "issue": "46(1)", "journal": "Transplantation proceedings", "keywords": null, "medline_ta": "Transplant Proc", "mesh_terms": "D000328:Adult; D000068338:Everolimus; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007231:Infant, Newborn; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D018811:Maternal Exposure; D061214:Patient Safety; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012306:Risk; D020123:Sirolimus; D016896:Treatment Outcome", "nlm_unique_id": "0243532", "other_id": null, "pages": "281-3", "pmc": null, "pmid": "24507068", "pubdate": "2014", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful maternal and fetal outcome in a kidney transplant patient with everolimus exposure throughout pregnancy: a case report.", "title_normalized": "successful maternal and fetal outcome in a kidney transplant patient with everolimus exposure throughout pregnancy a case report" }	[ { "companynumb": "US-MYLANLABS-2015M1013051", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "MYCOPHENOLATE MOFETIL" }, "drugadditional": n...
{ "abstract": "Two patients, aged 44 and 68 years, presented with generalized seizures either witnessed or highly suspected. Both patients had laboratory-proven subtherapeutic anticonvulsant serum levels. The patients differed with regard to risk; one patient had existing cardiopulmonary disease, and the other was free of such risk factors except liver disease. An apparently appropriate dose of intravenous phenytoin was initiated in each case, and the patients were monitored appropriately and given supplemental oxygen. Bradycardia, hypotension, respiratory distress, and, ultimately, cardiopulmonary arrest occurred in both. The criteria proposed by Earnest et al. should be implemented for each seizure case that requires a decision on the urgent need for therapeutic anticonvulsant levels, whether by mechanical infusion, manual intravenous push, or oral loading. The mechanical infusion is the easiest method to standardize and monitor. The manual intravenous push has a greater possibility of inadvertent overdosage during some small time frame, as well as more local symptoms by some reports. Record et al. have recommended oral loading in selected patients. Careful consideration must be made of the choice of environment in which intravenous loading is done (e.g., emergency department, intensive care unit), as dictated by patient parameters, nursing staff levels, and planned disposition. The crucial factors contributing to the deterioration of both patients in the two cases presented were the concentration of phenytoin manually infused and the possibility that their high-risk status made them poor candidates for manual intravenous phenytoin. Dose and a hypersensitivity reaction were doubtful factors in these cases.", "affiliations": "Emergency Medicine Service, Walter Reed Army Medical Center, Washington, DC.", "authors": "York\|R C\|RC\|;Coleridge\|S T\|ST\|", "chemical_list": "D010672:Phenytoin", "country": "United States", "delete": false, "doi": "10.1016/0735-6757(88)90012-5", "fulltext": null, "fulltext_license": null, "issn_linking": "0735-6757", "issue": "6(3)", "journal": "The American journal of emergency medicine", "keywords": null, "medline_ta": "Am J Emerg Med", "mesh_terms": "D000368:Aged; D005260:Female; D006323:Heart Arrest; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D010672:Phenytoin; D012640:Seizures", "nlm_unique_id": "8309942", "other_id": null, "pages": "255-9", "pmc": null, "pmid": "3370103", "pubdate": "1988-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cardiopulmonary arrest following intravenous phenytoin loading.", "title_normalized": "cardiopulmonary arrest following intravenous phenytoin loading" }	[ { "companynumb": "US-PFIZER INC-2016160764", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PHENYTOIN SODIUM" }, "drugadditional": null, ...
{ "abstract": "BACKGROUND\nShort intensive chemotherapy is the standard of care for adult patients with Burkitt's leukaemia or lymphoma. Findings from single-arm studies suggest that addition of rituximab to these regimens could improve patient outcomes. Our objective was to test this possibility in a randomised trial.\n\n\nMETHODS\nIn this randomised, controlled, open-label, phase 3 trial, we recruited patients older than 18 years with untreated HIV-negative Burkitt's lymphoma (including Burkitt's leukaemia) from 45 haematological centres in France. Exclusion criteria were contraindications to any drug included in the chemotherapy regimens, any serious comorbidity, poor renal (creatinine concentration >150 μmol/L) or hepatic (cirrhosis or previous hepatitis B or C) function, pregnancy, and any history of cancer except for non-melanoma skin tumours or stage 0 (in situ) cervical carcinoma. Patients were stratified into two groups based on disease extension (absence [group B] or presence [group C] of bone marrow or central nervous system involvement). Patients were further stratified in group C according to age (<40 years, 40-60 years, and >60 years) and central nervous system involvement. Participants were randomly assigned in each group to either intravenous rituximab injections and chemotherapy (lymphome malin B [LMB]) or chemotherapy alone by the Groupe d'Etude des Lymphomes de l'Adulte datacentre. Randomisation was stratified by treatment group and centre using computer-assisted permuted-block randomisation (block size of four; allocation ratio 1:1). We gave rituximab (375 mg/m(2)) on day 1 and day 6 during the first two courses of chemotherapy (total of four infusions). The primary endpoint is 3 year event-free survival (EFS). We analysed all patients who had data available according to their originally assigned group. This trial is registered with ClinicalTrials.gov, number NCT00180882.\n\n\nRESULTS\nBetween Oct 14, 2004, and Sept 7, 2010, we randomly allocated 260 patients to rituximab or no rituximab (group B 124 patients [64 no rituximab; 60 rituximab]; group C 136 patients [66 no rituximab; 70 rituximab]). With a median follow-up of 38 months (IQR 24-59), patients in the rituximab group achieved better 3 year EFS (75% [95% CI 66-82]) than did those in the no rituximab group (62% [53-70]; log-rank p stratified by treatment group=0·024). The hazard ratio estimated with a Cox model stratified by treatment group, assuming proportionality, was 0·59 for EFS (95% CI 0·38-0·94; p=0·025). Adverse events did not differ between the two treatment groups. The most common adverse events were infectious (grade 3-4 in 137 [17%] treatment cycles in the rituximab group vs 115 [15%] in the no rituximab group) and haematological (mean duration of grade 4 neutropenia of 3·31 days per cycle [95% CI 3·01-3·61] vs 3·38 days per cycle [3·05-3·70]) events.\n\n\nCONCLUSIONS\nAddition of rituximab to a short intensive chemotherapy programme improves EFS in adults with Burkitt's leukaemia or lymphoma.\n\n\nBACKGROUND\nGustave Roussy Cancer Campus, Roche, Chugai, Sanofi.", "affiliations": "Department of Medicine, Gustave Roussy, Université Paris Saclay, Villejuif, France. Electronic address: vincent.ribrag@gustaveroussy.fr.;Biostatistics and Epidemiology Unit, Gustave Roussy, Université Paris Saclay, Villejuif, France; Centre for Research in Epidemiology and Population Health, Institut national de la santé et de la recherche médicale U1018, Université Paris-Sud, Villejuif, France.;Department of Biopathology, Morphology Unit, Gustave Roussy, Université Paris Saclay, Villejuif, France.;Service d'hématologie clinique et thérapie cellulaire, Hôpital du Haut-Lévèque, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.;Service d'hématologie Clinique, Centre Hospitalier Universitaire Dijon, Dijon, France.;Department of Oncology and Hematology, Hôpital de Hautepierre Université de Strasbourg, Strasbourg, France.;Service d'Hématologie, Institut Universitaire du Cancer de Toulouse Oncopole, Toulouse, France.;Onco-Hematology, Centre Léon Bérard, Université Claude Bernard Lyon 1, Lyon, France.;Service des Maladies du Sang, Hôpital Huriez, Université de Lille, Unité Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France.;Hématologie Clinique et Thérapie Cellulaire, Centre Hospitalier Universitaire Limoges, Limoges, France.;Department of Hematology, Institut national de la santé et de la recherche médicale, Unité Mixte de Recherche 892, Equipe 10, Nantes Institut national de la santé et de la recherche médicale, Centre d'Investigation Clinique 004, Nantes University Hospital, Nantes, France.;Department of Hematology and Cellular Therapy Unit, Hôpital Emile Muller, Centre de Competences on Thrombotic Microangiopathies, Mulhouse, France.;Department of Haematology, Grenoble University Hospital, Grenoble, France.;Département d'Hématologie, Institut de Cancérologie Lucien Neuwirth, Saint-Priest en Jarez, France.;Department of Hematology, Unité Mixte de Recherche Centre national de la recherche scientifique 5235, Centre Hospitalier Universitaire Montpellier, Montpellier, France.;Haematology Unit, Gustave Roussy, Université Paris Saclay, Villejuif, France.;Département de Biopathologie, Centre Léon Bérard, Lyon, France.;Service d'hématologie clinique, Centre Hospitalier Universitaire Paris, Groupe Hospitalier Saint-Louis, Lariboisière, Fernand-Widal, Hôpital Saint-Louis, Paris, France.;Hématologie Clinique, Hospices Civils de Lyon, Centre Hospitalier Lyon-Sud, Pierre-Bénite, France.;Department of Clinical Hematology, Rennes University Hospital, Rennes, France; Institut national de la santé et de la recherche médicale Unité Mixte de Recherche 917, Faculté de médecine, Université Rennes 1, Rennes Department of Clinical Investigation, Rennes University Hospital, Rennes, France.;Centre Henri Becquerel, Université de Rouen, Rouen, France.;Hospices Civils de Lyon, Université Lyon 1, Pierre Bénite, France.", "authors": "Ribrag\|Vincent\|V\|;Koscielny\|Serge\|S\|;Bosq\|Jacques\|J\|;Leguay\|Thibaut\|T\|;Casasnovas\|Olivier\|O\|;Fornecker\|Luc-Mathieu\|LM\|;Recher\|Christian\|C\|;Ghesquieres\|Hervé\|H\|;Morschhauser\|Franck\|F\|;Girault\|Stéphane\|S\|;Le Gouill\|Steven\|S\|;Ojeda-Uribe\|Mario\|M\|;Mariette\|Clara\|C\|;Cornillon\|Jerome\|J\|;Cartron\|Guillaume\|G\|;Verge\|Veronique\|V\|;Chassagne-Clément\|Catherine\|C\|;Dombret\|Hervé\|H\|;Coiffier\|Bertrand\|B\|;Lamy\|Thierry\|T\|;Tilly\|Hervé\|H\|;Salles\|Gilles\|G\|", "chemical_list": "D014408:Biomarkers, Tumor; D003561:Cytarabine; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone; D006854:Hydrocortisone; D008775:Methylprednisolone; D008727:Methotrexate", "country": "England", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0140-6736", "issue": "387(10036)", "journal": "Lancet (London, England)", "keywords": null, "medline_ta": "Lancet", "mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D019046:Bone Marrow Neoplasms; D002051:Burkitt Lymphoma; D016543:Central Nervous System Neoplasms; D003520:Cyclophosphamide; D003561:Cytarabine; D004317:Doxorubicin; D004334:Drug Administration Schedule; D005260:Female; D005602:France; D006801:Humans; D006854:Hydrocortisone; D007275:Injections, Intravenous; D008297:Male; D008727:Methotrexate; D008775:Methylprednisolone; D008875:Middle Aged; D009367:Neoplasm Staging; D016017:Odds Ratio; D018579:Patient Selection; D011241:Prednisone; D016016:Proportional Hazards Models; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine", "nlm_unique_id": "2985213R", "other_id": null, "pages": "2402-11", "pmc": null, "pmid": "27080498", "pubdate": "2016-06-11", "publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Rituximab and dose-dense chemotherapy for adults with Burkitt's lymphoma: a randomised, controlled, open-label, phase 3 trial.", "title_normalized": "rituximab and dose dense chemotherapy for adults with burkitt s lymphoma a randomised controlled open label phase 3 trial" }	[ { "companynumb": "FR-JNJFOC-20160808849", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", "...
{ "abstract": "OBJECTIVE\nThe aim of this study is to report the case of the orthodontic treatment in a patient affected by primary hyperoxaluria type 1 and subjected to a combinate liver-kidney transplant.\n\n\nRESULTS\nThe 9-year patient was admitted to our department for the presence of facial dysmorphism. The patient was affected by primary hyperoxaluria type 1 and has undergone a combined liver-kidney transplantation. At the time of the visit, he was in treatment with immunosuppressive drugs and received a corticosteroid and an antibiotic therapy monthly. An intraoral and extraoral examination, as well as radiographic and model analysis, was performed in order to define an accurate diagnosis and a proper rehabilitation planning. An orthopedic-orthodontic treatment was performed and satisfactory final results obtained. A laser gingivectomy was also realized for eliminate the gengival hyperplasia probably induced by cyclosporine assumption. Both skeletal and dental relationships were improved by the treatment, reaching a good dental arches alignment.\n\n\nCONCLUSIONS\nAn early diagnosis, as well as a multidisciplinary approach, is very important in patients with rare diseases. An appropriate treatment allowed us to achieve acceptable results and improve the patient quality of life.", "affiliations": "Department of Odontostomatology and Surgery, University of Bari, Bari, Italy.;Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.;Department of Odontostomatology and Surgery, University of Bari, Bari, Italy.;Department of Odontostomatology and Surgery, University of Bari, Bari, Italy.;Department of Odontostomatology and Surgery, University of Bari, Bari, Italy.;Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.;Department of Life, Health and Environmental Sciences, Dental Clinic, University of L'Aquila, L'Aquila, Italy.;Department of Odontostomatology and Surgery, University of Bari, Bari, Italy.;Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.;Department of Clinical and Experimental Medicine, University of Foggia, Foggia, Italy.", "authors": "Cazzolla\|A P\|AP\|http://orcid.org/0000-0003-0842-7351;Zhurakivska\|K\|K\|http://orcid.org/0000-0002-2153-0778;Ciavarella\|D\|D\|;Lacaita\|M G\|MG\|;Favia\|G\|G\|;Testa\|N F\|NF\|;Marzo\|G\|G\|;La Carbonara\|V\|V\|;Troiano\|G\|G\|;Lo Muzio\|L\|L\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1111/scd.12302", "fulltext": null, "fulltext_license": null, "issn_linking": "0275-1879", "issue": "38(4)", "journal": "Special care in dentistry : official publication of the American Association of Hospital Dentists, the Academy of Dentistry for the Handicapped, and the American Society for Geriatric Dentistry", "keywords": "orthodontics; pediatric dentistry; rare disorders", "medline_ta": "Spec Care Dentist", "mesh_terms": "D002648:Child; D005885:Gingival Hyperplasia; D006801:Humans; D006960:Hyperoxaluria, Primary; D016030:Kidney Transplantation; D016031:Liver Transplantation; D008297:Male; D008313:Malocclusion, Angle Class III; D009059:Mouth Diseases; D009971:Orthodontics, Corrective; D011862:Radiography, Panoramic", "nlm_unique_id": "8103755", "other_id": null, "pages": "259-265", "pmc": null, "pmid": "29882304", "pubdate": "2018-07", "publication_types": "D002363:Case Reports", "references": null, "title": "Primary hyperoxaluria: Orthodontic management in a pediatric patient: A case report.", "title_normalized": "primary hyperoxaluria orthodontic management in a pediatric patient a case report" }	[ { "companynumb": "IT-TEVA-2019-IT-1003299", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": "3", ...
{ "abstract": "Drug-induced kidney disease is a frequent cause of renal dysfunction; however, there are no standards to identify and characterize the spectrum of these disorders. We convened a panel of international, adult and pediatric, nephrologists and pharmacists to develop standardized phenotypes for drug-induced kidney disease as part of the phenotype standardization project initiated by the International Serious Adverse Events Consortium. We propose four phenotypes of drug-induced kidney disease based on clinical presentation: acute kidney injury, glomerular, tubular, and nephrolithiasis, along with the primary and secondary clinical criteria to support the phenotype definition, and a time course based on the KDIGO/AKIN definitions of acute kidney injury, acute kidney disease, and chronic kidney disease. Establishing causality in drug-induced kidney disease is challenging and requires knowledge of the biological plausibility for the specific drug, mechanism of injury, time course, and assessment of competing risk factors. These phenotypes provide a consistent framework for clinicians, investigators, industry, and regulatory agencies to evaluate drug nephrotoxicity across various settings. We believe that this is the first step to recognizing drug-induced kidney disease and developing strategies to prevent and manage this condition.", "affiliations": "University of California San Diego School of Medicine, La Jolla, California, USA.;University of California San Diego Skaggs School of Pharmacy, La Jolla, California, USA.;Royal Free Hospital and University College Medical School, UCL Centre for Nephrology, London, UK.;University College Dublin School of Medicine and Medical Science, Health Sciences Centre, Belfield, Dublin, Ireland.;University of São Paolo, São Paolo, Brazil.;Albany Medical College, Albany, New York, USA.;Care Hospitals, Hyderabad, Telangana, India.;International Serious Adverse Event Consortium, Chicago, Illinois, USA.;Division of Nephrology and Hypertension at Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.", "authors": "Mehta\|Ravindra L\|RL\|;Awdishu\|Linda\|L\|;Davenport\|Andrew\|A\|;Murray\|Patrick T\|PT\|;Macedo\|Etienne\|E\|;Cerda\|Jorge\|J\|;Chakaravarthi\|Raj\|R\|;Holden\|Arthur L\|AL\|;Goldstein\|Stuart L\|SL\|", "chemical_list": "D001639:Bicarbonates; D004573:Electrolytes; D010710:Phosphates; D003404:Creatinine; D008274:Magnesium; D011188:Potassium", "country": "United States", "delete": false, "doi": "10.1038/ki.2015.115", "fulltext": null, "fulltext_license": null, "issn_linking": "0085-2538", "issue": "88(2)", "journal": "Kidney international", "keywords": null, "medline_ta": "Kidney Int", "mesh_terms": "D058186:Acute Kidney Injury; D001639:Bicarbonates; D001706:Biopsy; D032921:Consensus; D003404:Creatinine; D003697:Delphi Technique; D004573:Electrolytes; D006029:Glycosuria; D006417:Hematuria; D006801:Humans; D007678:Kidney Glomerulus; D007684:Kidney Tubules; D008274:Magnesium; D009336:Necrosis; D009395:Nephritis, Interstitial; D053040:Nephrolithiasis; D010641:Phenotype; D010710:Phosphates; D011188:Potassium; D011507:Proteinuria; D013997:Time Factors", "nlm_unique_id": "0323470", "other_id": "EMS62528", "pages": "226-34", "pmc": null, "pmid": "25853333", "pubdate": "2015-08", "publication_types": "D016446:Consensus Development Conference; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "15458458;7249508;15947990;21428769;21212419;21544079;22362062;24996668", "title": "Phenotype standardization for drug-induced kidney disease.", "title_normalized": "phenotype standardization for drug induced kidney disease" }	[ { "companynumb": "US-BAXTER-2015BAX048281", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "VANCOMYCIN" }, "drugadditional": null, ...
{ "abstract": "Acute pancreatitis is most commonly attributed to gallstones, alcohol abuse, and metabolic disorders such as hyperlipidemia and hypercalcemia. Medications are an infrequent yet commonly overlooked etiology of pancreatitis. Although several drugs have been implicated, antidiabetic agents are a rare cause for drug-induced pancreatitis. Canagliflozin is a new drug in the class of SGLT-2 inhibitors used for the treatment of type 2 diabetes mellitus. Serious reported side effects include renal impairment, hyperkalemia, and hypotension. Pancreatitis as a result of canagliflozin, however, is exceedingly rare. Here we describe a case of a 33-year old female who presented with severe acute pancreatitis in the setting of recent initiation of canagliflozin. Given the timing of her presentation and after excluding all other possible etiologies, it was determined that canagliflozin was the likely source of her illness. This case highlights the importance of identifying drug-induced pancreatitis, especially in novel drugs, as it is commonly neglected in patients with multiple medical comorbidities and those taking numerous medications. Prompt identification of drug-induced pancreatitis can improve management as well as decrease morbidity and mortality in these individuals.", "affiliations": "Department of Internal Medicine, Mercer University School of Medicine, Macon, GA, USA.;Department of Internal Medicine, Mercer University School of Medicine, Macon, GA, USA.;Department of Internal Medicine, New York University Langone Medical Center, New York, NY, USA.", "authors": "Chowdhary\|Mudit\|M\|;Kabbani\|Ahmad A\|AA\|;Chhabra\|Akansha\|A\|", "chemical_list": null, "country": "New Zealand", "delete": false, "doi": "10.2147/TCRM.S86641", "fulltext": "\n==== Front\nTher Clin Risk ManagTher Clin Risk ManagTherapeutics and Clinical Risk ManagementTherapeutics and Clinical Risk Management1176-63361178-203XDove Medical Press 10.2147/TCRM.S86641tcrm-11-991Case ReportCanagliflozin-induced pancreatitis: a rare side effect of a new drug Chowdhary Mudit 1Kabbani Ahmad A 1Chhabra Akansha 21 Department of Internal Medicine, Mercer University School of Medicine, Macon, GA, USA2 Department of Internal Medicine, New York University Langone Medical Center, New York, NY, USACorrespondence: Mudit Chowdhary, Department of Internal Medicine, Mercer University School of Medicine, 707 Pine Street, Macon, GA 31201, USA, Email mu.chowdhary@gmail.com2015 26 6 2015 11 991 994 © 2015 Chowdhary et al. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2015The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Acute pancreatitis is most commonly attributed to gallstones, alcohol abuse, and metabolic disorders such as hyperlipidemia and hypercalcemia. Medications are an infrequent yet commonly overlooked etiology of pancreatitis. Although several drugs have been implicated, antidiabetic agents are a rare cause for drug-induced pancreatitis. Canagliflozin is a new drug in the class of SGLT-2 inhibitors used for the treatment of type 2 diabetes mellitus. Serious reported side effects include renal impairment, hyperkalemia, and hypotension. Pancreatitis as a result of canagliflozin, however, is exceedingly rare. Here we describe a case of a 33-year old female who presented with severe acute pancreatitis in the setting of recent initiation of canagliflozin. Given the timing of her presentation and after excluding all other possible etiologies, it was determined that canagliflozin was the likely source of her illness. This case highlights the importance of identifying drug-induced pancreatitis, especially in novel drugs, as it is commonly neglected in patients with multiple medical comorbidities and those taking numerous medications. Prompt identification of drug-induced pancreatitis can improve management as well as decrease morbidity and mortality in these individuals.\n\nKeywords\ncanagliflozinInvokanapancreatitisdrug-induced pancreatitisSGLT-2 inhibitor\n==== Body\nIntroduction\nAcute pancreatitis (AP) is an inflammatory condition of the pancreas characterized clinically by intense epigastric pain radiating to the back along with elevated levels of pancreatic enzymes in the blood. Although pancreatitis is a leading cause of hospitalization in the United States,1 the pathogenesis for this condition is not fully understood. Nevertheless, various etiologies have been shown to increase the risk for and to cause pancreatitis.\n\nGallstones are the most common cause for AP, accounting for 35%–40% of cases worldwide, and together with alcohol, and metabolic disorders such as hyperlipidemia and hypercalcemia make up around 90% of all cases.2 Medications are infrequently associated with pancreatitis with a reported incidence of only 0.1%–2%3,4 although several drugs have been implicated including diuretics, didanosine, tetracycline, sulfonamides, and steroids, among others.\n\nDiabetic medications have rarely been associated with pancreatitis with the majority of reported cases involving DPP-4 inhibitors (sitagliptin, saxagliptin) and GLP-1 receptor antagonists (exenatide, liraglutide).5 Canagliflozin is a new drug in the class of sodium-glucose cotransporter-2 (SGLT-2) inhibitors used for the treatment of type 2 diabetes mellitus (T2DM). Here we describe a patient who developed a severe manifestation of AP soon after initiation of canagliflozin therapy.\n\nCase presentation\nA 33-year old African–American female presented to the emergency room with a 2-day history of progressively worsening nausea, vomiting, and severe abdominal pain. The patient denied any cardiovascular, respiratory, or urinary symptoms nor had she been around any sick contacts. The patient denied any abdominal surgeries or prior history of gallstones, dyslipidemia or pancreatitis. She denied any alcohol, cigarette use, or illicit drug use. She had a history of diabetes mellitus, hypertension and hypothyroidism; however, there was no family history of autoimmune conditions or AP. Her home medications included long-term metformin and levothyroxine. In addition, the patient recently began canagliflozin therapy 2 weeks prior to her admission.\n\nIn the emergency department, she was found to be hypotensive with a blood pressure of 79/36, heart rate of 118 bpm, and a respiratory rate of 27. Her temperature was 40.3 degrees Celsius. Serum chemistries revealed leukocytosis with a white blood cell count of 23.6×103/mm3, creatinine of 3.19 mg/dL, calcium of 9.3 mg/dL, amylase 535 IU/L, and lipase 373 IU/L. HbA1c was recorded as 13.5% and her triglyceride level was within normal limits. Additionally, she displayed an elevated anion gap of 19 and acidosis with a pH of 6.89 with blood glucose level of 563 mg/dL and positive urine ketones (beta-hydroxybutyrate: 2.90). Subsequent arterial blood gas revealed PCO2 of 48.8 and FiO2 of 100. Maximum blood alcohol was negative. She was initially diagnosed with diabetic ketoacidosis (DKA) and given several liters of normal saline followed by a bicarbonate and insulin drip. Urine and blood cultures were drawn and she was started on broad-spectrum antibiotics for her fever and leukocytosis. A computerized tomography (CT) scan of the abdomen was obtained due to the elevated pancreatic enzymes and it showed evidence of AP with peripancreatic inflammation and ascites (Figure 1). Chest X-ray additionally revealed bilateral pleural effusions. Echocardiogram though was unremarkable.\n\nDespite aggressive fluid resuscitation, the patient became progressively more hypotensive and became unresponsive. She was started on a norepinephrine drip, intubated and admitted to the intensive care unit. Her renal function deteriorated with decreased urine output and increasing serum creatinine reaching 4.26 (pre-morbid creatinine: 1.0) with persistent acidemia requiring continuous renal replacement therapy. In the intensive care unit, an APACHE (Acute Physiology and Chronic Health Evaluation) II score was calculated for the patient and revealed an estimated mortality rate of 97.2%.\n\nDespite the poor prognosis the patient’s condition remarkably improved and vasopressors were discontinued and she was successfully extubated after 4 days. The source of leukocytosis was indeterminate as cultures of blood, urine, and mini bronchoalveolar lavage were all negative. After excluding all other causes for her symptoms and given the chronology of her presentation, it was determined that canagliflozin was likely the source of her illness. Canagliflozin was discontinued and the patient has remained stable since discharge.\n\nDiscussion\nWhile metformin has been widely accepted as the initial drug of choice for T2DM6 numerous second-line classes of diabetic medications exist for clinicians to choose from, with individual choice determined largely by factors including cost and risk for adverse effects. Canagliflozin is the first SGLT-2 inhibitor approved by the FDA (US Food and Drug Administration) for the treatment of T2DM.7\n\nNormally, plasma glucose is freely filtered by the glomerulus and reabsorbed in the proximal renal tubule, with a small amount excreted directly in the urine. Ninety percent of renal glucose reabsorption occurs in the proximal tubule as a result of SGLT-2.8 Canagliflozin works by inhibiting SGLT-2, causing a dramatic reduction in the kidneys’ capacity to reabsorb glucose, thus leading to a decrease in plasma glucose levels.9 Clinical studies have shown remarkable efficacy with this drug. The Canagliflozin Treatment and Trial Analysis-Monotherapy Trial demonstrated a baseline HbA1c reduction by 0.91%–1.16%, a reduction in systolic blood pressure and body weight, and an increased high-density lipoprotein level.10 Additionally, studies have also shown a 0.81%–0.93% decrease in HbA1c when canagliflozin was given in conjunction with metformin.11\n\nThe most common side effects of canagliflozin are urinary tract infections and genital mycotic infections, which occur more frequently in women. Additional potential side effects include nausea, renal impairment, hyperkalemia, and hypoglycemia. Pancreatitis as a result of canagliflozin is exceedingly rare, with an incidence rate of only 2.7 per 1,000 patient-years.12\n\nThe exact mechanism of canagliflozin-induced pancreatitis is currently unclear; however, the underlying pathogenesis is unlikely to differ from other causes of AP. In fact, the majority of drug-induced pancreatitis (DIP) appears to be idiosyncratic in nature.13 Idiosyncratic drug reactions are adverse effects not directly related to pharmacodynamic drug mechanisms. These spontaneous and unpredictable adverse complications are a result of abnormal interactions between specific drugs and the patient themselves, and are typically mediated by immunologic or cytotoxic effects triggered by the drug or its metabolites on a specific organ system.14\n\nNevertheless, DIP is a serious complication and very easily overlooked in patients with multiple comorbidities, those on multiple medications, or those with potential underlying risk factors such as gallstones or alcohol abuse.\n\nWe believe this is the second reported incidence of canagliflozin-induced pancreatitis as a PubMed literature search for several variations of “canagliflozin” and “pancreatitis” revealed only one additional case.15 Our case is further unique in that pancreatitis was also associated with acute kidney injury. It remains to be seen whether kidney injury was a sequela of the pancreatitis or a simultaneous additional side effect of canagliflozin. It is important to note that the patient had been on long-term metformin and levothyroxine when this occurred, albeit without a history of pancreatitis or other side effects. Several case reports have suggested a possible role of metformin in causing AP, specifically during periods of renal insufficiency.16,17 Therefore, it is possible that metformin also played a role in precipitating this episode of AP.\n\nSpecial care must also be given to patients who present with DKA and concurrent abdominal pain. Nair et al18 reported an association between DKA and AP, though the pathogenesis primarily involved transient hyperlipidemia rather than DIP. Regardless, DKA may mask a coexisting AP in 10%–15%.18 The key treatment for DIP is early recognition, exclusion of all other etiologies, and discontinuation of the possible causative medication followed by supportive therapy.\n\nIn our case, the adverse event occurred within a reasonable period of drug administration. Laboratory data and radiological imaging confirmed the diagnosis of AP. Additionally, there were no other changes to the patient’s drug regimen in the weeks preceding pancreatitis aside from the addition of canagliflozin. Furthermore, the event was not attributable to any other etiology, as our patient did not have a history of recent infection, gallstones, hypertriglyceridemia, or alcohol intake. Finally, there was no recurrence of pancreatitis following discontinuation of canagliflozin. Therefore, according to the Naranjo probability scale, the adverse event was most likely related to canagliflozin.19\n\nConclusion\nAs the prevalence of diabetes in the United States increases, the amount of new medications designed to combat it will increase as well. Our case illustrates the importance of being aware of new antidiabetic drugs such as canagliflozin as potential treatment options for T2DM as well as remaining up to date on potential side effects and drug interactions of these newer agents. DIP is an uncommon yet potentially serious complication of canagliflozin. It remains to be seen whether this is as a result of canagliflozin monotherapy or due to an interaction with metformin in the setting of acute kidney injury. Regardless, DIP may easily be overlooked in patients due to its low incidence, and confounded by the presence of comorbidities, and potential of multiple medication use. Thus it is imperative for clinicians to keep a high index of suspicion in order to prevent morbidity and mortality from disease progression.\n\nAcknowledgments\nNo outside funding was utilized in this study.\n\nDisclosure\n\nThe authors declare that there is no conflict of interests in this work.\n\nFigure 1 Abdominal computerized tomography scan revealing acute pancreatitis (red arrow).\n==== Refs\nReferences\n1 Peery AF Dellon ES Lund J Burden of gastrointestinal disease in the United States: 2012 update Gastroenterology 2012 143 5 1179 1187 e1 3 22885331 \n2 Forsmark CE Baillie J AGA Institute Clinical Practice and Economics Committee; AGA Institute Governing Board AGA Institute technical review on acute pancreatitis Gastroenterology 2007 132 5 2022 2044 17484894 \n3 Spanier BW Tuynman HA van der Hulst RW Dijkgraaf MG Bruno MJ Acute Pancreatitis and Concomitant Use of Pancreatitis-Associated Drugs Am J Gastroenterol 2011 106 12 2183 2188 21912439 \n4 Balani AR Grendell JH Drug-induced pancreatitis: incidence, management and prevention Drug Saf 2008 31 10 823 837 18759507 \n5 Cohen D Reports of pancreatitis are 20–30 times more likely with GLP-1 drugs, analysis finds BMJ 2013 346 f2607 23613543 \n6 American Diabetes Association Standards of medical care in diabetes – 2014 Diabetes Care 2014 37 Suppl 1 S14 S80 24357209 \n7 US Food and Drug Administration FDA approves Invokana to treat type 2 diabetes [press release] US Food and Drug Administration 2013 Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm345848.htm Accessed February 22, 2015 \n8 Chao EC Henry RR SGLT2 inhibition-a novel strategy for diabetes treatment Nat Rev Drug Discov 2010 9 7 551 559 20508640 \n9 Sha S Devineni D Ghosh A Canagliflozin, a novel inhibitor of sodium glucose co-transporter 2, dose dependently reduces calculated renal threshold for glucose excretion and increases urinary glucose excretion in healthy subjects Diabetes Obes Metab 2011 13 7 669 672 21457428 \n10 Stenlof K Cefalu WT Kim KA Efficacy and safety of Canagliflozin monotherapy in subjects with type 2 diabetes mellitus inadequately controlled with diet and exercise Diabetes Obes Metab 2013 15 4 372 382 23279307 \n11 Valentine V Hinnen D Clinical implications of canagliflozin treatment in patients with type 2 diabetes Clin Diabetes 2015 33 1 5 13 25653467 \n12 Invokana® (canagliflozin) [prescribing information] Titusville, NJ Janssen Pharmaceuticals, Inc 2014 \n13 Hung WY Abreu Lanfranco O Contemporary review of drug-induced pancreatitis: A different perspective World J Gastrointest Pathophyiol 2014 5 4 405 415 \n14 Badalov N Baradarian R Iswara K Li J Steinberg W Tenner S Drug-induced acute pancreatitis: an evidence-based review Clin Gastroenterol Hepatol 2007 5 6 648 651 17395548 \n15 Verma R Canagliflozin-Associated Acute Pancreatitis Am J Ther Epub 2014 Sep 2 \n16 Fimognari FL Corsonello A Pastorell R Antonelli-Incalzi R Metformin-induced pancreatitis Diabetes Care 2006 29 5 1183 16644670 \n17 Alsubaie S Almalki MH Metformin induced acute pancreatitis Dermatoendocrinol 2013 5 2 317 318 24194972 \n18 Nair S Yadav D Pitchumoni CS Association of diabetic ketoacidosis and acute pancreatitis: observations in 100 consecutive episodes of DKA Am J Gastroenterol 2000 95 10 2795 2800 11051350 \n19 Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 7249508\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1176-6336", "issue": "11()", "journal": "Therapeutics and clinical risk management", "keywords": "Invokana; SGLT-2 inhibitor; canagliflozin; drug-induced pancreatitis; pancreatitis", "medline_ta": "Ther Clin Risk Manag", "mesh_terms": null, "nlm_unique_id": "101253281", "other_id": null, "pages": "991-4", "pmc": null, "pmid": "26170677", "pubdate": "2015", "publication_types": "D002363:Case Reports", "references": "21457428;25187092;20508640;24357209;25653467;25400984;17484894;23279307;17395548;18759507;7249508;22885331;11051350;21912439;23613543;24194972;16644670", "title": "Canagliflozin-induced pancreatitis: a rare side effect of a new drug.", "title_normalized": "canagliflozin induced pancreatitis a rare side effect of a new drug" }	[ { "companynumb": "US-JNJFOC-20150717501", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CANAGLIFLOZIN" }, "drugadditional": null, ...
{ "abstract": "•Cutaneous metastases are rare and clinically challenging to manage. When present, they often represent end-stage disease.•Treatments for cutaneous metastases are limited, and primarily palliative in nature.", "affiliations": "Department of Obstetrics and Gynecology, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USA.;Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.;Department of Gynecologic Oncology, University of Tennessee College of Medicine, Knoxville, TN 37920, USA.;Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.", "authors": "Craig\|Christine D\|CD\|;Iglesias\|David A\|DA\|;Watkins\|Jack\|J\|;Coleman\|Robert L\|RL\|;Kilgore\|Larry\|L\|;Ramirez\|Pedro T\|PT\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": "10.1016/j.gynor.2013.05.005", "fulltext": "\n==== Front\nGynecol Oncol Case RepGynecol Oncol Case RepGynecologic Oncology Case Reports2211-338XElsevier S2211-338X(13)00042-210.1016/j.gynor.2013.05.005Case ReportExtensive cutaneous metastases of ovarian cancer after prolonged response to liposomal doxorubicin☆☆☆☆☆☆ Craig Christine D. aIglesias David A. bWatkins Jack cColeman Robert L. bKilgore Larry dRamirez Pedro T. peramire@mdanderson.orgb⁎a Department of Obstetrics and Gynecology, St. Joseph's Hospital and Medical Center, Phoenix, AZ 85013, USAb Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAc Division of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USAd Department of Gynecologic Oncology, University of Tennessee College of Medicine, Knoxville, TN 37920, USA⁎ Corresponding author at: Department of Gynecologic Oncology, Unit 1362, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA. Fax: + 1 713 792 7586. peramire@mdanderson.org19 5 2013 19 5 2013 8 2013 5 64 66 30 3 2013 11 5 2013 © 2013 The Authors2013This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.Highlights\n• Cutaneous metastases are rare and clinically challenging to manage. When present, they often represent end-stage disease.\n\n• Treatments for cutaneous metastases are limited, and primarily palliative in nature.\n\n\n\nKeywords\nOvarian cancerSkin recurrenceLiposomal doxorubicin\n==== Body\nIntroduction\nIn 2012, an estimated 22,280 women were diagnosed with ovarian cancer and 15,500 died of the disease [1]. Approximately seventy-five percent of women diagnosed with ovarian cancer in the United States have stage III or more advanced disease at diagnosis. Although most patients respond to initial treatment, the rate of recurrence after initial treatment of ovarian cancer is as high as 65% to 75%. The most common site of recurrence is within the peritoneal cavity. In a postmortem study, Rose et al. evaluated the patterns of ovarian cancer metastasis and found that the most common sites of metastasis were the peritoneal cavity, paraaortic lymph nodes, large intestine, pelvic lymph nodes, and liver [2].\n\nOvarian cancer can metastasize by direct extension and transport throughout the peritoneal cavity and/or through lymphatic or hematogenous spread. Cutaneous metastases are rare, occurring in 1.9% to 5.1% of patients [3]. Cutaneous metastases are often a late manifestation of the disease and have a propensity to occur within previous surgical scars, although cases of cutaneous metastases to the limbs have also been reported. Cutaneous metastases most commonly manifest as small nodular lesions but can also manifest as herpetiform erythematous lesions and scarring plaques.\n\nTreatment of recurrent metastatic ovarian cancer involves systemic chemotherapy with agents chosen on the basis of previously demonstrated platinum sensitivity or resistance. Pegylated liposomal doxorubicin (PLD) is a cytotoxic agent that has demonstrated efficacy in the treatment of recurrent platinum-sensitive and platinum-resistant ovarian cancer. In patients with platinum-resistant ovarian cancer, PLD as a single agent has shown a survival benefit nearly equal to what is observed with other cytotoxic agents but is associated with less toxicity. Given these findings and its relatively convenient dosing, PLD is often chosen as the preferred agent for patients with recurrent platinum-resistant ovarian cancer.\n\nCase\nA 64-year-old woman was diagnosed with at least stage IA high-grade serous ovarian carcinoma following a laparoscopic bilateral salpingo-oophorectomy. The patient was subsequently referred to The University of Texas MD Anderson Cancer Center for further treatment. Initial evaluation by computed tomography (CT) demonstrated indeterminate subcentimeter liver lesions and a 1.8 cm lesion along the right external iliac vessels. As such, the patient was treated with six cycles of paclitaxel (175 mg/m2) and carboplatin (AUC = 5), which were completed in May 2006. She had no evidence of disease upon completion of therapy. The patient underwent BRCA testing which demonstrated no detectable mutations or large gene rearrangements.\n\nApproximately 5 months after completion of therapy, CT revealed disease recurrence in the form of a 1-cm subcutaneous nodule involving the left rectus abdominus muscle and small peritoneal deposits within the pelvis and a lesion on the right external iliac vessels. The serum CA-125 level was 7.1 U/mL. Given that disease had recurred within 5 months of platinum-based therapy, the decision was made to treat the patient with single-agent PLD (40 mg/m2) every 28 days. The patient experienced an infusion reaction with the first cycle, and consequently the dose was reduced to 35 mg/m2. In October 2009, the patient had completed a total of 34 cycles of treatment with PLD and requested a chemotherapy treatment break. Throughout the course of treatment with PLD, periodic CT had demonstrated a stable metastatic focus adjacent to the left rectus abdominus muscle. To evaluate whether this residual lesion was metabolically active, positron emission tomography (PET)-CT was performed before therapy was stopped. The focus was not fluorodeoxyglucose avid and thus was judged not to represent active disease. The CA-125 level was 11.4 U/mL. Chemotherapy was stopped, and the patient was placed on surveillance.\n\nIn April 2010, follow-up PET-CT revealed new metastases in the omentum and peritoneum. In May 2010, the patient underwent an exploratory laparotomy, total abdominal hysterectomy, omentectomy, splenectomy, resection of a right-sided pelvic wall mass, resection of anterior abdominal wall nodule, and optimal tumor-reductive surgery. The final pathology report after that surgery indicated high-grade serous carcinoma in the omentum and anterior abdominal wall nodule. In June 2010, PLD at 35 mg/m2 every 28 days was reinitiated; the patient received an additional 8 cycles of this treatment.\n\nIn February 2011, PET-CT showed low-grade FDG uptake in a peritoneal nodule as well as new subcutaneous nodules that were too small to characterize. In March 2011, treatment was changed to letrozole 2.5 mg by mouth daily. The patient was treated with letrozole for 2 months. In May 2011, reassessment with PET-CT demonstrated progression of disease with enlargement of peritoneal implants and subcutaneous nodules. The CA-125 level was 166.6 U/mL. At that time, the patient was switched from letrozole back to PLD, but in July 2011, after the patient had received two cycles of this drug, PLD was discontinued because of a national drug shortage. The patient was subsequently treated with tamoxifen 20 mg twice daily. Two months later, she was changed to single-agent etoposide administered in 21-day cycles consisting of 50 mg by mouth for 2 weeks followed by a 1-week break.\n\nAfter 2 months of treatment with etoposide, the patient noted progression of subcutaneous disease in the suprapubic region. In December 2011, etoposide was stopped, and the patient received 13 fractions of localized radiation at an outside facility. The CA-125 level at this time was 1133 U/mL (Fig. 1). After completion of radiation therapy, PLD was restarted. After the patient had received an additional four cycles of PLD, for a cumulative total of 48 cycles, PLD was stopped and single-agent paclitaxel (60 mg/m2 weekly) was started because of concerns about radiation recall and progression of the abdominal wall and cutaneous disease. The patient received one cycle of paclitaxel. She had progression of disease and was then switched to a combination of cyclophosphamide and bevacizumab at an outside institution. She completed three cycles of this treatment and was noted to have progression of disease with extensive cutaneous involvement of the abdominal wall with multiple nodular and ulcerative lesions on gross abdominal inspection (Fig. 2) and on PET-CT (Fig. 3). The wound care team at MD Anderson evaluated the patient's multiple and confluent abdominal wall lesions. Wound care specialists recommended daily cleansing of the wounds with saline followed by application of Xeroform and Aquaphor ointment to affected areas. The patient was referred to hospice care in August 2012. Two months after referral to hospice, she died.\n\nComment\nRobinson et al. recently reported that in a series of 233 patients with recurrence after treatment for stage III ovarian cancer, only two patients (0.8%) had recurrence in cutaneous tissue [4]. Another group documented six cases of cutaneous metastases (0.9%) in 645 patients diagnosed with epithelial ovarian carcinoma [5]. The majority of these cutaneous recurrences were within previous laparotomy scars or drainage site scars. All studies of cutaneous metastases that were reviewed showed that such metastases from any visceral organ are associated with a very poor prognosis. Survival has been reported to be anywhere from 3 to 8 months after diagnosis of a cutaneous lesion in ovarian cancer.\n\nThe majority of patients with ovarian cancer eventually have a relapse, which is associated with poor long-term survival. Approximately 20% of patients with relapse have platinum-resistant disease.\n\nPLD is a preferred treatment for such patients because it is among the non-platinum-based agents with the highest activity against recurrent platinum-resistant ovarian cancer. Etoposide is another agent with similar efficacy [6]. In the event that the patient cannot tolerate the cytotoxic nature of these drugs, hormonal agents such as letrozole and tamoxifen have proven effective in certain subtypes of platinum resistant disease [7,8]. However, the role of these agents, especially PLD, in the management of cutaneous metastases has not been fully evaluated.\n\nManagement of cutaneous metastases varies widely and remains a clinical challenge, especially if primary excision is not feasible because of the location or extent of disease. Previously evaluated systemic chemotherapies have had minimal effect. Earlier studies suggested that electrocoagulation, electron beam therapy, and phototherapy may be effective in treating cutaneous lesions. At present, the topical Toll-like receptor 7 agonist imiquimod and electrochemotherapy are being studied for treatment of cutaneous metastases. Imiquimod exerts its effects by activating local macrophages through its binding of toll-like receptor 7, which leads to release of pro-inflammatory cytokines that are responsible for the cytotoxicity of this drug [9]. Electrochemotherapy, historically used in the treatment of metastatic head and neck cancers, has been explored in the treatment of cutaneous disease in patients with chest wall recurrence of breast cancer. In electrochemotherapy, a local electrical current is applied to the lesion, which causes cellular membranes to become more permeable to the chemotherapy agent being used. In the case of bleomycin-based electrochemotherapy, the electric current increases permeability to the drug by 700-fold [10]. In a phase II study by Campana et al., bleomycin-based electrochemotherapy produced a complete response in 54% of the patients, and 81% of the patients were alive at 3 years [10]. However, it has been suggested that the aim of electrochemotherapy in patients with extensive disease is to maintain stable disease. Limited data exist on the utility of this technology in patients with cutaneous metastases from ovarian cancer.\n\nIn conclusion, cutaneous metastases from ovarian cancer are rare and portend a poor prognosis. Management of cutaneous metastases remains a clinical challenge. Further studies evaluating the role of specific therapies are needed to guide treatment.\n\nConflict of interest statement\nThe authors of this paper have no conflicts of interest to declare.\n\n☆ This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-No Derivative Works License, which permits non-commercial use, distribution, and reproduction in any medium, provided the original author and source are credited.\n\n☆☆ The University of Texas MD Anderson Cancer Center is supported in part by the National Institutes of Health through Cancer Center Support GrantCA016672.\n\n☆☆☆ Précis: Cutaneous metastases from ovarian cancer are rare and are associated with potentially severe morbidity. Such metastases present a clinical therapeutic challenge.\n\nFig. 1 CA-125 level over the course of the patient's treatment with various chemotherapy agents.\n\nFig. 2 Cutaneous metastases on the abdominal wall in a patient with recurrent ovarian cancer.\n\nFig. 3 Axial positron emission tomography image demonstrating fluorodeoxyglucose-avid lesions within the subcutaneous tissue of the lower abdomen.\n==== Refs\nReferences\n1 Siegel R. Naishadham D. Jemal A. Cancer statistics, 2012 CA Cancer J. Clin. 62 1 2012 10 29 22237781 \n2 Rose P.G. Piver M.S. Tsukada Y. Lau T.S. Metastatic patterns in histologic variants of ovarian cancer. An autopsy study Cancer 64 7 1989 1508 1513 2776109 \n3 Cormio G. Capotorto M. Di Vagno G. Cazzolla A. Carriero C. Selvaggi L. Skin metastases in ovarian carcinoma: a report of nine cases and a review of the literature Gynecol. Oncol. 90 3 2003 682 685 13678747 \n4 Robinson W.R. Beyer J. Griffin S. Kanjanavaikoon P. Extraperitoneal metastases from recurrent ovarian cancer Int. J. Gynecol. Cancer 22 1 2012 43 46 22193642 \n5 Cheng B. Lu W. Xiaoyun W. YaXia C. Xie X. Extra-abdominal metastases from epithelial ovarian carcinoma: an analysis of 20 cases Int. J. Gynecol. Cancer 19 4 2009 611 614 19509558 \n6 Rose P.G. Bleseing J.A. Mayer A.R. HomesleyHD. Prolonged oral etoposide as second line therapy for platinum resistant and platinum-sensitive ovarain carcinoma: a gynecologic oncology group study J. Clin. Oncol. 16 1998 405 410 9469322 \n7 Ramirez P.T. Schmeler K.M. Milam M.R. Efficacy of Letrozole in treatment of recurrent platinum- and taxane-resistant high grade cancer of the ovary or peritoneum Gynecol. Oncol. 110 2008 56 59 18457865 \n8 Markman M. Iseminger K.A. Hatch K.D. Tamoxifen in platinum refractory ovarian cancer: a Gynecological Oncology Group Ancillary Report Gynecol. Oncol. 62 1996 4 6 8690289 \n9 Stanley M.A. Imiquimod and the imidazoquinolones: mechanism of action and therapeutic potential Clin. Exp. Dermatol. 27 7 2002 571 577 12464152 \n10 Campana L.G. Valpione S. Falci C. The activity and safety of electrochemotherapy in persistent chest wall recurrence from breast cancer after mastectomy: a phase-II study Breast Cancer Res. Treat. 134 3 2012 1169 1178 22821399\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2211-338X", "issue": "5()", "journal": "Gynecologic oncology case reports", "keywords": "Liposomal doxorubicin; Ovarian cancer; Skin recurrence", "medline_ta": "Gynecol Oncol Case Rep", "mesh_terms": null, "nlm_unique_id": "101599306", "other_id": null, "pages": "64-6", "pmc": null, "pmid": "24371701", "pubdate": "2013", "publication_types": "D016428:Journal Article", "references": "8690289;22237781;9469322;22193642;19509558;18457865;13678747;22821399;2776109;12464152", "title": "Extensive cutaneous metastases of ovarian cancer after prolonged response to liposomal doxorubicin.", "title_normalized": "extensive cutaneous metastases of ovarian cancer after prolonged response to liposomal doxorubicin" }	[ { "companynumb": "US-JNJFOC-20130707762", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "DOXORUBICIN" }, "drugadditional": null, ...
{ "abstract": "BACKGROUND\nSupportive care improves outcomes in many cancers. In the pivotal STORM study selinexor, a first-in-class, oral, selective exportin 1 inhibitor, and low-dose dexamethasone proved to be an effective treatment for patients with triple-class refractory myeloma. We conducted a post-hoc analysis to test the hypothesis that increased utilization of supportive care measures in a sub-cohort of the STORM study prolonged treatment duration with- and improved efficacy of- selinexor.\n\n\nMETHODS\nThe STORM protocol included specific recommendations for dose modifications and supportive care to mitigate selinexor most common adverse events (AEs) including nausea, fatigue, and thrombocytopenia. The Tisch Cancer Center at Mount Sinai School of Medicine (MSSM) incorporated additional supportive care strategies within the framework of the STORM protocol.\n\n\nRESULTS\nOf 123 patients enrolled in STORM, 28 were enrolled at MSSM. The overall response rate was 26.2% in the overall STORM population and 53.6% in the MSSM cohort. Moreover, duration of response, progression free survival, and overall survival were longer in the MSSM cohort. AEs and dose modification events were similar in the 2 groups. The MSSM cohort had more dose reductions (67.9% vs. 50.5%), and higher use of multiple antiemetic agents (71.4% vs. 50.1%) and romiplostim (32.1% vs. 6.3%), but less discontinuations due to treatment-related AEs (3.6% vs. 25.3%).\n\n\nCONCLUSIONS\nThese results suggests that in addition to more frequent dose reductions, prompter and more aggressive supportive care may have contributed to the low discontinuation rate, longer duration therapy, and greater efficacy rates observed in the MSSM cohort. (ClinicalTrials.gov NCT02336815).", "affiliations": "Icahn School of Medicine at Mount Sinai, New York, NY. Electronic address: ajai.chari@mountsinai.org.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.;Icahn School of Medicine at Mount Sinai, New York, NY.", "authors": "Chari\|Ajai\|A\|;Florendo\|Erika\|E\|;Mancia\|Ines Stefania\|IS\|;Cho\|Hearn\|H\|;Madduri\|Deepu\|D\|;Parekh\|Samir\|S\|;Richter\|Josh\|J\|;Dhadwal\|Amishi\|A\|;Thomas\|Joanne\|J\|;Jiang\|Grace\|G\|;Lagana\|Alessandro\|A\|;Bhalla\|Sherry\|S\|;Jagannath\|Sundar\|S\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1016/j.clml.2021.07.014", "fulltext": null, "fulltext_license": null, "issn_linking": "2152-2669", "issue": "21(12)", "journal": "Clinical lymphoma, myeloma & leukemia", "keywords": "Adverse effects; Anti-emetic; Efficacy; Palliative care; Prophylactic", "medline_ta": "Clin Lymphoma Myeloma Leuk", "mesh_terms": null, "nlm_unique_id": "101525386", "other_id": null, "pages": "e975-e984", "pmc": null, "pmid": "34404623", "pubdate": "2021-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Optimal Supportive Care With Selinexor Improves Outcomes in Patients With Relapsed/Refractory Multiple Myeloma.", "title_normalized": "optimal supportive care with selinexor improves outcomes in patients with relapsed refractory multiple myeloma" }	[ { "companynumb": "US-AMGEN-USASP2019140446", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CARFILZOMIB" }, "drugadditional": "4", ...
{ "abstract": "We describe long-lasting and incompletely resolved thrombocytopenia after transient profound pancytopenia in a 62-year-old female patient with glioblastoma after short-term radiotherapy with temozolomide. Pancytopenia was present for more than 4 weeks and thrombocytopenia for more than 6 months, without platelet recovery to normal levels.\nSome patients may experience severe haematological manifestations after even short-term radiotherapy with temozolomide.In everyday practice, clinical models precisely predicting the haematological toxicity of concomitant treatment with temozolomide and radiotherapy is necessary, especially in countries where genetic tests are not available.Incomplete recovery of the cells of a particular bloodline over a long period may necessitate permanent discontinuation of chemotherapy or radiotherapy.", "affiliations": "Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.;Institute for Oncology and Radiology of Serbia, Belgrade, Serbia.;Faculty of Medicine, University of Belgrade, Belgrade, Serbia.;Faculty of Medicine, University of Belgrade, Belgrade, Serbia.", "authors": "Stepanović\|Aleksandar\|A\|;Nikitović\|Marina\|M\|;Bogdanović\|Andrija\|A\|;Grujičić\|Danica\|D\|", "chemical_list": null, "country": "Italy", "delete": false, "doi": "10.12890/2020_001785", "fulltext": null, "fulltext_license": null, "issn_linking": "2284-2594", "issue": "7(10)", "journal": "European journal of case reports in internal medicine", "keywords": "Glioblastoma; pancytopenia; temozolomide; thrombocytopenia", "medline_ta": "Eur J Case Rep Intern Med", "mesh_terms": null, "nlm_unique_id": "101648453", "other_id": null, "pages": "001785", "pmc": null, "pmid": "33083356", "pubdate": "2020", "publication_types": "D016428:Journal Article", "references": "28436299;29375866;15758010;20925470;25359262;15758009;27130558;19179423", "title": "Long-lasting Thrombocytopenia after Transient Pancytopenia Induced by Short-Term Concomitant Radiotherapy and Temozolomide.", "title_normalized": "long lasting thrombocytopenia after transient pancytopenia induced by short term concomitant radiotherapy and temozolomide" }	[ { "companynumb": "RS-AMGEN-SRBSP2020187544", "fulfillexpeditecriteria": "2", "occurcountry": "RS", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "TEMOZOLOMIDE" }, "drugadditional": null, ...
{ "abstract": "Cancer treatments including chemotherapy and radiotherapy treat cancer by targeting rapidly dividing cells. Although these forms of treatment damage rapidly dividing cancer cells, they are also toxic to the cells of the gastrointestinal tract, leading to inflammation of the mucosal layer (mucositis) and causing nausea, vomiting, diarrhea, and abdominal pain. Improvement in symptoms may allow patients to have better performance status permitting ongoing treatment and possibly a better prognosis. This article describes the pathophysiology of chemotherapy-induced mucositis and includes 3 case reports of treatment of mucositis with serum bovine immunoglobulin.", "affiliations": "1 Department of Internal Medicine, East Tennessee State University, Johnson City, TN, USA.;1 Department of Internal Medicine, East Tennessee State University, Johnson City, TN, USA.;1 Department of Internal Medicine, East Tennessee State University, Johnson City, TN, USA.;1 Department of Internal Medicine, East Tennessee State University, Johnson City, TN, USA.;2 Department of Hospice and Palliative Medicine, Wellmont Health System, Kingsport, TN, USA.", "authors": "Arikapudi\|Sowminya\|S\|;Rashid\|Saima\|S\|;Al Almomani\|Laith Adel\|LA\|;Treece\|Jennifer\|J\|;Baumrucker\|Steven J\|SJ\|", "chemical_list": "D000970:Antineoplastic Agents; D007136:Immunoglobulins", "country": "United States", "delete": false, "doi": "10.1177/1049909117735831", "fulltext": null, "fulltext_license": null, "issn_linking": "1049-9091", "issue": "35(5)", "journal": "The American journal of hospice & palliative care", "keywords": "adverse effects; chemotherapy; chemotherapy-induced mucositis; inflammatory bowel disease; irritable bowel syndrome; mucositis; serum bovine immunoglobulin; therapy", "medline_ta": "Am J Hosp Palliat Care", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D005260:Female; D005767:Gastrointestinal Diseases; D006801:Humans; D007136:Immunoglobulins; D052016:Mucositis; D009369:Neoplasms", "nlm_unique_id": "9008229", "other_id": null, "pages": "814-817", "pmc": null, "pmid": "29020798", "pubdate": "2018-05", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Serum Bovine Immunoglobulin for Chemotherapy-Induced Gastrointestinal Mucositis.", "title_normalized": "serum bovine immunoglobulin for chemotherapy induced gastrointestinal mucositis" }	[ { "companynumb": "US-TEVA-2018-US-966563", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "LEUCOVORIN CALCIUM" }, "drugadditional": null, ...
{ "abstract": "We report the youngest patient ever reported in the literature to exhibit pleuroparenchymal fibroelastosis (PPFE) as a late-onset pulmonary toxicity after treatment with anticancer chemotherapy. The patient was diagnosed with mature B-cell leukemia at age 14. He was successfully treated with intensive chemotherapy; however, 7 years later, he experienced recurrent pneumothoraces. He was clinically diagnosed with upper lobe pulmonary fibrosis. At age 28, he underwent single left lung transplantation. Histologic examination of the resected lung revealed PPFE in the upper lobe and constrictive bronchiolitis obliterans in the lower lobe, which implied a close relationship between PPFE and constrictive bronchiolitis obliterans.", "affiliations": "Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: hdate@kuhp.kyoto-u.ac.jp.;Department of Pediatrics, Nishi-Kobe Medical Center, Kobe, Japan.;Department of Diagnostic Pathology, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Respirology, Nishi-Kobe Medical Center, Kobe, Japan.;Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan.", "authors": "Chen\|Fengshi\|F\|;Matsubara\|Kousaku\|K\|;Miyagawa-Hayashino\|Aya\|A\|;Tada\|Kimihide\|K\|;Handa\|Tomohiro\|T\|;Yamada\|Tetsu\|T\|;Sato\|Masaaki\|M\|;Aoyama\|Akihiro\|A\|;Date\|Hiroshi\|H\|", "chemical_list": "D000970:Antineoplastic Agents", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0003-4975", "issue": "98(5)", "journal": "The Annals of thoracic surgery", "keywords": null, "medline_ta": "Ann Thorac Surg", "mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D001706:Biopsy; D001989:Bronchiolitis Obliterans; D005500:Follow-Up Studies; D006801:Humans; D015448:Leukemia, B-Cell; D016040:Lung Transplantation; D008297:Male; D010995:Pleural Diseases; D013902:Radiography, Thoracic", "nlm_unique_id": "15030100R", "other_id": null, "pages": "e115-7", "pmc": null, "pmid": "25441830", "pubdate": "2014-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Lung transplantation for pleuroparenchymal fibroelastosis after chemotherapy.", "title_normalized": "lung transplantation for pleuroparenchymal fibroelastosis after chemotherapy" }	[ { "companynumb": "JP-TEVA-577633ISR", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": null, "dru...
{ "abstract": "Antiphospholipid syndrome and heparin-induced thrombocytopenia are immune-mediated thrombotic conditions initiated by 2 distinct antibodies each targeting a discrete protein-antigen complex. Although produced by 2 different types of antibodies, they are similar in their autoimmune and pathophysiologic mechanisms. We present a case with simultaneous antiphospholipid syndrome and heparin-induced thrombocytopenia syndromes that sheds light on the correlation between these 2 syndromes.", "affiliations": "From the *Department of Anesthesiology, University of Cincinnati, Cincinnati, Ohio; †Department of Anesthesiology, University of Nebraska, Omaha, Nebraska; and Departments of ‡Internal Medicine and §Emergency Medicine, University of Cincinnati, Cincinnati, Ohio.", "authors": "Abd-Elsayed\|Alaa A\|AA\|;Lisco\|S J\|SJ\|;Alsidawi\|Said\|S\|;Bonomo\|J\|J\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1097/ACC.0b013e3182a1afc9", "fulltext": null, "fulltext_license": null, "issn_linking": "2325-7237", "issue": "2(1)", "journal": "A & A case reports", "keywords": null, "medline_ta": "A A Case Rep", "mesh_terms": null, "nlm_unique_id": "101637720", "other_id": null, "pages": "9-10", "pmc": null, "pmid": "25612260", "pubdate": "2014-01-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Simultaneous antiphospholipid syndrome and heparin-induced thrombocytopenia in a single patient.", "title_normalized": "simultaneous antiphospholipid syndrome and heparin induced thrombocytopenia in a single patient" }	[ { "companynumb": "PHHY2014US103538", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ARGATROBAN" }, "drugadditional": null, "drug...
{ "abstract": "The purpose of this study was to determine the frequency of clinically actionable treatment-relevant germline pharmacogenomic variants in patients with cancer and assess the real-world clinical utility of universal screening using whole-exome sequencing in this population. Cancer patients underwent research-grade germline whole-exome sequencing as a component of sequencing for somatic variants. Analysis in a clinical bioinformatics pipeline identified clinically actionable pharmacogenomic variants. Clinical Pharmacogenetics Implementation Consortium guidelines defined clinical actionability. We assessed clinical utility by reviewing electronic health records to determine the frequency of patients receiving pharmacogenomically actionable anti-cancer agents and associated outcomes. This observational study evaluated 291 patients with cancer. More than 90% carried any clinically relevant pharmacogenetic variant. At least one disease-relevant variant impacting anti-cancer agents was identified in 26.5% (77/291). Nine patients with toxicity-associated pharmacogenomic variants were treated with a relevant medication: seven UGT1A1 intermediate metabolizers were treated with irinotecan, one intermediate DPYD metabolizer was treated with 5-fluorouracil, and one TPMT poor metabolizer was treated with mercaptopurine. These individuals were more likely to experience treatment-associated toxicities than their wild-type counterparts (p = 0.0567). One UGT1A1 heterozygote died after a single dose of irinotecan due to irinotecan-related adverse effects. Identifying germline pharmacogenomic variants was feasible using whole-exome sequencing. Actionable pharmacogenetic variants are common and relevant to patients undergoing cancer treatment. Universal pharmacogenomic screening can be performed using whole-exome sequencing data originally obtained for quality control purposes and could be considered for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, and mercaptopurine.", "affiliations": "Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.;Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY 40536, USA.;Department of Pathology and Laboratory Medicine, University of Kentucky Chandler Medical Center, Lexington, KY 40536, USA.;Department of Pathology and Laboratory Medicine, University of Kentucky Chandler Medical Center, Lexington, KY 40536, USA.;Department of Pharmacy, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA.;Department of Clinical Research, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.;Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, USA.;Division of Medical Oncology, Department of Internal Medicine, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.;Division of Surgical Oncology, Department of Surgery, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.;Division of Medical Oncology, Department of Internal Medicine, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.;Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.", "authors": "Hutchcraft\|Megan L\|ML\|0000-0002-8611-6324;Lin\|Nan\|N\|;Zhang\|Shulin\|S\|;Sears\|Catherine\|C\|;Zacholski\|Kyle\|K\|;Belcher\|Elizabeth A\|EA\|;Durbin\|Eric B\|EB\|;Villano\|John L\|JL\|;Cavnar\|Michael J\|MJ\|;Arnold\|Susanne M\|SM\|;Ueland\|Frederick R\|FR\|0000-0003-1213-7509;Kolesar\|Jill M\|JM\|0000-0003-1802-6439", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.3390/cancers13184524", "fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n10.3390/cancers13184524\ncancers-13-04524\nArticle\nReal-World Evaluation of Universal Germline Screening for Cancer Treatment-Relevant Pharmacogenes\nhttps://orcid.org/0000-0002-8611-6324\nHutchcraft Megan L. 1\nLin Nan 2\nZhang Shulin 3\nSears Catherine 3\nZacholski Kyle 4\nBelcher Elizabeth A. 5\nDurbin Eric B. 67\nVillano John L. 8\nCavnar Michael J. 9\nArnold Susanne M. 8\nhttps://orcid.org/0000-0003-1213-7509\nUeland Frederick R. 1\nhttps://orcid.org/0000-0003-1802-6439\nKolesar Jill M. 12\nHertz Daniel L. Academic Editor\n1 Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA; megan.hutchcraft@uky.edu (M.L.H.); fuela0@uky.edu (F.R.U.)\n2 Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY 40536, USA; nan.lin@uky.edu\n3 Department of Pathology and Laboratory Medicine, University of Kentucky Chandler Medical Center, Lexington, KY 40536, USA; shulin.zhang@uky.edu (S.Z.); catherine.sears@uky.edu (C.S.)\n4 Department of Pharmacy, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA; kyle.zacholski@vcuhealth.org\n5 Department of Clinical Research, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA; elizabeth.belcher@uky.edu\n6 Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, USA; e.durbin1@uky.edu\n7 Kentucky Cancer Registry, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA\n8 Division of Medical Oncology, Department of Internal Medicine, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA; jlvillano@uky.edu (J.L.V.); susanne.arnold@uky.edu (S.M.A.)\n9 Division of Surgical Oncology, Department of Surgery, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA; michael.cavnar@uky.edu\n Correspondence: jill.kolesar@uky.edu; Tel.: +1-(859)-323-4978\n08 9 2021\n9 2021\n13 18 452418 8 2021\n03 9 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nGermline pharmacogenomic variants impact the toxicity of many cancer treatment drugs. Though testing for pharmacogenomic variants prior to initiating systemic cancer treatment is not routine, the Clinical Pharmacogenetics Implementation Consortium recommends dosing modifications for six cancer treatment drugs based on variant genotypes: irinotecan and UGT1A1; 5-fluorouracil and capecitabine and DPYD; 6-mercaptopurine and thioguanine and TPMT; and tamoxifen and CYP2D6. The purpose of this study was to assess the frequency of cancer treatment-relevant germline pharmacogenomic variants in patients with cancer using residual germline whole-exome sequencing. We also evaluated the association of disease-relevant pharmacogenomic variants with treatment-associated toxicities. Approximately one-quarter of cancer patients carried a disease-relevant pharmacogenomic variant. Patients with toxicity-associated pharmacogenomic variant genotypes were more likely to experience drug-related toxicity than their wild-type counterparts. Universal pharmacogenomic screening is feasible using whole-exome sequencing originally obtained for quality control purposes and may be an effective germline pharmacogenomic screening strategy for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, or 6-mercaptopurine.\n\nAbstract\n\nThe purpose of this study was to determine the frequency of clinically actionable treatment-relevant germline pharmacogenomic variants in patients with cancer and assess the real-world clinical utility of universal screening using whole-exome sequencing in this population. Cancer patients underwent research-grade germline whole-exome sequencing as a component of sequencing for somatic variants. Analysis in a clinical bioinformatics pipeline identified clinically actionable pharmacogenomic variants. Clinical Pharmacogenetics Implementation Consortium guidelines defined clinical actionability. We assessed clinical utility by reviewing electronic health records to determine the frequency of patients receiving pharmacogenomically actionable anti-cancer agents and associated outcomes. This observational study evaluated 291 patients with cancer. More than 90% carried any clinically relevant pharmacogenetic variant. At least one disease-relevant variant impacting anti-cancer agents was identified in 26.5% (77/291). Nine patients with toxicity-associated pharmacogenomic variants were treated with a relevant medication: seven UGT1A1 intermediate metabolizers were treated with irinotecan, one intermediate DPYD metabolizer was treated with 5-fluorouracil, and one TPMT poor metabolizer was treated with mercaptopurine. These individuals were more likely to experience treatment-associated toxicities than their wild-type counterparts (p = 0.0567). One UGT1A1 heterozygote died after a single dose of irinotecan due to irinotecan-related adverse effects. Identifying germline pharmacogenomic variants was feasible using whole-exome sequencing. Actionable pharmacogenetic variants are common and relevant to patients undergoing cancer treatment. Universal pharmacogenomic screening can be performed using whole-exome sequencing data originally obtained for quality control purposes and could be considered for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, and mercaptopurine.\n\npharmacogenomics\ncancer\nreal word\nirinotecan\n5-fluorouracil\nmercaptopurine\n==== Body\npmc1. Introduction\n\nGermline pharmacogenomic variants influence the metabolism of environmental toxins and affect patient response to medications. In 2009, the United States (US) Food and Drug Administration (FDA) added drug labeling for pharmacogenomic considerations [1], and the list now includes over 450 drugs [2]. The Clinical Pharmacogenetics Implementation Consortium (CPIC) helps clinicians and pharmacists navigate this complex genetic information and highlights the level of evidence supporting each pharmacogenomic variant’s importance [3,4]. CPIC provides evidence-based variant-specific prescribing guidance; currently, there are twenty pharmacogenes classified in level A status [3,4].\n\nOncology medications comprise 41.4% (189/457) of all medicines listed by the US FDA with pharmacogenomic considerations and 57.1% (108/189) of these medications are listed for reasons due to risk of adverse events, contraindications, boxed and other warnings, and medication precautions [2]. In addition, our institution previously reported that 65% of advanced cancer patients were taking a pharmacogenomically actionable medication [5].\n\nDespite data suggesting benefit, pharmacogenomic screening is not routinely performed in clinical practice [6] due to logistical barriers, cost, and lack of clinical utility [7]. A possible solution to overcome logistical obstacles is the implementation of universal actionable pharmacogenomic variant screening [7]. Additionally, somatic mutation testing to guide treatment is now routine for many patients with cancer and paired somatic/germline sequencing is often performed to reliably distinguish between germline and somatic mutations. While initially used as a quality control measure to avoid reporting incidental germline findings [8], this germline testing may provide an opportunity to also assess pharmacogenomic variants using existing sequencing data [9,10]. Hertz and colleagues (2018) reported that the Michigan Oncology Sequencing program could determine germline TPMT, DPYD, and CYP2C19 genotype at no additional cost [11]. The purpose of this study is to determine the frequency of clinically actionable germline variants in patients with cancer and assess the real-world clinical utility of universal screening using germline whole-exome sequencing (WES) originally obtained for quality control purposes.\n\n2. Results\n\n2.1. Study Population and Pharmacogenomic Landscape\n\nBetween October 2018 and January 2021, we prospectively enrolled 291 cancer patients, regardless of cancer type. Table 1 summarizes the demographic characteristics. The median age was 61 (inter-quartile range 52–68), and most individuals were non-Hispanic and White (277/291, 95.2%), with fourteen (14/291, 4.8%) non-Hispanic and Black individuals also participating. Approximately equal numbers of men and women participated.\n\nPharmacogenomic variants were common and are reported in Table 2. Overall, 90.4% (263/291) of cancer patients carried any pharmacogenomic variant. No CFTR, CYP2C19, CACNA1S, or HLA-B variants were detected; however, testing was limited for CFTR (c.1652G>A only), CYP2C19 (7 only), and HLA-B (57:01, 15:02, and 58:01 only). A full listing of variants included in analysis is available in Appendix A. Although population allele frequencies vary by race and ethnicity, allele frequencies in our cohort were similar to expected American or European population frequencies [3] except for a higher than expected frequency of RYR1 variants, which was present in two patients and demonstrated an allele frequency of 0.0034.\n\n2.2. Clinical Impact\n\nMany (189/291, 64.9%) oncology patients harbored pharmacogenomic variants in genes that metabolize cancer therapeutic agents. Approximately one-quarter (26.5%, 77/291) carried at least one pharmacogenomic variant for at least one therapeutic option indicated in their disease type. Table 3 summarizes the association between pharmacogenes, their associated anti-cancer agents, National Comprehensive Cancer Network (NCCN) guideline-recommended anti-cancer drugs, and the number of patients at risk. Although most patients received systemic cancer treatments at our institution, several patients were treated elsewhere. Follow-up data were not available for six colorectal, one pancreatic, and one hepatobiliary cancer patient.\n\nConsistent with the expected American/European population frequency, UGT1A1 variants were common (157/291, 54%). UGT1A1 genotype status impacts irinotecan metabolism, often indicated for front-line treatment of gastrointestinal malignancies [14,15]. Over half (45/86, 52.3%) of the patients who could potentially receive irinotecan as a component of an NCCN “preferred” regimen harbored a UGT1A1 variant. The fluoropyrimidines capecitabine and fluorouracil are commonly included in cancer treatment regimens [16], and several patients (14/291, 4.8%) carried a DPYD variant, which affects the metabolism of these drugs. Similarly, TPMT is involved in the metabolism of 6-mercaptopurine (6-MP) [17], which is often administered in acute lymphoblastic leukemia (ALL) [18]; however, few ALL patients were enrolled in our study, and only one received 6-MP.\n\n2.2.1. Adverse Effects\n\nFigure 1 illustrates the association between treatment-relevant genotype and treatment tolerance for patients prescribed CPIC level A drugs as a component of their cancer therapy. Treatment and tolerance details for each patient are available in Appendix B. Associated dosing of each treatment regimen is available in Appendix C. Of the six normal irinotecan metabolizers (UGT1A1 1/1), only one (1/6, 16.7%) experienced irinotecan-related diarrhea requiring a dose reduction. Five of seven (71.4%) UGT1A1 28 heterozygotes (irinotecan intermediate metabolizers) experienced any irinotecan-related toxicity. Toxicities resulted in dose reductions (2/7, 14.3%), delays (1/7, 14.3%), and discontinuation (1/7, 14.3%); one patient received one cycle of irinotecan and presented with severe diarrhea, ultimately resulting in renal failure and death after a protracted hospital stay (1/7 14.3%).\n\nSimilarly, the only DPYD intermediate metabolizer (c.557A>G heterozygote) treated with a fluorouracil-containing regimen at our institution required treatment discontinuation after one cycle due to poor tolerance. Fluorouracil-related treatment toxicity was experienced by 40% (12/30) of normal DPYD metabolizers. Finally, the only patient in our cohort treated with 6-MP was not clinically tested prior to treatment and experienced profound cytopenia after the first dose. Genomic testing later revealed this patient was a poor TPMT metabolizer (TPMT 3B/3C).\n\nThough our statistical power is limited by a small sample size, patients with toxicity-associated variant alleles were more likely to experience toxicities resulting in treatment delays, dose reductions, or discontinuation of chemotherapy than those who did not carry a variant metabolism gene (7/9, 77.8% vs. 13/36, 36.1%; p = 0.0567) when treated with a pharmacogenomically-relevant drug.\n\n2.2.2. Efficacy\n\nIn our cohort, one intermediate tamoxifen metabolizer (CYP2D61/6) was treated with tamoxifen. This patient experienced progressive disease with standard (20 mg daily) tamoxifen dosing and required alternative anti-estrogen treatment with an aromatase inhibitor and surgical castration. No additional patients were treated with tamoxifen for comparison purposes.\n\n3. Discussion\n\nOur results suggest the feasibility and potential benefit of pharmacogenomic variant genotyping for cancer patients using WES obtained for quality control purposes in a real-world setting. Though our numbers are small, patients with treatment-relevant pharmacogenomic variants experienced increased rates of toxicity compared to normal metabolizers. FDA labeling does not require pharmacogenomic testing before initiating any CPIC level A cancer drugs [19]; however, our results suggest an increased risk of toxicity, including death, requiring clinical intervention for patients with treatment-relevant pharmacogenomic variants.\n\nThough variant-associated toxicity is established for TPMT [17], UGT1A1 [15], and DPYD [16] intermediate and poor metabolizers, testing is not routinely performed and clinical management guidelines for dosing are inconsistent. This is likely related to logistical barriers, lack of clinical utility, and cost associated with routine pharmacogenomic screening [7,11]. This research demonstrates germline WES data originally obtained for quality control purposes may be used to report pharmacogenomic variants. Germline sequencing data are increasingly available because of targeted treatment options and somatic mutation testing [10,11] and may represent a cost-effective strategy for both overcoming barriers to pharmacogenetic testing and integrating germline and somatic sequencing to expand precision cancer care.\n\nOur results also demonstrate that pharmacogenomic variants are common; more than 90% of cancer patients carried at least one clinically actionable pharmacogenetic variant. Furthermore, our findings suggest potential clinical utility. In this unselected population, 15.8% (46/291) of individuals received a genotype-relevant anti-cancer drug and ten of these individuals carried a variant pharmacogene. Importantly, while our numbers are small, patients with treatment-relevant pharmacogenomic variants experienced increased rates of toxicity requiring clinical intervention and death compared to normal metabolizers.\n\nUS FDA labeling does not require pharmacogenomic testing before initiating any CPIC level A cancer medications [19]. Regarding practice guidelines, ALL is the only disease in which the NCCN recommends, but does not require, testing for the presence of TPMT variants before 6-MP initiation [18]. The NCCN colon cancer guidelines advise caution and suggest alternative dosing strategies for UGT1A1 poor metabolizers (UGT1A28 homozygous variants) scheduled to receive irinotecan; however, no testing guidelines have been established [19,20]. Conversely, these same guidelines note DPYD variants are inconsistently associated with fluoropyrimidine toxicity and do not currently recommend pre-treatment testing [20]. Despite the role of irinotecan, fluorouracil, and capecitabine in preferred NCCN treatment regimens for pancreatic [21] and gastroesophageal [22,23] cancers, these pharmacogenomic variants are not discussed in the guidelines.\n\nThe oncology community has hesitated to initiate lower fluoropyrimidine doses for patients with DPYD variants and lower irinotecan doses for UGT1A1 intermediate metabolizers because not all poor and intermediate metabolizers experience toxicity [15,16,24] and treating with a lower dose may decrease the drug’s therapeutic efficacy [24]. In fact, recent research demonstrated genotype-directed irinotecan dosing resulted in improved pathologic complete responses and decreased irinotecan-related toxicity for UGT1A1 intermediate metabolizers (1/28) undergoing neoadjuvant chemoradiation for locally advanced rectal cancer [25]. Similarly, DPYD genotype-directed fluoropyrimidine dosing demonstrated improved patient safety outcomes [26] without compromising efficacy in a diverse group of patients treated with capecitabine or fluorouracil containing regimens [27].\n\nAvoiding treatment-related toxicity is critical; patients who experience treatment-related adverse events are more likely to discontinue treatment altogether [28], experience dose reductions and delays, and ultimately experience worse survival outcomes [29,30]. Additionally, preemptive pharmacogenomic screening for DPYD variants is a cost-effective approach for patients scheduled to receive fluoropyrimidine-based chemotherapy [31,32]; however, data remain mixed for assessing for TPMT variants in patients scheduled to receive 6-MP [33,34] and UGT1A1 variants in patients scheduled to receive irinotecan [35,36,37,38]. Therefore, we suggest an individualized genotype-directed dosing strategy for patients scheduled to receive a pharmacogenomically-relevant anti-cancer medication.\n\nStrengths of this study include a prospective population-level approach, novel use of quality control germline data for identifying pharmacogenes, and assessment of the real-world impact of pharmacogenes in patients with cancer. In addition, variant calling was performed in a Clinical Laboratory Improvement Amendments setting with annotation by a pathologist.\n\nA potential limitation is the use of research-grade sequencing, which typically has lower coverage than clinical sequencing; however, allele frequencies were consistent with expected population allele frequencies suggesting this limitation is of minimal practical consequence. As a single institutional study treating a largely rural and predominantly non-Hispanic White population, generalizability may be limited. Furthermore, pharmacogenomic allele frequencies vary by race and ethnicity and our screening strategy has not been tested in a diverse population. We also did not collect blood samples, precluding an analysis of drug exposure, metabolizer status, and toxicity. Though patients were prospectively enrolled in this study, clinical outcome data were collected retrospectively, limiting clinical actionability. Finally, as our institution is a tertiary care center, many patients enrolled in this study underwent surgical treatment at our institution but received chemotherapy elsewhere, limiting sample size and follow-up data.\n\n4. Materials and Methods\n\n4.1. Study Design and Data Sources\n\nThis observational cohort study compared research-grade germline WES results to clinical treatment data and patient outcomes. Patients treated at the University of Kentucky Markey Cancer Center enrolled in the Total Cancer Care (TCC)® protocol.\n\nTCC is a multi-institutional prospective cohort study and comprises data collected from eighteen member institutions of the Oncology Research Information Exchange Network (ORIEN). This cancer precision medicine initiative was first developed by the Moffitt Cancer Center in Tampa, Florida, USA [39,40]. To date, over 315,000 participants have enrolled, undergone germline and tumor somatic sequencing, and agreed to lifetime follow-up [41].\n\nDemographic and clinical data were obtained from the Kentucky Cancer Registry (KCR). Kentucky state statute (KRS 214.556) requires all cases of cancer diagnosed and/or treated in Kentucky to be reported to this registry. This population-based cancer registry reports demographic and clinical information, including the genetic data generated as a component of the TCC protocol.\n\nThe Markey Cancer Center Cancer Research Informatics Shared Resource Facility (CRI SRF) served as the honest broker and distributed data stored in the KCR. A contractual agreement was previously established through M2GEN (Hudson, FL, USA) to permit data sharing between ORIEN/TCC and KCR. All data were fully anonymized prior to analysis. The final dataset for this study comprised the linked demographic, clinical, and genomic data from KCR and ORIEN/TCC.\n\n4.2. Study Population\n\nBetween October 2018 and January 2021, patients presenting to Markey Cancer Center for cancer treatment were invited to enroll in TCC. Treating physicians informed eligible patients about this study, and subjects were recruited during routine clinic visits. Eligibility criteria for TCC required patients to be at least 18 years of age and have a diagnosis of cancer. To be included in this analysis, each patient must have had germline WES results available. All subjects provided written informed consent prior to study enrollment. This study was conducted according to the guidelines of the Declaration of Helsinki, in accordance with the US Common Rule and was approved by the Institutional Review Board (IRB protocol code #44224, initial date of approval 28 June 2017 and modified to permit return of research results to enrolling physicians on 12 October 2018) at the University of Kentucky. Demographic variables included gender, race, and age at diagnosis. Clinical variables included primary cancer site, histology, and American Joint Committee on Cancer stage at diagnosis. Additional data elements, including treatment regimens, duration of therapy, and adverse effects, were retrospectively abstracted from the electronic health record under a separate IRB approval (IRB protocol code #51483, initial date of approval 3 June 2019). Data were collected and managed using Research Electronic Data Capture (REDCap) hosted at the University of Kentucky [42,43].\n\n4.3. Sequencing Methods\n\nBuccal swabs were used to obtain samples for germline testing. Germline WES was performed as a quality control measure as a component of the ORIEN/TCC protocol. Preparation of M2GEN WES libraries involved hybrid capture using an enhanced Integrated DNA Technology (Coralville, IA, USA) WES kit (38.7 megabases) with additional custom-designed probes for double coverage of 440 cancer genes. Library hybridization is performed at either single or 8-plex and sequenced on an Illumina (San Diego, CA, USA) NovaSeq 6000 instrument generating 100 base pair paired reads. WES is performed on tumor/normal matched samples with the normal covered at 100X and the tumor covered at 300X (additional 440 cancer genes covered at 600X) depth. We performed both tumor/normal concordance and gender identity quality control checks. The minimum threshold for hybrid selection was >80% of bases with >20X fold coverage; M2GEN WES libraries typically met or exceeded 90% of bases with >50X fold coverage for tumor and 90% of bases with >30X fold coverage for normal samples.\n\n4.4. Pharmacogenomic Variant Interpretation and Reporting of Results\n\nAn in-house bioinformatics pipeline was developed for analyzing and annotating germline variants in fifteen of the twenty genes with CPIC level A drug recommendations. NUDT15 and HLA-A variants were not included because probe coverage was suboptimal. IFNL3 and IFNL4 variants were not included because of the uncommon clinical usage of peginterferon alfa-2a and 2b. Haplotypes for each pharmacogene included in the testing process are reported in Appendix A.\n\nBriefly, FASTQ files generated from an Illumina sequencer were aligned to the reference sequence of human genome (GRCh37) using Burrows–Wheeler Aligner (BWA 0.7.8) [44]. Aligned reads were converted to Binary Alignment Map format using Sequence Alignment/Map tools software (V1.8) [45]. Variant calling was carried out using Genome Analysis Toolkit (V4.0.12.0) [46] and VarScan (v2.3.9) [47]. Variants were annotated using Ensembl Variant Effect Predictor (VEP_89) [48] and public databases, including ClinVar [49], 1000 Genomes [50], and the Genome Aggregation Database (gnomAD) [12].\n\nResults of pharmacogenomic testing, including pharmacogene, variant allele, and zygosity were reported to the Markey Cancer Center precision medicine team. This team reviewed results and reported findings in a letter to the enrolling oncologist, which was uploaded into the electronic medical record.\n\n4.5. Assessment of Potential and Actual Risk for Pharmacogenomic Adverse Outcomes\n\nCPIC defines level A evidence for drug–gene pairs where the preponderance of the evidence is moderate or strong in favor of making drug prescribing changes based on a pharmacogenomic marker [3]. In this study, we defined anti-cancer agents as medications intended to treat cancer. Based on these criteria, there are currently six anti-cancer agents with a CPIC level A recommendation: irinotecan and UGT1A1; 5-fluorouracil and capecitabine and DPYD; 6-MP and thioguanine and TPMT; and tamoxifen and CYP2D6. To determine the number of patients potentially at risk for anti-cancer agent and pharmacogene-associated adverse effects, we first reviewed NCCN guidelines for individual tumor types included in our population for “preferred” and “other” regimens (Appendix D) that included CPIC level A anti-cancer agents. Drugs included in “regimens useful in certain instances” for specified malignancy were included in NCCN “other” regimens. Patients with disease types with a “preferred” or “other” regimen specified in NCCN guidelines [51] were considered potentially impacted by a pharmacogenomic variant.\n\nThe actual impact of pharmacogenomic variants on cancer treatment was determined by assessing dosing changes, discontinuation, hospitalization, or treatment-related death resulting from known adverse effects associated with variant genotypes. These included cytopenia and diarrhea for irinotecan; cytopenia, diarrhea, hepatotoxicity, mucositis/stomatitis, and cardiotoxicity for fluoropyrimidines; and cytopenia for 6-MP. Specifically, allergic reactions, fatigue, or patient requests resulting in drug discontinuation or dose reductions were not considered dose- or genotype-related. Patients were evaluated for toxicity by each CPIC level A drug and by individual genotype and, as a result, may have been included in more than one toxicity analysis.\n\n4.6. Statistical Analysis\n\nWe performed a descriptive analysis of clinical variable and genotype frequencies. Expected monoallelic population pharmacogene frequencies were obtained from CPIC [3] when available. When unavailable, the population expected frequencies were obtained from the Exome Aggregation Consortium (ExAC) database [13] or gnomAD [12]. Expected American population frequencies were prioritized, followed by expected European population frequencies as the Kentucky population is 84% non-Hispanic White [52] and allele frequencies vary by race and ethnicity. Fisher’s exact test was used to compare genotype and frequency of treatment-related toxicity.\n\n5. Conclusions\n\nPharmacogenomically actionable variants are common in patients with cancer and were identified using a whole-exome sequencing approach. Individuals receiving relevant anti-cancer drugs experienced more toxicities than wild-type individuals. Therefore, universal pharmacogenomic screening using this approach could be considered for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, and 6-MP.\n\nAuthor Contributions\n\nConceptualization, M.L.H. and J.M.K.; methodology, M.L.H. and J.M.K.; software, S.Z. and C.S.; validation, S.Z. and C.S.; formal analysis, M.L.H. and N.L.; investigation, M.L.H., S.Z. and C.S.; resources, E.B.D., J.L.V., M.J.C., S.M.A., F.R.U. and J.M.K.; data curation, M.L.H., N.L. and E.A.B.; writing—original draft preparation, M.L.H.; writing—review and editing, M.L.H., S.Z., C.S., K.Z., M.J.C., F.R.U. and J.M.K.; visualization, M.L.H.; supervision, J.M.K.; project administration, J.M.K.; funding acquisition, J.M.K. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research was funded by the Markey Cancer Research Informatics Shared Resource Facility National Cancer Institute Cancer Center Support Grant, grant number P30 CA177558. This research was supported by the Oncogenomics Shared Resource of the University of Kentucky Markey Cancer Center.\n\nInstitutional Review Board Statement\n\nThis study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the Institutional Review Board (IRB protocol code #44224, initial date of approval 28 June 2017 and #51483, initial date of approval 3 June 2019) at the University of Kentucky.\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in this study.\n\nData Availability Statement\n\nThe authors received no special privileges in accessing the data. Raw data cannot be shared because they are both potentially identifying and contain sensitive patient data, including geographic location and specific dates of diagnosis, testing, and receipt of a drug. Additionally, there are contractual agreements between the University of Kentucky and the Kentucky Cancer Registry that preclude data sharing. Any requests for data must be submitted to: Jacyln K. McDowell, Epidemiologist, Kentucky Cancer Registry 2365 Harrodsburg Rd, Suite A230 Lexington, KY 40504; phone: (859)-218-2228; email: Jacyln.McDowell@uky.edu.\n\nPrior Presentation\n\nThe results from the gynecologic cancer patients were presented as an abstract and poster presentation at the 2021 Society of Gynecologic Oncology Annual Meeting, which was held virtually.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nAppendix A\n\ncancers-13-04524-t0A1_Table A1 Table A1 Genes and Variants Detectable from Whole-Exome Sequencing.\n\nGene\tDetectable Variants\t\nCACNA1S\tAll pathogenic/likely pathogenic variants a\t\nCFTR\tc.1652G>A\t\nCYP2C19\t3, 5, 7, 10\t\nCYP2C9\t3, 5, 6\t\nCYP2D6\t6, 8, 14\t\nCYP3A5\t2, 4, 6, 7, 8\t\nCYP4F2\t3\t\nDPYD\t2A, HapB3, 3, 7, 8, 10, 12, 13, c.557A>G, c.2846A>T\t\nG6PD\tClass I deficiency\t\nG6PD\tClass II deficiency\t\nG6PD\tClass III deficiency\t\nHLA-B\t57:01, 15:02, 58:01 b\t\nRYR1\tAll pathogenic/likely pathogenic variants a\t\nSLCO1B1\t5, 15/17 c\t\nTPMT\t2, 3A, 3B, 3C, 4, 11, 14, 15, 23, 29, 41\t\nUGT1A1\t6, 27, 28, 36, 37\t\nVKORC1\t1173C>T (in linkage with c.-1639G>A)\t\na CACNA1S and RYR1 were assessed as standard genes; all pathogenic and likely pathogenic variants were reported. b These HLA-B variants were determined by the process of elimination. For example, if there are five mismatched amino acids in the sequence to a specific genotype, then that genotype was excluded. c The depth of sequencing reads were not enough to differentiate 15 and 17, so these variants were reported together.\n\nAppendix B\n\ncancers-13-04524-t0A2_Table A2 Table A2 Patient tolerance to genomically-relevant preferred anti-cancer agents by disease type. Toxicities resulting in dosing modifications, cycle delays, or discontinuation are reported. Dosing for each regimen is available in Appendix C. Only patients treated at our institution, for whom systemic treatment details were available, are reported. Irinotecan toxicities included cytopenia and diarrhea; fluoropyrimidine toxicities included cytopenia, diarrhea, hepatotoxicity, mucositis/stomatitis, and cardiotoxicity; 6-mercaptopurine toxicity included cytopenia. All histologies were adenocarcinoma.\n\nRelevant Genotype\tPrimary Site\tStage\tRegimen\tCycles\tNotes\t\nUGT1A1: Irinotecan Intermediate Metabolizers\t\n1/28\tColon\tIIA\tFOLFIRI + bevacizumab\t14\tNo documented toxicity\t\n1/28\tColon\tIIB\tFOLFIRI\t3\tToxicity-unrelated discontinuation\t\n1/28\tColon\tIVA\tFOLFIRI + panitumumab\t38\tToxicity-related cycle delay\t\n1/28\tRectum\tIVA\tFOLFIRI\t4\tToxicity-related dose reduction\t\n1/28\tPancreas\tIB\tFOLFIRINOX\t15\tToxicity-related dose reduction\t\n1/28\tPancreas\tIII\tLiposomal irinotecan + 5-FU\t2\tToxicity-related discontinuation\t\n1/28\tRectum\tIIA\tXELIRI\t1\tToxicity-related hospitalization, death\t\nUGT1A1: Irinotecan Normal Metabolizers\t\n1/1\tRectum\tIV\tFOLFIRI\nIrinotecan + cetuximab\t6\n8\tNo documented toxicity\nNo documented toxicity\t\n1/1\tColon\tIIIC\tFOLFIRI\t8\tNo documented toxicity\t\n1/1\tColon\tIVA\tXELIRI\t7\tNo documented toxicity\t\n1/1\tColon\tIIIB\tXELIRI\t11\tNo documented toxicity\t\n1/1\tPancreas\tIII\tFOLFIRINOX\t3\tToxicity-unrelated discontinuation\t\n1/1\tPancreas\tIIB\tFOLFIRINOX\t12\tToxicity-related dose reduction\t\nDPYD: Intermediate Fluoropyrimidine Metabolizers 1\t\nc.557A>G/wt\tStomach\tIB\tFOLFOX\t1\tToxicity-related discontinuation\t\nDPYD: Normal Fluoropyrimidine Metabolizers 2\t\nwt\tStomach\tIII\tFOLFOX\t10\tNo documented toxicity\t\nwt\tGastric\tIV\tXELOX\t4\tNo documented toxicity\t\nwt\tGastric\tIIA\tFLOT\t4\tNo documented toxicity\t\nwt\tRectum\tIIIC\tCapecitabine + RT\nCapecitabine\t25 d\n7\tNo documented toxicity\nNo documented toxicity\t\nwt\tColon\tIIIC\tXELOX\t6\tNo documented toxicity\t\nwt\tRectum\tII\tXELOX\t4\tNo documented toxicity\t\nwt\tColon\tIIIB\tFOLFOX\t12\tNo documented toxicity\t\nwt\tRectum\tI\tCapecitabine + RT\t45 d\tNo documented toxicity\t\nwt\tColon\tIV\tFOLFOX + bevacizumab\t10\tNo documented toxicity\t\nwt\tPancreas\tIII\tGemcitabine + capecitabine\t8\tNo documented toxicity\t\nwt\tPancreas\tIIIB\tGemcitabine + capecitabine\t6\tNo documented toxicity\t\nwt\tColon\tIIIC\tFOLFIRI\t8\tNo documented toxicity\t\nwt\tColon\tIVA\tXELIRI\t7\tNo documented toxicity\t\nwt\tColon\tIIIB\tXELIRI\t11\tNo documented toxicity\t\nwt\tRectum\tIV\tFOLFIRI\t6\tToxicity-unrelated dose reduction\t\nwt\tEsophagus\tIII\tFOLFOX\nCisplatin + capecitabine\t12\n2\tNo documented toxicity\nToxicity-unrelated discontinuation\t\nwt\tPancreas\tIB\tGemcitabine + capecitabine\t1\tToxicity-unrelated discontinuation\t\nwt\tPancreas\tIII\tFOLFIRINOX\t3\tToxicity-unrelated discontinuation\t\nwt\tColon\tIIA\tFOLFOX\t10\tToxicity-related dose reduction\t\nwt\tColon\tIIB\tFOLFOX\t7\tToxicity-related dose reduction, cycle delay\t\nwt\tColon\tIIIB\tFOLFOX + bevacizumab\t11\tToxicity-related dose reduction\t\nwt\tEsophagus\tIVC\tFLOT\t4\tToxicity-related dose reduction\t\nwt\tStomach\tII\tFLOT\nXELOX\t3\n2\tToxicity-related discontinuation\nToxicity-related discontinuation\t\nwt\tEsophagus\tIIIB\tXELOX\nFOLFOX\t3\n6\tToxicity-related discontinuation\nToxicity-related dose reduction\t\nwt\tColon\tIIIA\tXELOX\t4\tToxicity-related dose reduction\t\nwt\tColon\tIV\tFOLFOX\nXELOX\t1\n10\tToxicity-related discontinuation\nToxicity-related dose reduction\t\nwt\tColon\tIII\tCapecitabine\t1\tToxicity-related discontinuation\t\nwt\tColon\tIVA\tXELIRI\t1\tToxicity-related discontinuation\t\nwt\tStomach\tII\tXELOX\nFOLFOX\t2\n8\tToxicity-related hospitalization, discontinuation\nToxicity-related dose reduction, cycle delay\t\nwt\tColon\tIIIB\tFOLFOX + bevacizumab\t5\tToxicity-related discontinuation, hospitalization\t\nTPMT: Poor Mercaptopurine Metabolizer\t\n3B/3C\tALL\tN/A\tPOMP\t17\tToxicity-related dose reduction\t\nCYP2D6: Intermediate Tamoxifen Metabolizer\t\n1/6\tBreast\tIV\tTamoxifen 20 mg daily\t8 mo\tProgressive disease; proceeded to surgical castration\t\nAbbreviations: wt: wild type; FOLFOX: folinic acid, fluorouracil, and oxaliplatin; FLOT: fluorouracil, leucovorin, oxaliplatin, and docetaxel; RT: radiation therapy; d: days; XELOX: capecitabine and oxaliplatin; 5-FU: 5-fluorouracil; FOLFIRI: folinic acid, fluorouracil, and irinotecan; FOLFIRINOX: folinic acid, fluorouracil, irinotecan, and oxaliplatin; ALL: acute lymphoblastic leukemia; POMP: prednisone, vincristine, methotrexate, 6-mercaptopurine; mg: milligrams; mo: months. 1 One pancreatic cancer patient whose genotype was DPYD2A/wt was treated with FOLFOX at an outside institution and follow-up data were not available for report. 2 Eight DPYD wild-type colorectal cancer patients were treated with fluoropyrimidine-containing regimens at outside institutions and follow-up data were not available for report.\n\nAppendix C\n\ncancers-13-04524-t0A3_Table A3 Table A3 Pharmacogenomically-relevant treatment regimens with associated dosing.\n\nRegimen\tDosing\t\nFOLFIRI\tIrinotecan 180 mg/m2, leucovorin 400 mg/m2, 5-FU 400 mg/m2 bolus, then 2400 mg/m2 CI every 14 d\t\nFOLFIRINOX\tIrinotecan 180 mg/m2, leucovorin 400 mg/m2, oxaliplatin 85 mg/m2, 5-FU 400 mg/m2 bolus, then 2400 mg/m2 CI every 14 d\t\nLiposomal irinotecan + 5-FU\tLiposomal irinotecan 70 mg/m2, leucovorin 400 mg/m2, 5-FU 2400 mg/m2 CI every 14 d\t\nXELIRI\tIrinotecan 80–200 mg/m2 and capecitabine 800–1000 mg/m2 twice daily every 21 d\t\nIrinotecan + cetuximab\tIrinotecan 180 mg/m2 and cetuximab 250–400 mg/m2 every 14 d\t\nFOLFOX\tLeucovorin 400 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2400 mg/m2 CI +/− 400 mg/m2 bolus every 14 d\t\nXELOX\tOxaliplatin 130 mg/m2 and capecitabine 850–1000 mg/m2 twice daily every 21 d or\nOxaliplatin 85 mg/m2 and capecitabine 850–1000 mg/m2 twice daily every 14 d\t\nFLOT\tLeucovorin 200 mg/m2, docetaxel 50 mg/m2, oxaliplatin 85 mg/m2, 5-FU 2600 mg/m2 CI every 14 d\t\nCapecitabine + RT\t825 mg/m2 twice daily during radiation treatments\t\nCapecitabine\t850 mg/m2 twice daily every 14–28 d\t\nGemcitabine + capecitabine\tGemcitabine 1000 mg/m2 weekly and capecitabine 650 mg/m2 twice daily every 21 d or\nGemcitabine 1000 mg/m2 weekly and capecitabine 830 mg/m2 twice daily every 14 d\t\nCisplatin + capecitabine\tCisplatin 80 mg/m2 and capecitabine 1000 mg/m2 twice daily every 21 d\t\nPOMP\tVincristine 1.4 mg/m2, mercaptopurine 60 mg/m2, methotrexate 20 mg/m2, prednisone 30 mg/m2 every 28 d\t\nAbbreviations: mg: milligrams; m2: meters squared; 5-FU: 5-fluorouracil; CI: continuous infusion; d: days; RT: radiation therapy.\n\nAppendix D\n\ncancers-13-04524-t0A4_Table A4 Table A4 List of CPIC level A pharmacogenes, associated anti-cancer drugs, and their indications.\n\nPharmacogene\tDrug\tIndication\t\nCYP2D6\tTamoxifen\tHormone-mediated cancers\t\nDPYD\tCapecitabine\nFluorouracil\tChemotherapy; see Table 3\nChemotherapy; see Table 3\t\nTPMT\tMercaptopurine\nThioguanine\tLeukemia, Chron disease/ulcerative colitis, other autoimmune disease\nLeukemia\t\nUGT1A1\tIrinotecan\tChemotherapy; see Table 3\t\n\nFigure 1 Patient tolerance to genomically-relevant anti-cancer agents. Toxicities resulting in dosing modifications, cycle delays, or discontinuation are reported. 6-mercaptopurine toxicity included cytopenia; irinotecan toxicities included cytopenia and diarrhea; fluoropyrimidine toxicities included cytopenia, diarrhea, hepatotoxicity, mucositis/stomatitis, and cardiotoxicity. Disease response is reported for the one patient who received tamoxifen as CYP2D6 is an efficacy-related pharmacogene. Abbreviations: CPIC: Clinical Pharmacogenetics Implementation Consortium; wt: wild type.\n\ncancers-13-04524-t001_Table 1 Table 1 Patient demographics and disease characteristics.\n\nCharacteristic\tPatients (n)\t%\t\nTotal\t291\t\t\nAge (median)\t61\tIQR: 52–68\t\nRace\t\t\t\nNon-Hispanic Black\t14\t4.8%\t\nNon-Hispanic White\t277\t95.2%\t\nGender\t\t\t\nFemale\t147\t50.5%\t\nMale\t139\t47.8%\t\nNon-Binary 1\t1\t0.3%\t\nPrimary Cancer Site\t\t\t\nColon/rectal\t55\t18.9%\t\nGynecologic\t49\t16.8%\t\nHead and neck\t36\t12.4%\t\nBrain\t25\t8.6%\t\nPancreatic\t16\t5.5%\t\nLeukemia/lymphoma\t15\t5.2%\t\nGastric/gastroesophageal\t15\t5.2%\t\nKidney and bladder\t14\t4.8%\t\nLung\t14\t4.8%\t\nSmall bowel 2\t12\t4.1%\t\nSkin\t12\t4.1%\t\nBreast\t7\t2.4%\t\nOther 3\t21\t7.2%\t\nCancer Stage\t\t\t\nI\t31\t10.7%\t\nII\t42\t14.4%\t\nIII\t93\t32.0%\t\nIV\t78\t26.8%\t\nN/A 4\t47\t16.2%\t\nAbbreviations: IQR: inter-quartile range; N/A: not available or not applicable. 1 One patient identified as a transgender and was assigned male at birth. 2 Small bowel histologies included adenocarcinoma, carcinoid/neuroendocrine tumor, and sarcoma. 3 Other primary sites included anus, peripheral nervous system, prostate, soft tissue, and thyroid gland. 4 N/A includes cancers that are not staged or whose stage was unavailable.\n\ncancers-13-04524-t002_Table 2 Table 2 Pharmacogenomic variants and patient frequencies. The number of patients and percentage refers to heterozygotes unless otherwise specified.\n\nPharmacogenomic Variant\tPatients with Variant Allele\nn (%)\tVariant Allele Frequency\tExpected Variant Allele\nFrequency 1\t\nAny\t263 (90.4%)\t\t\t\nUGT1A1\t\t\t\t\n28\t\t0.3093\t0.3165\t\nHomozygote\t23 (7.9%)\t\nHeterozygote\t134 (46.0%)\t\nTotal UGT1A1\t157 (54.0%)\t0.3093\t0.3165\t\nDPYD\t\t\t\t\nc.2846A>T\t1 (0.3%)\t0.0017\t0.0037\t\n2A\t4 (1.4%)\t0.0069\t0.0079\t\nHapB3\t7 (2.4%)\t0.0120\t0.0237\t\nc.557A>G\t1 (0.3%)\t0.0017\t0.0001\t\n7\t1 (0.3%)\t0.0017\t0.0002\t\nTotal DPYD\t14 (4.8%)\t0.0240\t0.0353\t\nTPMT\t\t\t\t\n3A\t\t0.0601\t0.0343\t\nHomozygote\t2 (0.7%)\t\nHeterozygote\t31 (10.7%)\t\n3B\t1 (0.3%)\t0.0017\t0.0027\t\n3C\t\t0.0123\t0.0047\t\nHomozygote\t1 (0.3%)\t\nHeterozygote\t3 (1.0%)\t\n2\t2 (0.7%)\t0.0034\t0.0021\t\nTotal TPMT\t40 (14.0%)\t0.0775\t0.0438\t\nCYP2D6\t\t\t\t\n6\t5 (1.7%)\t0.0086\t0.0025\t\nCYP2C9\t\t\t\t\n3\t37 (12.7%)\t0.0636\t0.0301\t\n11\t2 (0.7%)\t0.0034\t0.0028\t\nTotal CYP2C9\t39 (13.4%)\t0.0670\t0.0329\t\nCYP3A5\t\t\t\t\n6\t3 (1.0%)\t0.0052\t0.0015\t\n7\t2 (0.7%)\t0.0034\t0.0000\t\nTotal CYP3A5\t5 (1.7%)\t0.0086\t0.0015\t\nG6PD\t\t\t\t\nA-202A_376G-III\t1 (0.3%)\t0.0017\t0.0000–0.0340 2\t\nCYP4F2\t\t\t\t\n3\t\t0.2629\t0.4108\t\nHomozygote\t21 (7.2%)\t\nHeterozygote\t111 (38.1%)\t\nTotal CYP4F2\t132 (45.0%)\t\t\t\nSLCO1B1\t\t\t\t\n15 or 17 3\t\t0.1186\t0.1214 (15); 0.0519 (17)\t\nHomozygote\t5 (1.7%)\t\nHeterozygote\t59 (20.3%)\t\n5\t\t0.0241\t0.0224\t\nHomozygote\t2 (0.7%)\t\nHeterozygote\t10 (3.4%)\t\nTotal SLCO1B1\t12 (4.1%)\t0.1427\t0.1957\t\nVKORC1\t\t\t\t\n1173C>T\t\t0.1409\t0.4643\t\nHomozygote\t11 (3.8%)\t\nHeterozygote\t60 (20.6%)\t\nTotal VKORC1\t71 (24.4%)\t\t\t\nRYR1\t\t\t\t\nc.7042_7044delGAG\t1 (0.3%)\t0.0017\t0.0000 4\t\nc.14818G>A\t1 (0.3%)\t0.0017\t0.0000 5\t\nTotal RYR1\t2 (0.6%)\t0.0034\t0.0000 4,5\t\n1 Expected American population variant allele frequencies were obtained from CPIC database [3] unless otherwise specified. When expected American population variant frequency was not available, expected European population frequencies were reported. 2 Caucasian prevalence of this G6PD variant is 0.0000; however, prevalence of any G6PD variant in the Americas is 0.0340. 3 Testing bait was unable to differentiate SLCO1B1 15 and 17 variants, so these frequencies were combined. 4 Population allele frequency for this variant was obtained from the Genome Aggregation Database (gnomAD) [12]. 5 Population allele frequency for this variant was obtained from the Exome Aggregation Consortium (ExAC) database [13].\n\ncancers-13-04524-t003_Table 3 Table 3 Pharmacogenes and their clinical relevance to cancer patients. Clinical Pharmacogenetics Implementation Consortium (CPIC) level A pharmacogenes are listed with their associated anti-cancer drugs and associated malignancies as per National Comprehensive Cancer Network (NCCN) guidelines. Patients at potential risk indicates patients with any disease-relevant pharmacogenomic variants for each specified malignancy regardless of treatment received. Numerator indicates patients with variant alleles and denominator includes all patients with specified malignancy. In other words, of the 55 patients with colon/rectal cancer, 33 had UGT1A1 variants. Patients at actual risk indicates patients with variant alleles for each associated malignancy who were treated with associated anti-cancer drugs at our institution. Numerator indicates patients treated with specified drug and denominator includes all patients with specified malignancy with associated variant allele. In other words, of the 55 patients with colon/rectal cancer, 27 patients had a UGT1A1 variant and were treated at our institution; five of those patients received irinotecan.\n\nPharmacogene\tAnti-Cancer Drug\tMalignancy\tPatients at Potential Risk (a 2/A 3)\tPatients at Actual Risk (b 4/B 5)\t\nToxicity-Associated Pharmacogenes\t\nUGT1A1\tIrinotecan\tColon/rectal P\t33/55\t5/27 1\t\nPancreas P\t7/16\t2/6 1\t\nGastric/gastroesophageal P\t4/15\t0/4\t\n\t\tCervix O\t1/1\t0/1\t\nOvary O\t16/25\t0/16\t\nHepatobiliary O\t5/7\t0/4 1\t\nCarcinoid/neuroendocrine O\t6/10\t0/6\t\nSmall bowel adenocarcinoma O\t0/2\tN/A 6\t\nDPYD\tCapecitabine\tColon/rectal P\t3/55\t0/2 1\t\nPancreas P\t1/16\t0/1\t\nBreast P\t0/7\tN/A\t\n\t\tOvary O\t2/25\t0/2\t\nCervix O\t0/1\tN/A\t\nAnus O\t0/1\tN/A\t\nBladder O\t0/3\tN/A\t\nDPYD\tFluorouracil\tColon/rectal P\t3/55\t0/2 1\t\nPancreas P\t1/16\t1/1\t\nGastric/gastroesophageal P\t1/15\t1/1\t\nHead and neck P\t0/36\tN/A\t\n\t\tAnus O\t0/1\tN/A\t\nVulva O\t0/1\tN/A\t\nBasal cell skin O\t0/1\tN/A\t\nSquamous cell skin O\t0/4\tN/A\t\nBladder O\t0/3\tN/A\t\nThyroid O\t0/4\tN/A\t\nSmall bowel adenocarcinoma O\t0/2\tN/A\t\nTPMT\tMercaptopurine\tAcute lymphoblastic leukemia P\t1/3\t1/1\t\nEfficacy-Associated Pharmacogenes\t\nCYP2D6\tTamoxifen\tBreast P\t1/7\t1/1\t\nOvary P\t1/25\t0/1\t\nUterus P\t0/22\tN/A\t\nAbbreviations: N/A: not available. P Drug is a component of an NCCN “preferred regimen” for specified malignancy. O Drug is a component of an NCCN “other regimen” and/or “regimen useful in certain instances” for specified malignancy. 1 Chemotherapy regimen was unknown for several patients who received treatment at outside institutions. 2 Number of patients with any variant allele. 3 Number of patients with this disease type. 4 Number of patients treated with drug; individuals treated outside of our institution are excluded. 5 Number of patients with any variant allele specific to drug; individuals treated outside of our institution are excluded. 6 If no patients with variant alleles were treated at our institution, ‘N/A’ is indicated.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Vivot A. Boutron I. Ravaud P. Porcher R. Guidance for pharmacogenomic biomarker testing in labels of FDA-approved drugs Genet. 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ClinVar: Improving access to variant interpretations and supporting evidence Nucleic Acids Res. 2018 46 D1062 D1067 10.1093/nar/gkx1153 29165669\n50. Fairley S. Lowy-Gallego E. Perry E. Flicek P. The International Genome Sample Resource (IGSR) collection of open human genomic variation resources Nucleic Acids Res. 2020 48 D941 D947 10.1093/nar/gkz836 31584097\n51. National Comprehensive Cancer Network NCCN Guidelines: Treatment by Cancer Type Available online: https://www.nccn.org/guidelines/category_1 (accessed on 14 April 2021)\n52. United States Census Bureau QuickFacts: Kentucky Available online: https://www.census.gov/quickfacts/KY (accessed on 14 April 2021)\n\n", "fulltext_license": "CC BY", "issn_linking": "2072-6694", "issue": "13(18)", "journal": "Cancers", "keywords": "5-fluorouracil; cancer; irinotecan; mercaptopurine; pharmacogenomics; real word", "medline_ta": "Cancers (Basel)", "mesh_terms": null, "nlm_unique_id": "101526829", "other_id": null, "pages": null, "pmc": null, "pmid": "34572750", "pubdate": "2021-09-08", "publication_types": "D016428:Journal Article", "references": "18929686;19451168;25521333;30628534;25877891;18466101;29045513;21270786;32832831;28605049;31078660;31584097;33119477;29165669;26537014;22157297;27248859;17008691;26098842;30485432;26417955;27268795;32461654;33235809;33693532;27899611;20803066;30447069;31361818;29570791;33805415;26556299;21486535;21344614;24438714;22300766;19505943;29152729;30288154", "title": "Real-World Evaluation of Universal Germline Screening for Cancer Treatment-Relevant Pharmacogenes.", "title_normalized": "real world evaluation of universal germline screening for cancer treatment relevant pharmacogenes" }	[ { "companynumb": "US-PFIZER INC-202101212133", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "IRINOTECAN HYDROCHLORIDE" }, "drugadditional...
{ "abstract": "BACKGROUND\nMethotrexate (MTX), an antimetabolite of folic acid, is the drug of choice for the nonsurgical management of ectopic pregnancy. MTX-related toxicity may include leukopenia, thrombocytopenia, pancytopenia, nausea, vomiting, stomatitis, mucositis, and liver and lung toxicity, depending primarily on the dosage of the drug and patients' renal function. Currently, the use of MTX in hemodialysis patients, even at a low dosage, is controversial, and no clear-cut guidelines are available.\n\n\nMETHODS\nWe report here a rare case of a life-threatening complication characterized by severe pancytopenia and skin and mucosal injury, which developed in a young patient on hemodialysis after oral treatment with MTX for ectopic pregnancy.\n\n\nCONCLUSIONS\nWe conclude that even low-dose MTX administration is not to be used in patients with renal insufficiency, and when no other therapeutic options are available we suggest taking several clinical measures to prevent or treat myelosuppression.", "affiliations": "Department of Internal Medicine B, Bnai-Zion Hospital, Haifa, Israel, nadav.willner@gmail.com.", "authors": "Willner\|Nadav\|N\|;Storch\|Shimon\|S\|;Tadmor\|Tamar\|T\|;Schiff\|Elad\|E\|", "chemical_list": "D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate", "country": "Germany", "delete": false, "doi": "10.1007/s00228-013-1608-3", "fulltext": null, "fulltext_license": null, "issn_linking": "0031-6970", "issue": "70(3)", "journal": "European journal of clinical pharmacology", "keywords": null, "medline_ta": "Eur J Clin Pharmacol", "mesh_terms": "D000964:Antimetabolites, Antineoplastic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008727:Methotrexate; D052016:Mucositis; D010198:Pancytopenia; D011247:Pregnancy; D011271:Pregnancy, Ectopic; D006435:Renal Dialysis; D012720:Severity of Illness Index; D012867:Skin; D055815:Young Adult", "nlm_unique_id": "1256165", "other_id": null, "pages": "261-3", "pmc": null, "pmid": "24276413", "pubdate": "2014-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "6965819;11328935;4723265;8823500;7859226;19502905;12376811;11865117;2369423;12034789;10381078;16526326;16449141", "title": "Almost a tragedy: severe methotrexate toxicity in a hemodialysis patient treated for ectopic pregnancy.", "title_normalized": "almost a tragedy severe methotrexate toxicity in a hemodialysis patient treated for ectopic pregnancy" }	[ { "companynumb": "PHHY2014IL029942", "fulfillexpeditecriteria": "1", "occurcountry": "IL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TRAMADOL" }, "drugadditional": "3", "drugadm...
{ "abstract": "We describe a 27-year-old female with repeated episodes of pulseless electrical activity due to intoxication with a substance that was unidentified at presentation. Severe QRS widening was observed and empiric treatment with sodium bicarbonate and intravenous lipid emulsion was administered. In this case, intraosseous administration of lipid emulsion failed to improve haemodynamic parameters, suggesting that this dose remained in the bone marrow compartment. We recommend that physicians become aware of this possibility and to avoid intraosseous administration of lipid emulsion.", "affiliations": "Department of Intensive Care, ZGT Hospital, Almelo, the Netherlands.", "authors": "Bethlehem\|C\|C\|;Jongsma\|M\|M\|;Korporaal-Heijman\|J\|J\|;Yska\|J P\|JP\|", "chemical_list": "D000962:Antimalarials; D002021:Buffers; D002317:Cardiovascular Agents; D005217:Fat Emulsions, Intravenous; D002738:Chloroquine; D017693:Sodium Bicarbonate; D002125:Calcium Gluconate", "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0300-2977", "issue": "77(5)", "journal": "The Netherlands journal of medicine", "keywords": null, "medline_ta": "Neth J Med", "mesh_terms": "D000328:Adult; D000962:Antimalarials; D002021:Buffers; D002125:Calcium Gluconate; D002317:Cardiovascular Agents; D002738:Chloroquine; D003422:Critical Care; D062787:Drug Overdose; D004562:Electrocardiography; D005217:Fat Emulsions, Intravenous; D005260:Female; D006323:Heart Arrest; D006801:Humans; D017148:Infusions, Intraosseous; D017693:Sodium Bicarbonate; D013406:Suicide, Attempted; D016896:Treatment Outcome", "nlm_unique_id": "0356133", "other_id": null, "pages": "186-188", "pmc": null, "pmid": "31264584", "pubdate": "2019-06", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cardiac arrest following chloroquine overdose treated with bicarbonate and lipid emulsion.", "title_normalized": "cardiac arrest following chloroquine overdose treated with bicarbonate and lipid emulsion" }	[ { "companynumb": "NL-MYLANLABS-2019M1012656", "fulfillexpeditecriteria": "1", "occurcountry": "NL", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXTROAMPHETAMINE" }, "drugadditional": "3", ...
{ "abstract": "BACKGROUND\nAlthough intravenous immunoglobulin (IVIG) is effective therapy for Kawasaki disease, 10-20% of patients have recrudescent fever as a sign of persistent inflammation and require additional treatment. We aimed to compare infliximab with a second infusion of IVIG for treatment of resistant Kawasaki disease.\n\n\nMETHODS\nIn this multicentre comparative effectiveness trial, patients (aged 4 weeks to 17 years) with IVIG resistant Kawasaki disease and fever at least 36 h after completion of their first IVIG infusion were recruited from 30 hospitals across the USA. Patients were randomly assigned (1:1) to second IVIG (2 g/kg over 8-12 h) or intravenous infliximab (10 mg/kg over 2 h without premedication), by using a randomly permuted block randomisation design with block size of two or four. Patients with fever 24 h to 7 days following completion of first study treatment crossed over to receive the other study treatment. The primary outcome measure was resolution of fever at 24 h after initiation of study treatment with no recurrence of fever attributed to Kawasaki disease within 7 days post-discharge. Secondary outcome measures included duration of fever from enrolment, duration of hospitalisation after randomisation, and changes in markers of inflammation and coronary artery Z score. Efficacy was analysed in participants who received treatment and had available outcome values. Safety was analysed in all randomised patients who did not withdraw consent. This clinical trial is registered with ClinicalTrials.gov, NCT03065244.\n\n\nRESULTS\nBetween March 1, 2017, and Aug 31, 2020, 105 patients were randomly assigned to treatment and 103 were included in the intention-to-treat population (54 in the infliximab group, 49 in the second IVIG group). Two patients randomised to infliximab did not receive allocated treatment. The primary outcome was met by 40 (77%) of 52 patients in the infliximab group and 25 (51%) of 49 patients in the second IVIG infusion group (odds ratio 0·31, 95% CI 0·13-0·73, p=0·0076). 31 patients with fever beyond 24 h received crossover treatment: nine (17%) in the infliximab group received second IVIG and 22 (45%) in second IVIG group received infliximab (p=0·0024). Three patients randomly assigned to infliximab and two to second IVIG with fever beyond 24h did not receive crossover treatment. Mean fever days from enrolment was 1·5 (SD 1·4) for the infliximab group and 2·5 (2·5) for the second IVIG group (p=0·014). Mean hospital stay was 3·2 days (2·1) for the infliximab group and 4·5 days (2·5) for the second IVIG group (p<0·001). There was no difference between treatment groups for markers of inflammation or coronary artery outcome. 24 (44%) of 54 patients in the infliximab group and 33 (67%) of 49 in the second IVIG group had at least one adverse event. A drop in haemoglobin concentration of at least 2g/dL was seen in 19 (33%) of 58 patients who received IVIG as either their first or second study treatment (three of whom required transfusion) and in three (7%) of 43 who received only infliximab (none required transfusion; p=0·0028). Haemolytic anaemia was the only serious adverse events deemed definitely or probably related to study treatment, and was reported in nine (15%) of 58 patients who received IVIG as either their first or second study treatment and none who received infliximab only.\n\n\nCONCLUSIONS\nInfliximab is a safe, well tolerated, and effective treatment for patients with IVIG resistant Kawasaki disease, and results in shorter duration of fever, reduced need for additional therapy, less severe anaemia, and shorter hospitalisation compared with second IVIG infusion.\n\n\nBACKGROUND\nPatient Centered Outcomes Research Institute.", "affiliations": "Rady Children's Hospital San Diego, San Diego, CA, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA. Electronic address: jcburns@health.ucsd.edu.;Rady Children's Hospital San Diego, San Diego, CA, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.;Rady Children's Hospital San Diego, San Diego, CA, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.;Biostatistics Research Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA.;Rady Children's Hospital San Diego, San Diego, CA, USA; Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.;CHOC Children's Hospital, Orange, CA, USA.;Biostatistics Research Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA; Maria Fareri Children's Hospital at Westchester Medical Center, New York Medical College, Valhalla, NY, USA.;Miller Children's Hospital Long Beach, Long Beach, CA, USA.;Children's Health, University of Texas Southwestern Medical Center, Dallas, TX, USA.;Primary Children's Hospital, University of Utah, Salt Lake City, UT, USA.;Indiana University School of Medicine, Indianapolis, IN, USA.;Betty Irene Moore School of Nursing, University of California Davis, Sacramento, CA, USA.;Biostatistics Research Center, Herbert Wertheim School of Public Health and Human Longevity Science, University of California San Diego, La Jolla, CA, USA; Maria Fareri Children's Hospital at Westchester Medical Center, New York Medical College, Valhalla, NY, USA.", "authors": "Burns\|Jane C\|JC\|;Roberts\|Samantha C\|SC\|;Tremoulet\|Adriana H\|AH\|;He\|Feng\|F\|;Printz\|Beth F\|BF\|;Ashouri\|Negar\|N\|;Jain\|Supriya S\|SS\|;Michalik\|David E\|DE\|;Sharma\|Kavita\|K\|;Truong\|Dongngan T\|DT\|;Wood\|James B\|JB\|;Kim\|Katherine K\|KK\|;Jain\|Sonia\|S\|;\|\|\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1016/S2352-4642(21)00270-4", "fulltext": null, "fulltext_license": null, "issn_linking": "2352-4642", "issue": "5(12)", "journal": "The Lancet. Child & adolescent health", "keywords": null, "medline_ta": "Lancet Child Adolesc Health", "mesh_terms": null, "nlm_unique_id": "101712925", "other_id": null, "pages": "852-861", "pmc": null, "pmid": "34715057", "pubdate": "2021-12", "publication_types": "D016428:Journal Article", "references": null, "title": "Infliximab versus second intravenous immunoglobulin for treatment of resistant Kawasaki disease in the USA (KIDCARE): a randomised, multicentre comparative effectiveness trial.", "title_normalized": "infliximab versus second intravenous immunoglobulin for treatment of resistant kawasaki disease in the usa kidcare a randomised multicentre comparative effectiveness trial" }	[ { "companynumb": "US-TAKEDA-2021TUS078216", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": "3...
{ "abstract": "Gingival overgrowth (GO) is among one of the most important clinical features of gingival pathology frequently seen in periodontal clinic. Amlodipine is a comparatively new calcium channel blocker and is being used with increasing frequency in the management of hypertension and angina. A 48-year-old Indian woman who was on amlodipine for 3 years for hypertension reported to the department of periodontics with the complaint of swollen, un esthetic gums. The patient developed GO 6 months before her first visit to dental hospital. She developed GO very rapidly due to the increase in amlodipine dose due to the severe angina attack 6 months before and due to the use of cholesterol (CHO) lowering drug. The main aim of the case report is to study the severity of amlodipine induced GO in a patient with cardiovascular disease (CVD) and to identify the role of subgingival microorganisms on inflammatory gingival enlargement in the same patient. The severity and rapidity of gingival enlargement in this report could have been triggered by doubling the dose of amlodipine and concomitant use of CHO lowering drug.", "affiliations": "Department of Periodontics, St. Joseph Dental College, Eluru, Andhra Pradesh, India.", "authors": "Pasupuleti\|Mohan Kumar\|MK\|;Musalaiah\|S V V S\|SV\|;Nagasree\|M\|M\|;Kumar\|P Aravind\|PA\|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.4103/2231-0770.118462", "fulltext": "\n==== Front\nAvicenna J MedAvicenna J MedAJMAvicenna Journal of Medicine2231-07702249-4464Medknow Publications & Media Pvt Ltd India AJM-3-6810.4103/2231-0770.118462Case ReportCombination of inflammatory and amlodipine induced gingival overgrowth in a patient with cardiovascular disease Pasupuleti Mohan Kumar Musalaiah S.V.V.S. Nagasree M. Kumar P. Aravind Department of Periodontics, St. Joseph Dental College, Eluru, Andhra Pradesh, IndiaAddress for correspondence: Dr. Mohan Kumar, Flat no. 303, R.K Gold Apartments, Sriram nagar, 5th Road, Eluru, West Godavari District, Andhra Pradesh, India. E-mail: suppimohan@gmail.comJul-Sep 2013 3 3 68 72 Copyright: © Avicenna Journal of Medicine2013This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Gingival overgrowth (GO) is among one of the most important clinical features of gingival pathology frequently seen in periodontal clinic. Amlodipine is a comparatively new calcium channel blocker and is being used with increasing frequency in the management of hypertension and angina. A 48-year-old Indian woman who was on amlodipine for 3 years for hypertension reported to the department of periodontics with the complaint of swollen, un esthetic gums. The patient developed GO 6 months before her first visit to dental hospital. She developed GO very rapidly due to the increase in amlodipine dose due to the severe angina attack 6 months before and due to the use of cholesterol (CHO) lowering drug. The main aim of the case report is to study the severity of amlodipine induced GO in a patient with cardiovascular disease (CVD) and to identify the role of subgingival microorganisms on inflammatory gingival enlargement in the same patient. The severity and rapidity of gingival enlargement in this report could have been triggered by doubling the dose of amlodipine and concomitant use of CHO lowering drug.\n\nAcute myocardial infarctionamlodipineanginagingival overgrowth\n==== Body\nINTRODUCTION\nThe gingiva and associated soft tissues of the periodontium may be enlarged in response to various interactions between the host and the environment. Etiology of gingival overgrowth (GO) is multifactorial. It has been frequently associated with inflammatory changes and the other factors related to this condition are hereditary, malignancies, and those resulting from adverse effects associated with the systemic administration of certain drugs.[1]\n\n“Gingival enlargement” or “gingival overgrowth” is the preferred term for all medication-related gingival lesions. Currently, more than 20 prescription medications are associated with gingival enlargement.[2]\n\nAnticonvulsants, cyclosporin A, and calcium channel blockers are the three different groups of pharmaceutical agents that have been commonly associated with the occurrence of GO in susceptible individuals.[3]\n\nAll these factors are associated with the disproportionate, disfiguring, and functionally compromising overgrowth of gingival tissues that have provided new niches for the growth of microorganisms, results in a serious concern for the patients. This made the clinicians to generate the most investigative attention in the scientific community on gingival enlargements.[13]\n\nPrevalence of the drug induced gingival enlargement is 3-20% compared to most important inflammatory gingival enlargements. Antihypertensive drugs in the calcium channel blocker group are used extensively in elderly patients who have angina or peripheral vascular disease. Amlodipine, an agent of dihydropyridine, a third generation calcium channel blocker that is used for treatment of hypertension and angina, causes GO as an adverse effect.[4]\n\nThough the pharmacologic effect of each class of the drugs causing GO is different and directed toward various primary target tissues, all of them seem to have similar adverse effect on a secondary target tissue, that is, the gingival connective tissue, causing common clinical and histopathological findings.[45]\n\nCalcium channel blockers act by inhibiting calcium ion influx across the cell membrane of cardiac and smooth muscle cells thereby blocking the intracellular mobilization of Ca++. It causes dilatation of coronary arteries and arterioles as well as decreased myocardial contractility and oxygen demand. The first report of occurrence of GO associated with calcium channel blocker (nifedipine) was reported by Ramon et al., 1984. Amilodipine, filodipine, diltazem, nitrendipine, and verapamil are the other agents associated with this side effect.[67]\n\nGO has been reported in 15-83% of patients taking nifedipine (Barak et al., 1987[8]; Fattore et al., 1991[9]), approximately 21% of patients taking diltiazem (Steel et al., 1994[10]), about 4% of those medicated with verapamil (Miller et al., 1992[11]) and 1.7% for amlodipine (Ellis et al., 1999).\n\nSeveral factors are responsible for the pathogenesis of drug induced GO as discussed by Seymour et al. These factors include: (1) Age, (2) genetic predisposition, (3) pharmacokinetic variables, (4) alteration in gingival connective tissue homeostasis, (5) histopathology, (6) ultrastructural factors, (7) inflammatory changes, and (8) drug action on growth factors.[612]\n\nA number of risk factors also relate closely to the development of atherosclerotic disease and risk for cardiovascular events (e.g., myocardial infarction and stroke), including age, gender, hypertension, diabetes mellitus, smoking, and low serum levels of high density lipoprotein (HDL) cholesterol (CHO). Over the past 2 decades, inflammation has emerged as an integrative cardiovascular disease (CVD) factor. Inflammation can operate in all stages of this disease from initiation through progression and, ultimately, the thrombotic complications of atherosclerosis.[13]\n\nIt is well recognized that calcium channel blockers, which are strong inhibitors of cytochrome P450 3A4, coadministered with statins that are metabolized by the same isoenzyme before biliary and renal excretion may lead to reduced clearance of both the drugs, with an increase in adverse effects.[14]\n\nNevertheless, when statins and calcium channel blockers are coprescribed, especially at high doses, there may possibly be an increase in adverse effects, such as GO. However, the exact mechanism remains unknown. This case report presents the management of a case of a combination of drug-influenced gingival enlargement with acute myocardial infarction.[1415]\n\nCASE PRESENTATION\nA 48-year-old Indian woman was referred to the department of periodontology, with the chief complaint of swollen gums. She felt discomfort with the disfigurement of gums which appeared un esthetic due to its more severity and there was bleeding and difficulty while chewing food.\n\nPast medical history revealed that she is under medication for hypertension with amlodipine (10 mg/day orally) for the last 2 years and 6 months. The amlodipine dose was increased to 50 mg/day orally and statins were prescribed due to the acute angina attack and hypercholesterolemia before 6 months of the dental visit.\n\nOral examination\nClinical examination was carried out by assessing the periodontal status by plaque index (PI), gingival index (GI), Russel's periodontal index. The patients oral hygiene status revealed the presence of more amount of plaque and some amount of calculus on both anterior and posterior surfaces of the teeth due to the presence of new niches for accumulation of plaque and microorganisms. There was generalized bleeding on probing and generalized probing depths ranging from 3 to 8 mm with greatest depths in relation to mandibular anteriors. Due to the outward enlargement of gingiva, there were no deep periodontal pockets.\n\nIntraorally, there was generalized GO on the labial and lingual/palatal surface of the maxillary and mandibular teeth, which was more pronounced in the labial surfaces than the lingual and palatal surfaces. The interdental papillae were enlarged, fibrous, and lobulated in appearance mainly around the mandibular and maxillary anterior teeth [Figure 1a].\n\nFigure 1 (a) Preoperative view showing gingival over growth, (b) Orthopantomograph showing generalized horizontal bone loss, (c) Plaque sample collected by paperpoints and sent for RNA hybridization (d) Histologic view showing elongated rete pegs and dense connective tissue, (e) Postoperative view\n\nIn this case report, photographic analysis by Ellis and Seymour was used for assessing the gingival encroachment or overgrowth on adjacent surfaces for a gingival unit (0 = no encroachment of interdental papilla on tooth surface, 1 = mild encroachment producing a blunted papilla tip, 2 = moderate encroachment involving lateral spread of papilla across buccal tooth surface of less than one quarter tooth width, 3 = marked encroachment of papilla, more than One-fourth tooth width with loss of interdental papilla form).[16] In this case report, score 3 severity of gingival enlargement was observed.\n\nGrade III mobility was observed in relation to mandibular anteriors. Generalized reddish color, purulent discharge in relation to mandibular anteriors and generalized bleeding on probing were observed due to the generalized inflammation of gingiva. Radiographic examination revealed generalized horizontal bone loss with more destruction of bone in relation to maxillary and mandibular anterior region [Figure 1b].\n\nLaboratory analysis\nBlood sample was taken at the patients first visit to the dental hospital. Serum total CHO, HDL, low density lipoprotein (LDL), and triglycerides (TG) were determined by autoanalyzer in the clinical laboratory.\n\nMicrobiologic tests\nSeveral methods have been employed for the detection of putative periodontal pathogens in subgingival samples to identify the microbiologic profile of periodontitis. Here we had chosen a genetic microbiologic test to identify microbiologic profile in amlodipine induced gingival enlargement with CVD.\n\nA paper point made of cellulose is introduced into the deep periodontal pocket. After 10 s, the point is withdrawn and placed in a RNA stabilizer buffer and sent for hybridization [Figure 1c]. The IAI Pado Test 4.5 (IAI ESCHENWEG 6. CH-4528 ZUCHWIL/SWITZERLAND) which is a genetic test used in this case study allowed for the identification and quantification of bacteria which have a preponderant pathogenic role in periodontitis.\n\nThe IAI Pado Test 4.5 is a biologic molecular test which allowed the identification and quantification. The specific periodontal pathogens like Aggregatibacter actinomycetemcomitans (Aa), Porphyromonas gingivalis (Pg), Tannerella forsythia (Tf), and Treponema denticola (Td) were identified by this test.\n\nHistologic examination\nBiopsy was taken during the surgical phase and sent to the laboratory. It revealed mixture of dense and loose fibrous components with the chronic inflammatory cell infiltrate in the connective tissue and elongation of rete pegs in the epithelium. On the basis of patient's history, clinical features, laboratory investigations for lipid profile, microbiologic profile, and biopsy reports, a diagnosis of amlodipine induced GO in a patient with CVD was made.\n\nCASE MANAGEMENT\nPrevention\nIn a drug induced gingival enlargement susceptible patient, GO cannot be prevented just by removing the local factors. Periodontal maintenance therapy for at least 3 months is recommended and each appointment should be scheduled by giving oral hygiene instructions with complete oral prophylaxis.\n\nTreatment\nDrug substitution\nSubstitution or withdrawal of drug causing gingival enlargement is more effective during treatment. The patient was referred to a physician to replace the drug causing the adverse side effect and after thorough assessment of the severity of gingival enlargement due to the combined effect of inflammation and amlodipine, the drug was substituted to atenolol 50 mg/day orally to treat hypertension.\n\nNonsurgical treatment\nComplete scaling and root planing was done for supragingival and subgingival calculus removal at the first visit. Review after 1 week showed some relief but there was not much noticeable reduction in overgrowth even after 1-3 months follow-up due to substitution of drug and periodontal maintenance therapy.\n\nThough the most effective treatment of drug related gingival enlargement is withdrawal or substitution of medication. Unfortunately, not all patients respond to this mode of treatment especially those with long standing gingival lesions. 3 month interval for periodontal maintenance therapy has been recommended after the substitution or cessation of drug in gingival enlargement patients. Surgical reduction of the enlarged tissue is frequently necessary to accomplish an esthetic and functional outcome when the drug substitution alone does not reduce GO.\n\nSurgical therapy\nPatient requested for surgical correction of gingival on upper and lower quadrants, except for lower anteriors which had grade II mobility. Gingival enlargement was resected segment wise by modified flap operation except for mandibular anteriors which had grade III mobility and was extracted later.\n\nClinical outcome and patient responses\nThere was no discomfort or side effects were observed in the postoperative period. At 3 months after the treatment of maxillary overgrowth, there was no recurrence of GO and the patient expressed a high level of satisfaction and willingness to treat remaining areas of overgrowth in mandibular posterior regions. No recurrence of GO observed at 6 months after the treatment.\n\nClinical parameters 6 months postoperative surgery were shown in Table 1.\n\nTable 1 Periodontal parameters\n\nDISCUSSION\nGingival enlargement has become a serious concern for both the patients and clinicians because of the disfigurement of gingiva which helped in the production of new niches for microorganisms. These implications lead to addition of inflammatory gingival enlargement to the drug induced gingival enlargement.[1718]\n\nClinical manifestation of GO commonly appears within 1-3 months after initiation of treatment with the associated drugs. In the present case, although the patient was taking 10 mg amlodipine for 2 years and 6 months, GO was noted only 6 months before her initial visit to the dental hospital. The severity of gingival enlargement is due to the increase in dose of amlodipine and also due to the prescription of CHO lowering drug.\n\nWhen statins and calcium channel blockers are prescribed together, especially at high doses, there may possibly be an increase in adverse effects, such as gingival enlargement. This is because calcium channel blockers, which are strong inhibitors of cytochrome P450 3A4, coadministered with statins that are metabolized by the same isoenzyme before biliary and renal excretion may lead to reduced clearance of both the drugs, with an increase in adverse effects.[141517]\n\nThis case report presents the management of a case of a combination of drug influenced gingival enlargement in a patient with CVD and hypercholesterolemia.\n\nBlood samples were taken on admission from the patient. Serum total CHO, HDL, LDL, and TG were determined by autoanalyzer in the clinical laboratory [Table 1].\n\nThe lipid profile showed low HDL and high LDL levels at base line when compared to the 2nd and 3rd visits. TG and CHO levels were high in 1st visit compared to 2nd and 3rd visits [Table 2].\n\nTable 2 Lipid profile\n\nIn this case, microbiologic analysis by IAI Pado Test 4.5 showed all the putative periodontal pathogens with detection frequency of A. actinomycetemcomitans, (12) P. gingivalis, (6) P. intermedia, (3) and T. forsythia (2) in the sites of more probing depths when compared to the levels after nonsurgical and surgical treatment [Table 3]. These results confirm the association of inflammatory gingival enlargement with drug induced overgrowth. These results are in accordance with the recent epidemiologic study by Li et al., in 2008 which showed the increase in attachment loss and bone loss in patients taking nifedipine as an antihypertensive.[19–21]\n\nTable 3 Detection frequency of microorganisms by IAI PADO TEST 4.5\n\nHistopathological examination revealed the mixture of dense and loose fibrous components with chronic inflammatory cell infiltrate in the connective tissue. Epithelium showed acanthosis and elongation of rete pegs [Figure 1d].\n\nGeneralized gingival enlargement was reported and the combination of inflammatory and drug induced overgrowth is more pronounced in mandibular anterior region due to the more plaque accumulation.[2223] Periodontal pocket depths from 3 to 8 mm were recorded with greater depths up to 8 mm in relation to mandibular anteriors. Grade III mobility was recorded in relation to mandibular anteriors which were extracted during the maintenance phase according to the patients’ acceptance.\n\nIn this case, surgical treatment was done only after 3 months after withdrawal of the drug causing overgrowth of gingival and even after the completion of the nonsurgical therapy.\n\nPatient was recalled for every 2 weeks up to 6 months for maintenance therapy [Figure 1e]. Patient was satisfied with the outcome of the treatment chosen for gingival enlargement and finally she accepted for the extraction of grade III mobile teeth in relation to mandibular anteriors which showed the combination of inflammatory and drug induced gingival GO.\n\nCONCLUSION\nThis case further highlights the role of amlodipine in gingival enlargements when the dose is increased along with the prescription of CHO lowering drug in a patient with CVD. I, further emphasize the importance of biopsy examination, microbiologic profile for the confirmation of results in every such cases with the combination of inflammatory and drug induced enlargements.\n\nACKNOWLEDGEMENT\nWe thank Prof. Dr. K. Krishna Murthy and Prof. Dr. D. Roopa and Prof. Dr. N. Ravindra Reddy, C.K.S Teja Institute of Dental Sciences for their extreme support throughout my post graduation studies. We also acknowledge Dr. Supraja, Mr. and Mrs. Sreedhar, Mr. and Mrs. Chandra Mohan, Mr. Vinod and Mrs. Usha Rani for partly funding for the parameters used in this case report.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nREFERENCES\n1 Newman MG Takei HH Klokkevold PR Carranza FA Text book of clinical Periodontology 11th ed Elsevier 373 88 \n2 Rees TD Levine RA Systemic drugs as a risk factor for periodontal disease initiation and progression Compend Contin Educ Dent 1995 16 20 42 \n3 Ellis JS Seymour RA Steele JG Robertson P Butler TJ Thomason JM Prevalence of gingival overgrowth induced by calcium channel blockers: A community-based study J Periodontol 1999 70 63 7 10052772 \n4 Seymour RA Thomason JM Ellis JS The pathogenesis of drug-induced gingival overgrowth J Clin Periodontol 1996 23 165 75 8707974 \n5 Hallmon WW Rossmann JA The role of drugs in the pathogenesis of gingival overgrowth. A collective review of current concepts Periodontol 2000 1999 21 176 96 10551182 \n6 Miranda J Brunet L Roset P Berini L Farre M Mendieta C Prevalence and risk of gingival enlargement in patients treated with nifedipine J Periodontol 2001 72 605 11 11394395 \n7 Ramon Y Behar S Kishon Y Engelberg IS Gingival hyperplasia caused by nifedipine- a preliminary report Int J Cardiol 1984 5 195 206 6607894 \n8 Barak S Engelberg IS Hiss Z Gingival hyperplasia caused by nifedipine: Histopathologic findings J Periodontol 1987 58 639 42 3477631 \n9 Fattore L Stablein M Bredfeldt G Semla T Moran M Doherty-Greenberg JM Gingival hyperplasia: A side effect of nifedipine and diltiazem Spec Care Dentist 1991 11 107 9 1887359 \n10 Steel RM Schuna AA Schreilber RT Calcium antagonist-induced gingival hyperplasia Ann Intern Med 1994 120 663 4 8135450 \n11 Miller CS Damm DD Incidence of verapamil-induced gingival hyperplasia in a dental population J Periodontol 1992 63 453 6 1527689 \n12 Meisel P Schwahn C John U Kroemer HK Kocher T Calcium antagonists and deep gingival pockets in the population-based SHIP study Br J Clin Pharmacol 2005 60 552 9 16236046 \n13 Friedewald VE Kornman KS Beck JD Genco R Goldfine A Libby P American Journal of Cardiology; Journal of Periodontology. The American Journal of Cardiology and Journal of Periodontology editors’ consensus: Periodontitis and atherosclerotic cardiovascular disease J Periodontol 2009 80 1021 32 19563277 \n14 Azie NE Brater DC Becker PA Jones DR Hall SD The interaction of diltiazem with lovastatin and pravastatin Clin Pharmacol Ther 1998 64 369 77 9797793 \n15 Smitha K Amlodipine-induced gingival overgrowth in a patient with uncontrolled type 2 diabetes mellitus with hypercholesterolemia: A case report Clinical Advances in Periodontics 2012 2 2 \n16 Ellis JS Seymour RA Robertson P Butler TJ Thomason JM Photographic scoring of gingival overgrowth J Clin Periodontol 2001 28 81 5 11142671 \n17 Boltchi FE Rees TD Iacopino AM Cyclosporine A - induced gingival overgrowth: A comprehensive review Quintessence Int 1999 30 775 83 10765878 \n18 Meller AT Rumjanek VM Sansone C Allodi S Oral mucosa alterations induced by cyclosporin in mice: Morphological features J Periodontal Res 2002 37 412 5 12472834 \n19 Triveni MG Rudrakshi C Mehta DS Amlodipine induced gingival overgrowth J Indian Soc Periodontal 2009 13 160 3 \n20 Shouda J Nakamoto H Sugahara S Okada H Suzuki H Incidence of gingival hyperplasia caused by calcium antagonists in continuous ambulatory peritoneal dialysis patients J Clin Periodontal 2004 31 126 31 \n21 Nakou M Kamma JJ Andronikaki A Mitsis F Subgingival microflora associated with nifedipine-induced gingival overgrowth J Periodontol 1998 69 664 9 9660335 \n22 Li X Luan Q Wang X Sha Y He L Cao C Nifedipine intake increases the risk for periodontal destruction in subjects with type 2 diabetes mellitus J Periodontol 2008 79 2054 9 18980513 \n23 Marshall RI Bartold PM A clinical review of drug-induced gingival overgrowth Aust Dent J 1999 44 219 32 10687229\n\n", "fulltext_license": "CC BY-NC-SA", "issn_linking": "2231-0770", "issue": "3(3)", "journal": "Avicenna journal of medicine", "keywords": "Acute myocardial infarction; amlodipine; angina; gingival overgrowth", "medline_ta": "Avicenna J Med", "mesh_terms": null, "nlm_unique_id": "101584155", "other_id": null, "pages": "68-72", "pmc": null, "pmid": "24251234", "pubdate": "2013-07", "publication_types": "D002363:Case Reports", "references": "18980513;20379416;10687229;1887359;11394395;6607894;8135450;8707974;1527689;9797793;10551182;16236046;10682092;11142671;3477631;12472834;19563277;7758039;9660335;10765878;10052772", "title": "Combination of inflammatory and amlodipine induced gingival overgrowth in a patient with cardiovascular disease.", "title_normalized": "combination of inflammatory and amlodipine induced gingival overgrowth in a patient with cardiovascular disease" }	[ { "companynumb": "IN-CIPLA-2014IN00066", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AMLODIPINE BESYLATE" }, "drugadditional": "1", ...
{ "abstract": "Granulocyte colony-stimulating factor (G-CSF) is commonly administered to prevent serious complications caused by chemotherapy-induced neutropenia; however, several cases of arteritis following the administration of G-CSF have been reported. Here, we report three cases of patients with non-Hodgkin lymphomas (NHLs) who developed arteritis after the administration of G-CSF, estimate the probability of adverse drug reaction caused by G-CSF with two distinct algorithms, and review the literatures. Both algorithms indicated a causal relationship between G-CSF and arteritis. In a literature review of seven reported cases, including our three patients, the time from the administration of G-CSF to the onset of arteritis ranged from 9 days to 6 months, and five patients were treated with steroids. In one of our three cases, a 62-year-old female with NHL developed arteritis twice in different courses of chemotherapy. Hydrocortisone was administered in the second event, leading to prompt relief of the manifestation and abnormal laboratory data. This finding suggests steroids may be effective for arteritis. In conclusion, although the number of reported cases is limited, there appears to be an association between arteritis and the administration of G-CSF, and steroids are an effective therapeutic option.", "affiliations": "Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-City, Tokyo, 113-8655, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-City, Tokyo, 113-8655, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-City, Tokyo, 113-8655, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-City, Tokyo, 113-8655, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-City, Tokyo, 113-8655, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-City, Tokyo, 113-8655, Japan.;Department of Radiology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Radiology, The University of Tokyo Hospital, Tokyo, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-City, Tokyo, 113-8655, Japan. kurokawa-tky@umin.ac.jp.", "authors": "Sasaki\|Ken\|K\|;Miyauchi\|Masashi\|M\|;Ogura\|Mizuki\|M\|;Shimura-Nukina\|Arika\|A\|;Toyama\|Kazuhiro\|K\|;Nakazaki\|Kumi\|K\|;Watadani\|Takeyuki\|T\|;Abe\|Osamu\|O\|;Kurokawa\|Mineo\|M\|http://orcid.org/0000-0002-4034-2422", "chemical_list": "D016179:Granulocyte Colony-Stimulating Factor", "country": "Japan", "delete": false, "doi": "10.1007/s12185-019-02662-6", "fulltext": null, "fulltext_license": null, "issn_linking": "0925-5710", "issue": "110(3)", "journal": "International journal of hematology", "keywords": "Arteritis; Granulocyte colony-stimulating factor (G-CSF); Lymphoma", "medline_ta": "Int J Hematol", "mesh_terms": "D000368:Aged; D001167:Arteritis; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged", "nlm_unique_id": "9111627", "other_id": null, "pages": "370-374", "pmc": null, "pmid": "31090035", "pubdate": "2019-09", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "14990294;15483015;18626004;19888788;20227994;26199061;27094941;29212975;7249508;902260", "title": "Arteritis after administration of granulocyte colony-stimulating factor: a case series.", "title_normalized": "arteritis after administration of granulocyte colony stimulating factor a case series" }	[ { "companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-220246", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PREDNISOLONE" }, "dr...
{ "abstract": "Hydralazine is an antihypertensive medication that has been associated with drug-induced lupus erythematosus (DIL) as well as ANCA-associated vasculitis (AAV). Although rare, early diagnosis is critical since drug cessation is the mainstay of therapy. This retrospective study aims to characterize the clinical, laboratory, and histopathologic features of this disease.\n\n\n\nOnce approval was obtained from the Institutional Review Board at the University of Iowa, all patients carrying a diagnosis of vasculitis (ICD9 code: 447.6 or ICD10 code: I77.6, I80, L95, M30, or M31) and positive ANCA lab results over the past 15 years were identified. Age, gender, comorbid conditions, medications taken over the prior 6 months, laboratory data, including electrolytes, urine studies and serologies, chest x-rays, CT scans, and pathologic biopsy records were abstracted from the electronic medical record.\n\n\n\n323 cases of AAV were identified, of which 12 were exposed to hydralazine, all at the time of diagnosis. The average duration of hydralazine therapy was 22 months and mean cumulative dose was 146g. Patients were typically older (70.3 years old) with slight female preponderance (7 females). Eleven patients presented with dyspnea, fatigue, and unintentional weight loss. Five had polyarthralgias and 8 had lower extremity petechiae. All 12 patients were both ANA and ANCA positive. ANA titers ranged from 1:160 and 1:2560. Ten were of diffuse pattern while 2 were nucleolar. ANCA titers ranged from 1:320 to 1:2560. Eleven had a pANCA pattern while one had cANCA. All 12 patients were positive for histone and 11 were positive for myeloperoxidase antibodies. Eleven also had dsDNA antibodies, and 4 had anti-cardiolipin IgG or IgM antibodies. Nine patients were also hypocomplementemic (mean C3 level: 88.4mg/dL; mean C4 level: 16.5mg/dL). All patients had variable levels of proteinuria (1+ to 3+) and eleven had active urine sediment. Urine protein:creatinine ratios ranged from 0.2 to 1.7. Of the 6 patients who underwent kidney biopsy, all 6 showed pauci-immune crescentic glomerulonephritis. Seven patients had bilateral pulmonary interstitial infiltrates and four had pleural effusions on CT scan. Four had pericardial effusions as demonstrated by echocardiography.\n\n\n\nHydralazine-associated vasculitis is a drug-associated autoimmune syndrome that presents with interstitial lung disease, hypocomplementemia, and pauci-immune glomerulonephritis. Patients have elements of both DIL and DIV, as manifested by high ANA and ANCA titers as well as the presence of histone and MPO antibodies. Further research is needed to understand the etiopathogenesis of this condition.", "affiliations": "Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242. Electronic address: Bharat-Kumar@UIowa.edu.;Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242.;Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242.;Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242.;Division of Immunology, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242.", "authors": "Kumar\|Bharat\|B\|;Strouse\|Jennifer\|J\|;Swee\|Melissa\|M\|;Lenert\|Petar\|P\|;Suneja\|Manish\|M\|", "chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D000959:Antihypertensive Agents; D006830:Hydralazine", "country": "United States", "delete": false, "doi": "10.1016/j.semarthrit.2018.01.005", "fulltext": null, "fulltext_license": null, "issn_linking": "0049-0172", "issue": "48(2)", "journal": "Seminars in arthritis and rheumatism", "keywords": "Lupus; Renal vasculitis; Vasculitis", "medline_ta": "Semin Arthritis Rheum", "mesh_terms": "D000368:Aged; D019268:Antibodies, Antineutrophil Cytoplasmic; D000959:Antihypertensive Agents; D005260:Female; D006801:Humans; D006830:Hydralazine; D008180:Lupus Erythematosus, Systemic; D008297:Male; D012189:Retrospective Studies; D014657:Vasculitis", "nlm_unique_id": "1306053", "other_id": null, "pages": "283-287", "pmc": null, "pmid": "29519741", "pubdate": "2018-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Hydralazine-associated vasculitis: Overlapping features of drug-induced lupus and vasculitis.", "title_normalized": "hydralazine associated vasculitis overlapping features of drug induced lupus and vasculitis" }	[ { "companynumb": "US-STRIDES ARCOLAB LIMITED-2018SP010276", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugaddi...
{ "abstract": "Extracorporeal membrane oxygenation (ECMO) is a life-saving therapy for those in cardiopulmonary failure, including post-cardiac arrest. Despite a high volume of ECMO patients using anti-seizure medication, there is a paucity of data concerning the dosing, levels, and clinical scenarios for their use.\nWe present three cases of ECMO patients post-PEA arrest who were on valproic acid (VPA) for treatment of seizure and/or myoclonus. The total and free levels of VPA are reported.\nThe trough levels are consistent throughout therapy, suggesting VPA is not significantly removed by the ECMO circuitry. Although the total serum levels remained below the toxic range, the free level was elevated in two patients. These patients did not develop signs of toxicity.\nVPA may be an effective anti-seizure medication in ECMO patients. Free VPA levels should be more readily available to better quantify efficacy or toxicity, especially in ECMO patients.", "affiliations": "Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department Cardiac Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Cardiovascular Surgical Intensive Care, Heart and Vascular Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Departments of Neurology, Neurological Intensive Care, Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Department of Pharmacy, Johns Hopkins Hospital, Baltimore, MD, USA.", "authors": "Hunt\|Megan F\|MF\|https://orcid.org/0000-0002-6240-9050;Clark\|Katharine T\|KT\|;Grant\|Michael C\|MC\|;Choi\|Chun Woo\|CW\|;Whitman\|Glenn\|G\|;Cho\|Sung-Min\|SM\|;Farrokh\|Salia\|S\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1177/0267659120972272", "fulltext": null, "fulltext_license": null, "issn_linking": "0267-6591", "issue": "36(8)", "journal": "Perfusion", "keywords": "Depakote; ECMO; extracorporeal membrane oxygenation; myoclonus; seizure; valproic acid", "medline_ta": "Perfusion", "mesh_terms": null, "nlm_unique_id": "8700166", "other_id": null, "pages": "868-872", "pmc": null, "pmid": "33198577", "pubdate": "2021-11", "publication_types": "D016428:Journal Article", "references": null, "title": "Therapeutic drug monitoring of valproic acid in extracorporeal membrane oxygenation.", "title_normalized": "therapeutic drug monitoring of valproic acid in extracorporeal membrane oxygenation" }	[ { "companynumb": "US-MYLANLABS-2020M1101806", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VALPROIC ACID" }, "drugadditional": "3", ...
{ "abstract": "We report a case of testicular malignant lymphoma in a hemodialysis patient. A 65-year-old man who had been undergoing hemodialysis for 8 years and 10 months consulted our hospital with right testicular enlargement in August 2012. Under a diagnosis of testicular cancer from manipulation test and ultrasonography, high orchiectomy was performed. Computed tomography showed swelling of the retroperitoneal lymph nodes. Histopathological examination revealed diffuse, non-Hodgkin B-cell lymphoma, CD20＋. R-CHOP chemotherapy was initiated and retroperitoneal lymph node swelling completely disappeared after 1 cycle of chemotherapy. After completing 2 cycles of chemotherapy, the patient developed interstitial pneumonia, and thus radiotherapy to the retroperitoneal space including the left testis was performed. As of July 2014, the patient remains alive without recurrence.", "affiliations": "The Department of Urology, Kamei Hospital.;The Department of Urology, Kamei Hospital.;The Department of Urology, Kamei Hospital.", "authors": "Nakatsuji\|Hiroyoshi\|H\|;Sakaki\|Manabu\|M\|;Hamao\|Takumi\|T\|", "chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0018-1994", "issue": "61(2)", "journal": "Hinyokika kiyo. Acta urologica Japonica", "keywords": null, "medline_ta": "Hinyokika Kiyo", "mesh_terms": "D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D003520:Cyclophosphamide; D004317:Doxorubicin; D005922:Glomerulonephritis, IGA; D006801:Humans; D017563:Lung Diseases, Interstitial; D016393:Lymphoma, B-Cell; D008297:Male; D009919:Orchiectomy; D011241:Prednisone; D006435:Renal Dialysis; D000069283:Rituximab; D013736:Testicular Neoplasms; D016896:Treatment Outcome; D014750:Vincristine", "nlm_unique_id": "0421145", "other_id": null, "pages": "67-70", "pmc": null, "pmid": "25812596", "pubdate": "2015-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Primary testicular malignant lymphoma in a hemodialysis patient : a case report.", "title_normalized": "primary testicular malignant lymphoma in a hemodialysis patient a case report" }	[ { "companynumb": "PHHY2015JP171021", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "RITUXIMAB" }, "drugadditional": null, "druga...
{ "abstract": "Metformin is a biguanide group drug commonly used in the treatment of Type 2 DM. Even though Metformin- Associated Lactic Acidosis (MALA) is not seen very frequently, MALA has a high mortality rate. This case is presented to draw attention to efficiency of hemodialysis and CVVHDF tin the treatment of MALA. A 25-year-old female patient was brought to the emergency service with abdominal pain and confusion. In her detailed history, it was learned that she took 100 tablets of metformin (1000 mg per tablet). Hemodialysis initiated because of severe metabolic acidosis, elevation of blood urea and hyperkalemia were seen in laboratory results. After that, patient was intubated because of low Glasgow Coma Scale (GCS:3) and vasopressor agent were started due to hypotension. In the intensive care unit, blood glucose was seen 44 mg dl-1 and treated with 10% dextrose solution. CVVHDF treatment was started because of anuria and metabolic acidosis. Patient who underwent CVVHDF treatment for 12-days transferred to nephrology service on the 23rd day of the ICU admission with full consciousness and stabilized vitals. In conclusion, hemodialysis and CVVHDF should be the first treatment methods to be considered in patients with metformin-associated lactic acidosis. Renal replacement therapies, initiated rapidly and maintained for an adequate time period are promising in this high mortality rate cases.", "affiliations": "Department of Anaesthesiology and Reanimation, Gaziosmanpasa Taksim Training and Research Hospital, Istanbul, Turkey.;Department of Anaesthesiology and Reanimation, Gaziosmanpasa Taksim Training and Research Hospital, Istanbul, Turkey.;Department of Anaesthesiology and Reanimation, Gaziosmanpasa Taksim Training and Research Hospital, Istanbul, Turkey.;Department of Anaesthesiology and Reanimation, Gaziosmanpasa Taksim Training and Research Hospital, Istanbul, Turkey.", "authors": "Vural\|Habibe Zehra\|HZ\|;Koseoglu\|Omer Faruk\|OF\|;Soylu\|Serhat\|S\|;Turkmen\|Ulku Aygen\|UA\|", "chemical_list": null, "country": "Turkey", "delete": false, "doi": "10.14744/SEMB.2018.35582", "fulltext": "\n==== Front\nSisli Etfal Hastan Tip Bul\nSisli Etfal Hastan Tip Bul\nThe Medical Bulletin of Sisli Etfal Hospital\n1302-7123 1308-5123 Kare Publishing Turkey \n\nMBSEH-54-252\n10.14744/SEMB.2018.35582\nCase Report\nMetformin-Associated Lactic Acidosis Developed as a Result of a Suicidal Attempt\nVural Habibe Zehra Koseoglu Omer Faruk Soylu Serhat Turkmen Ulku Aygen Department of Anaesthesiology and Reanimation, Gaziosmanpasa Taksim Training and Research Hospital, Istanbul, Turkey\nAddress for correspondence: Habibe Zehra Vural, MD. Gaziosmanpasa Taksim Egitim ve Arastirma Hastanesi, Anestezi ve Reanimasyon Klinigi, Istanbul, Turkey Phone: +90 535 604 76 53 E-mail:vuralhabibe@gmail.com\n2020 \n15 6 2020 \n54 2 252 256\n28 5 2018 12 6 2018 Copyright: © 2020 by The Medical Bulletin of Sisli Etfal Hospital2020This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).Metformin is a biguanide group drug commonly used in the treatment of Type 2 DM. Even though Metformin- Associated Lactic Acidosis (MALA) is not seen very frequently, MALA has a high mortality rate. This case is presented to draw attention to efficiency of hemodialysis and CVVHDF tin the treatment of MALA.\n\nA 25-year-old female patient was brought to the emergency service with abdominal pain and confusion. In her detailed history, it was learned that she took 100 tablets of metformin (1000 mg per tablet). Hemodialysis initiated because of severe metabolic acidosis, elevation of blood urea and hyperkalemia were seen in laboratory results. After that, patient was intubated because of low Glasgow Coma Scale (GCS:3) and vasopressor agent were started due to hypotension. In the intensive care unit, blood glucose was seen 44 mg dl-1 and treated with 10% dextrose solution. CVVHDF treatment was started because of anuria and metabolic acidosis. Patient who underwent CVVHDF treatment for 12-days transferred to nephrology service on the 23rd day of the ICU admission with full consciousness and stabilized vitals.\n\nIn conclusion, hemodialysis and CVVHDF should be the first treatment methods to be considered in patients with metformin-associated lactic acidosis. Renal replacement therapies, initiated rapidly and maintained for an adequate time period are promising in this high mortality rate cases.\n\nHemodialysislactic acidosismetformin intoxication\n==== Body\nMetformin is a biguanide antidiabetic agent frequently used in the treatment of type-2 diabetes mellitus.[1] Metformin is an anti-hyperglycemic agent used to achieve euglycemia. Lactic acidosis can be seen in acute and chronic use of biguanides. Although the incidence of acidosis is 5-9 per 100.000,[3] metformin-associated lactic acidosis (MALA) has high mortality rates.[4, 5] Plasma half-life of metformin is approximately six hours. Its small molecular weight (165.8kD) and insignificant binding to plasma proteins increase the distribution volume of the drug (63-276 L).[6] Its sequestration in blood cells, such as erythrocytes and platelets, can extend its elimination half-life up to 17 hours.[7, 8]\n\nThe major mechanism in the excretion of metformin is tubular secretion, and metformin is largely excreted unchanged in the urine. Its estimated renal clearance is 507±129 ml/min which is more than three times its creatinine clearance. However, in cases, such as the presence of underlying chronic renal failure and/or high doses of metformin used for suicidal intent, renal clearance is exceeded and drug excretion decreases. As a result of this situation, lactic acidosis with high anion gap occurs.[9, 10]\n\nLactic acidosis seen in human beings is divided into two forms as type A and type B. Type A lactic acidosis arises from the cells’ orientation to non-oxidative breathing for energy production as a result of poor perfusion of tissues. Type B, on the other hand, occurs with an external agent that may cause intoxication in tissues without initial perfusion defect or with a decrease in lactate clearance.[10, 11]\n\nMetformin intoxication may present with nonspecific symptoms, such as nausea, vomiting, abdominal pain, hypoglycemia, hypothermia, tachypnea, tachycardia/bradycardia, hypotension/hypertension, agitation, somnolence, stupor and coma. Therefore, anamnesis is important to make differential diagnosis.[12, 13]\n\nThe classical triad of metformin toxicity can be listed as acute renal failure, high plasma metformin concentration and severe lactic acidosis.[7] Concerning its mechanism of action, metformin inhibits the complex necessary for hepatic gluconeogenesis and oxidative respiration in mitochondria and directs cells, primarily hepatocytes and intestinal cells, to anaerobic respiration (Fig. 1).\n\nFigure 1 Metformin’s mechanism of action.\n\nAMPK: AMP –activated protein kinase; ACC: Acetyl -CoA carboxylase; SREBP-1. Sterol regulatory element –binding protein -1; GV-LDL, Group V LDL.\n\nAs a result, lactate accumulates in the body. Lactate formed may lead to high anion-gaped metabolic asidois even in patients with normal renal function.[7] Severe metabolic acidosis may disrupt the neurological condition and endanger the patient’s airway. In addition, since metabolic acidosis may cause cardiovascular instability at a high rate, patients are usually followed up in controlled mechanical ventilation.\n\nGiven that metformin preparations are cheap and sold without a prescription makes access to the drug quite easily. In addition, metformin has become a drug that can be easily accessed by the young population due to its use in the treatment of obesity in type 2 diabetes mellitus and nondiabetic patients. This easily available drug can be used for suicidal purposes like many other drugs that are easily available.\n\nIn this case, we aimed to draw attention to acute metformin intoxication treatment protocols in people without additional disease history by sharing the intensive care follow-up process of a patient who received a total of 100 g (1530mg/kg) of metformin to commit suicide and brought to our hospital emergency room.\n\nCase Report\nA 25-year-old female patient without additional disease history was brought to the emergency room of our hospital with complaints of nausea, vomiting, abdominal pain and confusion. It was learned from her family that the patient who had received 100 tablets of 1000 mg metformin was sent to hemodialysis unit by the emergency clinic after being consulted with nephrology upon the presence of severe lactic acidosis in the arterial blood gas, urea-creatinine elevation and hyperkalemia in blood biochemistry. The consultation was requested by our clinic in the emergency room for the patient whose inotropic support was initiated due to closure of consciousness and hypotension after hemodialysis. The general health condition of the patient was poor. Besides, loss of conscious IR -/-, fixed and dilated pupillas accompanied by GKS: E1 M1 V1 and hypotension (68/42 mmHg) were detected despite inotropic treatment. Then, the patient was taken to the intensive care unit after orotracheal intubation.\n\nThe patient was started to undergo invasive mechanical ventilation, and after the development of hypoglycemia (44 mg dL-1), 10% dextrose IV was administered. In addition, despite the infusion of dopamine, her mean arterial pressure was <60 mmHg, so noradrenaline infusion together with continuous treatment with veno-venous hemodiafiltration (CVVHDF) was initiated (Table 1). The patient who was hypothermic (33.2 oC) was heated with a blow heater. Despite CVVHDF treatment, her blood pH remained at <7.15. Then, sodium bicarbonate infusion was initiated. When her pH was >7.15, sodium bicarbonate infusion was stopped. The patient regained consciousness on the 4th day of her intensive care stay. However, as a result of spontaneous ventilation attempts, sufficient ventilation capacity could not be seen, and mechanical ventilation was continued under the infusion of dexmedetomidine. In the intensive care follow-up, liver function parameters (AST, ALT) increased (Table 2) and platelet counts decreased, therefore consultations from departments of internal medicine and gastroenterology were requested.\n\nTable 1 Parameters of the blood gas and infection\n\n\tEmergency service\tICU 1.hr\tICU 24. hr\tICU 2. day\tICU 4. day\tICU 10. day\tICU 17. day\tICU 23. day\t\npH\t7.03\t7.11\t6.90\t7.26\t7.30\t7.37\t7.40\t7.42\t\npCO2\t30.4\t32.5\t56.7\t36.3\t38.5\t49.5\t41.4\t35.3\t\npO2\t93.6\t204\t79\t114\t90.4\t96.5\t151\t109\t\nHCO3\t7.8\t10\t10.6\t15.9\t26.9\t28\t25.5\t28.4\t\nBE\t-20.7\t-17.6\t-19.7\t-9.8\t1.2\t3.1\t1.3\t5.2\t\nsO2, %\t91.9\t98.9\t90\t97.9\t95.6\t96.9\t99.4\t99.7\t\nLac\t19\t17\t22\t8\t6.2\t1.2\t1\t1.1\t\nPCT\t0.20\t0.35\t0.50\t4.1\t4.0\t1.2\t0.75\t0.39\t\nCRP\t0.5\t0.3\t1.3\t7.9\t168.1\t134\t27.2\t21.1\t\nHb\t11.8\t8.1\t9.6\t10.6\t8.5\t10.5\t8.3\t7.5\t\nHct\t36.7\t25.9\t30.7\t32.6\t24\t29.5\t23.9\t22.1\t\nWBC\t10.94\t27\t31.52\t33.71\t31.98\t27.69\t10.54\t8.46\t\nNeu, %\t51.4\t80.5\t90.8\t88.1\t96.8\t87.4\t79.3\t75\t\nPlt\t272\t195\t124\t41\t18\t48\t140\t225\t\nPCT: procalcitonin; Lac: lactate.\n\nTable 2 Biochemical tests and blood parameters\n\n\tEmergency service\tICU 1.hr\tICU 24. hr\tICU 2. day\tICU 4. day\tICU 10. day\tICU 17. day\tICU 23. day\t\nUrea\t15.83\t10.65\t11.36\t31\t42\t122.09\t90\t107.62\t\nCre\t2\t1.63\t1.34\t1.33\t1.15\t1.79\t2.93\t3.79\t\neGFR\t34\t47\t57\t58\t67\t43\t26\t20\t\nAST\t21\t59\t106\t308\t501\t64\t20\t27\t\nALT\t13\t37\t74\t148\t223\t85\t11\t11\t\nT. Bil\t0.80\t0.96\t1.02\t1.42\t1.83\t3.26\t1.16\t0.89\t\nD.Bil\t0.16\t0.74\t0.72\t0.75\t0.80\t1.05\t0.41\t0.26\t\nAlbumin\t3.75\t3.02\t2.61\t3.41\t3.31\t2.74\t2.80\t2.94\t\nPT\t32.2\t22.2\t23.6\t14.4\t12.9\t13.3\t12.7\t13.3\t\naPTT\t178\t38.7\t59.5\t33.8\t31.5\t32.4\t28.9\t30.1\t\nINR\t2.9\t1.95\t2.01\t1.22\t1.08\t1.12\t1.05\t1.14\t\nGlucose\t49\t241\t139\t147\t158\t89\t115\t108\t\nNa+\t140\t139\t154\t146\t132\t140\t138\t139\t\nK+\t4.29\t3.21\t2.88\t4.35\t4.14\t2.86\t3.64\t3.75\t\nCa+2\t9.70\t7.10\t7.80\t8.60\t8.40\t7.10\t9.30\t8.50\t\nCl-\t105\t92\t97\t95\t101\t101\t102\t100\t\nCK-MB\t18.20\t14.30\t\t\t\t\t\t\t\nTrop I\t0.010\t0.020\t\t\t\t\t\t\t\nβ-hCG\t0.48\t0.44\t\t\t\t\t\t\t\nTrop: Troponin; T, bil: Total bilirubin; D.bil: Direct bilirubin.\n\nPseudotrombocytopenia was excluded based on the results of the peripheral smear test performed by the department of internal medicine, and thrombocytopenia was associated with metformin overdose and no recommendation was made except for replacement with pooled platelet suspension. Gastroenterology suggested avoidance of hepatotoxic drug use.\n\nNasal discharge, sputum, and urine samples of the patient whose infection parameters (CRP, procalcitonin) tended to increase were sent for antibiotic susceptibility tests and broad-spectrum antibiotherapy (meropenem, teicoplanin) was initiated by the department of infectious diseases. Contact isolation was applied, and colistimethate sodium was added to antibiotherapy in accordance with culture antibiogram sensitivity.\n\nCVVHDF was terminated in the patient who had spontaneous urine output on the 17th day of the intensive care stay was started on intermittent diuretic therapy (furosemide).\n\nIn addition, the patient whose pneumonia improved and had adequate spontaneous breathing was intubated and noninvasive mechanical ventilation was performed intermittently according to arterial blood gas results.\n\nNephrology consultation was requested for the patient (Table 2) who did not have sufficient urine output and had high urea and creatinine value despite diuretic treatment. Then, the patient was included in the hemodialysis program by nephrology. On the 23rd day of the intensive care stay, the patient was in good general condition, conscious, cooperative, orientated, hemodynamically stable, so noninvasive mechanical ventilation was not required. However, her urea-creatinine level remained at high levels, so she was transferred to the nephrology service for the maintenance of her treatment.\n\nDiscussion\nMetformin, which is a frequently used agent in the treatment of type 2 diabetes mellitus, may rarely cause lactic acidosis.[3] Lactic acidosis occurs due to the development of chronic kidney failure or acute kidney failure in people using normal doses of metformin. In addition, severe lactic acidosis, which may be life-threatening, can be observed in cases of acute intake of high doses of the drug for suicidal intent.\n\nMetformin toxicity causes atypical symptoms and signs. As we encountered in our case, most of the patients apply to the emergency department with gastrointestinal symptoms (nausea-vomiting, diarrhea, epigastric pain), hypotension/hypertension, bradycardia/tachycardia, hypoglycemia, hypothermia, tachypnea, neurological changes (convulsion, somnolence, stupor, coma). Therefore, a detailed anamnesis constitutes a special place in terms of differential diagnosis.[12, 13]\n\nThe resulting metabolic acidosis affects the cardiovascular system negatively by depressing the calcium channels that open slowly. As a result of cardiovascular system depression, decreased systemic vascular resistance, severe arrhythmias (with the effects of hyperkalemia), profound hypotension and cardiac arrest can be seen. These cardiac effects may cause organ hypoperfusion, leading to multi-organ failure, especially renal failure.\n\nWe also encountered multi-organ failure, particularly renal failure in our patient. Arıkan et al.[14] stated that they applied sodium bicarbonate and diuretic therapy to MALA patients with the normal state of consciousness, hemodynamically stable, good renal functions, and pH >7.20, and achieved successful results. However, the treatment for the cause of metabolic acidosis was incomplete.\n\nIndeed, the decrease in plasma bicarbonate value is the body’s response to metabolic acidosis; in other words, bicarbonate deficiency is a result of a decrease in arterial blood gas values. In addition, sodium bicarbonate applied without eliminating metformin and lactate from plasma may cause excessive sodium burden and vasodilation. In addition, the pH value that shifts towards alkaline level after application of sodium bicarbonate increases the displacement of the hemoglobin-oxygen dissociation curve to the left and increases the oxygen affinity of hemoglobin and causes development of hypoxia at the tissue level. As a result, intracellular acidosis increases paradoxically. Therefore, when pH >7.15 was seen in this case, bicarbonate infusion was stopped and treatment was continued with CVVHDF until hemodynamic stability was achieved. In addition, the frequency of coagulopathy has increased in patients with MALA.[15] Akıncı et al.[15] explained the situation of developing coagulopathy with a decreased synthesis of coagulation factors produced in the liver. Indeed, in our case, the coagulation parameters measured at the beginning were above the normal values (Table 2). Hemodialysis or continuous renal replacement treatments (e.g., CVVHDF) are preferred to eliminate drug overdose, normalize serum potassium level and eliminate lactate, which is the cause of metabolic acidosis.[16, 17] Renal replacement therapies are generally preferred primarily because they provide better stability in hemodynamic parameters. Relative hemodynamic stability is a positive condition for the patient, although it takes a longer time for toxin and lactate elimination in continuous renal replacement therapies. However, any significant difference was not seen between both methods in terms of their effects on mortality.[5] Long-term and/or intermittent renal replacement therapies may be required, as in our case, because of the large distribution volume of metformin and its accumulation in blood cells in MALA.[18–21] In our patient, CVVHDF was applied for a total of 12 days all along with her hospital stay. Informed consent was obtained from our patient for this case presentation.\n\nConclusion\nIn conclusion, hemodialysis or continuous renal replacement therapies should be considered firstly in patients diagnosed with MALA caused by metformin, which can also be used without requiring a prescription for slimming purposes. Renal replacement therapies, which are started quickly and maintained for a sufficient period, continue to give hope even in this condition with high mortality rates.\n\nDisclosures\nInformed consent: Written informed consent was obtained from the patient for the publication of the case report and the accompanying images.\n\nPeer-review: Externally peer-reviewed.\n\nConflict of Interest: None declared.\n\nAuthorship Contributions: Concept – O.F.K.; Design – H.Z.V.; Supervision – U.A.T.; Materials – S.S.; Data collection &/or processing – O.F.K.; Analysis and/or interpretation – H.Z.V.; Literature search – O.F.K.; Writing – H.Z.V.; Critical review – U.A.T.\n==== Refs\n1 Pilmore HL Review:metformin:potential benefits and use in chronic kidney disease Nephrology (Carlton) 2010 15 412 8 20609092 \n2 Lalau JD Lacroix C Compagnon P de Cagny B Rigaud JP Bleichner G Role of metformin accumulation in metformin-associated lactic acidosis Diabetes Care 1995 18 779 84 7555503 \n3 Salpeter SR Greyber E Pasternak GA Salpeter EE Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus Cochrane Database Syst Rev 2010 CD002967 \n4 Biradar V Moran JL Peake SL Peter JV Metformin-associated lactic acidosis (MALA):clinical profile and outcomes in patients admitted to the intensive care unit Crit Care Resusc 2010 12 191 5 21261578 \n5 Nguyen HL Concepcion L Metformin intoxication requiring dialysis Hemodial Int 2011 15 Suppl 1 S68 S71 22093605 \n6 Acquistapace G Rossi M Garbi M Cosci P Canetta C Manelli A Ricevuti G Acute metformin intoxication:2012 experience of Emergency Departement of Lodi, Italy Clin Chem Lab Med 2014 52 1489 97 24940713 \n7 Protti A Lecchi A Fortunato F Artoni A Greppi N Vecchio S Fagiolari G Moggio M Comi GP Mistraletti G Lanticina B Faraldi L Gattinoni L Metforminoverdosecausesplateletmitochondrialdysfunction in humans Critical Care 2012 16 R180 23034133 \n8 Piel S Ehinger JK Elmér E Hansson MJ Metformin induces lactate production in peripheral blood mononuclear cells and platelets through specific mitochondrial complex I inhibition Acta Physiol (Oxf) 2015 213 171 80 24801139 \n9 Scheen AJ Clinical pharmacokinetics of metformin Clin Pharmacokinet 1996 30 359 71 8743335 \n10 Bailey CJ Turner RC Metformin N Engl J Med 1996 334 574 9 8569826 \n11 Lalau JD Mourlhon C Bergeret A Lacroix C Consequences of metformin intoxication Diabetes Care 1998 21 2036 7 9802770 \n12 Friesecke S Abel P Roser M Felix SB Runge S Outcome of severe lactic acidosis associated with metformin accumulation Crit Care 2010 14 R226 21171991 \n13 Soyoral YU Begenik H Emre H Aytemiz E Ozturk M Erkoc R Dialysis therapy for lactic acidosis caused by metformin intoxication:presentation of two cases Hum Exp Toxicol 2011 30 1995 7 21441284 \n14 Arıkan Ş Tuzcu A Bahçeci M Kaplan MA Gökalp D Massive Metformin Overdose in Two Subjects with Suicidal Behavior:Brief Communication Turkiye Klinikleri J Med Sci 2012 32 559 62 \n15 Akinci B Yener S Bengi G Yesil S Alterations of coagulation in metformin intoxication Hormones (Athens) 2008 7 325 9 19121994 \n16 Teale KF Devine A Stewart H Harper NJ The management of metformin overdose Anaesthesia 1998 53 698 701 9771180 \n17 Lalau JD Andrejak M Morinière P Coevoet B Debussche X Westeel PF Hemodialysis in the treatment of lactic acidosis in diabetics treated by metformin:a study of metformin elimination Int J Clin Pharmacol Ther Toxicol 1989 27 285 8 2500402 \n18 Regolisti G Antoniotti R Fani F Greco P Fiaccadori E Treatment of Metformin Intoxication Complicated by Lactic Acidosis and Acute Kidney Injury:The Role of Prolonged Intermittent Hemodialysis Am J Kidney Dis 2017 70 290 6 28223003 \n19 Turkcuer I Erdur B Sari I Yuksel A Tura P Yuksel S Severe metformin intoxication treated with prolonged haemodialyses and plasma exchange Eur J Emerg Med 2009 16 11 3 18931616 \n20 Rifkin SI McFarren C Juvvadi R Weinstein SS Prolonged hemodialysis for severe metformin intoxication Ren Fail 2011 33 459 61 21529276 \n21 Lacher M Hermanns-Clausen M Haeffner K Brandis M Pohl M Severe metformin intoxication with lactic acidosis in an adolescent Eur J Pediatr 2005 164 362 5 15729560\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1302-7123", "issue": "54(2)", "journal": "Sisli Etfal Hastanesi tip bulteni", "keywords": "Hemodialysis; lactic acidosis; metformin intoxication", "medline_ta": "Sisli Etfal Hastan Tip Bul", "mesh_terms": null, "nlm_unique_id": "9424130", "other_id": null, "pages": "252-256", "pmc": null, "pmid": "32617068", "pubdate": "2020", "publication_types": "D002363:Case Reports", "references": "28223003;21261578;2500402;19121994;22093605;21171991;21441284;8743335;20091535;23034133;9802770;18931616;8569826;24940713;7555503;21529276;20609092;24801139;15729560;9771180", "title": "Metformin-Associated Lactic Acidosis Developed as a Result of a Suicidal Attempt.", "title_normalized": "metformin associated lactic acidosis developed as a result of a suicidal attempt" }	[ { "companynumb": "TR-INDICUS PHARMA-000699", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, "drugadditional": ...
{ "abstract": "Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.", "affiliations": "Department of Clinical Pharmacology and Pharmacovigilance, University Hospital of Nancy Brabois, Biologie Médicale & Biopathologie, Rue du Morvan, 54511, Vandoeuvre Lès Nancy, France.;Department of Clinical Pharmacology and Pharmacovigilance, University Hospital of Nancy Brabois, Biologie Médicale & Biopathologie, Rue du Morvan, 54511, Vandoeuvre Lès Nancy, France.;Department of Clinical Pharmacology and Pharmacovigilance, University Hospital of Marseille, 270 Boulevard Sainte Marguerite, 13009, Marseille, France.;Department of Pharmacology, University Hospital of Caen, Avenue de la Côte de Nacre, 14000, Caen, France.;Department of Pharmacovigilance, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Henri Mondor Hospital, 94010, Créteil, France.;Department of Clinical Pharmacology and Pharmacovigilance, University Hospital of Nancy Brabois, Biologie Médicale & Biopathologie, Rue du Morvan, 54511, Vandoeuvre Lès Nancy, France.;Department of Endocrinology and Medical Gynecology, University Hospital of Nancy, rue du Morvan, 54500, Vandœuvre-lès-Nancy, France.;Department of Endocrinology and Medical Gynecology, University Hospital of Nancy, rue du Morvan, 54500, Vandœuvre-lès-Nancy, France.;Department of Clinical Pharmacology and Pharmacovigilance, University Hospital of Nancy Brabois, Biologie Médicale & Biopathologie, Rue du Morvan, 54511, Vandoeuvre Lès Nancy, France. pierre.gillet@univ-lorraine.fr.", "authors": "Garon-Czmil\|Julie\|J\|;Petitpain\|Nadine\|N\|;Rouby\|Franck\|F\|;Sassier\|Marion\|M\|;Babai\|Samy\|S\|;Yéléhé-Okouma\|Mélissa\|M\|;Weryha\|Georges\|G\|;Klein\|Marc\|M\|;Gillet\|Pierre\|P\|http://orcid.org/0000-0002-0598-7508", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1038/s41598-019-56026-5", "fulltext": "\n==== Front\nSci RepSci RepScientific Reports2045-2322Nature Publishing Group UK London 5602610.1038/s41598-019-56026-5ArticleImmune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database Garon-Czmil Julie 123Petitpain Nadine 1Rouby Franck 4Sassier Marion 5Babai Samy 6Yéléhé-Okouma Mélissa 1Weryha Georges 2Klein Marc 2http://orcid.org/0000-0002-0598-7508Gillet Pierre pierre.gillet@univ-lorraine.fr 131 0000 0004 1765 1301grid.410527.5Department of Clinical Pharmacology and Pharmacovigilance, University Hospital of Nancy Brabois, Biologie Médicale & Biopathologie, Rue du Morvan, 54511 Vandoeuvre Lès Nancy, France 2 0000 0004 1765 1301grid.410527.5Department of Endocrinology and Medical Gynecology, University Hospital of Nancy, rue du Morvan, 54500 Vandœuvre-lès-Nancy, France 3 0000 0004 1758 9034grid.463896.6UMR 7365 CNRS-Université de Lorraine, IMoPA, Campus Brabois Santé, 9 Avenue de la forêt de Haye, BP 20199, 54505 Vandœuvre-lès-Nancy, France 4 0000 0001 0407 1584grid.414336.7Department of Clinical Pharmacology and Pharmacovigilance, University Hospital of Marseille, 270 Boulevard Sainte Marguerite, 13009 Marseille, France 5 0000 0004 0472 0160grid.411149.8Department of Pharmacology, University Hospital of Caen, Avenue de la Côte de Nacre, 14000 Caen, France 6 0000 0001 2292 1474grid.412116.1Department of Pharmacovigilance, Hôpital Henri Mondor, Assistance Publique Hôpitaux de Paris, Henri Mondor Hospital, 94010 Créteil, France 19 12 2019 19 12 2019 2019 9 1941917 7 2019 30 11 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/.Immune control point (ICI) inhibitors represent a significant advance in the management and survival of cancers such as melanoma or non-small cell bronchial carcinoma. However, they induce unusual side effects, such as hypophysitis, which are rarely described elsewhere. This nationwide retrospective study describes the characteristics of hypophysitis reported in the French pharmacovigilance database (FPVD). We requested for all cases of ICI-related hypophysitis registered in the FPVD before May 2018. An endocrinologist and a pharmacologist reviewed all cases. About 94 pituitary cases were selected, involving 49 females and 45 men. Ipilimumab alone or in combination was the most represented ICI (56%). Most cases (61%) were grade 3 severity and the majority (90%) were corticotropic deficiency cases. Cases with thyroid and/or gonadotropic involvement were 21% and 1% respectively. Five patients (8%) had panhypopituitarism. Pituitary MRI, when performed, was in favor of hypophysitis in 50%. No patient recovered his previous hormonal function. The mean time of onset was significantly shorter with ipilimumab than other ICIs. ICI-related hypophysitis generate deficits that do not spontaneously recover, even at a distance from the event, unlike thyroiditis. Patients must then benefit from long-term coordinated onco-endocrinological management, adapted to their own specific deficits.\n\nSubject terms\nCancer immunotherapyMultihormonal system disordersGW consulted for Novartis and Theramex and received punctual compensations.issue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\nRecently, immune checkpoint inhibitors (ICIs) have become the preferred treatment for many advanced solid tumours such as melanoma, non-small-cell lung cancer (NSCLC), and clear cell renal cancer1. Ipilimumab was the first authorized ICI, acting via cytotoxic T-lymphocyte antigen-4 (CTLA-4) blockade, followed by nivolumab and pembrolizumab, which both target the programmed death 1 receptor (PD-1), an effector ligand of the immune checkpoint pathway. More recently two other ICIs, atezolizumab and avelumab, which both target the PD1 ligand (PD-L1) have also been authorized for treating such diseases.\n\nThe mechanism of action of ICIs is to utilize the patient’s own immune system to destroy tumour cells or inhibit tumour growth, by restoring the decreased cellular immunity as well as boosting the production and proliferation of T lymphocytes. This ingenious mechanism of action has been shown to be efficient in terms of survival and disease-free survival but is jeopardized by the development of numerous and various immune related adverse effects (IRAEs), including endocrinological disorders as well as dermatological, digestive, cardiac, pulmonary, muscular, and haematological disorders, with all organs being potentially affected. Among the endocrinological damages, thyroiditis and hypophysitis seem to be the most common2–7. Unlike thyroiditis, hypophysitis does not commonly affect people and has dramatically emerged since the launch of ICI therapies8–12.\n\nIn order to achieve real-life data about the characteristics, diagnosis and management of this adverse effect related to the use of the most commonly used ICIs (ipilimumab, nivolumab and pembrolizumab), we performed a retrospective and descriptive analysis of cases of hypophysitis reported inadverse dru reaction the French network of regional pharmacovigilance centres since the marketing of these drugs.\n\nMaterials and Methods\nData collection\nThe data source used was the French Pharmacovigilance Database (FPVD)13. Briefly, the French Pharmacovigilance database was created in 1973 and, since 1985, all spontaneous reports of ADR have been recorded in the FPVD. According to French law, every health professional must report “serious” and/or “unexpected” adverse drug reactions to their regional centres of pharmacovigilance (31 in France). For each ADR report, information about the patient (age, sex, medical history), drug exposure (to the suspected drug and other associated non-suspected drugs) and ADR characteristics (“serious” or “non-serious”, “expected” or “unexpected”, causality score, outcomes) are recorded in the FPVD.\n\nThe FPVD was searched in April 2018 for all cases of endocrinological disorders (MedDRA system organ class (SOC) « endocrine disorders ») and hormonal biological abnormalities (within MedDRA SOC « investigations ») involving ipilimumab, nivolumab and/or pembrolizumab. No cases involving atezolizumab or avelumab were recorded. All anonymized recorded cases in the FPVD (General Data Protection Regulation Law) were reviewed by an endocrinologist and a pharmacologist to select confirmed hypophysitis cases and discard those with any aetiology other than iatrogenic. The French Pharmacovigilance Database was approved by the French Data Protection Agency (CNIL). No additional approval was required for studies based on this database, because all records respect the patient’s and notifier’s anonymity. We also attest that all our data originated from this database. Thus, this observational study did not require patient consent or ethics committee approval. Additionally, we certify that this study was approved by the French network of Regional Pharmacovigilance Centres.\n\nCase selection\nHypophysitis patients had to display (i) clinical symptoms such as cephalalgia associated with blurred vision, nausea or vomiting or clinical signs of anterior pituitary failure; and/or (ii) biological results consistent with a trophic hormone deficiency: prolactin (PRL), growth hormone (GH), adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone (LH) and/or follicle-stimulating hormone (FSH) in females, and testosterone in males; and/or (iii) abnormal MRI consistent with hypophysitis. Suspected cases of peripheral adrenal insufficiency without fludrocortisone supplementation were considered as adrenocorticotropic insufficiency secondary to hypophysitis6.\n\nVariables\nWe collected the characteristics of the patients (sex, age, previous immune disorder), suspected treatment (drug(s), dose, number of injections), hypophysitis (clinical symptoms, biological abnormalities, imaging, time to onset after start of ICI, outcomes), and patient’s medication (type of hormonal supplementation, weaning). The severity of hypophysitis was graded according to the CTCAE-NCI v4.0 (grade 1: asymptomatic patients, no treatment required; grade 2: symptoms not requiring hospitalization; grade 3: functional impairment limiting activities of daily living and requiring hospitalization; grade 4: life-threatening symptoms; and grade 5: death).\n\nStatistical analysis\nThe mean, standard deviation and median with minimal and maximal values were used to express quantitative variables, while qualitative variables were expressed with numbers and rates. The comparison of the averages was based on the ANOVA test together with Student’s t test when relevant. SAS software version 9·3 (SAS Institute, Cary, NY) was used to draw the analysis.\n\nResults\nAmong the 249 cases corresponding to an endocrinological disorder associated with ipilimumab, nivolumab or pembrolizumab, 94 corresponded to hypophysitis (Table 1). Among these latter cases, ipilimumab was the most-involved ICI, either alone (43%) or in combination with nivolumab (14%). Four patients received previous ICI treatment before the diagnosis (6·6%). The patients included 49 females and 45 males, whose mean age was 64·5 years (+/−14·1), and the most frequent indication was melanoma (74·5%). None of these patients displayed a previous immune disorder.Table 1 Treatment characteristics, demographic and clinic-biological data of ICI-related hypophysites recorded in the French Pharmacovigilance Database (FPVD) until May 2018.\n\nPatients\tImmune Check Point Inhibitor(s) (ICI)\t\nipilimumab (ipi)\tnivolumab (nivo)\tPembrolizumab (pembro)\tipilimumab + nivolumab (ipi + nivo)\t\nNumber of cases\t40\t28\t13\t13\t\nWomen n (%)\t21 (52·5)\t12 (49·9)\t7 (53·8)\t9 (69·2)\t\nAge (mean ± SD) (years)\t68·4 (±15·2)\t62·8 (±9·8)\t65·4 (±15·8)\t55·5 (±13·7)\t\nBody Mass Index (mean ± SD) (kg/m2)\t27·1 (±4·9)\t23·7 (±4·42)\t22·3 (±3·9)\t25·37 (±3·94)\t\nPrevious immunotherapy (n)\t2\t1\t1\t0\t\nICI treatment (median [min-max])\t\nNumber of courses\t4[1–7]\t10[1–33]\t7[1–19]\t3[2–4]\t\nDose per course (mg)\t235 [150–330]\t242 [123–354]\t136 [88–190]\tipi 7460–90 + nivo 229 [190–260]\t\nCumulated dose before hypophysitis (mg)\t756 [495–1140]\t1901 [294–8910]\t616 [120–3610]\tipi 255 [146–300] + nivo 770 [438–924]\t\nTime of onset (days)\t79 [14–506]\t155·5 [5–552]\t184 [6–686]\t119 [18–500]\t\nIndication\t\nMelanoma\t40\t7\t13\t11\t\nNon small cell type lung cancer\t0\t17\t0\t1\t\nSmall cell type lung cancer\t0\t1\t0\t0\t\nColorectal cancer\t0\t1\t0\t0\t\nRenal cell carcinoma\t0\t2\t0\t0\t\nPleural mesothelioma\t0\t0\t0\t1\t\nHypophysitis severity/outcome/MRI\t\nGrade 1\t0\t0\t0\t0\t\nGrade 2\t9\t4\t4\t4\t\nGrade 3\t17\t22\t9\t9\t\nGrade 4\t5\t2\t0\t0\t\nGrade 5\t3\t0\t0\t0\t\nRecovered\t1\t0\t1\t0\t\nMRI with pituitary enlargement\t7\t2\t1\t6\t\nManagement\t\nLevothyroxine supplementation\t15\t1\t1\t3\t\nHydrocortisone supplementation\t32\t28\t13\t12\t\nOther supplementation\t1\t0\t0\t0\t\nImmunotherapy continuation\t4\t14\t8\t9\t\nQualitative data are expressed as number and rates, and qualitative ones as mean (±SD) or median with [minimal and maximal values]. Gradation of severity is detailed in the Methods section. MRI: magnetic resonance imaging.\n\nWithout enough evidence to exclude disease progression fatality.\n\n\n\nMost of them (88%) expressed clinical symptoms, mainly fatigue and cephalalgia, justifying biological and morphological explorations and finally leading to the diagnosis of hypophysitis. Hyponatremia and arterial hypotension were exceptionally present. Five patients had pan-hypopituitarism. No patient had insipidus diabetes. Pituitary MRI results were available in 40 patients and only half of them demonstrated a hypophysitis aspect, whereas one patient had a pituitary micro-adenoma, another patient had an empty sella turcica, and the remaining patients had normal pituitary imaging. The only two patients with documented abnormal pituitary MRI recovered after hydrocortisone supplementation.\n\nThe median delay period for hypophysitis to develop, after the start of ICI treatment, was significantly shorter with ipilimumab alone or combined with nivolumab (83 days; min 14 - max 506) than with nivolumab or pembrolizumab alone (165 days; min 5 - max 686; p = 0·0001) (Table 1). The median number of cycles and the median cumulated dose before hypophysitis were not significantly higher for nivolumab than for the other drugs.\n\nNo cases corresponded to grade 1 hypophysitis. Three patients treated with ipilimumab with severe general state deterioration had rapid (24 to 48 hours) fatal outcome after hypophysitis diagnosis, which could eventually be considered as grade 5 hypophysitis, but without enough evidence to exclude disease progression fatality. One patient had concomitant myasthenia and died from respiratory failure. The second patient died from acute liver cytolysis and shock after decompensated adrenocorticotropic failure and the third died from melanoma progression. Nivolumab was also associated with severe (grade 4) hypophysitis in 2 patients of whom one finally died due to lung cancer progression. Patients treated with pembrolizumab had less severe disorders (grade 3 or 2), but one patient had fatal outcomes due to melanoma progression.\n\nHydrocortisone supplementation was provided to 85 patients (90·4%) and L-thyroxin supplementation to 20 patients (21.3%). Only one case of testosterone supplementation was started concomitantly with hydrocortisone for a man with panhypopituitarism, while in the other cases of panhypopituitarism, 3 women received hydrocortisone plus levothyroxine supplementation, and 1 man received hydrocortisone only. No patient was weaned from hormonal supplementation according to the last available information, except one male patient who had received short-term hydrocortisone treatment and thereafter displayed a normal ACTH stimulation test. The only patient who received no supplementation had her ICI treatment discontinued.\n\nDiscussion\nTo the best of our knowledge, this series of 94 patients with ICI-induced hypophysitis is, as of today, the largest reported series. It provides complementary insights into the previously available data3,4,11,14 and case-series8,10,15, and, especially, reinforces clinical trial data16 by including patients with a potential previous ICI exposure or autoimmune history. In fact, no patient in our series had previous immune disease recorded in his or her medical file, which leads us to confirm, similarto the cas in other IRAEs, that the development of hypophysitis is not triggered by a pre-existing immune condition.\n\nHypophysitis was initially considered a specific IRAE of ipilimumab considering the presence of pituitary expression of CTLA-4 antigens17. Our series, with 41 cases (28 related to nivolumab and 13 to pembrolizumab), confirms previous literature reports showing that hypophysitis can also occur while anti PD-114 and anti-PD-L1 are present18. It is, however, interesting to note that we observed a significantly shorter delay of onset with ipilimumab than with anti-PD1. Our results and literature data definitely illustrate that hypophysitis can occur regardless of the ICI target (CTLA4, PD1 or PD-L1) and its indication.\n\nIn accordance with literature stating that thyroid hormone deficiency appears to be less frequently reported than adrenocorticotropic or gonadotropic deficiencies, our series includes a larger proportion of patients requiring hydrocortisone supplementation than thyroidal supplementation. Clinical signs of adrenocorticotropic failure may be less often detected and underestimated for patients with advanced cancer with marked asthenia, nausea and vomiting. We observed that pituitary MRI contributed less to the findings of our cases than in the cases-series reported in the literature. Faje et al.9 reported that 100% of patients had abnormal MRI, but abnormalities were previously observed in 7/18 patients before symptoms occurred.\n\nHormonal supplementation weaning appears difficult to achieve, especially for hydrocortisone19 and this was confirmed in our series. However, we are also aware that weaning success assessments may be lowered by too short of a follow-up in prospective studies or a lack of information in retrospective studies; this phenomenon is one of the limitation of our study, with very few patients benefiting from a sufficient retrospective update.\n\nPanhypopituitarism, although rare, should not be ignored. We observed that supplementation with gonadotropic hormones was rarely performed and we propose that it should be more often considered, especially in non-menopausal women to limit the consequences of oestrogens deficiency, such as osteoporosis. Considering the variable delay of hypophysitis development and the therapeutic regimens with ICI administrations every 2 or 3 weeks, the results of the clinical survey regarding hypophysitis appear to be helpful at any time of treatment, regardless of the ICI type. Delayed signs after treatment cessation can also occur20 and, therefore, hypophysitis should be kept in mind for any patient with present or past ICI exposure(s).\n\nThe main limitation of our work is the very probable underreporting of ICI-induced hypophysitis because these cases are now expected, especially non-severe cases (grades 1 and 2). This limitation persists despite the fact that since 2011, French health professionals have an obligation to report any suspected drug-induced adverse reaction, regardless of its expectedness or seriousness. Another main limitation is related to the retrospective collection of data, generating missing information, and thus potential uncertainties. However, the practitioners’ expertise in regional pharmacovigilance centres and the specific review of all cases by an endocrinologist warrant the accuracy of a diagnosis of hypophysitis and a good assessment of patients’ clinical histories and condition, but it must be acknowledged that, when detailed ACTH levels or stimulation tests to confirm primary versus secondary adrenal insufficiency were not available (10 cases), reliance on imperfect secondary markers was made. Therefore, it is possible that some misclassification occurred.\n\nConclusion\nHypophysitis is definitely not a specific IRAE of ipilimumab treatment for melanoma. It occurs with any type of currently available ICI, anti-CTLA4, anti-PD1 or anti PD-L1, at any time of treatment and regardless of the type of cancer. Adrenocorticotropic deficiency may be more frequent than thyroidal deficiency and hormonal supplementation is required and has been proven to be difficult, if not impossible, to wean. Gonadotropic hormonal supplementation should probably be more often considered. The management of patients clearly requires long-term onco-endocrinological care.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAuthor contributions\nJ.G.C., N.P. and P.G. conceived the study. J.G.C., N.P., F.R., M.S., S.B., M.Y.O. and P.G. did the literature search. J.G.C., N.P. and M.Y.O. analyzed the data. F.R., M.S., S.B., M.Y.O., G.W. and M.K. contributed to study protocol. J.G.C., N.P., G.W., M.K. and P.G. contributed to key data interpretation. JGC, NP, MYO, and PG wrote the manuscript. F.R., M.S., S.B., G.W. and M.K. critically revised the manuscript. All contributors approved the final accepted version of the manuscript.\n\nData availability\nRestrictions apply to the availability of data generated or analyzed during this study because they were used under the authority of the French Drug Agency (ANSM). The corresponding author will on request detail the restrictions and any conditions under which access to some data may be provided.\n\nCompeting interests\nJ.G.C., N.P., F.R., M.S., S.B., M.Y.O., M.K. and P.G. declare no financial competing interests. GW consulted for Novartis and Theramex and received punctual compensations. Nadine PETITPAIN: unpaid membership as expert of the French Drug Agency (ANSM), Unpaid member of the coordination committee of an academic interventional clinical trial (NCT02250729) funded by a consortium of 15 companies marketing pholcodine containing drugs (Bouchara-Recordati, Hepatoum, Biocodex/Leurquin, Pierre Fabre, Sanofi, Urgo, Zambon, Alliance, Bells healthcare, Boots, Ernest Jackson, GSK, Medgenix, Pinewood, Vemedia). Franck ROUBY: unpaid membership as expert of the French Drug Agency (ANSM), unpaid expert (Co-investigator) for clinical Trials (Biogen, Theranexus, Inflectis Bioscience, Roche Genentech, Abbvie, Roche). Marion SASSIER: unpaid membership as expert of the French Drug Agency (ANSM), Samy BABAI: unpaid membership as expert of the French Drug Agency (ANSM), unpaid expert in a multicentric academic study on tranexamic acid. Mélissa YELEHE-OKOUMA: unpaid membership as expert of the French Drug Agency (ANSM), Pierre GILLET: unpaid membership as expert of the French Drug Agency (ANSM), Unpaid member of the coordination committee of an academic interventional clinical trial (NCT02250729) funded by a consortium of 15 companies marketing pholcodine containing drugs (Bouchara-Recordati, Hepatoum, Biocodex/Leurquin, Pierre Fabre, Sanofi, Urgo, Zambon, Alliance, Bells healthcare, Boots, Ernest Jackson, GSK, Medgenix, Pinewood, Vemedia).\n==== Refs\nReferences\n1. Gonzalez-Rodriguez E Rodriguez-Abreu D Spanish Group for Cancer, I.-B.: Immune Checkpoint Inhibitors: Review and Management of Endocrine Adverse Events Oncologist 2016 21 7 804 816 10.1634/theoncologist.2015-0509 27306911 \n2. Iglesias P Cancer immunotherapy-induced endocrinopathies: Clinical behavior and therapeutic approach Eur J Intern Med 2018 47 6 13 10.1016/j.ejim.2017.08.019 28826822 \n3. Barroso-Sousa R Endocrine dysfunction induced by immune checkpoint inhibitors: Practical recommendations for diagnosis and clinical management Cancer 2018 124 6 1111 1121 10.1002/cncr.31200 29313945 \n4. Joshi MN Whitelaw BC Palomar MT Wu Y Carroll PV Immune checkpoint inhibitor-related hypophysitis and endocrine dysfunction: clinical review Clin Endocrinol (Oxf) 2016 85 3 331 339 10.1111/cen.13063 26998595 \n5. Michot JM Immune-related adverse events with immune checkpoint blockade: a comprehensive review Eur J Cancer 2016 54 139 148 10.1016/j.ejca.2015.11.016 26765102 \n6. Barroso-Sousa R Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA Oncol 2018 4 2 173 182 10.1001/jamaoncol.2017.3064 \n7. Illouz F Endocrine toxicity of immune checkpoint inhibitors: essential crosstalk between endocrinologists and oncologists Cancer Med 2017 6 8 1923 1929 10.1002/cam4.1145 28719055 \n8. Lammert A Hypophysitis caused by ipilimumab in cancer patients: hormone replacement or immunosuppressive therapy Exp Clin Endocrinol Diabetes 2013 121 10 581 587 10.1055/s-0033-1355337 24122241 \n9. Faje A Hypophysitis: Evaluation and Management Clin Diabetes Endocrinol 2016 2 15 10.1186/s40842-016-0034-8 28702249 \n10. Carpenter KJ Murtagh RD Lilienfeld H Weber J Murtagh FR Ipilimumab-induced hypophysitis: MR imaging findings AJNR Am J Neuroradiol 2009 30 9 1751 1753 10.3174/ajnr.A1623 19474123 \n11. Brilli L Prevalence of hypophysitis in a cohort of patients with metastatic melanoma and prostate cancer treated with ipilimumab Endocrine 2017 58 3 535 541 10.1007/s12020-017-1289-2 28401443 \n12. Bellastella G Revisitation of autoimmune hypophysitis: knowledge and uncertainties on pathophysiological and clinical aspects Pituitary 2016 19 6 625 642 10.1007/s11102-016-0736-z 27503372 \n13. Vial T French pharmacovigilance: Missions, organization and perspectives Therapie 2016 71 2 143 150 10.1016/j.therap.2016.02.029 27080832 \n14. Baxi S Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis BMJ 2018 360 k793 10.1136/bmj.k793 29540345 \n15. Lupu J Transient pituitary ACTH-dependent Cushing syndrome caused by an immune checkpoint inhibitor combination Melanoma Res 2017 27 6 649 652 10.1097/CMR.0000000000000405 29036015 \n16. Torino F Corsello SM Salvatori R Endocrinological side-effects of immune checkpoint inhibitors Curr Opin Oncol 2016 28 4 278 287 10.1097/CCO.0000000000000293 27136136 \n17. Iwama S Pituitary expression of CTLA-4 mediates hypophysitis secondary to administration of CTLA-4 blocking antibody Sci Transl Med 2014 6 230 230ra245 10.1126/scitranslmed.3008002 \n18. Kanie K Two Cases of Atezolizumab-Induced Hypophysitis J Endocr Soc 2018 2 1 91 95 10.1210/js.2017-00414 29362727 \n19. Park SM Clinical characteristics, management, and outcome of 22 cases of primary hypophysitis Endocrinol Metab (Seoul) 2014 29 4 470 478 10.3803/EnM.2014.29.4.470 25325267 \n20. Joshi MN Whitelaw BC Carroll PV Mechanisms in Endocrinology: Hypophysitis: diagnosis and treatment Eur J Endocrinol 2018 179 3 R151 R163 10.1530/EJE-17-0009 29880706\n\n", "fulltext_license": "CC BY", "issn_linking": "2045-2322", "issue": "9(1)", "journal": "Scientific reports", "keywords": null, "medline_ta": "Sci Rep", "mesh_terms": "D000368:Aged; D016208:Databases, Factual; D005260:Female; D005602:France; D006801:Humans; D000072659:Hypophysitis; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D060735:Pharmacovigilance; D012189:Retrospective Studies", "nlm_unique_id": "101563288", "other_id": null, "pages": "19419", "pmc": null, "pmid": "31857638", "pubdate": "2019-12-19", "publication_types": "D016428:Journal Article", "references": "28973656;29540345;26765102;28401443;29880706;28702249;24695685;27136136;26998595;28719055;27080832;27306911;25325267;19474123;24122241;28826822;27503372;29036015;29362727;29313945", "title": "Immune check point inhibitors-induced hypophysitis: a retrospective analysis of the French Pharmacovigilance database.", "title_normalized": "immune check point inhibitors induced hypophysitis a retrospective analysis of the french pharmacovigilance database" }	[ { "companynumb": "FR-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-096675", "fulfillexpeditecriteria": "1", "occurcountry": "FR", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "NIVOLUMAB" }, "drugaddi...
{ "abstract": "The treatment of intractable vasogenic brain edema (VBE) caused by tumor and irradiation is challenging. Traditional intervention strategy includes dehydration and glucocorticoids accompanied by obvious side effects and minor effects after long-term use. Novel treatment needs to be found urgently. Recently, vascular endothelial growth factor (VEGF)/VEGFR pathway has been revealed to be essential in VBE. Therefore, tyrosine kinase inhibitor (TKI) targeting VEGFR which blocks (VEGF)/VEGFR signal might be effective. However, such reports have seldom been described. Herein, we documented a heavily-treated breast cancer patient experienced progressive aphasia, limb activity disorder and intermittent convulsion 10 months after radiotherapy of brain metastasis (BM). Cranial MRI demonstrated large peritumoral brain edema (PTBE). High dose of steriods and dehydration had no improvement. Apatinib with a dose of 250mg daily was initiated and all her discomforts disappeared after 10 days of use. The brain MRI of taking apatinib 5 weeks demonstrated remarkable shrinkage of edema. Our case indicates that apatinib, a potent small-molecular TKI targeted VEGFR2 is promising for intractable VBE for satisfactory efficacy and safety. This case is of great value in its rarity and because it provides new insight into PTBE management in clinical practice.", "affiliations": "a Department of Medical Oncology, Cancer Center, The First Hospital , Jilin University , Changchun , China.;b Department of Radiation Oncology, The First Hospital , Jilin University , Changchun , China.;a Department of Medical Oncology, Cancer Center, The First Hospital , Jilin University , Changchun , China.;b Department of Radiation Oncology, The First Hospital , Jilin University , Changchun , China.", "authors": "Song\|Yanqiu\|Y\|;Liu\|Bailong\|B\|;Guan\|Meng\|M\|;Liu\|Min\|M\|", "chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C553458:apatinib", "country": "United States", "delete": false, "doi": "10.1080/15384047.2018.1491502", "fulltext": "\n==== Front\nCancer Biol TherCancer Biol. TherKCBTkcbt20Cancer Biology & Therapy1538-40471555-8576Taylor & Francis 30081717149150210.1080/15384047.2018.1491502Bedside to Bench ReportSuccessful treatment using apatinib in intractable brain edema: A case report and literatures review Y. SONG ET AL.CANCER BIOLOGY & THERAPYSong Yanqiu MD, PhDaLiu Bailong MD, PhDbGuan Meng Master of MedicineaLiu Min ba Department of Medical Oncology, Cancer Center, The First Hospital, Jilin University, Changchun, Chinab Department of Radiation Oncology, The First Hospital, Jilin University, Changchun, ChinaCONTACT Min Liu, MD, PhD lmin99@jlu.edu.cnDepartment of Radiation Oncology, The First Hospital, Jilin University, 71 Xinmin Street, Changchun, 130021, ChinaColor versions of one or more of the figures in the article can be found online at www.tandfonline.com/kcbt.\n\n2018 6 8 2018 6 8 2018 19 12 1093 1096 29 3 2018 1 6 2018 17 6 2018 © 2018 The Author(s). Published by Taylor & Francis.2018The Author(s)This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited, and is not altered, transformed, or built upon in any way.ABSTRACT\nThe treatment of intractable vasogenic brain edema (VBE) caused by tumor and irradiation is challenging. Traditional intervention strategy includes dehydration and glucocorticoids accompanied by obvious side effects and minor effects after long-term use. Novel treatment needs to be found urgently. Recently, vascular endothelial growth factor (VEGF)/VEGFR pathway has been revealed to be essential in VBE. Therefore, tyrosine kinase inhibitor (TKI) targeting VEGFR which blocks (VEGF)/VEGFR signal might be effective. However, such reports have seldom been described. Herein, we documented a heavily-treated breast cancer patient experienced progressive aphasia, limb activity disorder and intermittent convulsion 10 months after radiotherapy of brain metastasis (BM). Cranial MRI demonstrated large peritumoral brain edema (PTBE). High dose of steriods and dehydration had no improvement. Apatinib with a dose of 250mg daily was initiated and all her discomforts disappeared after 10 days of use. The brain MRI of taking apatinib 5 weeks demonstrated remarkable shrinkage of edema. Our case indicates that apatinib, a potent small-molecular TKI targeted VEGFR2 is promising for intractable VBE for satisfactory efficacy and safety. This case is of great value in its rarity and because it provides new insight into PTBE management in clinical practice.\n\nKeywords\nApatinibperitumoral brain edemaintractableradiotherapyVEGFVEGFR2TKIScience and Technology Department of Jilin Province20160101028JCNational Natural Science Foundation of China (NSFC)81602659This study was supported by research program from the National Natural Science Foundation of China (Grant No. 81602659) and Science and Technology Department of Jilin Province (Grant No.20160101028JC) Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal; Science and Technology Department of Jilin Province [20160101028JC]; National Natural Science Foundation of China (NSFC) [81602659].\n==== Body\nIntroduction\nBrain metastases (BM) is a common neurological complication of malignancy.1 With the improvement of anti-tumor treatment and extended survival of cancer patients, the incidence of BM keeps increasing overtime. PTBE is frequently encountered in BM, which belongs to VBE by most researchers. PTBE causes or aggravates neurological dysfunction and intracranial hypertension. Steroids has been applied to the treatment of PTBE since 1960. However, glucocorticoid therapy has numerous adverse effects, usually in a dose-dependent manner. Dehydration such as mannitol is useful for relieving intracranial hypertension but also accompanied with “rebound phenomenon”. Increased blood-brain barrier permeability is a key factor in the development of PTBE.2 Radiotherapy, as an irreplaceable part in the treatment of BM, induces blood vessel damage and ultimately aggravates VBE. The secretion of VEGF by tumor cells plays a critical role in VBE and VEGF antibody bevacizumab gained certain anti-edema effect.2 In view of high cost of bevacizumab, other novel VEGF inhibitors should be urgently explored to solve this difficult situation.\n\nCase presentation\nA 49-year-old Chinese female was admitted in January, 2015 for painless mass in left breast. The subsequent biopsy demonstrated invasive breast carcinoma with immunohistochemical results of ER(-), PR(-), HER-2(3+), Ki67(+ 20%) and P53(+ 90%)(Figure1). Systemic evaluation showed bilateral lung metastases (0.1–0.9cm) and hepatic metastases (0.7–1.0cm) in addition with primary left breast cancer (33.9 × 18.3mm) and left axillary lymph node involvement (56.8 × 33.0mm). The patient refused molecular targeted therapy for economic reasons and underwent chemotherapy (six cycles of TAC: Pirarubicin, Cyclophosphamide, Paclitaxel and one cycle of T: Paclitaxel). The response was evaluated as partial remission (PR).10.1080/15384047.2018.1491502-F0001Figure 1. Immunohistochemical results of the primary invasive left breast carcinoma (original magnification, 200×). The tumor stained negative for both ER (A) and PR (B) but strongly positive for HER-2 (C) and exhibited a Ki-67 proliferation index of 20% (D) .\n\n\n\nIn September, 2015, her hepatic metastases progressed rapidly (1.0–1.9cm). Then she was enrolled in the clinical trial and randomly assigned to the control group (Lapatinib plus Capecitabine). In March, 2017, she complained of dizziness. The brain MRI with contrast revealed a lesion measuring about 3.1 × 2.7cm located in the left frontal lobe with circular enhancement and edema around, consistent with metastasis (Figure 2A,B). Local radiotherapy with a dose of 48Gy/16f was performed to the single BM and her discomfort disappeared. However, 3 months later, her disease progressed (lung metastases: 0.2–2.7cm, liver metastases: 1.2–4.3cm) and the BM shrank to 1.5 × 1.5cm. In August, the patient experienced recurrence in the left chest wall and further progression of liver metastases. Systemic therapy was switched to NP (Vinorelbine and Cisplatin) plus Herceptin. The lesions demontrated PR response to 4 cycles of NP plus Herceptin. Due to gastrointestinal side effects and grade 3 myelosuppression, the fifth and sixth chemotherapy regimen was adjusted to NC (Vinorelbine and Carboplatin) and N (Vinorelbine), respectively.10.1080/15384047.2018.1491502-F0002Figure 2. Brain MRIs of the patient revealed the size of BM lesion and PTBE. (A,C,E,G) The BM maximum diameter slice of T1-weighted MRI with contrast in 03/2017, 11/2017, 02/2018 and 03/2018 respectively. (B,D,F,H) The most obvious slice of PTBE in Flair-weighted MRI in 03/2017, 11/2017, 02/2018 and 03/2018 respectively. As Figure 1F shows, extensive PTBE caused progressive neurological deficits of the patient in 02/2018 which failed to be improved by high dose of steroids and dehydrants. As Figure 1H demonstrates, the PTBE shrank dramatically after use of apatinib 35 days.\n\n\n\nIn February, 2018, she complained of aphasia and intermittent convulsion. The brain MRI with contrast manifested a lesion in the left frontal lobe with obvious ring enhancement. Flair-weighted MRI showed large area of PTBE, resulting in compression and deformation of bilateral ventricle and midline structure shift to the right (Figure 2E,F). Comparing with the brain MRI in November, 2017 (Figure 2C,D), the BM demonstrated slight increase (2.5 × 2.0cm to 3.8 × 2.2cm) while PTBE increased significantly. Conventional intervention with dehydration (mannitol: 250ml, q8h, from 02/01/2018 to 02/07/2018; 250mg, q6h, from 02/08/2018 to 02/10/2018; glycerol fructose: 250ml, q12h, from 02/01/2018 to 02/10/2018) and glucocorticoid (dexamethasone: 20mg daily, from 02/08/2018 to 02/10/2018) was given. However, there was no improvement. The patient developed progressive aphasia and right-side limb activity disorder. Apatinib, with a dose of 250mg daily, was initiated. Surprisingly, after 3 days of use, the aphasia disappeared and she could communicate with others normally. After 10 days of use, her right-side limb activity recovered completely. The subsequent brain MRI (March, 16, 2018) revealed remarkable shrinkage of PTBE and no obvious change in the BM lesion (Figure 2G,H). Now, she takes apatinib 250mg daily and no common apatinib related side effects were observed.\n\nDiscussion\nBM is frequently encountered in clinical practice. 8–10% of cancer patients suffered from symptomatic BM according to population-based data.3,4 Peritumoral edema, the most common concomitant of BM, adversely affects the life quality and survival of BM patients. PTBE can further aggravate the original space occupying effect of the tumor, induce or aggravate the corresponding symptoms of nerve loss when involving the functional areas of the brain, result in intracranial hypertension, and in severe cases, brain hernia. PTBE can affect tumor exposure and increase the difficulty of tumor resection. Mortality and disability rate of brain tumor patients with PTBE increased significantly.\n\nSeveral molecular mechanisms have been reported to underlie the PTBE formation. BM, as like brain injury, primary brain tumor and inflammation, destroys the blood-brain barrier (BBB), which makes the plasma macromolecular substance permeate through the vascular lumen to the brain cell space. Therefore, it is considered that the damage of function and structure of BBB is the pathological basis of PTBE.2 Treatment for BM, radiotherapy particularly, inevitably cause vascular endothelial damage and lead to the BBB breakdown.5,6 Radiation causes swelling, exudation, degeneration, and exfoliation of vascular endothelial cells.\n\nVEGF/VEGFR pathway has been revealed to be closely associated with the development of PTBE.7,8 Central nervous system neoplastic cells typically secretes multiple cytokines to act on the endothelial cells within or around the tumor.2 VEGF is one of the most important mediators of vascular permeability.9,10 VEGFR family has three members: VEGFR1, VEGFR2 and VEGFR3.11 VEGFR2 monitors the function of vascular endothelium.11 When VEGF ligand binds to the extracellular segment of VEGFR2, specific intracellular tyrosine residues phosphorylated. After binding of PLC-γ to pY1175, PIP2 hydrolyzes and generates the second messengers IP3 and diacylglycerol (DAG). DAG activates PKC whilst IP3 acts on receptors in the endoplasmic reticulum (E.R.), increasing the concentration of intracellular calcium. Activated PKC and increased intracellular calcium activate endothelial nitric oxide synthase (eNOS) then promote the generation of nitric oxide (NO). Increased intracellular calcium also boost the cytosolic phospholipase A (cPLA) and prostaglandin production. NO and prostaglandin cause vascular cell permeablility.11,12 Despite of tumor-derived VEGF, the local microenvironmental disorders due to tumor or radiotherapy, cause hypoxia which stimulates the astrocyte and vascular endothelial cell to produce VEGF.5 Furthermore, newly formed microvessels in the tumor are lack of tight connection. VEGF inhibits the function of tight junction associated protein claudin-1, which destroys the tight junction and leads to increased vascular permeability13 (Figure 3).10.1080/15384047.2018.1491502-F0003Figure 3. The mechanism of VEGF mediated increase in vascular permeability and aptinib treatment in the intractable PTBE.\n\n\n\nSteroids are the mainstay of treatment in PTBE for the symptoms relief and cost-effectiveness. However, the obvious toxicity of steriods limit their unrestricted use. Hypertension, hyperglycemia and hypokalemia are common side effects of glucocorticoids use. Long-term intake might give rise to osteoporosis, necrosis of femoral head, peptic ulcer and active bleeding, suppressed immunity, all kinds of opportunistic infections and even fatal infection.2 Therefore, new agents with steroid-sparing effect is in great need to be explored, aiming to minimize the steroids’ administration when possible. The deep understanding of molecular determinants in the PTBE is critical for us to find out the alternatives which can replace or at least reduce the dose of steroid.2 Bevacizumab, a recombinant humanized monoclonal antibody targeted VEGF, can achieve a radiological relief and reduction of PTBE in glioblastoma.14 Bevacizumab, has been proved effective in radiation-induced brain necrosis.15,16 However, the high cost of Bevacizumab limit its wide application. Furthermore, the adverse effects of Bevacizumab need more attention in view of high rate of occurence.17\n\nApatinib, a small-molecular TKI against VEGFR2, potently blocks the VEGF/VEGFR2 signal transduction, and then reduce the permeability of blood vessels. Comparing with other TKI such as Sorafenib, Sunitinib or Pazopanib, apatinib showed a strong inhibitory effect of VEGFR2 with IC50 of 2nM.18 The IC50 of Sorafenib, Sunitinib or Pazopanib was 90, 10, 30, respectively.19–21 Apatinib has been approved for the third-line or later-phase treatment for recurrent or advanced gastric adenocarcinoma. However, its application in PTBE has never been documented. After extensive literature review in Pubmed, only one article documented the dramatic effect of apatinib in refractory radiation-induced brain edema.5 Our case focuses on the key mechanism that VEGF/VEGFR2 regulated PTBE and illustrates the potent role of apatinib in PTBE. Additionally, apatinib has a high cost- effectiveness and generally mild toxicity such as hypertension, proteinuria and hand foot syndrome which can be easily controlled by supportive management. Thus, apatinib is promising in the handling of PTBE and need to be further testified by large-scale clinical trial.\n\nConclusion\nPTBE is common and hardly solved by conventional steroid and dehydration. Novel approach is in urgent need. VEGF/VEGFR2 pathway is fundamental in the regulation of vascular cell permeablility, which resulting in the development of PTBE. Apatinib, a potent and highly selective TKI targeting VEGFR2, is dramatically effective in PTBE demonstrated by our case. Apatinib is promising in the treatment of PTBE for satisfactory effect, toxicity and cost-effectivity. In the future, clinical trial will be launched to clarify apatinib in PTBE.\n==== Refs\nReferences\n1. Soffietti R , Abacioglu U , Baumert B , Combs SE , Kinhult S , Kros JM , Marosi C , Metellus P , Radbruch A , Villa Freixa SS , et al \nDiagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO) . Neuro Oncol . 2017 \n4 \n10 ;19 (2 ):162 –174 . Epub \nPubMed PMID: 28391295; PubMed Central PMCID: PMCPMC5620494 . doi:10.1093/neuonc/now241 .28391295 \n2. Roth P , Regli L , Tonder M , Weller M. \nTumor-associated edema in brain cancer patients: pathogenesis and management . Expert Rev Anticancer Ther . 2013 \n10 \n25 ;13 (11 ):1319 –1325 . Epub \nPubMed PMID: 24152171 . doi:10.1586/14737140.2013.852473 .24152171 \n3. Barnholtz-Sloan JS , Sloan AE , Davis FG , Vigneau FD , Lai P , Sawaya RE \nIncidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the metropolitan detroit cancer surveillance system . J Clin Oncol . 2004 \n7 \n16 ;22 (14 ):2865 –2872 . Epub \nPubMed PMID: 15254054 . doi:10.1200/jco.2004.12.149 .15254054 \n4. Schouten LJ , Rutten J , Huveneers HA , Twijnstra A \nIncidence of brain metastases in a cohort of patients with carcinoma of the breast, colon, kidney, and lung and melanoma . Cancer . 2002 \n8 \n14 ;94 (10 ):2698 –2705 . Epub \nPubMed PMID: 12173339 .12173339 \n5. Hu WG , Weng YM , Dong Y , Li XP , Song QB \nApatinib in refractory radiation-induced brain edema: A case report . Medicine (Baltimore) . 2017 \n11 \n18 ;96 (46 ). e7358 \nEpub \nPubMed PMID: 29145238; PubMed Central PMCID: PMCPMC5704783 . doi:10.1097/md.0000000000007358 .29145238 \n6. Hladik D , Tapio S \nEffects of ionizing radiation on the mammalian brain . Mutat Res . 2016 \n12 \n07 ;770 (Pt B ):219 –230 . Epub \nPubMed PMID: 27919332 . doi:10.1016/j.mrrev.2016.08.003 27919332 \n7. Piazza M , Munasinghe J , Murayi R , Edwards N , Montgomery B , Walbridge S , Merrill M , Chittiboina P \nSimulating vasogenic brain edema using chronic VEGF infusion . J Neurosurg . 2017 \n1 \n07 ;127 (4 ):905 –916 . Epub \nPubMed PMID: 28059647; PubMed Central PMCID: PMCPMC5542877 . doi:10.3171/2016.9.jns1627 .28059647 \n8. Hou J , Kshettry VR , Selman WR , Bambakidis NC \nPeritumoral brain edema in intracranial meningiomas: the emergence of vascular endothelial growth factor-directed therapy . Neurosurg Focus . 2013 \n12 03 ;35 (6 ):E2 \nEpub \nPubMed PMID: 24289127 . doi:10.3171/2013.8.focus13301 .\n9. Sabang RL , Gandhiraj D , Fanucchi M , Epelbaum O \nRole of bevacizumab in the management of the patient with malignant pleural effusion: more questions than answers . Expert Rev Respir Med . 2018 ;12 (2 ):87 –94 . Epub [2017 12 14 ]. PubMed PMID: 29235400 . doi:10.1080/17476348.2018.1417042 .29235400 \n10. Yang GL , Zhao `Z , Qin TT , Wang D , Chen L , Xiang R , Xi Z , Jiang R , Zhang ZS , Zhang J , et al . TNFSF15 inhibits VEGF-stimulated vascular hyperpermeability by inducing VEGFR2 dephosphorylation . FASEB J . 2017 \n2 \n12 ;31 (5 ):2001 –2012 . Epub \nPubMed PMID: 28183800 . doi:10.1096/fj.201600800R .28183800 \n11. Holmes K , Roberts OL , Thomas AM , Cross MJ \nVascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic inhibition . Cell Signal . 2007 \n7 \n31 ;19 (10 ):2003 –2012 . Epub \nPubMed PMID: 17658244 . doi:10.1016/j.cellsig.2007.05.013 .17658244 \n12. Ivy SP , Wick JY , Kaufman BM \nAn overview of small-molecule inhibitors of VEGFR signaling . Nat Rev Clin Oncol . 2009 \n9 \n09 ;6 (10 ):569 –579 . Epub \nPubMed PMID: 19736552 . doi:10.1038/nrclinonc.2009.130 .19736552 \n13. Antonetti DA , Barber AJ , Hollinger LA , Wolpert EB , Gardner TW \nVascular endothelial growth factor induces rapid phosphorylation of tight junction proteins occludin and zonula occluden 1. A potential mechanism for vascular permeability in diabetic retinopathy and tumors . J Biol Chem . 1999 \n8 \n07 ;274 (33 ):23463 –23467 . Epub \nPubMed PMID: 10438525 .10438525 \n14. De Bonis P , Marziali G , Vigo V , Peraio S , Pompucci A , Anile C , Mangiola A \nAntiangiogenic therapy for high-grade gliomas: current concepts and limitations . Expert Rev Neurother . 2013 \n11 \n02 ;13 (11 ):1263 –1270 . Epub \nPubMed PMID: 24175724 . doi:10.1586/14737175.2013.856264 .24175724 \n15. Glitza IC , Guha-Thakurta N , D’Souza NM , Amaria RN , McGovern SL , Rao G , Li J \nBevacizumab as an effective treatment for radiation necrosis after radiotherapy for melanoma brain metastases . Melanoma Res . 2017 \n8 \n18 ;27 (6 ):580 –584 . Epub \nPubMed PMID: 28817446 . doi:10.1097/cmr.0000000000000389 .28817446 \n16. Ma Y , Zheng C , Feng Y , Xu Q \nBevacizumab for the Treatment of Gammaknife Radiosurgery-Induced Brain Radiation Necrosis . J Craniofac Surg . 2017 \n7 \n28 ;28 (6 ):e569 –e71 . Epub \nPubMed PMID: 28749838 . doi:10.1097/scs.0000000000003874 .28749838 \n17. Chinot OL , Wick W , Mason W , Henriksson R , Saran F , Nishikawa R , Carpentier AF , Hoang-Xuan K , Kavan P , Cernea D , et al . Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma . N Engl J Med . 2014 \n2 \n21 ;370 (8 ):709 –722 . Epub \nPubMed PMID: 24552318 . doi:10.1056/NEJMoa1308345 .24552318 \n18. Li J , Zhao X , Chen L , Guo H , Lv F , Jia K , Yv K , Wang F , Li C , Qian J , et al \nSafety and pharmacokinetics of novel selective vascular endothelial growth factor receptor-2 inhibitor YN968D1 in patients with advanced malignancies . BMC Cancer . 2010 \n10 \n07 ;10 :529 \nEpub \nPubMed PMID: 20923544; PubMed Central PMCID: PMCPMC2984425 . doi:10.1186/1471-2407-10-529 20923544 \n19. Wilhelm SM , Carter C , Tang L , Wilkie D , McNabola A , Rong H , Chen C , Zhang X , Vincent P , McHugh M , et al \nBAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis . Cancer Res . 64 (19 ):7099 –7109 . Epub \nPubMed PMID: 15466206 . doi:10.1158/0008-5472.can-04-1443 .\n20. Mendel DB , Laird AD , Xin X , Louie SG , Christensen JG , Li G , Schreck RE , Abrams TJ , Ngai TJ , Lee LB , et al \nIn vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship . Clin Cancer Res . 2003 ;9 (1 ):327 –337 . Epub 2003/ 01/23.PubMed PMID: 12538485 .12538485 \n21. Harris PA , Boloor A , Cheung M , Kumar R , Crosby RM , Davis-Ward RG , Epperly AH , Hinkle KW , Hunter RN 3rd, Johnson JH , et al \nDiscovery of 5-[[4-[(2,3-dimethyl-2H-indazol −6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl-b enzenesulfonamide (Pazopanib), a novel and potent vascular endothelial growth factor receptor inhibitor . J Med Chem . 2008 \n7 \n16 ;51 (15 ):4632 –4640 . Epub \nPubMed PMID: 18620382 . doi:10.1021/jm800566m .18620382\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1538-4047", "issue": "19(12)", "journal": "Cancer biology & therapy", "keywords": "Apatinib; TKI; VEGF; VEGFR2; intractable; peritumoral brain edema; radiotherapy", "medline_ta": "Cancer Biol Ther", "mesh_terms": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D001929:Brain Edema; D001932:Brain Neoplasms; D002199:Capillary Permeability; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011878:Radiotherapy; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A", "nlm_unique_id": "101137842", "other_id": null, "pages": "1093-1096", "pmc": null, "pmid": "30081717", "pubdate": "2018", "publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review", "references": "27919332;28059647;24289127;12173339;19736552;20923544;28749838;28817446;28183800;28391295;18620382;24175724;12538485;15254054;24152171;29235400;10438525;29145238;15466206;24552318;17658244", "title": "Successful treatment using apatinib in intractable brain edema: A case report and literatures review.", "title_normalized": "successful treatment using apatinib in intractable brain edema a case report and literatures review" }	[ { "companynumb": "CN-PFM-2019-00225", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "VINORELBINE TARTRATE" }, "drugadditional": "3", ...
{ "abstract": "Persistence of disease after salvage therapy among relapsed or refractory Hodgkin lymphoma (HL) patients predicts poor outcome. Here, we report on 41 HL patients with active disease after salvage therapy and who received high-dose melphalan (HD-PAM) and auto-SCT as a bridge to a second autologous or an allogeneic transplantation between 2002 and 2013 at our center. Disease response was based on 18-fluoro-deoxyglucose-positron emission tomography results in all patients. Overall response rate after HD-PAM was 78% and it did not differ among PR or stable/progressive disease patients (P=1.00). Response was associated with better OS: hazard ratio=0.32 (95% confidence interval: 0.13-0.77, P=0.01) irrespective of disease status before HD-PAM. Thirty-three patients (80%) were able to complete the planned treatment, intended as tandem autologous or auto-allo transplant. Hematological and extrahematological toxicity of HD-PAM was manageable, without any treatment-related death. In conclusion, HD-PAM is a valuable therapeutic option in relapsed/refractory HL patients with active disease after salvage therapy, with an impressive 78% overall response rate and 80% rate of proceeding to further transplantation. The present data may be integrated with the growing literature on new drugs in the field of relapsed/refractory HL.", "affiliations": "Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Statistic Unit, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Nuclear Medicine Department, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.;Department of Oncology and Hematology, Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Milan, Italy.", "authors": "Castagna\|L\|L\|;Crocchiolo\|R\|R\|;Giordano\|L\|L\|;Bramanti\|S\|S\|;Carlo-Stella\|C\|C\|;Sarina\|B\|B\|;Chiti\|A\|A\|;Mauro\|E\|E\|;Gandolfi\|S\|S\|;Todisco\|E\|E\|;Balzarotti\|M\|M\|;Anastasia\|A\|A\|;Magagnoli\|M\|M\|;Brusamolino\|E\|E\|;Santoro\|A\|A\|", "chemical_list": "D018906:Antineoplastic Agents, Alkylating; D008558:Melphalan", "country": "England", "delete": false, "doi": "10.1038/bmt.2014.304", "fulltext": null, "fulltext_license": null, "issn_linking": "0268-3369", "issue": "50(4)", "journal": "Bone marrow transplantation", "keywords": null, "medline_ta": "Bone Marrow Transplant", "mesh_terms": "D000293:Adolescent; D000328:Adult; D018906:Antineoplastic Agents, Alkylating; D064592:Autografts; D018572:Disease-Free Survival; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D012008:Recurrence; D033581:Stem Cell Transplantation; D015996:Survival Rate", "nlm_unique_id": "8702459", "other_id": null, "pages": "499-504", "pmc": null, "pmid": "25621797", "pubdate": "2015-04", "publication_types": "D016428:Journal Article", "references": "22547596;20660832;22732704;20665491;17448919;16980994;22786877;17242396;21993674;22155507;24606548;23248254;23645687;22429186;9113932;22611160;22454421;17019686;16533726;23065511;25008328;18398740;23167437;12086759;7581076;22271893;17623832;19018090;20220116;15020611;18489989;22184409;17229633;15129236;16042685", "title": "High-dose melphalan with autologous stem cell support in refractory Hodgkin lymphoma patients as a bridge to second transplant.", "title_normalized": "high dose melphalan with autologous stem cell support in refractory hodgkin lymphoma patients as a bridge to second transplant" }	[ { "companynumb": "IT-GLAXOSMITHKLINE-IT2015GSK026389", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MELPHALAN" }, "drugadditional": null...
{ "abstract": "BACKGROUND\nContinuation of antiplatelet medications through major urologic surgery may increase the risk of intraoperative and postoperative bleeding complications. However, withdrawal of antiplatelet therapy may place some patients at high risk of serious cardiovascular or cerebrovascular complications. We assess the feasibility of performing robotic partial nephrectomy (RPN) in patients maintained on aspirin or dual antiplatelet therapy with aspirin and clopidogrel.\n\n\nMETHODS\nPerioperative data was collected prospectively on 230 subjects undergoing RPN enrolled in an IRB approved quality of life study. We analyzed subjects who were maintained on either aspirin alone or both aspirin and clopidogrel throughout the operative and perioperative period.\n\n\nRESULTS\nOf the 230 patients, six were identified who continued antiplatelet medication throughout the perioperative period. Four patients were maintained on 81 mg of aspirin and two patients continued aspirin and clopidogrel. Average RENAL score was 7 with mean tumor size of 4.1 cm. There were no intraoperative complications and no conversions to open surgery. Average estimated blood loss was 242 mL. Ninety day complication rate was 33%. One patient had postoperative bleeding on day 14 after restarting coumadin in addition to their aspirin.\n\n\nCONCLUSIONS\nWe present a case series demonstrating that in carefully selected patients, RPN on aspirin and clopidogrel is feasible and safe. This is the first report of patients who underwent RPN while on both aspirin and clopidogrel.", "affiliations": "Department of Surgery, Division of Urology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.", "authors": "Althaus\|Adam B\|AB\|;Dovirak\|Ostap\|O\|;Chang\|Peter\|P\|;Taylor\|Kimberly N\|KN\|;O'Halloran\|Thomas D\|TD\|;Wagner\|Andrew A\|AA\|", "chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin", "country": "Canada", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1195-9479", "issue": "22(5)", "journal": "The Canadian journal of urology", "keywords": null, "medline_ta": "Can J Urol", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001241:Aspirin; D016063:Blood Loss, Surgical; D000077144:Clopidogrel; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D009392:Nephrectomy; D018579:Patient Selection; D059035:Perioperative Period; D010975:Platelet Aggregation Inhibitors; D019106:Postoperative Hemorrhage; D065287:Robotic Surgical Procedures; D013988:Ticlopidine; D028761:Withholding Treatment", "nlm_unique_id": "9515842", "other_id": null, "pages": "7984-9", "pmc": null, "pmid": "26432969", "pubdate": "2015-10", "publication_types": "D016428:Journal Article", "references": null, "title": "Aspirin and clopidogrel during robotic partial nephrectomy, is it safe?", "title_normalized": "aspirin and clopidogrel during robotic partial nephrectomy is it safe" }	[ { "companynumb": "US-BAYER-2015-447053", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "dr...
{ "abstract": "A 26-year-old man had a history of severe atopic dermatitis. He was taking immunosuppressive drug. Mitral valve replacement (MVR) had been performed for infective endocarditis March 2008. He came to our hospital in July 2012 complaining of fever of 39 degrees Celsius. According to computed tomography (CT) and transesophageal echocardiography (TEE), we diagnosed that he had cerebral embolism and bacterial infection of prosthetic valve. Antibiotic treatment was performed for 2 weeks after the onset of cerebral infarction. Then we conducted re-MVR. The postoperative course was satisfactory. He showed a gradual improvement in the level of consciousness and was discharged. In patients with atopic dermatitis, bacteria can penetrate into the blood from the skin easily. So they are often affected by bacteremia. There are some reports that infective endocarditis is likely to occur in immunosuppressed patients. It is suggested that immunosuppressive drug was involved in the development of prosthetic valve endocarditis (PVE) in addition to atopic dermatitis in this patient.", "affiliations": "Department of Cardiovascular Surgery, National Osaka Minami Medical Center, Kawachinagano, Japan.", "authors": "Tanioka\|Hideki\|H\|;Iwata\|Keiji\|K\|;Marumoto\|Akira\|A\|;Kaneko\|Mitsunori\|M\|", "chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine", "country": "Japan", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0021-5252", "issue": "68(5)", "journal": "Kyobu geka. The Japanese journal of thoracic surgery", "keywords": null, "medline_ta": "Kyobu Geka", "mesh_terms": "D000328:Adult; D016572:Cyclosporine; D003876:Dermatitis, Atopic; D004697:Endocarditis, Bacterial; D006350:Heart Valve Prosthesis; D006801:Humans; D007166:Immunosuppressive Agents; D020766:Intracranial Embolism; D008297:Male; D013203:Staphylococcal Infections; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "0413533", "other_id": null, "pages": "383-6", "pmc": null, "pmid": "25963789", "pubdate": "2015-05", "publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article", "references": null, "title": "Prosthetic Valve Endocarditis using Immunosuppressive Agent for Atopic Dermatitis;Report of a Case.", "title_normalized": "prosthetic valve endocarditis using immunosuppressive agent for atopic dermatitis report of a case" }	[ { "companynumb": "PHJP2015JP008190", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOSPORINE" }, "drugadditional": null, "dr...
{ "abstract": "We previously observed encouraging results and acceptable toxicity in phase II trials testing preoperative split-course thoracic radiation and simultaneous cisplatin, etoposide, and 5-fluorouracil in stage III non-small cell lung cancer patients. We decided to delete 5-fluorouracil and to incorporate paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) into our combined-modality treatment. The first group of patients received carboplatin dosed at an area under the concentration-time curve of 4 on day 2, etoposide 50 mg orally days 1 to 5 and 8 to 12, cisplatin 50 mg/m2 on day 21, and paclitaxel 35 mg/m2 escalated to 45 mg/m2 on days 1 and 8. Group 2 patients received carboplatin dosed at an area under the concentration-time curve of 4 on day 1, etoposide 45 mg/m2 intravenously daily on days 2 to 5, and paclitaxel 80 mg/m2 (escalating to 120 mg/m2) on day 1. Patients in group 3 received carboplatin dosed at an area under the concentration-time curve of 4 on day 1 and paclitaxel 120 mg/m2 (escalating to 140 mg/m2) on day 1. Each patient received radiation 2 Gy daily on days 1 to 5 and 8 to 12, and a total of two cycles was given at 28-day intervals. Twenty-one patients received preoperative chemoradiotherapy: group 1, five patients; group 2, 11 patients; and group 3, five patients. Thoracotomy was not done in five patients due to cerebrovascular accident in one and progressive tumor in four. The remaining 16 patients had the following procedures: pneumonectomy, eight; lobectomy, six; chest wall resection, one; and no resection, one. Postoperative complications included bronchopleural fistula in one patient each in groups 1 and 3, hypoxia in one patient in group 1, pulmonary hypertension in one patient in group 2, pneumonia in one patient in group 2, and adult respiratory distress syndrome in one patient in group 3, which proved lethal. Thus, six of 16 patients had serious postoperative complications. The relatively high incidence of postoperative bronchopulmonary complications suggests that the use of preoperative paclitaxel-containing chemotherapy and simultaneous thoracic radiation may not be feasible.", "affiliations": "Department of Thoracic Surgery, Rush University Medical Center, Chicago, IL 60612, USA.", "authors": "Bonomi\|P\|P\|;Faber\|L P\|LP\|;Warren\|W\|W\|;Lincoln\|S\|S\|;LaFollette\|S\|S\|;Sharma\|M\|M\|;Recine\|D\|D\|", "chemical_list": "D005047:Etoposide; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0093-7754", "issue": "24(4 Suppl 12)", "journal": "Seminars in oncology", "keywords": null, "medline_ta": "Semin Oncol", "mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002945:Cisplatin; D003131:Combined Modality Therapy; D004334:Drug Administration Schedule; D005047:Etoposide; D005260:Female; D006801:Humans; D008171:Lung Diseases; D008175:Lung Neoplasms; D008297:Male; D009367:Neoplasm Staging; D017239:Paclitaxel; D011013:Pneumonectomy; D011183:Postoperative Complications; D011878:Radiotherapy; D011879:Radiotherapy Dosage", "nlm_unique_id": "0420432", "other_id": null, "pages": "S12-123-S12-129", "pmc": null, "pmid": "9331136", "pubdate": "1997-08", "publication_types": "D016430:Clinical Trial; D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Postoperative bronchopulmonary complications in stage III lung cancer patients treated with preoperative paclitaxel-containing chemotherapy and concurrent radiation.", "title_normalized": "postoperative bronchopulmonary complications in stage iii lung cancer patients treated with preoperative paclitaxel containing chemotherapy and concurrent radiation" }	[ { "companynumb": "US-PFIZER INC-2018332365", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "3", ...
{ "abstract": "Introduction. Antitumor necrosis factor (TNF) alpha agents are commonly used biologic therapies for a wide variety of rheumatic and inflammatory diseases. Here, we present a case of hemorrhagic pericarditis as a consequence of infliximab and review the literature on pericardial complications stemming from this drug class. Methods. For the literature review, search terms using versions of antitumor necrosis factor alpha AND pericardial effusion OR pericarditis OR pleuropericarditis OR cardiac tamponade were used. Results. Pericarditis is a rare but serious complication of anti-TNF based therapy, and hemorrhagic fluid is even more rare, with only one additional case reported. It is likely that this complication was secondary to a robust immune response to very high titer anti-infliximab antibodies. Providers should be aware that this complication can occur and that abnormal elevations in procalcitonin may accompany this unusual finding.", "affiliations": "University of Michigan Medical School, Ann Arbor, MI, USA.;Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.", "authors": "Lather\|Henry D\|HD\|;Kahlenberg\|J Michelle\|JM\|0000-0002-4006-8945", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2016/2576496", "fulltext": "\n==== Front\nCase Rep RheumatolCase Rep RheumatolCRIRHCase Reports in Rheumatology2090-68892090-6897Hindawi Publishing Corporation 10.1155/2016/2576496Case ReportHemorrhagic Pericardial Effusion with Tamponade: A Rare Adverse Effect of Infliximab—Case Report and Literature Review Lather Henry D. \n1\nhttp://orcid.org/0000-0002-4006-8945Kahlenberg J. Michelle \n2\n\n\n1University of Michigan Medical School, Ann Arbor, MI, USA2Department of Internal Medicine, Division of Rheumatology, University of Michigan, Ann Arbor, MI, USAJ. Michelle Kahlenberg: mkahlenb@med.umich.eduAcademic Editor: Shigeko Inokuma\n\n2016 16 10 2016 2016 257649614 7 2016 28 9 2016 Copyright © 2016 H. D. Lather and J. M. Kahlenberg.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nIntroduction. Antitumor necrosis factor (TNF) alpha agents are commonly used biologic therapies for a wide variety of rheumatic and inflammatory diseases. Here, we present a case of hemorrhagic pericarditis as a consequence of infliximab and review the literature on pericardial complications stemming from this drug class. Methods. For the literature review, search terms using versions of antitumor necrosis factor alpha AND pericardial effusion OR pericarditis OR pleuropericarditis OR cardiac tamponade were used. Results. Pericarditis is a rare but serious complication of anti-TNF based therapy, and hemorrhagic fluid is even more rare, with only one additional case reported. It is likely that this complication was secondary to a robust immune response to very high titer anti-infliximab antibodies. Providers should be aware that this complication can occur and that abnormal elevations in procalcitonin may accompany this unusual finding.\n\nNational Institute of Arthritis and Musculoskeletal and Skin DiseasesNational Institutes of HealthK08AR063668\n==== Body\n1. Introduction\nAntitumor necrosis factor alpha (anti-TNFα) agents are widely used therapies in autoimmune diseases. Here, we present a rare case of hemorrhagic pericardial effusion induced by infliximab and review all reported cases of pericardial effusion during anti-TNFα therapy.\n\n2. Case Report\nWe present a 60-year-old man with a history significant for ulcerative colitis requiring total colectomy, primary sclerosing cholangitis requiring liver transplant, chronic renal insufficiency, hypertension, psoriasis, and spondyloarthritis manifested by nearly fused sacroiliac joints, enthesopathies, bursitis, and severe stiffness. He had excellent control of arthritis symptoms on infliximab (5 mg/kg Q6 weeks) but self-discontinued in 2013 for insurance reasons.\n\nIn July 2014, he received another infliximab infusion secondary to worsening joint pain. One week later, he began to develop shortness of breath, diffuse joint swelling and aches, and general malaise. Nine days after his infusion, he presented to the Emergency Department with severe joint pain in all major joints. He was afebrile, tachycardic (100 s bpm), and hypertensive (140 s–160 s/100 s mmHg). Knee arthrocentesis showed noninflammatory fluid without crystals. Labs were remarkable for white blood cell (WBC) count of 17.1 K/μL (neutrophils 86%), creatinine stable at 2.38 mg/dL, C-reactive protein (CRP) elevated to 4.2 mg/dL (reference < 0.6 mg/dL), total bilirubin elevated to 1.9 mg/dL, and alkaline phosphatase elevated to 208 IU/L. Notably, procalcitonin (PCT) was 118 ng/mL (reference range < 0.05 ng/mL). He was empirically treated with hydration and antibiotics and subsequently began to improve (PCT 56 ng/mL on hospital day (HD) 4). On HD 3, transthoracic echocardiogram (TTE) showed small pericardial effusion and no vegetation. No source of infection was found. Blood, joint fluid, stool, and nasal and urine cultures were negative; urinalysis was unremarkable; viral titers and bacterial serologies were negative; and chest X-ray was unremarkable. Rheumatologic studies were also unremarkable, including C3, C4, ANA, anti-dsDNA, cryoglobulins, and extractable nuclear antigens. He was discharged from the hospital five days after admission and instructed to complete a course of antibiotics. Nine days after discharge, he was again admitted for progressive shortness of breath and recumbent chest pain. Inflammatory labs were elevated as follows: PCT 0.57 ng/mL, CRP 5.3 mg/dL, and Westergren sedimentation rate 82 mm (reference range < 15 mm). TTE following computer tomography on admission showed a moderate-to-large pericardial effusion (Figure 1) with echocardiographic evidence of cardiac tamponade.\n\nPericardiocentesis was performed and 480 mL of hemorrhagic fluid was drained. Bacterial, tuberculosis, and fungal cultures of pericardial fluid were all negative and no organisms were seen on gram, acid fast bacillus, or fungal stains. Cytology was negative for malignancy. Blood cultures were negative. Anti-histone antibody, rheumatoid factor, and anti-cyclic citrullinated peptide antibody were negative. The patient was started on steroids 60 mg per day, and repeat TTE the next day showed interval decrease in pericardial effusion size. The pericardial drain was pulled the next day and he was discharged home. TTE 2 months after infusion revealed only trace pericardial effusion.\n\nFive weeks after infliximab infusion, anti-infliximab serum antibodies were strongly positive (628,550 ng/mL with reference < 22 ng/mL). Due to absence of documented infection or other identifiable causes of pericardial effusion and in light of highly elevated antibodies against infliximab, it was felt that an immune reaction to anti-TNFα therapy was responsible. He was able to taper off high-dose steroids without issue. Two years later, the effusion has not recurred, but he has struggled to manage his joint symptoms without anti-TNFα therapy.\n\n3. Literature Review\nTwenty cases of pericardial complications while on anti-TNFα therapy were identified and results are summarized in Table 1.\n\nThirteen cases of noninfectious pericardial effusion occurred in patients with rheumatoid arthritis (RA), one of which was hemorrhagic [1–7]. It has been suggested that the cause is failure of anti-TNFα therapy to control the extra-articular manifestations of RA [3–6], of which pericarditis is common. All 3 cases of infectious pericardial effusion occurred in patients with RA as well [1, 2, 7]. Immunosuppression is likely to have played a role given that patients on anti-TNFα therapy are at increased risk of infection [8]. Two of the 4 patients with inflammatory bowel disease (IBD) developed drug-induced lupus erythematosus (DILE), which is thought to have led to pericardial effusion in these patients [9, 10].\n\nNeither RA nor DILE was involved in only 2 cases (including ours). The other case occurred in psoriatic arthritis with adalimumab; however, pericardial fluid was not drained so the fluid type was unknown [11]. Additionally, a case of pericarditis without effusion occurred in a patient with IBD on infliximab [12]. The presumed pathophysiology in all three patients is a hypersensitivity type III immune-complex reaction.\n\nEight of 20 patients from the literature were known to have continued or restarted the same or different anti-TNFα agent without recurrence of effusions within follow-up period. All but one had RA without purulent effusion; he had IBD and noneffusive pericarditis while on infliximab and he was treated with NSAIDs for 2 weeks and at a later time resumed adalimumab with no problems during follow-up [12].\n\n4. Discussion\nHemorrhagic pericardial effusion with cardiac tamponade has previously been described in a single case report in a patient with RA receiving the anti-TNFα agent adalimumab [5]. Here we present a second patient with hemorrhagic effusion after an infusion of infliximab. Our patient had seronegative arthritis with sacroiliac inflammation, IBD and psoriasis. Although still rare, most patients with pericardial effusion during anti-TNFα therapy have RA or DILE whereas ours is only the third reported case of pericarditis without evidence of RA or DILE.\n\nWe presume that this complication was secondary to the very high titers of anti-infliximab antibodies present in this patient. This case demonstrates how autoimmune reaction to anti-TNFα therapy can initially mimic infection. Our patient presented with tachycardia, leukocytosis, and markedly elevated PCT. Even in autoimmune disease, specificity of PCT (cutoff > 0.5 ng/mL) for bacterial infection is 0.95 in febrile patients [13], but because our patient remained afebrile throughout his initial admission, specificity is unknown. While PCT is known to be slightly elevated in several other noninfectious conditions (e.g., severe organ dysfunction) [14], very high PCT levels in drug hypersensitivity reactions, infusion reactions, and anaphylaxis are rare but do occur, including one case of an infusion reaction against rituximab [15] and one case of anaphylactic shock to risedronate [16].\n\nAs illustrated by our case, clinicians should be aware of both noninfectious elevations in PCT and anti-TNFα-induced pericardial effusion as rare, but life-threatening adverse effects.\n\nAcknowledgments\nJ. Michelle Kahlenberg was supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health under Award no. K08AR063668.\n\nCompeting Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 CT of the chest demonstrates a new, moderate, loculated, pericardial effusion and a small left-sided pleural effusion. Right and left atria are normal in diameter.\n\nTable 1 Anti-TNFα-associated pericardial complications (including our case).\n\nDisease\tDrug\tPericardial fluid type (number of patients)\t\nInfectious\tSerous\tHemorrhagic\tUnknown\tNone\t\nRA\tAdalimumab\t—\t2\t1\t1\t—\t\nEtanercept\t2\t1\t—\t5\t—\t\nInfliximab\t1\t1\t—\t2\t—\t\n\n\n\t\nIBD\tInfliximab\t—\t—\t1\t2\t1\t\n\n\n\t\nPsoriatic arthritis\tAdalimumab\t—\t—\t—\t1\t—\n==== Refs\n1 Harney S. O'Shea F. D. FitzGerald O. Peptostreptococcal pericarditis complicating anti-tumour necrosis factor α treatment in rheumatoid arthritis Annals of the Rheumatic Diseases 2002 61 7 653 654 10.1136/ard.61.7.653 2-s2.0-0036288769 12079913 \n2 Sweet D. D. Isac G. Morrison B. Fenwick J. Dhingra V. Purulent pericarditis in a patient with rheumatoid arthritis treated with etanercept and methotrexate Canadian Journal of Emergency Medicine 2007 9 1 40 42 2-s2.0-33847137315 17391602 \n3 Ambrose N. L. O'Connell P. G. Anti-TNF α therapy does not always protect rheumatoid arthritis patients against developing pericarditis Clinical and Experimental Rheumatology 2007 25 4 p. 660 \n4 Hall S. J. L. Hickling P. Failure of etanercept to control extra-articular manifestations of rheumatoid arthritis Journal of Clinical Rheumatology 2007 13 1 p. 54 10.1097/01.rhu.0000255806.90022.2f \n5 Soh M. C. Hart H. H. Corkill M. Pericardial effusions with tamponade and visceral constriction in patients with rheumatoid arthritis on tumour necrosis factor (TNF)-inhibitor therapy International Journal of Rheumatic Diseases 2009 12 1 74 77 10.1111/j.1756-185x.2009.01387.x 2-s2.0-63849174150 20374322 \n6 Edwards M. H. Leak A. M. Pericardial effusions on anti-TNF therapy for rheumatoid arthritis—a drug side effect or uncontrolled systemic disease? Rheumatology 2009 48 3 316 317 10.1093/rheumatology/ken463 2-s2.0-61349127957 19106166 \n7 Taylor G. K. Elliott L. Sosin M. D. Soo S. S. Complication of etanercept treatment for rheumatoid arthritis-purulent pericarditis caused by a commensal organism BMJ Case Reports 2012 8, article 2012 10.1136/bcr.01.2012.5644 \n8 Hanauer S. Review article: safety of infliximab in clinical trials Alimentary Pharmacology and Therapeutics 1999 13 s4 16 22 10.1046/j.1365-2036.1999.00027.x 10597335 \n9 Burke J. P. Kelleher B. Ramadan S. Quinlan M. Sugrue D. O'Donovan M. A. Pericarditis as a complication of infliximab therapy in Crohn's disease Inflammatory Bowel Diseases 2008 14 3 428 429 10.1002/ibd.20270 2-s2.0-41149178676 17924565 \n10 Harnett D. T. Chandra-Sekhar H. B. Hamilton S. F. Drug-induced lupus erythematosus presenting with cardiac tamponade: a case report and literature review Canadian Journal of Cardiology 2014 30 2 247.e11 247.e12 10.1016/j.cjca.2013.11.011 \n11 Ozkan H. Cetinkaya A. S. Yildiz T. Bozat T. A rare side effect due to TNF-alpha blocking agent: acute pleuropericarditis with adalimumab Case Reports in Rheumatology 2013 2013 2 985914 10.1155/2013/985914 \n12 Devasahayam J. Pillai U. Lacasse A. A rare case of pericarditis, complication of infliximab treatment for Crohn's disease Journal of Crohn's and Colitis 2012 6 6 730 731 10.1016/j.crohns.2012.02.016 2-s2.0-84862210987 \n13 Wu J.-Y. Lee S.-H. Shen C.-J. Use of serum procalcitonin to detect bacterial infection in patients with autoimmune diseases: a systematic review and meta-analysis Arthritis and Rheumatism 2012 64 9 3034 3042 10.1002/art.34512 2-s2.0-84865638942 22605405 \n14 Meisner M. Update on procalcitonin measurements Annals of Laboratory Medicine 2014 34 4 263 273 10.3343/alm.2014.34.4.263 2-s2.0-84904416980 24982830 \n15 Robier C. Neubauer M. Reicht G. Marked elevation of procalcitonin in a patient with a drug related infusion reaction to rituximab Clinical Chemistry and Laboratory Medicine 2016 54 3 e101 e103 10.1515/cclm-2015-0772 2-s2.0-84958739584 26389633 \n16 Kim Y. J. Kang S. W. Lee J. H. Cho J. H. Marked elevation of procalcitonin level can lead to a misdiagnosis of anaphylactic shock as septic shock International Journal of Infectious Diseases 2015 37 93 94 10.1016/j.ijid.2015.06.012 2-s2.0-84937002907 26119856\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6897", "issue": "2016()", "journal": "Case reports in rheumatology", "keywords": null, "medline_ta": "Case Rep Rheumatol", "mesh_terms": null, "nlm_unique_id": "101585353", "other_id": null, "pages": "2576496", "pmc": null, "pmid": "27822400", "pubdate": "2016", "publication_types": "D016428:Journal Article", "references": "23970991;12079913;24982830;26389633;10597335;20374322;24373757;17924565;17278957;26119856;22605835;22465046;19106166;17391602;22605405;17888231", "title": "Hemorrhagic Pericardial Effusion with Tamponade: A Rare Adverse Effect of Infliximab-Case Report and Literature Review.", "title_normalized": "hemorrhagic pericardial effusion with tamponade a rare adverse effect of infliximab case report and literature review" }	[ { "companynumb": "US-JNJFOC-20161117169", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": "1", "...
{ "abstract": "OBJECTIVE\nThe recent guidelines on management of aneurysmal subarachnoid hemorrhage (aSAH) advise pharmacological thromboprophylaxis (PTP) after aneurysm obliteration. However, no study has addressed the safety of PTP in the aSAH population. Therefore, the aim of this study was to assess the safety of early PTP after aSAH.\n\n\nMETHODS\nRetrospective cohort of aSAH patients admitted between January 2012 and June 2013 in a single high-volume aSAH center. Traumatic SAH and perimesencephalic hemorrhage patients were excluded. Patients were grouped according to PTP timing: early PTP group (PTP within 24 hours of aneurysm treatment), and delayed PTP group (PTP started > 24 hours).\n\n\nRESULTS\nA total of 174 SAH patients (mean age 56.3±12.5 years) were admitted during the study period. Thirty-nine patients (22%) did not receive PTP, whereas 135 patients (78%) received PTP after aneurysm treatment or negative angiography. Among the patients who received PTP, 65 (48%) had an external ventricular drain. Twenty-eight patients (21%) received early PTP, and 107 (79%) received delayed PTP. No patient in the early treatment group and three patients in the delayed PTP group developed an intracerebral hemorrhagic complication. Two required neurosurgical intervention and one died. These three patients were on concomitant PTP and dual antiplatelet therapy.\n\n\nCONCLUSIONS\nThe initiation of PTP within 24 hours may be safe after the treatment of a ruptured aneurysm or in angiogram-negative SAH patients with diffuse aneurysmal hemorrhage pattern. We suggest caution with concomitant use of PTP and dual antiplatelet agents, because it possibly increases the risk for intracerebral hemorrhage.", "affiliations": "1Department of Critical Care Medicine,Trauma & Neurosurgical Intensive Care Unit.;2Department of Medical Imaging,Interventional Neuroradiology.;1Department of Critical Care Medicine,Trauma & Neurosurgical Intensive Care Unit.;2Department of Medical Imaging,Interventional Neuroradiology.;2Department of Medical Imaging,Interventional Neuroradiology.;2Department of Medical Imaging,Interventional Neuroradiology.;2Department of Medical Imaging,Interventional Neuroradiology.;1Department of Critical Care Medicine,Trauma & Neurosurgical Intensive Care Unit.", "authors": "Manoel\|Airton Leonardo de Oliveira\|AL\|;Turkel-Parrella\|David\|D\|;Germans\|Menno\|M\|;Kouzmina\|Ekaterina\|E\|;Almendra\|Priscila da Silva\|Pda S\|;Marotta\|Thomas\|T\|;Spears\|Julian\|J\|;Abrahamson\|Simon\|S\|", "chemical_list": "D006495:Heparin, Low-Molecular-Weight; D006493:Heparin", "country": "England", "delete": false, "doi": "10.1017/cjn.2014.16", "fulltext": null, "fulltext_license": null, "issn_linking": "0317-1671", "issue": "41(5)", "journal": "The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques", "keywords": null, "medline_ta": "Can J Neurol Sci", "mesh_terms": "D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D006493:Heparin; D006495:Heparin, Low-Molecular-Weight; D006801:Humans; D008297:Male; D008875:Middle Aged; D056990:Post-Exposure Prophylaxis; D012189:Retrospective Studies; D013345:Subarachnoid Hemorrhage; D013921:Thrombocytopenia; D015912:Thrombolytic Therapy; D013997:Time Factors; D016896:Treatment Outcome; D014463:Ultrasonography", "nlm_unique_id": "0415227", "other_id": null, "pages": "554-61", "pmc": null, "pmid": "25373803", "pubdate": "2014-09", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Safety of early pharmacological thromboprophylaxis after subarachnoid hemorrhage.", "title_normalized": "safety of early pharmacological thromboprophylaxis after subarachnoid hemorrhage" }	[ { "companynumb": "PHHY2015CA148071", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ASPIRIN" }, "drugadditional": null, "drugadm...
{ "abstract": "A 58-year-old woman was found to have bilateral ptosis and downward gaze deviation immediately after elective shoulder surgery with general anesthesia and supraclavicular nerve block. A code stroke was activated due to concern for the neurologic process, but neuroimaging did not reveal acute changes or vascular abnormality. Her symptoms gradually resolved in the following hours with supportive care and were ultimately deemed to be related to anesthetic and transdermal scopolamine exposures layered upon her underlying comorbidities. Transient bilateral ophthalmoplegia after general anesthetics has been previously described; drug effect should be considered in the differential of this alarming presentation, which can mimic acute stroke and/or Horner syndrome.", "affiliations": "Department of Pharmacy, OhioHealth Grant Medical Center, Columbus, USA.;Department of Neurocritical Care, OhioHealth Riverside Methodist Hospital, Columbus, USA.;Department of Hospital Medicine, OhioHealth Grant Medical Center, Columbus, USA.;Department of Pharmacy, OhioHealth Grant Medical Center, Columbus, USA.;Department of Anesthesia, OhioHealth Grant Medical Center, Columbus, USA.", "authors": "Hyland\|Sara J\|SJ\|;Kavi\|Tapan R\|TR\|;Smith\|Nicole R\|NR\|;Lin\|Jacky\|J\|;Catton\|Mark D\|MD\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.7759/cureus.18802", "fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184\nCureus Palo Alto (CA)\n\n10.7759/cureus.18802\nAnesthesiology\nNeurology\nOphthalmology\nTransient Bilateral Ophthalmoplegia: A Case of a Forgotten Anesthetic Medication Effect\nMuacevic Alexander\nAdler John R\nHyland Sara J 1\nKavi Tapan R 2\nSmith Nicole R 3\nLin Jacky 1\nCatton Mark D 4\n1 Department of Pharmacy, OhioHealth Grant Medical Center, Columbus, USA\n2 Department of Neurocritical Care, OhioHealth Riverside Methodist Hospital, Columbus, USA\n3 Department of Hospital Medicine, OhioHealth Grant Medical Center, Columbus, USA\n4 Department of Anesthesia, OhioHealth Grant Medical Center, Columbus, USA\nSara J. Hyland sara.jordan@ohiohealth.com\n15 10 2021\n10 2021\n13 10 e1880215 10 2021\nCopyright © 2021, Hyland et al.\n2021\nHyland et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nThis article is available from https://www.cureus.com/articles/68806-transient-bilateral-ophthalmoplegia-a-case-of-a-forgotten-anesthetic-medication-effect\nA 58-year-old woman was found to have bilateral ptosis and downward gaze deviation immediately after elective shoulder surgery with general anesthesia and supraclavicular nerve block. A code stroke was activated due to concern for the neurologic process, but neuroimaging did not reveal acute changes or vascular abnormality. Her symptoms gradually resolved in the following hours with supportive care and were ultimately deemed to be related to anesthetic and transdermal scopolamine exposures layered upon her underlying comorbidities. Transient bilateral ophthalmoplegia after general anesthetics has been previously described; drug effect should be considered in the differential of this alarming presentation, which can mimic acute stroke and/or Horner syndrome.\n\ncode stroke\nophthalmoplegia\ngeneral anesthesia\nscopolamine\nstroke mimic\neye ptosis\ngaze palsy\nadverse drug effect\nnerve block\nThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\npmcIntroduction\n\nWe present a case of new-onset extraocular movement abnormalities discovered immediately after elective shoulder surgery with general anesthesia and supraclavicular nerve block. Acute neurologic workup with computed tomography (CT) of the head and angiogram did not reveal any abnormalities and her symptoms, fortunately, were transient as they resolved in a few hours. We believe these symptoms were a medication effect of the anesthetics and transdermal scopolamine she was exposed to, superimposed upon her underlying chronic conditions. Our review of the literature revealed that transient external ophthalmoplegia may be unexpectedly common after general anesthesia, occurring in 46% of patients in one study [1]. Additionally, transient microvascular ischemic third nerve palsy is possible in this type of patient and may be more common than previously thought [2-4]. Furthermore, oculomotor function is heavily dependent upon cholinergic innervation, and common perioperative anticholinergic medications could have measurable impacts on eye function in susceptible patients [5,6]. This case promotes increased awareness of ophthalmological effects of common anesthetic medications among perioperative providers in order to support accurate diagnosis and avoid unnecessary workup or high-risk therapies when this type of presentation is encountered. This study was approved by the OhioHealth Institutional Review Board after written informed patient consent and Health Insurance Portability and Accountability Act (HIPAA) authorization was obtained. This study adheres to the case report reporting guidelines (CARE) [7].\n\nCase presentation\n\nA 58-year-old woman who weighs 87.5 kg presented for revision to reverse left total shoulder arthroplasty. Her past medical and surgical histories were significant for type II diabetes mellitus, obstructive sleep apnea (non-dependent on positive airway pressure ventilation), migraines, anxiety, osteoarthritis, postoperative nausea and vomiting, antithrombin III deficiency with prior deep venous thromboses, thyroid cancer, left reverse total shoulder arthroplasty, and left blepharoplasty approximately two years prior for lifelong left-sided ptosis. \n\nIn the preoperative area, she received routine preemptive oral analgesics (acetaminophen 975 mg, gabapentin 300 mg), application of a scopolamine patch to the right mastoid for postoperative nausea and vomiting (PONV) prevention, and intravenous fentanyl 100 mcg and midazolam 2 mg to facilitate placement of left supraclavicular nerve block by the attending anesthesiologist. The block was placed under ultrasound guidance with a total volume of 30 mL local anesthetic (10 mL of 0.5% ropivacaine and 20 mL of 2 % lidocaine, both without epinephrine). She was taken to the operating suite where she was provided general anesthesia induction with intravenous propofol 200 mg and succinylcholine 140 mg then maintenance with inhaled sevoflurane and intravenous rocuronium 50 mg. She received routine intravenous antiemetics (ondansetron 4 mg and dexamethasone 4 mg) and prophylactic antibiotics (intravenous cefazolin 2 g and topical vancomycin 1000 mg onto the surgical site) throughout an uneventful operative course of approximately two hours. The operation was pursued via the prior reverse total shoulder arthroplasty incision site with the patient in a supine \"beach chair\" position and included removal and replacement of all prior prosthetic components. At the end of the case, a qualitative train-of-four measurement yielded 4/4 twitches and she was administered intravenous neostigmine 3 mg with glycopyrrolate 0.6 mg. She was successfully extubated and transferred to the post-anesthesia care unit (PACU). \n\nUpon interview by the admitting hospitalist in the PACU, approximately 20 minutes after PACU handoff by the anesthesia providers, the patient was noted to have new-onset bilateral ptosis (left initially greater than right), bilateral downward gaze deviation, and inability to open her eyelids or move her eyes vertically or horizontally (Figures 1, 2). Her pupils were difficult to assess due to the significant downward gaze and dark iris coloration. The patient was appropriately drowsy but completely responsive and also endorsed an acute onset holocephalic headache. Physical examination was also noteworthy for left-side diminished facial sensation to light touch, though she reported this to be intermittent and chronic for her. Her vital signs remained stable and within normal limits, and the physical examination was otherwise unremarkable and appropriate for immediate postoperative shoulder surgical status. \n\nFigure 1 Patient exhibiting bilateral ptosis immediately after surgery\n\nFigure 2 Patient exhibiting downgaze deviation immediately after surgery\n\nA medical provider is holding the patient's eyelids open to demonstrate.\n\nThe attending anesthesiologist was called to evaluate the patient at this time and a stroke alert was also activated due to concern for acute neurologic process. Acute neurologic processes such as ischemic stroke, Horner’s syndrome, and others were considered but were ruled out based on bilaterality of symptoms and after reviewing emergent CT scan and CT angiogram. As per vascular neurologist recommendation, supportive care was started for possible migraine with intravenous valproic acid 500 mg and crystalloid maintenance fluid. The scopolamine patch was removed for possible anticholinergic cause of her symptoms as per clinical pharmacist recommendation. \n\nThe patient’s symptoms gradually improved in the following evening hours and were noted to be completely resolved the next morning (Figure 3). A magnetic resonance imaging (MRI) scan was completed postoperative day one and revealed mild chronic white matter microvascular ischemic changes without evidence of acute intracranial abnormality. The inpatient neurology service evaluated the patient and felt the patient’s previous symptoms were likely explained by migrainous syndrome and/or anesthetic drug effect. The patient’s hospital course was also complicated by acute kidney injury, though this also resolved quickly with supportive care and she was discharged home in good condition on postoperative day two. \n\nFigure 3 Patient back to baseline on morning of the first postoperative day\n\nThe patient was unable to follow up with the neurology clinic after hospital discharge from this encounter for further testing or evaluation. She did have a successful outpatient podiatric surgery several months later, however, during which she was exposed to some of the same medications (cefazolin, general anesthesia with propofol but without paralytics or inhaled anesthetics, local lidocaine infiltration, intravenous dexamethasone, routine opioids). A history and physical examination completed at pre-admission testing for this procedure were unremarkable and noted her pupils to be equal and reactive to light. She had an uneventful surgical and anesthetic course without mention of ocular aberrations and was discharged home in good condition from the PACU at that time. A phone interview completed by the study investigators, with patient permission, suggested that the patient had not experienced ophthalmoplegia at any point prior to her revision shoulder surgery admission nor had she experienced any recurrence afterward.\n\nDiscussion\n\nThe differentials for this acute presentation include Horner syndrome, acute stroke with vertebrobasilar syndrome, myasthenic crisis, ophthalmoplegic migraine, and anesthetic effect (persistent partial neuromuscular block in the peri-operative period). Horner syndrome is characterized by unilateral ptosis, miosis, and anhidrosis resulting from disruption of sympathetic innervation [8]. Though this has been reported with supraclavicular block, we felt it was unlikely given the patient’s bilateral symptoms and complete ptosis [9]. Acute vertebrobasilar syndrome and resultant ischemic stroke were also considered, but as imaging revealed patency of posterior circulation and as the patient had preserved extremity function, this was considered unlikely. The brain MRI later in the course showing absence of any ischemic injury also supports an etiology other than acute stroke. Myasthenic crisis can lead to ophthalmoplegia, but this also seemed very unlikely without any medical history or previous symptoms and also considering her complete ophthalmoplegia rather than characteristic fatigability. Ophthalmoplegic migraine was also considered and she was given relevant treatment with intravenous fluids and valproic acid, but the bilateral nature of symptoms and no prior similar symptoms make this unlikely as well. Moreover, this is usually seen in younger patients and our patient demographic would not be typical. Acute Wernicke’s syndrome with thiamine deficiency can also cause ophthalmoplegia but rapid improvement in symptoms without thiamine replacement suggests otherwise. The cranial variant of Guillain-Barre syndrome known as Miller-Fisher syndrome is characterized by extraocular muscle and facial muscle involvement, however, the sudden nature and lack of facial involvement in our patient along with quick recovery go against it [10]. A transient microvascular ischemic ocular nerve palsy is possible, especially given the patient’s medical risk factors. However, given the bilateral nature of her symptoms, involvement of extraocular muscles supplied by multiple cranial nerves, and prompt recovery, it was also considered unlikely [2-4]. Parinaud syndrome as an anesthetic complication was also considered [11]. Due to her restriction of eye movement in both horizontal and vertical directions as opposed to just vertical, Parinaud was considered unlikely. After pursuing an exhaustive review of pathophysiological differentials and assessing the temporal sequence of events, an anesthetic medication effect seemed like the most likely cause of the symptoms in our patient.\n\nA literature search revealed that transient external ophthalmoplegia may be unexpectedly common after intravenous anesthesia. A prospective case series by Marsch and Schaefer evaluated eye-opening and movement functions immediately after recovery from total intravenous anesthesia with propofol, fentanyl, and atracurium [1]. Out of the 110 patients in the study, all of which had normal eye and eyelid mobility prior to induction of anesthesia, 51 patients (46%) either had the complete inability to open their eyes or showed some impairment of eye-opening and/or eye movement immediately following the operation. A total of 21 patients (19%) exhibited a complete inability to open their eyes combined with a total gaze paresis. The ophthalmoplegic symptoms were bilateral, did not affect vision, and proved transient; by the time 20 minutes had passed, almost all patients had fully recovered eye function. The authors were unable to make a determination if one specific medication caused the ophthalmoplegia, but suggest that one or more drugs may have selectively affected the supranuclear centers in the pontine and midbrain reticular formation, given that both horizontal and vertical eye movements were affected bilateral and synchronously [1]. Our patient experienced a similar presentation of bilateral external ophthalmoplegia and total gaze paresis, though symptoms resolved more gradually over the first few postoperative hours.\n\nThe patient’s transdermal scopolamine exposure may also have contributed to her symptoms since cholinergic pathways play a role in oculomotor function [5,12]. Central anticholinergic medications such as scopolamine can impair eye movements in healthy individuals due to decreased cholinergic transmission, in addition to the better-known effects of mydriasis and increased intraocular pressure [5,6,13-16]. Anticholinergic activity may not completely explain her extraocular symptoms, however, so we concluded her presentation was likely a combination of her anesthetic and anticholinergic drug exposure to which her mild chronic white matter microvascular ischemia may have rendered her susceptible. Another possible differential is unmasking of subclinical ocular myasthenia gravis by administration of rocuronium and succinylcholine especially given the patient's history of ptosis. Another possible differential is unmasking of subclinical ocular myasthenia gravis by administration of rocuronium and succinylcholine, especially given the patient's history of ptosis. This theory is plausible given her spontaneous recovery, which could be due to the paralytic drug effect wearing off. The patient did receive neostigmine which should reverse the effects of neuromuscular blockade by the paralytic agents mentioned above, however, it is possible that administration of an agent such as sugammadex may have been more effective at reversal than neostigmine. Also, given the lack of progression of symptoms and spontaneous recovery, testing for acetylcholine receptor antibodies for a diagnosis of ocular myasthenia gravis would not be indicated.\n\nConclusions\n\nIn conclusion, acute postoperative onset of bilateral ptosis and extraocular movement abnormalities with spontaneous downward gaze deviation caused initial concern for an emergent neurologic pathology such as an ischemic stroke but proved transient and likely medication-related in a vulnerable patient. The likely causes in this patient being anesthetic effects on midbrain and pontine gaze centers, anticholinergic effects of scopolamine, or unmasking of subclinical ocular myasthenia gravis by administration of succinylcholine and rocuronium. Transient bilateral ophthalmoplegia after anesthesia and paralytics may be common but easily overlooked in the immediate recovery phase of care. Increased understanding of the ocular effects of common anesthetic medications can be valuable in avoiding the dangers and costs of an incorrect stroke diagnosis.\n\nThe authors would like to thank Dr. Marie Lockhart, Ph.D., for her assistance in IRB submission.\n\nHuman Ethics\n\nThe authors have declared that no competing interests exist.\n\nConsent was obtained or waived by all participants in this study. OhioHealth Institutional Review Board issued approval N/A\n==== Refs\nReferences\n\n1 External ophthalmoplegia after total intravenous anaesthesia Anaesthesia Marsch SC Schaefer HG 525 527 49 1994 8017599\n2 Self-resolving ischemic third nerve palsy EyeRounds.org Canady FJ Ricca AM Stiff HA Shriver EM Ko AC Iowa City, IA University of Iowa Health Care 2018 https://webeye.ophth.uiowa.edu/eyeforum/cases/280-self-resolving-ischemic-TNP.htm\n3 Incidence and etiologies of acquired third nerve palsy using a population-based method JAMA Ophthalmol Fang C Leavitt JA Hodge DO Holmes JM Mohney BG Chen JJ 23 28 135 2017 27893002\n4 Microvascular non-arteritic ocular motor nerve palsies-what we know and how should we treat? Neuroophthalmology Galtrey CM Schon F Nitkunan A 1 11 39 2015 27928323\n5 Anticholinergic activity in the nervous system: consequences for visuomotor function Physiol Behav Naicker P Anoopkumar-Dukie S Grant GD Kavanagh JJ 6 11 170 2017 27965143\n6 Pharmacological treatment effects on eye movement control Brain Cogn Reilly JL Lencer R Bishop JR Keedy S Sweeney JA 415 435 68 2008 19028266\n7 CARE guidelines for case reports: explanation and elaboration document J Clin Epidemiol Riley DS Barber MS Kienle GS 218 235 89 2017 28529185\n8 Horner syndrome: a clinical review ACS Chem Neurosci Martin TJ 177 186 9 2018 29260849\n9 A case of Horner's syndrome following ultrasound-guided infraclavicular brachial plexus block Case Rep Anesthesiol Walid T Mondher BA Mohamed Anis L Mustapha F 2012 2012\n10 Characteristics of pupil palsy in miller-fisher syndrome: case reports and review of the literature Neurol Sci Lee JH Jang Y Kim SJ Jung JH 2021\n11 Parinaud syndrome, a rare complication of general anesthesia. [Article in French] Bull Soc Ophtalmol Fr Rougier S 376 378 5 1961 https://pubmed.ncbi.nlm.nih.gov/14039051/ 14039051\n12 Autonomic control of the eye Compr Physiol McDougal DH Gamlin PD 439 473 5 2015 25589275\n13 Ocular and visual side effects of systemic drugs: clinically relevant toxicology and patient management J Behav Optom Wren VQ 149 157 11 2000 https://oepf.org/wp-content/uploads/2021/08/11-620Valeriewren1.pdf\n14 Impairment of saccadic eye movements by scopolamine treatment Percept Mot Skills Oliva GA Bucci MP Fioravanti R 159 167 76 1993 8451122\n15 The effect of transdermal scopolamine for the prevention of postoperative nausea and vomiting Front Pharmacol Antor MA Uribe AA Erminy-Falcon N Werner JG Candiotti KA Pergolizzi JV Bergese SD 5 2014\n16 Anisocoria secondary to inadvertent contact with scopolamine patch BMJ Case Rep Shah J Jiang A Fekete Z 2017 2017\n\n", "fulltext_license": "CC BY", "issn_linking": "2168-8184", "issue": "13(10)", "journal": "Cureus", "keywords": "adverse drug effect; code stroke; eye ptosis; gaze palsy; general anesthesia; nerve block; ophthalmoplegia; scopolamine; stroke mimic", "medline_ta": "Cureus", "mesh_terms": null, "nlm_unique_id": "101596737", "other_id": null, "pages": "e18802", "pmc": null, "pmid": "34804664", "pubdate": "2021-10", "publication_types": "D002363:Case Reports", "references": "29260849;14039051;8017599;27893002;28529185;22957277;27965143;33825117;27928323;19028266;24782768;25589275;8451122;28928255", "title": "Transient Bilateral Ophthalmoplegia: A Case of a Forgotten Anesthetic Medication Effect.", "title_normalized": "transient bilateral ophthalmoplegia a case of a forgotten anesthetic medication effect" }	[ { "companynumb": "US-GLAXOSMITHKLINE-USCH2021GSK085159", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "SCOPOLAMINE" }, "drugadditional": ...
{ "abstract": "Tandem cycles of high-dose chemotherapy are an increasingly being used as alternative to radiation treatment in the management of infants and young children with central nervous system (CNS) tumors. Most of these protocols have a carboplatinum and thiotepa backbone. The toxicities of these regimens have been reported extensively; however, pulmonary arterial vasculopathy (PAV) with pulmonary arterial hypertension (PAH) has not been previously documented in patients treated with this approach. PAH is a disorder of the pulmonary vasculature characterized by a progressive increase in pulmonary vascular resistance, leading to right heart failure and potentially death. We evaluated PAH as a complication after high-dose chemotherapy and autologous stem cell transplantation (SCT). We performed a retrospective evaluation of all pediatric patients diagnosed with a CNS tumor between 2001 and 2010 scheduled to receive 3 cycles of high-dose chemotherapy with carboplatinum (17 mg/kd/day for 2 days) and thiotepa (10 mg/kg/day for 2 days), followed by autologous SCT. Our primary objective was to evaluate the incidence of PAV and PAH in this population, as well as patient outcomes after the development of PAH. Our cohort comprised 20 patients with a median age at diagnosis of 28 months (range, 3-131 months). Three patients developed biopsy-confirmed PAV with PAH, the 2 patients who developed PAV with PAH at the end of the third cycle succumbed to PAH. Death due to PAV and PAH was the sole toxic mortality observed during the study period. PAV with PAH is a major and possibly fatal complication after high-dose chemotherapy and sequential autologous SCT using carboplatinum and thiotepa in a tandem fashion. There is an urgent need to evaluate PAH as a potential complication after each cycle of high-dose chemotherapy when using such regimens in pediatric patients with CNS tumors.", "affiliations": "Blood and Marrow Transplantation Section, Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada. Tal.schechter-finkelstein@sickkids.ca", "authors": "Schechter\|Tal\|T\|;Leucht\|Stephan\|S\|;Bouffet\|Eric\|E\|;Cutz\|Ernest\|E\|;Gassas\|Adam\|A\|;Huang\|Annie\|A\|;Bartels\|Ute\|U\|;Humpl\|Tilman\|T\|;Doyle\|John\|J\|", "chemical_list": null, "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "19(2)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": null, "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D001932:Brain Neoplasms; D016543:Central Nervous System Neoplasms; D002675:Child, Preschool; D015331:Cohort Studies; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D008297:Male; D033581:Stem Cell Transplantation; D014182:Transplantation, Autologous; D014652:Vascular Diseases", "nlm_unique_id": "9600628", "other_id": null, "pages": "235-9", "pmc": null, "pmid": "23022389", "pubdate": "2013-02", "publication_types": "D016428:Journal Article", "references": null, "title": "Pulmonary hypertensive vasculopathy following tandem autologous transplantation in pediatric patients with central nervous system tumors.", "title_normalized": "pulmonary hypertensive vasculopathy following tandem autologous transplantation in pediatric patients with central nervous system tumors" }	[ { "companynumb": "CA-ADIENNEP-2014AD000041", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "THIOTEPA" }, "drugadditional": "3", ...
{ "abstract": "To pool data from published cases of tracheoinnominate artery fistula (TIF) treated with surgical or endovascular techniques along with reporting a case of similar presentation. A total of 261 cases in 137 published case reports and case series were identified through a comprehensive systematic literature review. Data regarding patient characteristics, treatment, and follow-up were extracted. A local case of a 14-year-old boy with TIF due to longstanding tracheostomy treated with stent-graft placement was added to the data. Comparison of the complication rates between surgical vs endovascular interventions was done with the chi-square test. Factors associated with longer survival were assessed by the Cox regression analysis. Thirty-three (12.6%) of the reported cases were treated endovascularly, 137 (52.3%) were treated surgically, and 92 (35.1%) were reported with no definitive treatment. Mean age was 34 ± 22 years, and 61% were males. The mean time interval between tracheotomy placement and bleeding was 1 ± 2.5 years. A lower procedure-related complication (30% vs 50%, P = 0.045) and 30-day mortality (9% vs 23%, P = 0.008) rates had been reported with percutaneous approaches compared to surgery. No percutaneous procedure was reported prior to year 2000. In multivariate analysis stratified by publication year, a shorter tracheostomy-to-bleeding time (year) was significantly associated with higher hazards of death (hazard ratio: 1.22, P = 0.017). Type of intervention (percutaneous vs surgery) was not associated with postintervention survival (adjusted hazard ratio: 0.78, P = 0.558). Endovascular stent grafting can have a comparable postprocedural survival and lower complication rates vs open surgical repair in treatment of TIF.", "affiliations": "School of Medicine, Oregon Health and Science University, Portland, Oregon.;Dotter Department of Interventional Radiology, Oregon Health and Science University, Portland, Oregon.;Dotter Department of Interventional Radiology, Oregon Health and Science University, Portland, Oregon. Electronic address: jahangiy@ohsu.edu.", "authors": "Taechariyakul\|Thotsophon\|T\|;Keller\|Frederick S\|FS\|;Jahangiri\|Younes\|Y\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1053/j.semtcvs.2019.08.006", "fulltext": null, "fulltext_license": null, "issn_linking": "1043-0679", "issue": "32(1)", "journal": "Seminars in thoracic and cardiovascular surgery", "keywords": "Case report; Pooled cohort analysis; Stent graft; Tracheoinnominate artery fistula", "medline_ta": "Semin Thorac Cardiovasc Surg", "mesh_terms": "D000293:Adolescent; D019917:Blood Vessel Prosthesis Implantation; D016122:Brachiocephalic Trunk; D057510:Endovascular Procedures; D006801:Humans; D008297:Male; D016156:Respiratory Tract Fistula; D018570:Risk Assessment; D012307:Risk Factors; D014133:Tracheal Diseases; D014139:Tracheostomy; D016896:Treatment Outcome; D016157:Vascular Fistula", "nlm_unique_id": "8917640", "other_id": null, "pages": "77-84", "pmc": null, "pmid": "31425754", "pubdate": "2020", "publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review", "references": null, "title": "Endovascular Treatment of Tracheoinnominate Artery Fistula: Case Report and Literature Review With Pooled Cohort Analysis.", "title_normalized": "endovascular treatment of tracheoinnominate artery fistula case report and literature review with pooled cohort analysis" }	[ { "companynumb": "US-BAYER-2020-052862", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CIPROFLOXACIN HYDROCHLORIDE" }, "drugadditional":...
{ "abstract": "Generalized periodic discharges with triphasic morphology (GPDs + TWm) have been reported with multiple metabolic and drug toxicities. Beta-lactam antibiotics in some cases can cause neurotoxicity with GPDs + TWm on EEG. There are no reports in the literature of aztreonam causing neurotoxicity and GPDs + TWm. Here we describe GPDs + TWm and encephalopathy developing in a patient with underlying dementia and acute kidney injury who was started on aztreonam for cystitis. Neurotoxic effects of beta-lactam antibiotics have been well studied at this point, likely related to GABA receptor antagonism by the beta lactam ring. Risk factors for toxicity include, advanced age, prior neurological injury and decreased renal clearance. This patient carried multiple risk factors for beta-lactam neurotoxicity. Discontinuation of aztreonam led to a resolution of GPDs + TWm on EEG, and regression of encephalopathy.", "affiliations": "Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.;Johns Hopkins Bayview Medical Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.", "authors": "Billnitzer\|Andrew\|A\|https://orcid.org/0000-0001-7062-7771;Kaplan\|Peter W\|PW\|", "chemical_list": "D001398:Aztreonam", "country": "United States", "delete": false, "doi": "10.1177/1550059420917842", "fulltext": null, "fulltext_license": null, "issn_linking": "1550-0594", "issue": "52(1)", "journal": "Clinical EEG and neuroscience", "keywords": "antibiotic; aztreonam; beta-lactam; encephalopathy; generalized periodic discharges with triphasic morphology; neurotoxicity; triphasic waves", "medline_ta": "Clin EEG Neurosci", "mesh_terms": "D000368:Aged; D001398:Aztreonam; D001921:Brain; D058256:Brain Waves; D004569:Electroencephalography; D005260:Female; D006801:Humans; D010351:Patient Discharge; D012640:Seizures", "nlm_unique_id": "101213033", "other_id": null, "pages": "66-68", "pmc": null, "pmid": "32401538", "pubdate": "2021-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Generalized Periodic Discharges With Triphasic Morphology in the Setting of Aztreonam Neurotoxicity.", "title_normalized": "generalized periodic discharges with triphasic morphology in the setting of aztreonam neurotoxicity" }	[ { "companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-070875", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "AZTREONAM" }, "drugaddi...
{ "abstract": "A 55-year-old man undergoing chemotherapy for recurrent multiple myeloma presented with a 2-day history of bilateral lower leg rash with pain and oedema. On examination, there were numerous non-palpable retiform pruritic patches over both lower legs. Skin pnch biopsy demonstrated a diffuse interstitial neutrophilic infiltrate with necrosis. Peripheral blood and skin tissue cultures both isolated Citrobacterfreundii, consistent with a rare form of ecthyma gangrenosum. The patient responded with appropriate antibiotic therapy and removal of medical port. He made a full recovery from this infectious complication of his underlying immunosuppression.", "affiliations": "Department of Anesthesiology, Brooke Army Medical Center, Fort Sam Houston, Texas, USA.;Department of Infectious Disease, Brooke Army Medical Center, Fort Sam Houston, Texas, USA.;Department of Dermatology, Brooke Army Medical Center, Fort Sam Houston, Texas, USA.;Department of Pulmonary and Critical Care, Brooke Army Medical Center, Fort Sam Houston, Texas, USA.", "authors": "Hawkley\|Tyson\|T\|;Chang\|David\|D\|;Pollard\|Whitney\|W\|;Ferraro\|David\|D\|", "chemical_list": "D000900:Anti-Bacterial Agents; D013845:Thienamycins; D000077731:Meropenem", "country": "England", "delete": false, "doi": "10.1136/bcr-2017-220996", "fulltext": null, "fulltext_license": null, "issn_linking": "1757-790X", "issue": "2017()", "journal": "BMJ case reports", "keywords": "dermatology; infections", "medline_ta": "BMJ Case Rep", "mesh_terms": "D000900:Anti-Bacterial Agents; D016971:Citrobacter freundii; D003646:Debridement; D004473:Ecthyma; D004756:Enterobacteriaceae Infections; D006801:Humans; D016867:Immunocompromised Host; D035002:Lower Extremity; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D009101:Multiple Myeloma; D035583:Rare Diseases; D013845:Thienamycins; D016896:Treatment Outcome", "nlm_unique_id": "101526291", "other_id": null, "pages": null, "pmc": null, "pmid": "28751433", "pubdate": "2017-07-27", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "11709338;1401278;15097944;18759794;19136439;22988648;25407372;27759698;5253645;7298930;9624195", "title": "Ecthyma gangrenosum caused by Citrobacter freundii.", "title_normalized": "ecthyma gangrenosum caused by citrobacter freundii" }	[ { "companynumb": "US-WEST-WARD PHARMACEUTICALS CORP.-US-H14001-17-03331", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "POMALIDOMIDE" }, ...
{ "abstract": "OBJECTIVE\nMedications are a major cause of acute liver failure (ALF) in the United States, but no population-based studies have evaluated the incidence of ALF from drug-induced liver injury. We aimed to determine the incidence and outcomes of drug-induced ALF in an integrated health care system that approximates a population-based cohort.\n\n\nMETHODS\nWe performed a retrospective cohort study using data from the Kaiser Permanente Northern California (KPNC) health care system between January 1, 2004, and December 31, 2010. We included all KPNC members age 18 years and older with 6 months or more of membership and hospitalization for potential ALF. The primary outcome was drug-induced ALF (defined as coagulopathy and hepatic encephalopathy without underlying chronic liver disease), determined by hepatologists who reviewed medical records of all KPNC members with inpatient diagnostic and laboratory criteria suggesting potential ALF.\n\n\nRESULTS\nAmong 5,484,224 KPNC members between 2004 and 2010, 669 had inpatient diagnostic and laboratory criteria indicating potential ALF. After medical record review, 62 (9.3%) were categorized as having definite or possible ALF, and 32 (51.6%) had a drug-induced etiology (27 definite, 5 possible). Acetaminophen was implicated in 18 events (56.3%), dietary/herbal supplements in 6 events (18.8%), antimicrobials in 2 events (6.3%), and miscellaneous medications in 6 events (18.8%). One patient with acetaminophen-induced ALF died (5.6%; 0.06 events/1,000,000 person-years) compared with 3 patients with non-acetaminophen-induced ALF (21.4%; 0.18/1,000,000 person-years). Overall, 6 patients (18.8%) underwent liver transplantation, and 22 patients (68.8%) were discharged without transplantation. The incidence rates of any definite drug-induced ALF and acetaminophen-induced ALF were 1.61 events/1,000,000 person-years (95% confidence interval, 1.06-2.35) and 1.02 events/1,000,000 person-years (95% confidence interval, 0.59-1.63), respectively.\n\n\nCONCLUSIONS\nDrug-induced ALF is uncommon, but over-the-counter products and dietary/herbal supplements are its most common causes.", "affiliations": "Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address: david.goldberg@uphs.upenn.edu.;Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Leonard Davis Institute of Health Economics, University of Pennsylvania, Philadelphia, Pennsylvania.;Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.;Division of Gastroenterology, University of Pennsylvania, Philadelphia, Pennsylvania.;Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; HealthCore, Inc, Wilmington, Delaware.;Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.;Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania.;Division of Research, Kaiser Permanente Northern California, Oakland, California.;Division of Research, Kaiser Permanente Northern California, Oakland, California.;Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Rutgers Biomedical and Health Sciences, Newark, New Jersey.;Division of Research, Kaiser Permanente Northern California, Oakland, California.;Center for Clinical Epidemiology and Biostatistics, Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania; Center for Pharmacoepidemiology Research and Training, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; Division of Infectious Diseases, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.", "authors": "Goldberg\|David S\|DS\|;Forde\|Kimberly A\|KA\|;Carbonari\|Dena M\|DM\|;Lewis\|James D\|JD\|;Leidl\|Kimberly B F\|KB\|;Reddy\|K Rajender\|KR\|;Haynes\|Kevin\|K\|;Roy\|Jason\|J\|;Sha\|Daohang\|D\|;Marks\|Amy R\|AR\|;Schneider\|Jennifer L\|JL\|;Strom\|Brian L\|BL\|;Corley\|Douglas A\|DA\|;Lo Re\|Vincent\|V\|", "chemical_list": "D004366:Nonprescription Drugs; D028321:Plant Preparations", "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0016-5085", "issue": "148(7)", "journal": "Gastroenterology", "keywords": "Acetaminophen; Acute Liver Failure; Drug-Induced Liver Injury", "medline_ta": "Gastroenterology", "mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002140:California; D056486:Chemical and Drug Induced Liver Injury; D016208:Databases, Factual; D019033:Delivery of Health Care, Integrated; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D015994:Incidence; D017114:Liver Failure, Acute; D008297:Male; D008875:Middle Aged; D004366:Nonprescription Drugs; D028321:Plant Preparations; D011379:Prognosis; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors", "nlm_unique_id": "0374630", "other_id": null, "pages": "1353-61.e3", "pmc": null, "pmid": "25733099", "pubdate": "2015-06", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.", "references": "23456678;17370334;8178358;17662100;24425668;10580593;21544079;20513004;20512999;24704526;21178089;14523675;8229111;16317692;19174782;19372904;17910762;25312984;16265706;17868274;18030002;22711078;16473644;20949552;24307821;17608778;23419359;10644272;16481640;8101303;18318440;16675324;23012597;19132805;25043597;12484709;16025496;16083708;23801638;20815829;9873089;17723917;25560583;15841455;15516343;15390328;12890847;15464251;7924752;21349301;12879990;22373724;8229110", "title": "Population-representative incidence of drug-induced acute liver failure based on an analysis of an integrated health care system.", "title_normalized": "population representative incidence of drug induced acute liver failure based on an analysis of an integrated health care system" }	[ { "companynumb": "US-IMPAX LABORATORIES, INC-2015-IPXL-00722", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METFORMIN HYDROCHLORIDE" }, ...
{ "abstract": "Secondary central nervous system involvement is an uncommon event that typically occurs early in the natural history of diffuse large B-cell lymphoma and presents as leptomeningeal dissemination in two-thirds of cases. The prognosis of this event is dismal, and treatment options are meagre. Although major validated risk factors for central nervous system dissemination are clinical, concomitant MYC/BCL2 rearrangements as well as MYC/BCL2 protein expression have been recently associated with an increased risk of this complication. Here we present the first case, to our knowledge, of a MYC/BCL6-positive double-hit diffuse large B-cell lymphoma relapsing in the leptomeninges that achieved an outstanding durable remission with single-agent lenalidomide following salvage chemotherapy. Copyright © 2016 John Wiley & Sons, Ltd.", "affiliations": "Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.;Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.;Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.;Department of Diagnostic, Clinical, and Public Health Medicine, University of Modena and Reggio Emilia, Modena, Italy.;Arcispedale Santa Maria Nuova IRCCS, Reggio Emilia, University of Modena and Reggio Emilia, Modena, Italy.", "authors": "Salati\|Massimiliano\|M\|;Tarantino\|Vittoria\|V\|;Maiorana\|Antonino\|A\|;Bettelli\|Stefania\|S\|;Luminari\|Stefano\|S\|", "chemical_list": "D013792:Thalidomide; D000077269:Lenalidomide", "country": "England", "delete": false, "doi": "10.1002/hon.2315", "fulltext": null, "fulltext_license": null, "issn_linking": "0278-0232", "issue": "35(4)", "journal": "Hematological oncology", "keywords": "CNS lymphoma; double-hit lymphoma; lenalidomide", "medline_ta": "Hematol Oncol", "mesh_terms": "D000368:Aged; D006801:Humans; D000077269:Lenalidomide; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D012008:Recurrence; D015996:Survival Rate; D013792:Thalidomide", "nlm_unique_id": "8307268", "other_id": null, "pages": "861-863", "pmc": null, "pmid": "27301994", "pubdate": "2017-12", "publication_types": "D002363:Case Reports", "references": null, "title": "Durable remission in a patient with leptomeningeal relapse of a MYC/BCL6-positive double-hit DLBCL treated with lenalidomide monotherapy.", "title_normalized": "durable remission in a patient with leptomeningeal relapse of a myc bcl6 positive double hit dlbcl treated with lenalidomide monotherapy" }	[ { "companynumb": "IT-CELGENEUS-ITA-2016064942", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "LENALIDOMIDE" }, "drugadditional": "1", ...
{ "abstract": "Clinical worsening during the course of multiple sclerosis (MS) might be secondary to not only an incomplete recovery after relapses, to progressive accumulation of deficits, but also to other etiologies, different from MS. This report discusses the cases of two MS patients showing a gradual and progressive deterioration of locomotor and cognitive functions which were due to the co-occurrence of MS and glioblastoma. Additional investigations (especially magnetic resonance imaging) are strongly recommended to exclude concomitant pathologies in MS patients suffering from new neurological symptoms over weeks to months, without remission, or an unexpected rapid and progressive accumulation of disability.", "affiliations": "Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina, 60, 20132, Milan, Italy.;Department of Neurology, Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.;Department of Neurology, Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.;Department of Neurology, Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.;Department of Neurology, Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.;Department of Neuroradiology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.;Department of Neurology, Division of Neuroscience, Institute of Experimental Neurology, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy.;Neuroimaging Research Unit, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina, 60, 20132, Milan, Italy. filippi.massimo@hsr.it.", "authors": "Preziosa\|Paolo\|P\|;Sangalli\|Francesca\|F\|;Esposito\|Federica\|F\|;Moiola\|Lucia\|L\|;Martinelli\|Vittorio\|V\|;Falini\|Andrea\|A\|;Comi\|Giancarlo\|G\|;Filippi\|Massimo\|M\|http://orcid.org/0000-0002-5485-0479", "chemical_list": null, "country": "Italy", "delete": false, "doi": "10.1007/s10072-016-2763-y", "fulltext": null, "fulltext_license": null, "issn_linking": "1590-1874", "issue": "38(2)", "journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology", "keywords": "Differential diagnosis; Glioblastoma; Magnetic resonance imaging; Multiple sclerosis", "medline_ta": "Neurol Sci", "mesh_terms": "D001932:Brain Neoplasms; D015897:Comorbidity; D005909:Glioblastoma; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive; D020529:Multiple Sclerosis, Relapsing-Remitting", "nlm_unique_id": "100959175", "other_id": null, "pages": "361-364", "pmc": null, "pmid": "27837369", "pubdate": "2017-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "22547311;24507525;25788892;25990103", "title": "Clinical deterioration due to co-occurrence of multiple sclerosis and glioblastoma: report of two cases.", "title_normalized": "clinical deterioration due to co occurrence of multiple sclerosis and glioblastoma report of two cases" }	[ { "companynumb": "IT-EMD SERONO-8153118", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "INTERFERON BETA-1A" }, "drugadditional": "3", ...
{ "abstract": "We report an autopsy case of bronchial asthma patient with a specific abdominal aortic aneurysm. The aneurysm did not show arteriosclerosis, and a specific saccular morphology was noted above the bifurcation. Histologically, necrosis of the media resembling acute aortic dissociation was observed. However, angiitis was ruled out. In addition, the aneurysm showed a cicatrized, old intimal crack in addition to the rupture site, suggesting repeated failures. The long-term steroid therapy-related fragility of the arterial wall may have been involved in the etiology of the aneurysm.", "affiliations": "Department of Forensic Medicine, Tokyo Medical University, Tokyo 160-8402, Japan; Tokyo Medical Examiner's Office, Tokyo Metropolitan Government, Tokyo 112-0012, Japan. Electronic address: mizukamh@tokyo-med.ac.jp.;Department of Forensic Medicine, Tokyo Medical University, Tokyo 160-8402, Japan.;Department of Forensic Medicine, Tokyo Medical University, Tokyo 160-8402, Japan.;Tokyo Medical Examiner's Office, Tokyo Metropolitan Government, Tokyo 112-0012, Japan; Department of Forensic Medicine, Saitama Medical University, Saitama 350-0495, Japan.;Tokyo Medical Examiner's Office, Tokyo Metropolitan Government, Tokyo 112-0012, Japan.;Department of Forensic Medicine, Tokyo Medical University, Tokyo 160-8402, Japan.;Tokyo Medical Examiner's Office, Tokyo Metropolitan Government, Tokyo 112-0012, Japan.", "authors": "Mizukami\|Hajime\|H\|;Hara\|Shuichi\|S\|;Kobayashi\|Masamune\|M\|;Takahashi\|Shirushi\|S\|;Mori\|Shinjiro\|S\|;Kuriiwa\|Fumi\|F\|;Fukunaga\|Tatsushige\|T\|", "chemical_list": "D013256:Steroids", "country": "Ireland", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1344-6223", "issue": "16(1)", "journal": "Legal medicine (Tokyo, Japan)", "keywords": "Acute aortic dissociation; Aortic aneurysm; Long-term steroid therapy; Necrosis of the media; bronchial asthma; medico-legal autopsy", "medline_ta": "Leg Med (Tokyo)", "mesh_terms": "D000328:Adult; D017544:Aortic Aneurysm, Abdominal; D001019:Aortic Rupture; D001249:Asthma; D001344:Autopsy; D005260:Female; D006801:Humans; D013256:Steroids", "nlm_unique_id": "100889186", "other_id": null, "pages": "33-5", "pmc": null, "pmid": "24156880", "pubdate": "2014-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Rupture of abdominal aortic aneurysm associated with long-term steroid therapy--a case report.", "title_normalized": "rupture of abdominal aortic aneurysm associated with long term steroid therapy a case report" }	[ { "companynumb": "JP-TEVA-548966ISR", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "EPINASTINE HYDROCHLORIDE" }, "drugadditional": null,...
{ "abstract": "Iron overload, resulting from blood transfusions in patients with chronic anemias, has historically been controlled with regular deferoxamine, but its parenteral requirement encouraged studies of orally-active agents, including deferasirox and deferiprone. Deferasirox, licensed by the US Food and Drug Administration in 2005 based upon the results of randomized controlled trials, is now first-line therapy worldwide. In contrast, early investigator-initiated trials of deferiprone were prematurely terminated after investigators raised safety concerns. The FDA declined market approval of deferiprone; years later, it licensed the drug as \"last resort\" therapy, to be prescribed only if first-line drugs had failed. We undertook to evaluate the long-term effectiveness and toxicities of deferiprone and deferasirox in one transfusion clinic.\n\n\n\nUnder an IRB-approved study, we retrospectively inspected the electronic medical records of consented iron-loaded patients managed between 2009 and 2015 at The University Health Network (UHN), Toronto. We compared changes in liver and heart iron, adverse effects and other outcomes, in patients treated with deferiprone or deferasirox.\n\n\n\nAlthough deferiprone was unlicensed in Canada, one-third (n = 41) of locally-transfused patients had been switched from first-line, licensed therapies (deferoxamine or deferasirox) to regimens of unlicensed deferiprone. The primary endpoint of monitoring in iron overload, hepatic iron concentration (HIC), increased (worsened) during deferiprone monotherapy (mean 10±2-18±2 mg/g; p < 0.0003), exceeding the threshold for life-threatening complications (15 mg iron/g liver) in 50% patients. During deferasirox monotherapy, mean HIC decreased (improved) (11±1-6±1 mg/g; p < 0.0001). Follow-up HICs were significantly different following deferiprone and deferasirox monotherapies (p < 0.0000002). Addition of low-dose deferoxamine (<40 mg/kg/day) to deferiprone did not result in reductions of HIC to <15 mg/g (baseline 20±4 mg/g; follow-up, 18±4 mg/g; p < 0.2) or in reduction in the proportion of patients with HIC exceeding 15 mg/g (p < 0.2). During deferiprone exposure, new diabetes mellitus, a recognized consequence of inadequate iron control, was diagnosed in 17% patients, most of whom had sustained HICs exceeding 15 mg/g for years; one woman died after 13 months of a regimen of deferiprone and low-dose deferasirox. During deferiprone exposure, serum ALT increased over baseline in 65% patients. Mean serum ALT increased 6.6-fold (p < 0.001) often persisting for years. During deferasirox exposure, mean ALT was unchanged (p < 0.84). No significant differences between treatment groups were observed in the proportions of patients estimated to have elevated cardiac iron.\n\n\n\nDeferiprone showed ineffectiveness and significant toxicity in most patients. Combination with low doses of first-line therapies did not improve the effectiveness of deferiprone. Exposure to deferiprone, over six years while the drug was unlicensed, in the face of ineffectiveness and serious toxicities, demands review of the standards of local medical practice. The limited scope of regulatory approval of deferiprone, worldwide, should restrict its exposure to the few patients genuinely unable to tolerate the two effective, first-line therapies.", "affiliations": "Medicine and Public Health Sciences, University of Toronto, Toronto, Ontario, Canada.;Medicine and Public Health Sciences, University of Toronto, Toronto, Ontario, Canada.;Department of Ophthalmology and Vision Science, Hospital for Sick Children, Toronto, Ontario, Canada.", "authors": "Olivieri\|Nancy F\|NF\|0000-0002-4053-2445;Sabouhanian\|Amir\|A\|;Gallie\|Brenda L\|BL\|0000-0002-9697-9211", "chemical_list": "D007502:Iron Chelating Agents; D000077543:Deferiprone; D000077588:Deferasirox", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0211942", "fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 3081143910.1371/journal.pone.0211942PONE-D-18-20266Research ArticleMedicine and Health SciencesPharmacologyDrug Research and DevelopmentDrug LicensingBiology and Life SciencesToxicologyToxicityMedicine and Health SciencesPathology and Laboratory MedicineToxicologyToxicityMedicine and Health SciencesEndocrinologyEndocrine DisordersDiabetes MellitusMedicine and Health SciencesMetabolic DisordersDiabetes MellitusMedicine and Health SciencesPharmacologyDrug Research and DevelopmentMedicine and Health SciencesPain ManagementArthralgiaPeople and placesGeographical locationsNorth AmericaCanadaResearch and Analysis MethodsResearch DesignClinical Research DesignAdverse EventsMedicine and Health SciencesDiagnostic MedicineClinical Laboratory SciencesTransfusion MedicineBlood TransfusionMedicine and Health SciencesHematologyTransfusion MedicineBlood TransfusionSingle-center retrospective study of the effectiveness and toxicity of the oral iron chelating drugs deferiprone and deferasirox Retrospective oral chelation outcomeshttp://orcid.org/0000-0002-4053-2445Olivieri Nancy F. ConceptualizationData curationFormal analysisInvestigationMethodologyProject administrationResourcesSupervisionValidationWriting – original draftWriting – review & editing12Sabouhanian Amir Data curationFormal analysisInvestigationMethodologyValidationVisualizationWriting – review & editing12http://orcid.org/0000-0002-9697-9211Gallie Brenda L. ConceptualizationData curationFormal analysisInvestigationValidationVisualizationWriting – original draftWriting – review & editing3451 \nMedicine and Public Health Sciences, University of Toronto, Toronto, Ontario, Canada2 \nToronto General Hospital, University Health Network, Toronto, Ontario, Canada3 \nDepartment of Ophthalmology and Vision Science, Hospital for Sick Children, Toronto, Ontario, Canada4 \nDepartments of Ophthalmology and Vision Science, Medical Biophysics and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada5 \nTechna Institute and Krembil Research Institute, University Health Network, Toronto, Ontario, CanadaBiemba Godfrey EditorPaediatric Centre of Excellence, ZAMBIACompeting Interests: Dr. Nancy F. Olivieri led two investigator-initiated trials of deferiprone begun in 1989 (partially funded by Apotex Inc. from 1993) at Toronto’s Hospital for Sick Children and the University of Toronto. In 1995, she identified concerns regarding long-term effectiveness and safety of deferiprone. In 1996, both Toronto trials were terminated abruptly and prematurely, and Dr. Olivieri was threatened with legal remedies should she make concerns public. Dr. Brenda L. Gallie, an independent researcher at The Hospital for Sick Children and the University, was involved directly in all related events over the subsequent decade of legal proceedings. An independent description of the first five years of this controversy provides additional details (Thompson J, Baird P, Downie J. The Olivieri Report: The complete text of the report of the independent committee of inquiry commissioned by the Canadian Association of University Teachers. Toronto: James Lorimer & Co. Publishers; 2001). In 2014, a final settlement respecting all legal matters was mediated between Dr. Olivieri and Apotex. This does not alter the authors' adherence to all PLOS ONE policies on sharing data and materials.\n\n E-mail: nancy@hemoglobal.org27 2 2019 2019 5 3 2019 14 2 e021194214 7 2018 25 1 2019 © 2019 Olivieri et al2019Olivieri et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nIron overload, resulting from blood transfusions in patients with chronic anemias, has historically been controlled with regular deferoxamine, but its parenteral requirement encouraged studies of orally-active agents, including deferasirox and deferiprone. Deferasirox, licensed by the US Food and Drug Administration in 2005 based upon the results of randomized controlled trials, is now first-line therapy worldwide. In contrast, early investigator-initiated trials of deferiprone were prematurely terminated after investigators raised safety concerns. The FDA declined market approval of deferiprone; years later, it licensed the drug as “last resort” therapy, to be prescribed only if first-line drugs had failed. We undertook to evaluate the long-term effectiveness and toxicities of deferiprone and deferasirox in one transfusion clinic.\n\nMethods and findings\nUnder an IRB-approved study, we retrospectively inspected the electronic medical records of consented iron-loaded patients managed between 2009 and 2015 at The University Health Network (UHN), Toronto. We compared changes in liver and heart iron, adverse effects and other outcomes, in patients treated with deferiprone or deferasirox.\n\nResults\nAlthough deferiprone was unlicensed in Canada, one-third (n = 41) of locally-transfused patients had been switched from first-line, licensed therapies (deferoxamine or deferasirox) to regimens of unlicensed deferiprone. The primary endpoint of monitoring in iron overload, hepatic iron concentration (HIC), increased (worsened) during deferiprone monotherapy (mean 10±2–18±2 mg/g; p < 0.0003), exceeding the threshold for life-threatening complications (15 mg iron/g liver) in 50% patients. During deferasirox monotherapy, mean HIC decreased (improved) (11±1–6±1 mg/g; p < 0.0001). Follow-up HICs were significantly different following deferiprone and deferasirox monotherapies (p < 0.0000002). Addition of low-dose deferoxamine (<40 mg/kg/day) to deferiprone did not result in reductions of HIC to <15 mg/g (baseline 20±4 mg/g; follow-up, 18±4 mg/g; p < 0.2) or in reduction in the proportion of patients with HIC exceeding 15 mg/g (p < 0.2). During deferiprone exposure, new diabetes mellitus, a recognized consequence of inadequate iron control, was diagnosed in 17% patients, most of whom had sustained HICs exceeding 15 mg/g for years; one woman died after 13 months of a regimen of deferiprone and low-dose deferasirox. During deferiprone exposure, serum ALT increased over baseline in 65% patients. Mean serum ALT increased 6.6-fold (p < 0.001) often persisting for years. During deferasirox exposure, mean ALT was unchanged (p < 0.84). No significant differences between treatment groups were observed in the proportions of patients estimated to have elevated cardiac iron.\n\nConclusions\nDeferiprone showed ineffectiveness and significant toxicity in most patients. Combination with low doses of first-line therapies did not improve the effectiveness of deferiprone. Exposure to deferiprone, over six years while the drug was unlicensed, in the face of ineffectiveness and serious toxicities, demands review of the standards of local medical practice. The limited scope of regulatory approval of deferiprone, worldwide, should restrict its exposure to the few patients genuinely unable to tolerate the two effective, first-line therapies.\n\nThe authors received no specific funding for this work. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nOver 40 years, the iron-chelating agent deferoxamine [1, 2] has transformed previously fatal iron-loading anemias into chronic conditions in high-resource countries [3–7]. The magnitude of the body iron burden is correlated with hepatic iron concentration (HIC) [8]. Thresholds of HIC predict the development of potentially fatal complications [9]: HIC exceeding 15 mg iron/gram liver, dry weight, and sustained elevations of serum ferritin (SF) over 2500 μg/L, increase the risk of premature death [5, 6].\n\nIn the 1980s, the parenteral requirement for deferoxamine stimulated studies of orally-active chelators. Deferasirox (Exjade, Novartis) was licensed as first line therapy by the FDA in 2005, following randomized trials comparing this drug, and demonstrating its non-inferiority, to deferoxamine\n\nBy contrast, the history of another orally active drug, deferiprone has been characterized by ongoing legal and academic conflict. In 1996, a prolonged controversy arose when a pharmaceutical company, Apotex, terminated two Toronto trials early after the investigators who had initiated both studies raised concerns about effectiveness and safety [10]. This raised issues around the ethics of industry-sponsored clinical trials and institutional conflicts of interest [11, 12]. A randomized controlled trial of deferoxamine and deferiprone, initiated under independent funding and at the direction of the FDA, indicated that deferiprone did not adequately control body iron in many patients [9], but publication of these findings, following repeated legal action by Apotex, did not proceed.\n\nIn 2009, 13 years after the two Toronto trials were terminated, the FDA declined Apotex’s request for approval of deferiprone as first-line therapy [13]. Formal inspection of the source data of the Toronto trials had revealed inconsistencies in the data that had been submitted for approval. In 2011, the FDA issued approval for deferiprone as “last resort” therapy, to be prescribed only after both first-line therapies had failed, [14] cautioning that no controlled trials of deferiprone had demonstrated direct treatment benefit. A 2013 Cochrane review asserted that the FDA’s decision “…arose from the lack of new RCT evidence, and the failure to provide answers to the FDA on efficacy and safety.” [15].\n\nThe objective of our current study was to compare the effectiveness and toxicity of two iron chelators, deferiprone (Ferriprox; Apotex) and deferasirox (Exjade; Novartis) as used at The University Health Network (UHN) which manages 80% of Canada’s hemoglobinopathy patients [16]. The endpoints were the accepted measurements of iron overload (SF, HIC, and myocardial T2* weighted MRI image, T2), hepatic and other toxicity, and other patient outcomes, as recorded in the electronic medical record (EMR).\n\nMethods\nSample and data collection\nIn 2000, the UHN Research Ethics Board approved Study REB 01-0170-B, which authorized us to study findings recorded in the EMR of consenting UHN iron-loaded patients. No physical examinations, specimen collections, or other interventions were required. We sought consent from all patients who were regularly transfused at UHN (an estimated 120 patients). Excluded were most patients transfused in other centers and those with sickle cell disease whose transfusion regimens differ from those of patients with thalassemia.\n\nWe invited 100 patients to participate in the study; 96 consented. Deferiprone was prescribed to 41 patients with thalassemia major; deferasirox was prescribed to 5 patients with either thalassemia major (52) or Diamond-Blackfan Anemia (4); more than one drug or combination was prescribed to 14 patients (S1 Data). This was a retrospective evaluation of the outcomes of iron chelating therapy in clinical practice.\n\nData up to January 2016 were collected. No data arising from any drug initiated after January 1, 2015 (that is, involving less than one year of therapy) were analyzed.\n\nIntervals of treatment\nDuring deferiprone exposures, regimens were altered frequently in the same patient over brief periods. Therefore, we sought to avoid erroneous attribution of effectiveness or toxicity to a drug or drug combination, by evaluating treatment intervals. An interval was defined as evaluable if (i) it was bracketed by baseline and follow-up HIC and/or cardiac T2; and (ii) throughout the interval, one drug or drug combination had been prescribed with no interruption longer than one month. We identified 132 evaluable intervals. Two additional intervals missing follow-up data are included because of serious adverse events (death and agranulocytosis). Sixteen of the 132 intervals (12%) in 12 patients were excluded because of rapid changes in therapy in parallel with absence of assessment of the above endpoints (S1 Table. Excluded intervals.)\n\nData collected and statistical analysis\nData were recorded from the EMRs according to the protocol, including: indications, if stated, for each regimen; symptoms; adverse effects; baseline and follow-up SF, HIC and T2; and proportions of intervals in which these measurements varied from established risk thresholds. To compare baseline and follow-up values within each treatment group, paired t-test was used; a two-sample t-test was used between treatment groups. Fisher’s exact test was used to compare proportions of intervals in which values exceeded established risk thresholds. All tests were two-tailed; 0.05 was considered of statistical significance. Minitab Express Statistical Software was used for analyses. To determine the rationale for use of deferiprone in each study patient, we examined the EMR for reference to a research protocol [17], for evidence that the patient had failed standard licensed therapies and evidence of the use of the Special Access Program, Health Canada as a mechanism to provide patients with this unlicensed drug.\n\nResults\nTreatment intervals\nThere were 36 monotherapy intervals with deferiprone and 62 with deferasirox. Deferiprone was combined with licensed therapy in another 34 intervals (S1 Data and Table 1, Fig 1). Two included treatment intervals are bracketed by SF but not HIC or T2 because of the consequences arising from the exposure to deferiprone (See Results/Adverse Effects/Death, Agranulocytosis). Fourteen patients were analyzable for more than one interval of a drug or drug combination.\n\n10.1371/journal.pone.0211942.g001Fig 1 Scatter plots of data points reflecting body iron load.\nMean±SEM (range) of values bracketing intervals of deferiprone (DFP) [36] and deferasirox (DFX) [62] monotherapy, and DFP with high dose (hd) [13] and low dose (ld) [13] DFO, and full dose (fd) DFX [6] combination therapies. Grey symbols are baseline (BL) values; black symbols are follow-up (FU) values. BL and FU values for each interval are connected by lines (red lines indicate worsening of iron load over the interval; green lines indicate improvement of iron load over the interval; p values corresponding to worsening body iron are red.\n\n10.1371/journal.pone.0211942.t001Table 1 Outcomes of chelation therapies.\nDoses of chelator drugs [recommended dose range, mg/kg/d]\tDeferiprone Mono-therapy\tDeferiprone with deferoxamine\tDeferiprone/ deferasirox\tDeferasirox mono-therapy\t\nFull–dose >40\tLow dose <40\tFull–dose ≥20\t\nDeferoxamine [40–50]\t \t47±2\t24±3\t \t \t\n(40–55)\t(8–37)\t\nDeferasirox [20–45]\t \t \t \t29±3\t26±1\t\n(20–42)\t(10–45)\t\nDeferiprone [75–100]\t104±2\t101±4\t99±5\t101±8\t \t\n(75–127)\t(76–20)\t(75–123)\t(69–120)\t\nDuration (months)\t32±4\t14±1\t21±3\t24±4\t66±4\t\nSF μg/L\tBL\t2665±420\t4640±904\t3823±1021\t2204±803\t2084±192\t\n(135–11455)\t(220–12373)\t(767–12715)\t(528–6024)\t(339–8117)\t\nFU\t3364±504\t2867±718\t3949±1113\t1465±555\t1645±215\t\n(311–12715)\t(232–8267)\t(159–14025)\t(135–3605)\t(161–9127)\t\nBL vs FU\tp < 0.03\tp < 0.05\tp < 1\tp < 0.4\tp < 0.03\t\nMonths between SF\t \t31±4\t14±1\t22±3\t22±5\t58±4\t\nProportion of intervals SF >2500 μg/L\tBL\t37%\t69%\t46%\t17%\t32%\t\nFU\t51%\t46%\t46%\t17%\t21%\t\nBL vs FU\tp < 0.3\tp < 0.5\tp < 1\tp < 1\tp < 0.3\t\nHIC mg/g\tBL\t10±2(1–43)\t25±5(3–4)\t20±4(2–43)\t7±2(1–13)\t11±1(1–38)\t\nFU\t18±2(2–43)\t8±2(1–26)\t18±4(1–43)\t5±2(1–11)\t6±1(0.4–33)\t\nBL vs FU\tp < 0.0003\tp < 0.003\tp < 0.2\tp < 0.5\tp < 0.00001\t\nMonths between HIC\t \t30±3\t15±2\t21±3\t26±7\t45±3\t\nProportion of intervals HIC ≤7 mg/g\tBL\t56%\t17%\t15%\t50%\t40%\t\nFU\t24%\t50%\t38%\t67%\t76%\t\nBL vs FU\tp < 0.008\tp < 0.1\tp < 0.4\tp < 1\tp < 0.0001\t\nProportion of intervals HIC ≥15 mg/g\tBL\t21%\t67%\t46%\t0\t27%\t\nFU\t50%\t8%\t46%\t0\t8%\t\nBL vs FU\tp < 0.02\tp < 0.009\tp < 1\tp < 1\tp < 0.02\t\nMyocardial T2* (msec)\tBL\t17±4(5–36)\t15±4(5–39)\t16±2(7–38)\t11±2(7–20)\t26±1(5–42)\t\nFU\t22±2(5–40)\t18±4(5–38)\t18±2(12–38)\t16±3(9–27)\t31±2(8–68)\t\nBL vs FU\tp < 0.3\tp < 0.04\tp < 0.2\tp < 0.2\tp < 0.001\t\nMonths between T2\t \t29±4\t15±1\t15±1\t22±6\t43±3\t\nProportion of intervals T2 ≤10 msec\tBL\t18%\t42%\t8%\t67%\t5%\t\nFU\t6%\t42%\t8%\t17%\t3%\t\nBL vs FU\tp < 0.3\tp < 1\tp < 1\tp < 0.2\tp < 0.7\t\nProportion intervals T2* <20 msec\tBL\t73%\t75%\t42%\t83%\t37%\t\nFU\t50%\t58%\t42%\t66%\t23%\t\nBL vs FU\tp < 0.1\tp < 0.5\tp < 1\tp < 1\tp < 0.2\t\nEF (%)\tBL\t61±2(48–75)\t59±3(37–74)\t62±2(53–73)\t59±2(54–66)\t61±1(48–72)\t\nFU\t60±1(51–73)\t61±2(50–67)\t64±2(54–75)\t61±1(57–66)\t61±1(39–69)\t\nBL vs FU\tp < 1\tp < 0.2\tp < 0.2\tp < 0.2\tp < 1\t\nMonths between EF\t \t29±4\t15±1\t24±3\t22±6\t43±3\t\nLab values of evaluable intervals available in S1 Data; mean±SEM (range); serum ferritin, SF; hepatic iron concentration, HIC; cardiac ejection fraction, EF; p value indicating improvement in iron load, bold, green cell; p value indicating worsening iron load, italics, red cell.\n\nWe identified 70 intervals of deferiprone, initiated in 2009 or later, in 41 patients: 23 patients had one analyzable interval, 11 had two, 5 had three, and 2 had five. We identified 62 intervals of deferasirox initiated in 2005 or later, in 55 patients; 48 patients had one analyzable interval, 4 had two, and 2 had three. Interval durations varied: HICs during deferiprone treatment combined with full–dose deferoxamine were separated by (mean±SEM) 14±2 months, while during deferasirox monotherapy, intervals were longer (mean±SEM) 45±3 months (Table 1, Fig 1) because regimens were switched less frequently.\n\nDosing\nDeferiprone exceeded the maximum recommended dose [100 mg/kg/day] in 38 (54%) treatment intervals, (mean±SEM and median doses: 113±1, and 114, mg/kg/day). Deferasirox was prescribed at (mean±SEM) 26±1 mg/kg/day [recommended, 20–45 mg/kg/day].\n\nAll patients: Effectiveness\nBaseline HIC in the intervals of deferiprone (monotherapy/combinations, n = 70) and of deferasirox (monotherapy, n = 62) were not significantly different (p < 0.1) (S2 Table. All DFP vs all DFX). During deferiprone, HIC, SF and the proportion of intervals at or exceeding thresholds of risk did not change (p < 0.1); by contrast, during deferasirox treatment HIC, SF (p <0.0001), and the proportion of intervals exceeding thresholds of risk were significantly reduced (improved) compared to baseline (p < 0.01).\n\nBaseline cardiac T2* was significantly lower in deferiprone- than deferasirox-treatment intervals (p <0.001); a comparable mean change in each group resulted in a persistent difference at follow-up (p < 0.0001). The proportion of intervals in which T2* remained ≤ 10 msec and 20 msec did not change in either group.\n\nMonotherapies: Deferiprone and deferasirox\nBetween intervals of deferiprone monotherapy (n = 36) and deferasirox monotherapy (n = 62) (Table 1, Fig 1, S1 Data. Lab values of included intervals), mean baseline HIC and SF were not different (p < 0.7 and p < 0.2 respectively); overall, HIC and SF worsened during deferiprone treatment (p < 0.001 and p < 0.0003, respectively), and improved during deferasirox treatment (p < 0.001 and p < 0.0001, respectively); follow-up HIC values differing between deferiprone and deferasirox monotherapies were highly significant (p < 0.0000002). Similarly, although at baseline the proportion of intervals in which HIC ≥15 mg/g did not differ (p < 0.6), the proportion of intervals more than doubled during deferiprone treatment but declined strikingly during deferasirox treatment and, by follow-up, this represented a 5-fold difference (p < 0.0001). Statistically significant improvements in T2* were observed during both deferiprone and deferasirox monotherapy, but the proportions of intervals in which T2* was ≤10 or ≤20 msec, and the mean ejection fraction, did not change significantly with either treatment (Table 1).\n\nThere were 20 intervals of deferiprone exposure during which HIC was maintained at/reduced to optimal concentrations (<7 mg/g liver) (S1 Data. Lab values of included intervals). In 12 of 20 intervals deferiprone was co-prescribed with licensed therapy (in 10, full doses of deferoxamine/deferasirox). In 8 of the 20 deferiprone monotherapy intervals, initial HIC was strikingly low (<2 mg/g) (patients 10, 17, 21, 27, 33); in 4/8 intervals, deferiprone dose was ≥110 mg/kg/day (upper recommended dose 100 mg/kg/day). In 4/8 intervals, follow-up T2* was recorded as improved (after a mean 54 months); the other 4 intervals showed no change or a decline in, or no assessment of T2. ALT increased in 7/8 intervals (including 6 with initial HIC <2 mg/g) and arthralgias were recorded in 4 intervals. Of the 8 intervals during which optimal HIC was achieved or maintained during deferiprone monotherapy, 4 exceeded 2.5 years, and the others spanned 12 to 26 months. In one interval deferiprone monotherapy reduced HIC >10 mg/g to optimal levels.\n\nOf 36 deferiprone monotherapy intervals (S1 Data. Lab values of evaluable intervals), one showed an HIC improvement to the optimal level (patient 4 interval 2, 10.9 to 2.3 mg/g). Two intervals showed a decline in HIC but remained above 7 mg/g (patient 18 interval 1, 37.8 to 18.9 mg/g; patient 28 interval 2, 19.6 to 14.2 mg/g). Of 62 deferasirox monotherapy intervals, one showed a poor response with elevation of HIC out of the optimal range (patient 47 interval 1, 5.3 to 13.4 mg/g) and two intervals that were abnormal at baseline worsened (patient 54 interval 1, 12.9 to 22.9 mg/g; patient 80 interval 1, 12.8 to 32.6 mg/g). These iron load changes were similarly reflected in SF.\n\nBecause the widespread prescribing of deferiprone had followed a staff change at UHN in 2009, exposure to deferiprone monotherapy (32±4 months) was shorter than to deferasirox monotherapy (66±4 months). To determine if differences were related to longer deferasirox exposures, we also documented relevant endpoints after 30±6 months of deferasirox. The data indicate that the greater effectiveness of deferasirox was unrelated to longer deferasirox exposures (S3 Table. All patients exposed 30 months).\n\nDeferiprone added to deferoxamine at therapeutic and low doses\nDeferiprone was added to therapeutic (≥40 mg/kg/day) deferoxamine (13 intervals), or to low-dose (<40 mg/kg/day) deferoxamine (13 other intervals) (Table 1, Fig 1). There was a striking difference between the two groups: after a short period (14.7±1.8 months), the addition of deferoxamine 47.2±1.4 mg/kg/day to deferiprone effected significant improvement in HIC (p < 0.003), T2 (p < 0.034), SF (p < 0.043), and in the proportion of intervals in which HIC exceeded 15 m/g (p < 0.009). By contrast, over 21.1±2.6 months, deferiprone combined with deferoxamine 24.2±2.8 mg/kg/day (equivalent to 4.2 days/week of therapeutic deferoxamine) did not significantly alter HIC, SF, the proportion of intervals in which HIC or SF exceeded risk thresholds, T2, or the proportions of intervals in which T2 remained ≤10 and ≤20 msec.\n\nDeferiprone combined with deferasirox at therapeutic and low doses\nSimilar results emerged during intervals of deferasirox added to deferiprone. When deferasirox 28.9±3.2 mg/kg/day was combined with deferiprone, mean HIC and SF remained within optimal range (Table 1). In six patients a mean increase of approximately 5 msec in T2* did not reach statistical significance (p < 0.1). In only two intervals low dose (<20 mg/kg/day) deferasirox was added to deferiprone; during one interval, the patient (#19) died after 13 months.\n\nAlterations in transfusion intensity\nIn seven deferiprone intervals, shortly following introduction of deferiprone, the EMR explicitly documented a plan to reduce volumes of transfused blood to attempt to ameliorate myocardial iron loading.\n\nMonitoring for agranulocytosis in deferiprone-exposed patients\nAgranulocytosis was recognized in early studies to be a risk of deferiprone [18, 19]. Weekly complete blood counts (CBCs) are mandated in the product monograph [20] and the UHN guidelines [21]. In 14 (34%) patient records, the failure to monitor weekly CBCs was noted in the EMR.\n\nAdverse effects\nDeath\nWhile on deferiprone with low-dose deferasirox over 13 months, patient #19 developed arthralgias, nausea, vomiting, headaches and visual disturbances, and died suddenly, presumably of cardiac failure. Pre-deferiprone HIC was 43 mg/g and T2* was 8.3±0.2 msec; these were not re-assessed over the 13 months of the regimen, in non-compliance with guidelines. Pre-deferiprone SF was 4071 μg/L; this had increased to 8018 μg/L in the months before death, during exposure to a regimen of 100 mg deferiprone/kg/day and alternate-week deferasirox (equivalent to 15 mg/kg/day, <50% of the recommended deferasirox dose for this elevation of HIC).\n\nNo death was recorded in deferasirox-treated patients\n\nElevations in serum alanine aminotransferase (ALT)\nMost ALT elevations above normal (40 units per liter; U/L) observed during deferiprone did not resolve within one interval (or at all); therefore, ALT changes were analyzed in individual patients rather than treatment intervals (Fig 2, Table 2).\n\n10.1371/journal.pone.0211942.g002Fig 2 ALT elevations correlating with deferiprone chelation.\n(A) Patient #34, (B) Patient #1, (C) Patient #19 (datafile). Normal ALT <40U/L, red line; deferiprone (DFP) red arrows and font; deferasirox (DFX), blue arrows and font; deferoxamine (DFO), green arrows and font.\n\n10.1371/journal.pone.0211942.t002Table 2 Patients with increased ALT (normal <40 U/L) up to January 2016.\nPatients [n]\tMeasurement\tMean±SEM\tMedian(range)\t\n[26]\nIncreased ALT upon first exposure to DFP [22] or dose escalation [4]; HepC positive [7].\tBL ALT\t25±4\t22(5–75)\t\nPeak ALT\t166±19\t139(59–395)\t\nFold increase over BL\t6.6\t6.3(2–24)\t\nMonths between BL and first ALT elevation over BL\t3±0.4\t2(1–9)\t\nMonths between BL and peak ALT\t14.9±2.2\t13(1–46)\t\nFU HIC\t15±2\t13(1–46)\t\n[21] remained on DFP:\n[5] ALT normalized;\n[16] ALT remained >40 U/L.\tBL ALT\t26±3\t24(5–75)\t\nFU ALT\t70±14\t55(9–305)\t\nP value BL to FU\tp < 0.01\t\t\nFold increase FU over BL\t2.7\t2.3(1–19)\t\nFU HIC\t15±3\t11(2–43)\t\n[16/21] ALT remains abnormal.\tBL ALT\t25 ± 4\t24(9–69)\t\nFU ALT\t87±17\t64(41–305)\t\nP value BL to FU\tp < 0.003\t\t\nFold increase FU over BL\t3.5\t2.7(1–19)\t\nHIC at censure of data\t18±4\t13(2–43)\t\nMonths on deferiprone\t49±6\t61(13–75)\t\nDFP, deferiprone; HIC, hepatic liver iron concentration; HepC, hepatitis C virus; Baseline, BL; Follow-up, FU; p value indicating worsening ALT, italics, red cell.\n\nIn 40/41 patients evaluable for changes in ALT, three patterns of changes were observed (Table 2).\n\nIn 26/40 (65%) evaluable patients, seven positive for hepatitis C, ALT increased over baseline following either introduction of deferiprone (in 22), or dose escalations to 111–127 mg/kg/day (in 4), of deferiprone. Elevations were recorded 3±0.4 months following introduction/escalation; mean peak elevation (6.6-fold; range 2-24-fold) was recorded 14.9±2.2 months following introduction/escalation.\n\nIn 4/40 of evaluable patients, three positive for hepatitis C, elevations of ALT followed deferiprone but fluctuating pre-deferiprone values prevented conclusions about their relationship to deferiprone. One patient died 13 months after introduction of deferiprone with low-dose deferasirox; one resumed deferoxamine monotherapy with a return to baseline ALTs; two remained on deferiprone (one monotherapy; one combined with deferasirox) with a return to baseline ALT values.\n\nIn 10/40 evaluable patients, four positive for hepatitis C, no increases in ALT were observed. Five of the 10 were prescribed full-dose deferoxamine or deferasirox along with deferiprone; five were receiving deferiprone monotherapy.\n\nContinued deferiprone despite to elevations in ALT. In 11/26 patients in whom ALTs increased, deferiprone was continued. Eight patients on deferiprone monotherapy had elevated ALT for years. Three patients continued on deferiprone, two combined with deferoxamine at 42 mg/kg/day and 16 mg/kg/day, respectively, and one combined with deferasirox 30 mg/kg/day. ALT elevations returned to baseline in three of the eight after 0.5, 0.5, and 5.5 years of deferiprone.\n\nAlteration in regimen. In 15/26 patients in whom ALTs had increased, regimens were altered; in 14/15, ALT elevations resolved completely. In 4/15 patients, deferiprone was withdrawn; ALT returned to pre-deferiprone values within two months. In 3/15, deferiprone dose was reduced (to 70 mg/kg/day, 65 mg/kg/day, and 59 mg/kg/day, respectively); ALT elevations partially (n = 1) or completely (n = 2) resolved over months. In the remaining 8/15 patients, licensed therapy with deferasirox or deferoxamine was added (in parallel, in two patients, with reduction of deferiprone dose); in all 8, ALT returned to pre-deferiprone values within two months.\n\nRe-challenge. Ten of 15 patients were re-challenged with their original regimens: two were re-prescribed deferiprone after it had been withdrawn; two re-prescribed full-dose deferiprone after temporary dose reduction; and six re-prescribed deferiprone monotherapy after an added licensed drug was stopped. In all 10, ALT re-surges followed re-challenge; three are shown in Fig 2.\n\nOverall, after ALT elevations were observed, deferiprone was continued in 21/26 patients. In five, ALT normalized: during monotherapy (3) or after addition of full-dose deferoxamine (1), or deferasirox (1). In 16 patients at the time of writing, ALT remained abnormal, elevated at 87±17 U/L (3.5-fold over baseline) after 49±6 months of exposure (p < 0.003).\n\nIn deferasirox-treated patients, ALT did not change between baseline (33±5 U/L) and follow-up (36±15 U/L; p < 0.84). Seven (12.5%) patients developed elevations over baseline. Four patients continued deferasirox and ALT normalized in three. Three patients resolved on deferoxamine, but rebounded when deferiprone monotherapy was introduced. ALT remained unresolved in two patients but normalized in one patient after 63 months on deferiprone.\n\nNew diabetes mellitus during deferiprone\nOf 36 non-diabetic patients, 6 (16.6%) were diagnosed with new diabetes during deferiprone (as monotherapy or combined with deferoxamine 7–28 mg/kg/day). In 4/6, HICs closest to the diagnosis of diabetes exceeded 20 mg/g. Of 51 deferasirox-exposed, non-diabetic patients, one (2%), whose parents are diabetic, was diagnosed with diabetes after seven years of excellent compliance with deferasirox; HIC closest to the diagnosis of diabetes was 1.6 mg/g.\n\nGI disturbances\nGI disturbances were reported in 7/41 (17%) of deferiprone-treated patients and 6/55 (11%) of deferasirox-treated patients.\n\nAgranulocytosis\nTwo episodes of agranulocytosis were recorded in patient #3 who 18 years previously developed agranulocytosis requiring hospitalization and infusions of Granulocyte Colony Stimulating Factor (G-CSF) [18] following deferiprone exposure. In 2012, the patient was again prescribed deferiprone monotherapy, despite good ongoing control of iron burden (pre-deferiprone HIC 0.9 mg/g; T2* 16 msec) during deferasirox therapy. Agranulocytosis again required hospitalization and G-CSF. One month after marrow recovery, deferiprone was prescribed a third time; agranulocytosis again required hospitalization and G-CSF. Repeated exposures to deferiprone after agranulocytosis is contraindicated by published guidelines.\n\nNeutropenia\nNeutopenia (Absolute Neutrophil Count <200) developed in another treatment interval, in a different patient, approximately 3.5 years after the introduction of deferiprone monotherapy. No agranulocytosis or neutropenia were reported in deferasirox-treated patients.\n\nArthralgias\nAn acknowledged adverse effect associated with deferiprone, arthralgias developed in 11 (27%) patients within months of introduction of deferiprone. This was frequently attributed in the clinical notes to alternative etiologies. In five patients, deferiprone was discontinued: in four patients, 22 to 38 months following onset of arthralgias and, in one patient, after 8 months when HIC was had increased from 23 to 30 mg/g. Arthralgias resolved in all five patients following deferiprone withdrawal. In six patients, deferiprone was not withdrawn; resolution in five was not recorded, and patient #19 complained of arthralgias until death.\n\nElevations in serum creatinine\nSerum creatinine values exceeding baseline for longer than one month were recorded in 10 (17.8%) deferasirox-exposed patients; in three, the relationship to deferasirox was uncertain. Five patients were switched to deferiprone; in another four, elevations resolved while deferasirox continued; in the tenth, creatinine peaked at 172 μmol/L, and declined to 130 μmol/L while deferasirox continued. No elevations in serum creatinine were reported during deferiprone.\n\nMechanism of prescription of deferiprone\nFrom 2009 to 2015, deferiprone was not licensed in Canada. There are two possible processes by which an unlicensed drug can be used in patient care in Canada: under the terms a formal research protocol of a (registered) clinical trial [17] or under Health Canada’s Special Access Program (SAP) which “considers requests …for access to unauthorized drugs for …serious or life-threatening conditions when conventional therapies … have failed, are unsuitable or unavailable.” [22].\n\nIndications for prescription of deferiprone\nDeferiprone was prescribed to 41 study patients between 2009 and 2015. We could identify in the EMR no explanation for a proposed switch to deferiprone that was supported by evidence of failure of licensed therapy prescribed as recommended. There was no indication that any patient switched to deferiprone over these six years had “failed” therapy with either deferoxamine or deferasirox. Most patients were recorded as tolerant of at least one and (in most), both licensed first-line chelating agents; some had sustained minor adverse events during deferasirox that had resolved by the time deferiprone was prescribed.\n\nBased upon pre-deferiprone HIC and T2, the 41 study patients switched to deferiprone could be assigned to one of four groups (S1 Text. Discussing Indications). Group I patients (16) had demonstrated optimal responses to licensed therapies; Group II patients (3) had a prolonged absence from chelation related to pregnancy, but licensed therapies had not “failed” and were not “unsuitable or unavailable”; Group III patients (13) had inadequate control of HIC concentration (without evidence of cardiac iron loading) in most following treatment with lower-than-recommended doses of licensed therapy; and Group IV patients (9) had reduced cardiac T2; half the Group IV patients had, in parallel, the highest HIC recorded in the clinic. According to guidelines, this situation is an indication for therapeutic doses of licensed chelation, not deferiprone.\n\nDiscussion\nWe report the effectiveness and toxicity of the two orally active iron chelator drugs, deferasirox and deferiprone in transfused patients managed at Canada’s largest transfusion program. This was not a prospective trial with study protocols, but rather examination of the EMR of patients who consented.\n\nBetween 2009 and 2015, one-third of iron-loaded patient were removed from first-line licensed drugs and prescribed regimens involving unlicensed deferiprone. This represents a higher proportion than expected from the literature on patients who have “failed” licensed therapies [3–5]. We were unable to identify in any patient switched to deferiprone evidence of failure, unsuitability, or unavailability of licensed therapies.\n\nDuring deferiprone monotherapy, body iron burden increased to levels placing patients at risk for glucose intolerance, cardiac disease, and premature death [5, 6]; one death occurred and new diabetes mellitus, a predictable consequence of uncontrolled iron burden, developed in 17% patients, five times the incidence reported in the modern era of deferoxamine [7]. Body iron burden decreased during deferasirox monotherapy. The frequent elevations in serum ALT observed during exposure to deferiprone in these patients are consistent with our previous observations of hepatic dysfunction arising and hepatic fibrosis progressing during deferiprone therapy, even in patients whose body iron had stabilized [23, 24]. Liver histology was not obtained in the patients in the present study, despite the observed sustained elevations in liver enzymes. Consequently, the etiology and potential hepatic damage associated with the liver enzymes remains undefined [24].\n\nAfter numerous subsequent studies provided “disparate findings in small series of patients” [15] the FDA approved deferiprone as “last resort” therapy [27], to be prescribed only after all first-line therapies had failed [14], while confirming that no controlled trials had demonstrated a direct treatment benefit [20]. Moreover, the FDA also judged that the year-long study, submitted as ‘pivotal’ evidence for the unique ‘cardio-protective’ effect of deferiprone, [25] did not establish this benefit [26]. Nonetheless, based upon a claimed ‘cardio-protective’ effect [27–29], deferiprone is prescribed worldwide as first line therapy, either as monotherapy (15%), or in regimens combining deferiprone with less-than -therapeutic doses of other drugs (25%) [30, 31]. Deferiprone is frequently prescribed as first line therapy even to children (for example, 68.3% of children in the Middle East [32], despite inadequate monitoring [33–35]). Its recommendation in pediatric practice persists despite higher rates of toxicity in children, including neutropenia (12.6%), agranulocytosis (5%) [35], and liver dysfunction [36, 37]), than were reported in the Apotex-directed “safety” study [34].\n\nThe results of this retrospective study of the EMR of patients in one Canadian institution contrast strikingly with the literature. They extend concerns arising from the two prematurely terminated Toronto trials of deferiprone [38], challenging the belief that deferiprone enhances organ-specific iron removal [27–29, 39–41]. In most previous studies of deferiprone, body iron as quantitated by HIC has been unreported, selectively reported, reported after short-term exposures, or reported as unchanged or having worsened [10, 18, 34, 42–74]. By contrast, two Apotex-funded studies have reported declines in HIC during combination therapy (deferiprone combined with deferoxamine) as comparable, or better, than during deferoxamine monotherapy but both studies administered deferoxamine monotherapy at less than 70% therapeutic dose [75, 76]; another uncontrolled study which claimed liver iron declined significantly during combination therapy reported a mean decline (in five patients) which derived from the exceptional reduction of liver iron in one patient.[77].\n\nHIC is the only parameter demonstrated to be directly correlated with body iron [78]. Hence, the lack of HIC data is difficult to reconcile with the idea that body iron is adequately reduced during deferiprone monotherapy or deferiprone when it is combined with less than therapeutic doses of deferoxamine [79].\n\nRarely discussed with respect to the issue of “combination” therapy is the dose of deferoxamine “combined” with deferiprone. Protocols of deferiprone with low-dose (2–3 infusions/week) deferoxamine, or therapeutic deferoxamine (≥40 mg/kg/day daily) are generally reported under the general rubric of combination therapy, without clarification of dose. For example, deferoxamine doses are reported as “20 to 60 mg/kg/day” [80] or “30 to 45 mg/kg/day, 5 to 7 days per week” [81], which represent between 40% and 120% of recommended dose and therefore cannot be considered a single regimen. No analyses of combination therapy have related the outcomes of therapy to the dose of deferoxamine administered with deferiprone. We were unable to identify a previous publication presenting evidence that deferiprone combined with deferoxamine at a less-than-therapeutic dose (<40 mg/kg/day) adequately reduced body iron burden. Our literature review and our present data by contrast indicate that during combination of deferiprone with deferoxamine, adequate control of body iron is achieved only when full-dose deferoxamine is prescribed. [69, 80–82] This suggests that effectiveness of combination therapy is related to the effectiveness of deferoxamine. Of further concern, combinations of therapy represent off-label prescribing in most jurisdictions, and impose a 3-fold increased risk of adverse events [15].\n\nDespite reports that cardiac iron is ‘uniquely’ improved by deferiprone [25, 27–29, 39, 41, 79, 83], our data comparing deferiprone and deferasirox showed comparable, and modest, changes in cardiac T2, with no differences in the proportions of patients estimated as having severe cardiac iron loading. Abnormal T2s persisted, while HICs remained elevated, or increased in elevation, during years of deferiprone exposure. This is entirely consistent with the acknowledged dynamics of slower cardiac iron deposition and removal compared to those of the liver, [84] and confirms that myocardial iron does not decline in isolation if body iron burden (quantitated by liver iron concentration) is insufficiently treated. Importantly, an industry-sponsored study submitted to FDA as “pivotal” to support superior cardio-protection of deferiprone monotherapy [25] failed to provide evidence for this benefit [26]. By contrast, the (only) independently funded, randomized, double-blinded, placebo-controlled study to have been reported in the literature confirmed a lack of superiority in ‘cardio-protection’ of deferiprone when combined with full-dose deferoxamine compared to deferoxamine monotherapy [85].\n\nWith respect to T2, most studies of deferiprone monotherapy, often with extended exposures, report no results, no change, improvements in selected patients only, or non-validated endpoints, and cardiac-related deaths [10, 18, 34, 42–61, 63–65, 69, 73, 74, 86–89]. With respect to combination therapy, most studies have not reported cardiac outcomes [57, 60, 61, 63, 64, 75, 90–103]. Uncontrolled studies often combining deferiprone with full-dose deferoxamine have reported changes, [62, 69, 70, 77, 80, 81, 104–109], but of the eight controlled studies in the literature, seven failed to show any difference in cardiac outcomes between combination therapy and deferoxamine monotherapy [65–67, 72, 73, 82, 85]. The eighth study compared a combination of deferiprone and deferoxamine to deferoxamine monotherapy prescribed at lower than therapeutic doses [76].\n\nWe observed another outcome not reported in most studies of deferiprone: new diabetes mellitus occurring during deferiprone exposure, as body iron burdens increased or remained elevated. This dreaded complication of poor iron control [5] developed in nearly 17% of deferiprone-exposed patients. One early (Apotex) study reported an incidence of new diabetes in 3.6% deferiprone-exposed patients [56]; however, the glucose intolerance in more than 50% of patients who prematurely stopped deferiprone in that safety study was not reported.\n\nHepatic dysfunction as reflected by elevations in serum ALT in 65% of UHN patients, sustained over years (Table 2), suggests direct hepato-toxicity. Our original concerns about deferiprone-associated liver toxicity [10] were dismissed [27, 28, 39] [110]; the incidence of deferiprone-associated ALT elevations was subsequently estimated as 7.5% [111]. However, most studies in the literature have failed to report ALT changes, or reported lack of changes after short-term exposures, or in selected patients only [10, 18, 44–47, 49, 51, 52, 56, 58, 62, 66–72, 86, 87, 112–114]. One large study recorded ALT surges 3-fold over baseline in 20% of patients [52]; another reported a 4-fold greater mean ALT elevation in deferiprone-exposed patients, than during deferoxamine, but claimed this to be not significantly different [25]. By contrast, the FDA observed that this observation might “signal[s] the potential for deferiprone induced liver toxicity.\" Often, “transient” ALT elevations [43, 48, 54, 59] have been later acknowledged as sustained: [51, 59, 60] the Apotex “safety” trial, for example, claimed initially that “increased ALT levels “usually stabilized or regressed after three to six months” [34], but later acknowledged mean ALT had remained significantly elevated over baseline over years [56].\n\nUniquely, we documented changes in ALT following discontinuation and re-challenge with deferiprone (Fig 2). Because liver enzymes reflect hepatocyte integrity rather than liver function [115], and because we did not record albumin or pro-thrombin values, liver functional status cannot be provided. However, our original concerns about deferiprone and hepatocyte integrity are clearly underscored by these findings.\n\nThe irregular monitoring for bone marrow toxicity in one-third of this clinic’s patients and the repeated prescribing of deferiprone following episodes of life-threatening agranulocytosis requiring hospitalization violate regulatory agency guidelines, including those of UHN itself [21]. Deaths related to agranulocytosis are reported in under-monitored patients [15] and demand compliance with guidelines specifying with weekly monitoring.\n\nLimitations of this single center analysis include that it does not represent a randomized prospective analysis, a limitation regrettably common in the deferiprone literature. In addition, liver iron concentration and T2 were often not clearly recorded prior to, and following, changes in regimens; as noted, changes were often undertaken without baseline and following data. We circumvented this potential confounder, which would have prevented a clear understanding of the outcomes of effectiveness and safety of different regimens, by defining treatment intervals bracketed by relevant endpoints. Finally, although we have full access to the EMR clinic notes, we are not privy to the reasons why treatment regimens were frequently altered without recording relevant endpoints, or to the rationale behind other clinical decisions not recorded in these notes.\n\nConclusion\nBetween 2009 and 2015, one-third of patients transfused and managed in Canada’s largest transfusion program were switched from first-line, licensed drugs to regimens of unlicensed deferiprone. Although there is suggestion of a research protocol in this clinic in an abstract [116], it appears that Health Canada’s Special Access Program that authorizes use of an unlicensed drug when conventional therapies have failed or are unsuitable or unavailable, was likely used to make deferiprone available to this large proportion of UHN patients. There was no evidence of a failure of first-line therapy in any patient switched to deferiprone.\n\nWe provide new evidence of inadequate reduction in hepatic iron, a 17% incidence of new diabetes, and new liver dysfunction in 65% of patients, many who were challenged and re-challenged with deferiprone despite elevated liver enzymes having developed during previous exposure. We identified no evidence of a ‘cardio-protective’ effect during deferiprone therapy.\n\nResources to examine these concerns about deferiprone in a prospective controlled study, as urged 20 years ago, will never now be made available. In an era when two highly effective, first-line, chelating agents—one orally active—are available, we caution doctors to reserve deferiprone for patients who have genuinely failed other treatments.\n\nJust as important and of concern are questions raised about the procedures by which a large proportion of patients at the largest Research Institute in Canada were switched from licensed therapies to regimens involving unlicensed deferiprone coincidentally corresponding to market approval of deferiprone. The use of Health Canada’s “Special Access Program” and the years of continued exposure of unlicensed deferiprone despite the ineffectiveness and toxicity observed in our study, indicates that issues arising from this analysis are not only scientific. The findings demand an urgent, transparent review of current standards of patient protection, informed consent, and medical practice.\n\nSupporting information\nS1 Table Excluded intervals.\n(PDF)\n\nClick here for additional data file.\n\n S2 Table All DFP vs all DFX.\nAll patients exposed to deferiprone compared to all patients exposed to deferasirox: Lab values indicating iron over-load (mean±SEM); Serum ferritin, SF; Hepatic iron concentration, HIC; (#), number of intervals; baseline, BL; follow-up, FU; significant p values, bold.\n\n(PDF)\n\nClick here for additional data file.\n\n S3 Table All patients exposed 30 months.\nAll patients exposed to deferiprone for 31.9±3.7 months compared to all patients exposed to deferasirox at 30±6 months. Lab values of iron over-load (mean±SEM(range)). Serum ferritin, SF; Hepatic iron concentration, HIC; baseline, BL; follow-up, FU; significant p values, bold; p values indicating worsening iron overload, red.\n\n(PDF)\n\nClick here for additional data file.\n\n S1 Data Lab values of included intervals.\n(XLSX)\n\nClick here for additional data file.\n\n S1 Text Discussing indications.\n(PDF)\n\nClick here for additional data file.\n\n Christine McClaren and Wen-Pin Chen conducted statistical analyses. Dr. Jacalyn Duffin, Dr. Jocelyn Downie and Dr. Ian Quirt provided editorial review. Students Arshia Javidan and Fred Zhao Xun Feng assisted with figures.\n==== Refs\nReferences\n1 Propper RD , Shurin SB , Nathan DG . Reassessment of the use of desferrioxamine B in iron overload . N Engl J Med . 1976 ;294 (26 ):1421 –3 . 10.1056/NEJM197606242942603 .1272274 \n2 Pippard MJ . Iron loading and chelation therapy In: Weatherall DJ , editor. The thalassemias. 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Hemoglobin . 2011 ;35 (3 ):206 –16 . 10.3109/03630269.2011.570674 WOS:000290797500004. 21599433 \n73 Cassinerio E , Roghi A , Pedrotti P , Brevi F , Zanaboni L , Graziadei G , et al\nCardiac iron removal and functional cardiac improvement by different iron chelation regimens in thalassemia major patients . Ann Hematol . 2012 ;91 (9 ):1443 –9 . 10.1007/s00277-012-1480-8 WOS:000307286000013. 22572843 \n74 Viprakasit V , Nuchprayoon I , Chuansumrit A , Torcharus K , Pongtanakul B , Laothamatas J , et al\nDeferiprone monotherapy reduces iron overload in transfusion-dependent thalassemias: 1-year results from a multicenter prospective, single arm, open label, dose escalating phase III pediatric study from Thailand . Am J Hematol . 2013 ;88 (4 ):251 –60 . 10.1002/ajh.23386 WOS:000316808800002. 23460233 \n75 Galanello R , Kattamis A , Piga A , Fischer R , Leoni G , Ladis V , et al\nA prospective randomized controlled trial on the safety and efficacy of alternating deferoxamine and deferiprone in the treatment of iron overload in patients with thalassemia . Haematologica . 2006 ;91 (9 ):1241 –3 . WOS:000240353100013. 16956824 \n76 Tanner MA , Galanello R , Dessi C , Smith GC , Westwood MA , Agus A , et al\nA randomized, placebo-controlled, double-blind trial of the effect of combined therapy with deferoxamine and deferiprone on myocardial iron in thalassemia major using cardiovascular magnetic resonance . Circulation . 2007 ;115 (14 ):1876 –84 . 10.1161/CIRCULATIONAHA.106.648790 WOS:000245574900008. 17372174 \n77 Tsironi M , Assimakopoulos G , Polonofi K , Rigaki K , Aessopos A . Effects of combined deferiprone and deferoxamine chelation therapy on iron load indices in beta-thalassemia . Hemoglobin . 2008 ;32 (1–2 ):29 –34 . 10.1080/03630260701680474 WOS:000253853400003. 18274980 \n78 Angelucci E , Brittenham GM , McLaren CE , Ripalti M , Baronciani D , Giardini C , et al\nHepatic iron concentration and total body iron stores in thalassemia major.[comment][erratum appears in N Engl J Med 2000 Dec 7;343(23):1740] . New England Journal of Medicine . 2000 ;343 (5 ):327 –31 . 10.1056/NEJM200008033430503 \n10922422 \n79 Kwiatkowski JL . Current recommendations for chelation for transfusion-dependent thalassemia\nTenth Cooley's Anemia Symposium . 1368 \nNew York : The New York Academy of Sciences ; 2016 p. 107 –14 .\n80 Farmaki K , Tzoumari I , Pappa C , Chouliaras G , Berdoukas V . Normalisation of total body iron load with very intensive combined chelation reverses cardiac and endocrine complications of thalassaemia major . British Journal Of Haematology . 2010 ;148 (3 ):466 –75 . 10.1111/j.1365-2141.2009.07970.x WOS:000273547000014. 19912219 \n81 Berdoukas V , Chouliaras G , Moraitis P , Zannikos K , Berdoussi E , Ladis V . The efficacy of iron chelator regimes in reducing cardiac and hepatic iron in patients with thalassaemia major: a clinical observational study. \nJ Cardiovasc Magn Reson . 2009 ;11 (1 ):20 \n10.1186/1532-429x-11-20 WOS:000268200000001. 19558722 \n82 Kolnagou A , Economides C , Eracleous E , Kontoghiorghes GJ . Long term comparative studies in thalassemia patients treated with deferoxamine or a deferoxamine/deferiprone combination. identification of effective chelation therapy protocols . Hemoglobin . 2008 ;32 (1–2 ):41 –7 . 10.1080/03630260701727085 WOS:000253853400005. 18274982 \n83 Hershko C , Cappellini MD , Galanello R , Piga A , Tognoni G , Masera G . Purging iron from the heart . British Journal Of Haematology . 2004 ;125 (5 ):545 –51 . 10.1111/j.1365-2141.2004.04946.x \n15147368 \n84 Noetzli LJ , Carson SM , Nord AS , Coates TD , JC. W. Longitudinal analysis of heart and liver iron in thalassemia major . Blood . 2008 ;112 :2973 –8 . 10.1182/blood-2008-04-148767 \n18650452 \n85 Porter JB , Wood J , Olivieri N , Vichinsky EP , Taher A , Neufeld E , et al\nTreatment of heart failure in adults with thalassemia major: response in patients randomised to deferoxamine with or without deferiprone . J Cardiov Magn Reson . 2013 ;15 :10 \n10.1186/1532-429x-15-38 WOS:000319740100001. 23688265 \n86 Del Vecchio GC , Crollo E , Schettini F , Fischer R , De Mattia D . Factors influencing effectiveness of deferiprone in a thalassaemia major clinical setting . Acta Haematol . 2000 ;104 (2–3 ):99 –102 . 10.1159/000039759 .11154982 \n87 Wu SF , Peng CT , Wu KH , Tsai CH . Liver fibrosis and iron levels during long-term deferiprone treatment of thalassemia major patients . Hemoglobin . 2006 ;30 (2 ):215 –8 . 10.1080/03630260600642534 WOS:000237623200010. 16798646 \n88 Filosa A , Vitrano A , Rigano P , Calvaruso G , Barone R , Capra M , et al\nLong-term treatment with deferiprone enhances left ventricular ejection function when compared to deferoxamine in patients with thalassemia major . Blood Cells Molecules and Diseases . 2013 ;51 (2 ):85 –8 . 10.1016/j.bcmd.2013.04.002 WOS:000320411900004. 23628348 \n89 Hejazi S , Safari O , Arjmand R , Qorbani M , Pourrostami K , Safari A , et al\nEffect of combined versus monotherapy with deferoxamine and deferiprone in iron overloaded thalassemia patients: a randomized clinical trial . Int J Pediatr . 2016 ;4 (6 ):1959 –65 . WOS:000376611100018.\n90 Wonke B , Wright C , Hoffbrand AV . Combined therapy with deferiprone and desferrioxamine . British Journal Of Haematology . 1998 ;103 (2 ):361 –4 . 9827905 \n91 Aydinok Y , Nisli G , Kavakli K . Alternate use of deferiprone and desferrioxamine in primary school children with thalassaemia major . British Journal Of Haematology . 1999 ;106 (1 ):252 –3 . .10444196 \n92 Balveer K , Pyar K , Wonke B . Combined oral and parenteral iron chelation in beta thalassaemia major . Med J Malaysia . 2000 ;55 (4 ):493 –7 . .11221163 \n93 Mourad FH , Hoffbrand AV , Sheikh-Taha M , Koussa S , Khoriaty AI , Taher A . Comparison between desferrioxamine and combined therapy with desferrioxamine and deferiprone in iron overloaded thalassaemia patients . British Journal of Haematology . 2003 ;121 (1 ):187 –9 . 10.1046/j.1365-2141.2003.04240.x WOS:000181966200027. 12670352 \n94 D'Angelo E , Mirra N , Rocca A , Carnelli V . Combined therapy with desferrioxamine and deferiprone: A new protocol for iron chelation in Thalassemia. \nJournal of Pediatric Hematology Oncology . 2004 ;26 (7 ):451 –3 . 10.1097/00043426-200407000-00011 WOS:000223113700011.\n95 Alymara V , Bourantas D , Chaidos A , Bouranta P , Gouva M , Vassou A , et al\nEffectiveness and safety of combined iron-chelation therapy with deferoxamine and deferiprone . Hematology Journal . 2004 ;5 (6 ):475 –9 . 10.1038/sj.thj.6200550 WOS:000227379500004. 15570288 \n96 Kattamis A , Ladis V , Berdousi H , Kelekis NL , Alexopoulou E , Papasotiriou I , et al\nIron chelation treatment with combined therapy with deferiprone and deferioxamine: A 12-month trial . Blood Cells Molecules and Diseases . 2006 ;36 (1 ):21 –5 . 10.1016/j.bcmd.2005.11.002 WOS:000234880000004. 16386928 \n97 Ricchi P , Ammirabile M , Spasiano A , Costantini S , Cinque P , Di Matola T , et al\nCombined chelation therapy in thalassemia major with deferiprone and desferrioxamine: a retrospective study . Eur J Haematol . 2010 ;85 (1 ):36 –42 . 10.1111/j.1600-0609.2010.01447.x WOS:000278920100006. 20331740 \n98 Tamaddoni A , Ramezani MS . Comparison between deferoxamine and combined therapy with deferoxamine and deferiprone in iron overloaded thalassemia patients . Iranian Red Crescent Medical Journal \n2010 ;12 (6 ):655 –9 . WOS:000285080500010.\n99 Lai ME , Grady RW , Vacquer S , Pepe A , Carta MP , Bina P , et al\nIncreased survival and reversion of iron-induced cardiac disease in patients with thalassemia major receiving intensive combined chelation therapy as compared to desferoxamine alone . Blood Cells Molecules and Diseases . 2010 ;45 (2 ):136 –9 . 10.1016/j.bcmd.2010.05.005 WOS:000283380600007. 20678715 \n100 Al Hawsawi ZM , Sairafy MH , Tarawah M , Zolaly MA , Rahman A , S AH . Experience with combination therapy of deferiprone and desferrioxamine in β-thalassemia major patients with iron overload at Maternity and Children Hospital, Saudi Arabia. \nJournal of Taibah University Medical Sciences . 2010 ;5 (1 ):27 –35 .\n101 Mirbehbahani N , Jahazi A , Abad H . The effect of combined therapy with deferoxamine and deferiprone on serum ferritin level of beta-thalassemic patients . Hematology . 2012 ;17 (3 ):183 –6 . 10.1179/102453312X13376952196610 WOS:000305275900010. 22664119 \n102 Danjou F , Origa R , Anni F , Saba L , Cossa S , Podda G , et al\nLongitudinal analysis of heart and liver iron in thalassemia major patients according to chelation treatment . Blood Cells Molecules and Diseases . 2013 ;51 (3 ):142 –5 . 10.1016/j.bcmd.2013.06.001 WOS:000322942800003. 23816436 \n103 Mirbehbahani N , Jahazi A , Amlashi HM , Behnampour N . Comparative efficacy of deferiprone, deferoxamine and combination of deferiprone and deferoxamine on serum ferritin value in beta-thalassemia patients . J Krishna Inst Med Sci Univ . 2015 ;4 (1 ):70 –6 . WOS:000359982400010.\n104 Origa R , Bina P , Agus A , Crobu G , Defraia E , Dessi C , et al\nCombined therapy with deferiprone and desferrioxamine in thalassemia major . Haematologica . 2005 ;90 (10 ):1309 –14 . WOS:000232614300017. 16219566 \n105 Daar S , Pathare A . Combined therapy with desferrioxamine and deferiprone in beta thalassemia major patients with transfusional iron overload . Ann Hematol . 2006 ;85 (5 ):315 –9 . 10.1007/s00277-005-0075-z \n16450126 \n106 Abdelrazik N. \nPattern of iron chelation therapy in Egyptian beta thalassemic patients: Mansoura University Children's Hospital experience. \nHematology . 2007 ;12 (6 ):577 –85 . 10.1080/10245330701521614 WOS:000251645500017. 17852442 \n107 Perifanis V , Christoforidis A , Vlachaki E , Tsatra I , Spanos G , Athanassiou-Metaxa M . Comparison of effects of different long-term iron-chelation regimens on myocardial and hepatic iron concentrations assessed with T2*magnetic resonance imaging in patients with beta-thalassemia major . International journal of hematology . 2007 ;86 (5 ):385 –9 . 10.1532/IJH97.E0734 WOS:000252493500001. 18192103 \n108 Tsiapras D , Fragatou S , Farmaki K , Kyrzopoulos S , Paraskevaidis I , Voudris V , et al\nEffect of combined chelation therapy with deferiprone and deferoxamine on left ventricular diastolic function in adult beta-thalassemia major patients . Hemoglobin . 2010 ;34 (3 ):210 –20 . 10.3109/03630269.2010.485120 WOS:000282888200003. 20524811 \n109 Alpendurada F , Smith GC , Carpenter JP , Nair SV , Tanner MA , Banya W , et al\nEffects of combined deferiprone with deferoxamine on right ventricular function in thalassaemia major . J Cardiovasc Magn Reson . 2012 ;14 :8 \n10.1186/1532-429X-14-8 \n22277065 \n110 Wanless IR , Sweeney G , Dhillon AP , Guido M , Piga A , Galanello R , et al\nLack of progressive hepatic fibrosis during long-term therapy with deferiprone in subjects with transfusion-dependent beta-thalassemia . Blood . 2002 ;100 (5 ):1566 –9 . 10.1182/blood-2002-01-0306 \n12176871 \n111 Saliba AN , El Rassi F , Taher AT . Clinical monitoring and management of complications related to chelation therapy in patients with beta-thalassemia . Expert review of hematology . 2016 ;9 (2 ):151 –68 . 10.1586/17474086.2016.1126176 WOS:000377976500004. 26613264 \n112 Hershko C , Hoffbrand AV , Olivieri NF , AlRefaie FN , Tondury P , Wonke B . The International Study Group on Oral Iron Chelators: Results of long-term deferiprone (L1) therapy . British Journal Of Haematology . 1996 ;93 :570 –. WOS:A1996UP11400570.\n113 Pootrakul P , Sirankapracha P , Sankote J , Kachintorn U , Maungsub W , Sriphen K , et al\nClinical trial of deferiprone iron chelation therapy in B-thalassaemia/haemoglobin E patients in Thailand . British Journal Of Haematology . 2003 ;122 (2 ):305 –10 . 12846901 \n114 Kolnagou A , Kontoghiorghes GJ . Manitenance of normal body range iron store level for up to 4.5 years in Thalassemia Major patients using deferiprone monotherapy . Hemoglobin . 2010 ;34 (3 ):204 –9 . 10.3109/03630269.2010.485890 WOS:000282888200002. 20524810 \n115 Giannini EG , Testa R , Savarino V . Liver enzyme alteration: a guide for clinicians . Canadian Medical Association Journal . 2005 ;172 (3 ):367 –79 . 10.1503/cmaj.1040752 WOS:000226492000025. 15684121 \n116 Miscevic F , Kuo K , Ward R . Single centre, North American experience with compassionate use of deferiprone in patients with beta-thalassemia major . Blood . 2011 ;118 (Suppl 1 ):3185a .\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "14(2)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D000284:Administration, Oral; D029503:Anemia, Diamond-Blackfan; D001803:Blood Transfusion; D000077588:Deferasirox; D000077543:Deferiprone; D057286:Electronic Health Records; D005260:Female; D006801:Humans; D007502:Iron Chelating Agents; D019190:Iron Overload; D008297:Male; D012189:Retrospective Studies; D065227:Transfusion Reaction; D017086:beta-Thalassemia", "nlm_unique_id": "101285081", "other_id": null, "pages": "e0211942", "pmc": null, "pmid": "30811439", "pubdate": "2019", "publication_types": "D016428:Journal Article", "references": "21902752;15147368;22279056;18055982;23460233;19558722;16450126;11221163;20662901;2567801;12670352;21322775;22664119;9668543;12176871;20884710;12756022;11099900;17852442;18650452;21599433;18274980;7877649;14767084;21120164;15477202;23816436;10922422;17372174;9700174;9827905;12064916;16798652;26613264;16798645;19236376;10444196;15218422;22572843;10681716;12763939;20524811;16352815;1419829;9414297;24627546;9633879;20331740;21226580;8047081;15570288;19912219;11154982;8047080;19233692;4000198;16798646;16956824;11051705;18351337;12100170;17042760;12846901;1638018;29079595;26893541;21738864;15564727;25376266;16627763;26419768;15737892;22160073;12397199;25820920;27186943;23628348;20678715;23688265;20524810;9028304;16386928;15080407;12779268;10691860;18192103;25671931;18274982;23966105;9676021;1272274;16540425;12661341;15684121;16219566;22277065;12788794", "title": "Single-center retrospective study of the effectiveness and toxicity of the oral iron chelating drugs deferiprone and deferasirox.", "title_normalized": "single center retrospective study of the effectiveness and toxicity of the oral iron chelating drugs deferiprone and deferasirox" }	[ { "companynumb": "PHHY2019CA053792", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "DEFERIPRONE" }, "drugadditional": null, "dru...
{ "abstract": "Peripartum vision loss, an uncommon, often reversible complication of pregnancy usually occurs in the setting of pre-eclampsia or eclampsia. The HELLP syndrome is characterized by hypertension, elevated liver enzymes and low platelets. This is a rare case of unilateral exudative retinal detachment associated with the Partial HELLP syndrome that occurred after delivery in a 23-year-old Indian woman. The retinal detachment subsequently reattached with good visual improvement under conservative treatment. This case highlights the importance of early intervention by the ophthalmologist when pregnant women complain about visual symptoms.", "affiliations": "Department of Ophthalmology, Sri Dharmasthala Manjunatheshwara College of Medical Sciences, Manjushree Nagar, Sattur, Dharwad 580009, Karnataka, India.;Department of Ophthalmology, Sri Dharmasthala Manjunatheshwara College of Medical Sciences, Manjushree Nagar, Sattur, Dharwad 580009, Karnataka, India.;Department of Obstetrics and Gynaecology, Sri Dharmasthala Manjunatheshwara College of Medical Sciences, Manjushree Nagar, Sattur, Dharwad 580009, Karnataka, India.", "authors": "Pradeep\|A V\|AV\|;Rao\|Sonali\|S\|;Ramesh Kumar\|R\|R\|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.1016/j.sjopt.2014.03.011", "fulltext": null, "fulltext_license": null, "issn_linking": "1319-4534", "issue": "28(4)", "journal": "Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society", "keywords": "Exudative retinal detachment; Partial HELLP syndrome; Pre-eclampsia", "medline_ta": "Saudi J Ophthalmol", "mesh_terms": null, "nlm_unique_id": "9425601", "other_id": null, "pages": "329-31", "pmc": null, "pmid": "25473354", "pubdate": "2014-10", "publication_types": "D016428:Journal Article", "references": "22615699;12403293;2763823;8238109;3604599;22526454;22869028;23613507;10707151;3826237;21719013;11097288", "title": "Partial HELLP syndrome with unilateral exudative retinal detachment treated conservatively.", "title_normalized": "partial hellp syndrome with unilateral exudative retinal detachment treated conservatively" }	[ { "companynumb": "IN-BAYER-2014-188252", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PRAZOSIN" }, "drugadditional": null, "d...
{ "abstract": "Purpose/aim: We describe, in detail, the first case of isotretinoin-induced aseptic meningitis. A brief summary of the literature on drug-induced aseptic meningitis (DIAM) is also presented.\n\n\nMETHODS\nA 20-year old female patient with probable (Naranjo adverse reaction probability score of 7) DIAM during treatment with isotretinoin therapy for nodular acne solely, presenting with headache. Pseudotumor cerebri was appropriately ruled-out.\n\n\nRESULTS\nSummary of data altogether lead us suggest that isotretinoin triggered DIAM, possible due to a delayed hypersensitivity mechanism type III or IV.\n\n\nCONCLUSIONS\nWe highlight a quite uncommon cause of DIAM that may be increasing in frequency due to the current increasing use of isotretinoin against nodular acne.", "affiliations": "a Department of Internal Medicine, Division of Dermatology , \"Saint Andrew's\" State General Hospital of Patras , Patras , Greece.;a Department of Internal Medicine, Division of Dermatology , \"Saint Andrew's\" State General Hospital of Patras , Patras , Greece.;a Department of Internal Medicine, Division of Dermatology , \"Saint Andrew's\" State General Hospital of Patras , Patras , Greece.;a Department of Internal Medicine, Division of Dermatology , \"Saint Andrew's\" State General Hospital of Patras , Patras , Greece.;b Mediterraneo Hospital, Headache Clinic , Glyfada , Greece.;c Department of Neurology , \"Saint Andrew's\" State General Hospital of Patras , Patras , Greece.;c Department of Neurology , \"Saint Andrew's\" State General Hospital of Patras , Patras , Greece.;c Department of Neurology , \"Saint Andrew's\" State General Hospital of Patras , Patras , Greece.", "authors": "Chalimou\|Ioanna\|I\|;Krilis\|Antonios\|A\|;Anastopoulou\|Garifallia G\|GG\|;Braun\|Heike\|H\|;Vikelis\|Michael\|M\|;Makridou\|Alexandra\|A\|;Makris\|Nicolaos\|N\|;Argyriou\|Andreas A\|AA\|", "chemical_list": "D015474:Isotretinoin", "country": "England", "delete": false, "doi": "10.1080/00207454.2018.1517763", "fulltext": null, "fulltext_license": null, "issn_linking": "0020-7454", "issue": "129(2)", "journal": "The International journal of neuroscience", "keywords": "Isotretinoin; adverse drug reaction; aseptic meningitis; headache; nodular acne", "medline_ta": "Int J Neurosci", "mesh_terms": "D000152:Acne Vulgaris; D005260:Female; D006261:Headache; D006801:Humans; D015474:Isotretinoin; D008582:Meningitis, Aseptic; D055815:Young Adult", "nlm_unique_id": "0270707", "other_id": null, "pages": "204-206", "pmc": null, "pmid": "30160569", "pubdate": "2019-02", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Acute aseptic meningitis during isotretinoin treatment for nodular acne solely presenting with headache: case report and brief review of the literature.", "title_normalized": "acute aseptic meningitis during isotretinoin treatment for nodular acne solely presenting with headache case report and brief review of the literature" }	[ { "companynumb": "GR-AKORN PHARMACEUTICALS-2018AKN01859", "fulfillexpeditecriteria": "1", "occurcountry": "GR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ISOTRETINOIN" }, "drugadditional"...
{ "abstract": "Stem cell treatment outside of studied and approved medical indications can have unforeseen adverse consequences. Here, we present a 74-year-old male that underwent such therapy. The patient presented to our institution with progressive lower extremity weakness and urinary incontinence. He had previously undergone intrathecal stem cell therapy in Moscow, Russia for weakness and fatigue. Magnetic resonance imaging of his thoracic and lumbar spine showed marked enlargement of the cauda equina nerve roots and abnormal mass-like soft tissue involving the thoracolumbar thecal sac. Surgical biopsy of the intrathecal soft tissue showed polyclonal lymphocytic and glial cell proliferation. The patient's symptoms did not improve with medical treatment or radiation, and he is currently under observation after multidisciplinary evaluation. Our patient's experience illustrates one of the potential risks of \"stem cell tourism\" and exemplifies the imaging and histopathologic features of this rare entity. We also compare our patient's treatment with other similar examples of stem cell treatments in our institution and others. These have had a wide spectrum of results. In some instances, intrathecal stem cells have caused abnormal imaging findings without any associated patient symptoms. In extreme examples, however, stem cell treatments have resulted in central nervous system neoplasms. Our patient's lesion is quite unique, with only one similar lesion having been previously published.", "affiliations": "Mayo Clinic, Department of Radiology, Division of Neuroradiology, Rochester, MN USA.;Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN USA.;Mayo Clinic, Department of Radiology, Division of Neuroradiology, Rochester, MN USA.;Mayo Clinic, Department of Radiology, Division of Neuroradiology, Rochester, MN USA.;Mayo Clinic, Department of Radiology, Division of Neuroradiology, Rochester, MN USA.;Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN USA.;Mayo Clinic, Department of Radiology, Division of Neuroradiology, Rochester, MN USA.", "authors": "Madhavan\|Ajay A\|AA\|https://orcid.org/0000-0003-1794-4502;Summerfield\|Dan\|D\|;Hunt\|Christopher H\|CH\|;Kim\|Dong K\|DK\|;Krecke\|Karl N\|KN\|;Raghunathan\|Aditya\|A\|;Benson\|John C\|JC\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1177/1971400920902451", "fulltext": null, "fulltext_license": null, "issn_linking": "1971-4009", "issue": "33(2)", "journal": "The neuroradiology journal", "keywords": "glial cell proliferation; intrathecal; stem cell; stem cell tourism", "medline_ta": "Neuroradiol J", "mesh_terms": "D000368:Aged; D001100:Arachnoiditis; D006801:Humans; D008159:Lumbar Vertebrae; D008279:Magnetic Resonance Imaging; D008297:Male; D057193:Medical Tourism; D033581:Stem Cell Transplantation; D013904:Thoracic Vertebrae", "nlm_unique_id": "101295103", "other_id": null, "pages": "174-178", "pmc": null, "pmid": "32013747", "pubdate": "2020-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "27784774;19226183;30063299;28058985;31423943;31008116;31424361;27331440;31393247;24148547;21241480;23740462;28137309;21799519;31152011;29300119", "title": "Polyclonal lymphocytic infiltrate with arachnoiditis resulting from intrathecal stem cell transplantation.", "title_normalized": "polyclonal lymphocytic infiltrate with arachnoiditis resulting from intrathecal stem cell transplantation" }	[ { "companynumb": "US-MYLANLABS-2020M1048888", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "HUMAN IMMUNOGLOBULIN G" }, "drugadditional": ...
{ "abstract": "There is little data describing the differences in epinephrine (epi) administration and cardiac complications among older and younger patients with anaphylaxis.\n\n\n\nThis retrospective cohort study was conducted at two urban emergency departments (ED) over a 5 year-period, and included adults who met a pre-specified criteria for anaphylaxis. Patients ≥50years of age were defined as \"older\". Univariate logistic regression was performed to compare the difference in frequency of epi administration between the \"older\" and \"younger\" groups. Among those who received epi, the proportion of patients who received doses exceeding the recommended maximum and who had pre-specified cardiovascular complications were compared between the two groups, stratified further by route of administration.\n\n\n\nOf 2995 allergy-related visits, 492 met criteria for anaphylaxis, including 122 (24.8%) older patients. Older patients were less likely to receive epi injection (36.1% vs. 60.5%). Of those who received epi, older patients were more likely to receive excessive dose of epi (7/44, 15.9% vs 2/225, 0.9%, unadjusted OR 20.7, 95% CI 3.8-211.7). Four (4/44, 9.1%) older patients experienced cardiovascular complications, compared to 1/225 (0.4%) in the younger group (unadjusted OR 22.4, 95% CI 2.1-1129.8). When examining only intra-muscular epinephrine, 1/31 older patients had cardiac complications, compared to 1/186 in the younger group.\n\n\n\nOlder patients with anaphylaxis were less likely to receive epi injection. Intramuscular epi appears safe in this population; however, the use of intravenous epi should be avoided in older patients due to the potential of developing serious cardiac complications.", "affiliations": "Department of Emergency Medicine, St. Paul's Hospital, Vancouver, BC, Canada; Department of Emergency Medicine, University of Fukui Hospital, Fukui Prefecture, Japan. Electronic address: Takahisa.Kawano@ubc.ca.;Department of Emergency Medicine, St. Paul's Hospital, Vancouver, BC, Canada; Department of Emergency Medicine, University of British Columbia, Vancouver, BC, Canada.;Department of Emergency Medicine, St. Paul's Hospital, Vancouver, BC, Canada; Department of Emergency Medicine, University of British Columbia, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada; Centre for Health Evaluation and Outcome Sciences, University of British Columbia, Vancouver, BC, Canada.;Department of Emergency Medicine and the School of Public Health, University of Alberta, Edmonton, AB, Canada.;Department of Emergency Medicine, St. Paul's Hospital, Vancouver, BC, Canada; Department of Emergency Medicine, University of British Columbia, Vancouver, BC, Canada; Centre for Health Evaluation and Outcome Sciences, University of British Columbia, Vancouver, BC, Canada.;Department of Emergency Medicine, St. Paul's Hospital, Vancouver, BC, Canada; Department of Emergency Medicine, University of British Columbia, Vancouver, BC, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada; Centre for Health Evaluation and Outcome Sciences, University of British Columbia, Vancouver, BC, Canada.", "authors": "Kawano\|Takahisa\|T\|;Scheuermeyer\|Frank Xavier\|FX\|;Stenstrom\|Robert\|R\|;Rowe\|Brian H\|BH\|;Grafstein\|Eric\|E\|;Grunau\|Brian\|B\|", "chemical_list": "D004837:Epinephrine", "country": "Ireland", "delete": false, "doi": "10.1016/j.resuscitation.2016.12.020", "fulltext": null, "fulltext_license": null, "issn_linking": "0300-9572", "issue": "112()", "journal": "Resuscitation", "keywords": "Anaphylaxis; Cardiovascular complications; Emergency department; Epinephrine; Older patients", "medline_ta": "Resuscitation", "mesh_terms": "D061605:Administration, Intravenous; D000328:Adult; D017677:Age Distribution; D000368:Aged; D000707:Anaphylaxis; D004837:Epinephrine; D005260:Female; D006331:Heart Diseases; D006801:Humans; D007273:Injections, Intramuscular; D016015:Logistic Models; D008297:Male; D008508:Medication Errors; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors", "nlm_unique_id": "0332173", "other_id": null, "pages": "53-58", "pmc": null, "pmid": "28069483", "pubdate": "2017-03", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Epinephrine use in older patients with anaphylaxis: Clinical outcomes and cardiovascular complications.", "title_normalized": "epinephrine use in older patients with anaphylaxis clinical outcomes and cardiovascular complications" }	[ { "companynumb": "CA-SA-2017SA028935", "fulfillexpeditecriteria": "1", "occurcountry": "CA", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM" }, "drugadditional":...
{ "abstract": "BACKGROUND\nWhile inhaled bronchodilators reduce symptoms and acute exacerbations of chronic obstructive pulmonary disease (COPD), their use is associated with increased cardiovascular events in some studies. This study investigates the risk of adverse events associated with the use of inhaled bronchodilators in COPD patients with multimorbidity.\n\n\nMETHODS\nA case-control study was conducted between January 2015 and December 2017, and patients with spirometry-confirmed diagnosis of COPD (N = 1565) using inhaled long-acting bronchodilators were enrolled. Medical records were reviewed and clinical data, including age, gender, smoking status, major comorbidities, lung function stage, history of exacerbations, bronchodilator regimens, and treatment duration were analyzed. Major adverse cardiovascular events occurring during long-acting bronchodilator use were recorded.\n\n\nRESULTS\nThe most common comorbidities were cardiovascular disease (CVD) (53.6%) and chronic kidney disease (CKD) (25.8%). We observed that CVD (odds ratio [OR], 5.77), CKD (OR, 2.02) and history of frequent exacerbations (OR, 2.37) were independent risk factors for cardiovascular events, regardless of the type of bronchodilators use. Moreover, COPD patients with both CKD and CVD had higher risk (6.32-fold) of adverse cardiovascular effects than those with neither comorbidity. Eighty-seven of 1565 (5.56%) COPD patients died during this study period. Of them, 21.8% (19/87) were cardiovascular-related and 73.6% (64/87) patients were respiratory-related mortality. Among COPD patients using long-acting bronchodilators, CKD was the only risk factor to predict cardiovascular events and cardiovascular-related mortality (OR, 4.87; 95% confidence interval [CI], 1.75-13.55].\n\n\nCONCLUSIONS\nCOPD patients had higher risk of cardiovascular events were associated with their CVD and/or CKD comorbidities and history of frequent exacerbations, rather than associated with their use of inhaled bronchodilators.", "affiliations": "Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, No.579, Sec. 2, Yunlin Rd., Douliu City, Yunlin County, 640, Taiwan, Republic of China.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, No.579, Sec. 2, Yunlin Rd., Douliu City, Yunlin County, 640, Taiwan, Republic of China.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, No.579, Sec. 2, Yunlin Rd., Douliu City, Yunlin County, 640, Taiwan, Republic of China.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, No.579, Sec. 2, Yunlin Rd., Douliu City, Yunlin County, 640, Taiwan, Republic of China. c8101147@ms16.hinet.net.;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan.", "authors": "Chen\|Yen-Fu\|YF\|;Cheng\|Yi-Ching\|YC\|;Chou\|Chien-Hong\|CH\|;Chen\|Chung-Yu\|CY\|http://orcid.org/0000-0001-9002-7255;Yu\|Chong-Jen\|CJ\|", "chemical_list": "D001993:Bronchodilator Agents", "country": "England", "delete": false, "doi": "10.1186/s12890-019-0999-z", "fulltext": "\n==== Front\nBMC Pulm MedBMC Pulm MedBMC Pulmonary Medicine1471-2466BioMed Central London 99910.1186/s12890-019-0999-zResearch ArticleMajor comorbidities lead to the risk of adverse cardiovascular events in chronic obstructive pulmonary disease patients using inhaled long-acting bronchodilators: a case-control study Chen Yen-Fu 12Cheng Yi-Ching 1Chou Chien-Hong 12http://orcid.org/0000-0001-9002-7255Chen Chung-Yu 886-5-5323911-5675c8101147@ms16.hinet.net 12Yu Chong-Jen 21 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, No.579, Sec. 2, Yunlin Rd., Douliu City, Yunlin County 640 Taiwan, Republic of China 2 0000 0004 0572 7815grid.412094.aDivision of Pulmonary and Critical Care Medicine, Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan 3 12 2019 3 12 2019 2019 19 23311 3 2019 19 11 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\nWhile inhaled bronchodilators reduce symptoms and acute exacerbations of chronic obstructive pulmonary disease (COPD), their use is associated with increased cardiovascular events in some studies. This study investigates the risk of adverse events associated with the use of inhaled bronchodilators in COPD patients with multimorbidity.\n\nMethods\nA case-control study was conducted between January 2015 and December 2017, and patients with spirometry-confirmed diagnosis of COPD (N = 1565) using inhaled long-acting bronchodilators were enrolled. Medical records were reviewed and clinical data, including age, gender, smoking status, major comorbidities, lung function stage, history of exacerbations, bronchodilator regimens, and treatment duration were analyzed. Major adverse cardiovascular events occurring during long-acting bronchodilator use were recorded.\n\nResults\nThe most common comorbidities were cardiovascular disease (CVD) (53.6%) and chronic kidney disease (CKD) (25.8%). We observed that CVD (odds ratio [OR], 5.77), CKD (OR, 2.02) and history of frequent exacerbations (OR, 2.37) were independent risk factors for cardiovascular events, regardless of the type of bronchodilators use. Moreover, COPD patients with both CKD and CVD had higher risk (6.32-fold) of adverse cardiovascular effects than those with neither comorbidity. Eighty-seven of 1565 (5.56%) COPD patients died during this study period. Of them, 21.8% (19/87) were cardiovascular-related and 73.6% (64/87) patients were respiratory-related mortality. Among COPD patients using long-acting bronchodilators, CKD was the only risk factor to predict cardiovascular events and cardiovascular-related mortality (OR, 4.87; 95% confidence interval [CI], 1.75–13.55].\n\nConclusions\nCOPD patients had higher risk of cardiovascular events were associated with their CVD and/or CKD comorbidities and history of frequent exacerbations, rather than associated with their use of inhaled bronchodilators.\n\nKeywords\nCardiovascular diseaseCardiovascular eventsChronic kidney diseaseChronic obstructive pulmonary diseaseComorbidityLong-acting bronchodilatorissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nChronic obstructive pulmonary disease (COPD) is a complex respiratory disorder characterized by chronic airflow limitations and increased inflammatory responses in the airways [1]. Comorbidities are frequent in COPD and significantly affect patient’s quality of life, exacerbation frequency, and survival [1, 2]. The most prevalent comorbidities include cardiovascular disease (hypertension, ischemic heart disease, heart failure), metabolic syndrome (diabetes mellitus, hyperlipidemia), osteoporosis and chronic kidney disease (CKD) [1, 3].\n\nInhaled bronchodilators, including long-acting β2-agonists (LABA) and long-acting muscarinic antagonists (LAMA), and inhaled corticosteroids (ICS) are the cornerstone therapies for COPD patients [1]. The clinical efficacy of inhaled bronchodilators has been demonstrated in clinical trials as quality of life improvement, prevention of lung function decline, and reduction of acute exacerbation frequency. However, several studies have raised concerns that inhaled bronchodilators increase the risk of cardiovascular events [4–10]. Moreover, renal impairment is also a common comorbidity in elderly COPD patients [11, 12] who may be at higher risk of adverse events due to decreased elimination and increased systemic effects of long-acting bronchodilators [13–15]. However, in large clinical trials, COPD patients with significant renal impairment or cardiac disease were usually excluded from the studies [16–18], therefore, the safety issue of COPD patient with significant renal or cardiovascular disease using long-acting bronchodilators is still being debated [9, 10, 15, 16, 19–21].\n\nA recent analysis showed that COPD patients with CKD had high risk of pre-existing cardiovascular comorbidity [21] and they found that the safety and tolerability of dual bronchodilator is comparable to the monocomponents, irrespective of the level of renal impairment. However, the number of patients with moderate to severe renal impairment at baseline in the study remained low (less than 15%), which may not reflect the conditions in real-life practice. Moreover, the adverse effects and the cause of mortality might not be well documented among COPD patients with major comorbidities using various inhaled medications in real-life care. Here we conducted a case-control study to investigate the association of common inhaled medications, including combining different classes of bronchodilators (LAMA and LABA) and different ICS, and the development of clinically important cardiovascular events and outcomes in COPD patients with major comorbidities.\n\nMethods\nStudy population\nThis study enrolled COPD patients who received inhaled long-acting bronchodilators from 2015 to 2017 at National Taiwan University Hospital (NTUH) Yunlin Branch. Eligible patients were ≥ 40 years of age, with a clinical diagnosis of COPD verified by spirometry defined as a post-bronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity (FVC) ratio (FEV1/FVC) ≤ 0.7 and treatment with either LAMA (tiotropium, RESPIMAT®), LABA (olodaterol RESPIMAT®), LAMA/LABA (umeclidinium/vilanterol and glycopyrronium/indacaterol), ICS/LABA (fluticasone/salmeterol and budesonide/formoterol) and triple therapies (ICS/LABA with tiotropium or LAMA+LABA with budesonide). Key exclusion criteria include the patients with incomplete spirometry data, clinical diagnosis of current asthma, maintenance treatment less than 30 days of continuous use or patients who inappropriately received overlapped bronchodilators (defined as patients receiving more than two bronchodilators or wrong dual or triple combinations, for example, LAMA with LABA/LAMA combination, ICS/LABA with LABA combination, ICS/LABA with other ICS combinations or two different classes of LAMA combinations... etc.) in the same period of time.\n\nMedical records were reviewed and clinical data, including age, gender, smoking status, comorbidities, lung function stage, history of exacerbations in the previous years, bronchodilator regimens, and treatment duration were analyzed. Major adverse cardiovascular events occurring after long-acting bronchodilator inhalation and inhaled ICS were recorded.\n\nDefinition of major comorbidities, cardiovascular events and outcomes\nCardiovascular diseases (CVD) were coded from medical records and included hypertension, heart failure, coronary artery disease, and arrhythmia. Metabolic diseases included hyperlipidemia and diabetes mellitus (DM). The estimated creatinine clearance rate (Ccr) was calculated using the Cockcroft–Gault formula, and patients with an estimated Ccr < 60 mL/min for 3 or more months, with or without identifiable kidney damage were defined having chronic kidney disease [22]. Cardiovascular events included tachyarrhythmia, ischemic heart disease, decompensated heart failure, and cerebrovascular stroke. Causes of mortality including sepsis, respiratory-related as acute exacerbation of COPD and pneumonia, and cardiovascular-related as sudden onset of cardiac arrest, acute myocardial infarction, acute decompensated heart failure, and cerebrovascular stroke.\n\nStatistical analysis\nBaseline characteristics of COPD patients are presented as the median with the range and percentage. One-way ANOVA was used to compare the means between patients under different long-acting bronchodilators and their combined with or without inhaled ICS treatment. Chi-square tests with Pearson values and odds ratios for categorical variables were used to investigate the risk factors of cardiovascular effects and cerebral strokes.\n\nThe association between cardiovascular events and clinical factors including basic characteristics, underlying comorbidities, and bronchodilators use was determined using conditional logistic regression for multivariate analysis. We also compared the cardiovascular risk and cerebral strokes associated with underlying comorbidities under inhaled bronchodilators use. All statistical tests were 2-sided, with statistical significance defined as p < 0.05. Analyses were performed using commercially available software (SPSS, version 22; IBM).\n\nResults\nClinical characteristics of COPD patients\nFrom the year 2015 to 2017, a total of 5130 patients were treated for COPD at National Taiwan University Hospital Yunlin Branch. Of them, 1561 patients lacked lung function spirometry data, and 813 patients were excluded for lung function with FEV1/FVC ≥ 0.7. Other exclusions include 98 patients with age < 40 years old, 278 patients receiving less than 30 continuous days of bronchodilator inhalation, and 815 patients who inappropriately receiving overlapped bronchodilators. Finally, a total of 1565 COPD patients were enrolled for further analysis.\n\nThe basic characteristics of patients with spirometry-confirmed diagnosis of COPD receiving inhaled long-acting bronchodilators are shown in Table 1. The median age was 73 years, and the majority of subjects (78.2%) were male. The major comorbidities, including hypertension (35.0%), CKD (25.8%), diabetes mellitus (18.0%) and hyperlipidemia (8.4%) were similarly distributed in each treatment cohorts. The most common inhaled therapy exposure for the COPD patients were LAMA (48.6%), followed by ICS/LABA (35.5%), LAMA/LABA (25.9%), triple therapy (13.5%) and LABA (10.3%). Regarding inhaler switching, majority of patients (n = 1185, 75.7%) exposed to only one inhaler, 254 (16.2%) patients exposed to two kinds of inhalers (inhaler switching once), 104 (6.6%) patients exposed to three kinds of inhalers (inhaler switching twice) and 22 (1.4%) patients exposed to 4 kinds of inhalers (inhaler switching three times). We classified the patients into different groups (LAMA, LABA, LABA/LAMA, ICS/LABA or triple therapy) according to the inhalers they were prescribed more than 30 days and recorded the events under the inhalers use. Therefore, some patients would be reclassified to different groups after inhaler switching.\nTable 1 Characteristics of 1565 spirometry-confirmed COPD patients receiving inhaled long-acting bronchodilators\n\nCharacteristics\tAll\tLAMA\tLABA\tLAMA + LABA\tLABA + ICS\tTriple therapy\t\nNumbers, (%)\t1565\t760 (48.6)\t161 (10.3)\t405 (25.9)\t556 (35.5)\t211 (13.5)\t\nAge (years), median (range)\t73 (40–98)\t73 (42–96)\t75 (43–94)\t73 (40–93)\t71.5 (40–98)\t77 (42–97)\t\nGender\t\n Male\t1224 (78.2)\t643 (84.6)\t137 (85.1)\t360 (88.9)\t362 (65.1)\t176 (83.4)\t\n Female\t341 (21.8)\t117 (15.4)\t24 (14.9)\t45 (11.1)\t194 (34.9)\t35 (16.6)\t\nBody mass index, median (range)\t24.2 (11.0–47.5)\t24.1 (11.2–46.2)\t23.5 (11.2–45.5)\t23.8 (12.0–44.1)\t24.5 (12.0–47.5)\t23.2 (12.8–44.2)\t\nCAT score, N(%)\t424 (27.1)\t240 (31.6)\t67 (41.6)\t173 (42.7)\t121 (21.8)\t73 (34.6)\t\nMean (SD)\t7.74 (6.35)\t7.44 (6.39)\t9.67(8.02)\t9.41 (7.21)\t7.06 (6.12)\t8.85 (6.04)\t\nHistory of exacerbations in the previous year\t\n 0\t1127 (72.0)\t546 (71.8)\t100 (62.1)\t251 (62.0)\t406 (73.0)\t124 (58.8)\t\n 1\t316 (20.2)\t150 (19.7)\t37 (23.0)\t104 (25.7)\t111 (20.0)\t58 (27.5)\t\n > 2\t122 (7.8)\t64 (8.4)\t24 (14.9)\t50 (12.3)\t39 (7.0)\t29 (13.7)\t\nSmoking Status\t\n Current\t266 (17.0)\t137 (18.0)\t30 (18.6)\t81 (20.0)\t80 (14.4)\t37 (17.5)\t\n Ex-smoker\t530 (33.9)\t284 (37.4)\t71 (44.1)\t186 (45.9)\t143 (25.7)\t90 (42.7)\t\n Never smoker\t769 (49.1)\t339 (44.6)\t60 (37.3)\t138 (34.1)\t333 (59.9)\t84 (39.8)\t\nSpirometry (FEV1, %)\t\n ≥ 80\t505 (32.3)\t315 (41.4)\t47 (29.2)\t75 (18.5)\t152 (27.3)\t36 (17.1)\t\n 50–79\t604 (38.6)\t257 (33.8)\t53 (32.9)\t159 (39.3)\t249 (44.8)\t55 (26.1)\t\n 30–49\t360 (23.0)\t146 (19.2)\t45 (28.0)\t132 (32.6)\t127 (22.8)\t80 (37.9)\t\n ≤ 29\t96 (6.1)\t42 (5.5)\t16 (9.9)\t39 (9.6)\t28 (5.0)\t40 (19.0)\t\nUnderlying Comorbidities\t\n Metabolic disease\t\n Diabetes mellitus\t282 (18.0)\t145 (19.1)\t31 (19.3)\t72 (17.8)\t95 (17.1)\t43 (20.4)\t\n Hyperlipidemia\t131 (8.4)\t77 (10.1)\t11 (6.8)\t41 (10.1)\t51 (9.2)\t12 (5.7)\t\n Cardiovascular disease\t\n Hypertension\t548 (35.0)\t260 (34.2)\t61 (37.9)\t144 (35.6)\t196 (35.5)\t93 (44.1)\t\n Coronary artery disease\t149 (9.5)\t74 (9.7)\t19 (11.8)\t47 (11.6)\t59 (10.6)\t21 (10.0)\t\n Heart failure\t93 (5.9)\t46 (6.0)\t12 (7.5)\t25 (6.2)\t34 (6.1)\t15 (7.1)\t\n Arrhythmia\t50 (3.2)\t24 (3.2)\t7 (4.3)\t12 (3.0)\t18 (3.2)\t8 (3.8)\t\nChronic kidney disease\t360/1393 (25.8)\t178/690 (25.8)\t39/152 (25.7)\t102/370 (27.6)\t114/479 (23.8)\t55/197 (27.9)\t\nMalignancy\t\n Lung cancer\t38 (2.4)\t22 (2.9)\t7 (4.3)\t13 (3.2)\t11 (2.0)\t2 (0.9)\t\n Other cancer\t27 (1.7)\t8 (1.1)\t2 (1.2)\t6 (1.5)\t9 (1.6)\t6 (2.8)\t\nLAMA long-acting muscarinic antagonists, LABA long-acting beta2-agonists, ICS inhaled corticosteroids, SD Standard deviation, FEV1 forced expiratory volume in 1 second, CAT COPD Assessment Test\n\n\n\nMajor comorbidities lead to adverse cardiovascular events\nDuring long-acting bronchodilator inhalation treatment, patients experienced a total of 141 cardiovascular events, including 80 ischemic heart disease attacks, 39 decompensated heart failure, 5 arrhythmia, and 17 cerebral vascular strokes. The associations of clinical characteristics with cardiovascular effects (n = 124) and cerebral vascular strokes (n = 17) in COPD patients are shown in Table 2. Our data showed that male patients (odds ratio [OR], 2.76; p = 0.001), current or ever smoker (OR, 1.59; p = 0.015), higher body mass index (BMI) (≥ 27: OR, 1.81; p = 0.002), poor pulmonary function (FEV1 < 50%: OR, 1.54; p = 0.025), history of frequent exacerbations (exacerbation > 2: OR, 3.59; p < 0.001) and with underlying comorbidities, including diabetes mellitus (OR, 1.90; p = 0.002), hyperlipidemia (OR, 2.96; p < 0.001), CVD (OR, 7.76; p < 0.001), and CKD (OR, 2.86; p < 0.001) would have higher risk of adverse cardiovascular effects. The only risk factor for cerebral vascular stroke was the patients with underlying CVD (OR, 6.50, p < 0.001). Furthermore, COPD patients who used LAMA for long-term control had a higher risk of adverse cardiovascular effects (OR, 1.75; p = 0.003). In contrast, COPD patients who treated with ICS/LABA had a lower risk of adverse cardiovascular effects (OR, 0.64; p = 0.031). The duration of treatment was not significantly associated with cardiovascular events for any of the maintenance therapies (Table 2).\nTable 2 The risk of cardiovascular effects and cerebral vascular strokes in COPD patients\n\nClinical characteristics\tCardiovascular effects (n = 124)\tCerebral vascular stroke (n = 17)\t\nOdds ratio\tP value\tOdds ratio\tP value\t\nMale\t2.76\t0.001\t0.90\t0.861\t\nAge ≥ 65 y/o\t1.52\t0.082\t2.41\t0.230\t\nCurrent or ever smoker\t1.59\t0.015\t0.52\t0.197\t\nBody mass index (BMI)\t\n BMI < 18.5\t0.46\t0.089\t2.50\t0.141\t\n BMI ≥ 27\t1.81\t0.002\t0.60\t0.582\t\nFEV1 < 50%\t1.54\t0.025\t0.75\t0.609\t\nHistory of exacerbations in the previous year\t\n 1\t2.17\t< 0.001\t1.42\t3.31\t\n ≥ 2\t3.59\t< 0.001\t2.13\t6.08\t\nMajor Comorbidities\t\n Diabetes mellitus\t1.90\t0.002\t0.28\t0.190\t\n Hyperlipidemia\t2.96\t< 0.001\t1.45\t0.619\t\n Cardiovascular disease\t7.76\t< 0.001\t6.50\t0.001\t\n CKD (Ccr < 60 ml/min)\t2.86\t< 0.001*\t1.20\t0.735\t\nBronchodilators and treatment duration\t\n LAMA\t1.75\t0.003\t1.52\t0.395\t\n ≥ 90 days\t0.85\t0.474\t0.99\t0.990\t\n ≥ 180 days\t0.96\t0.866\t0.42\t0.134\t\n ≥ 360 days\t1.07\t0.762\t0.32\t0.120\t\n LABA\t1.12\t0.702\tN/A\t0.160\t\n ≥ 90 days\t1.26\t0.518\tN/A\t0.297\t\n ≥ 180 days\t1.54\t0.295\tN/A\t0.404\t\n ≥ 360 days\t1.46\t0.536\tN/A\t0.583\t\n LAMA/LABA\t1.46\t0.057\t1.57\t0.373\t\n ≥ 90 days\t1.01\t0.974\t1.96\t0.200\t\n ≥ 180 days\t1.07\t0.788\t1.27\t0.711\t\n ≥ 360 days\t1.12\t0.727\t2.48\t0.144\t\n ICS/LABA\t0.64\t0.031\t0.39\t0.121\t\n ≥ 90 days\t0.87\t0.504\t0.59\t0.352\t\n ≥ 180 days\t0.99\t0.953\t0.74\t0.601\t\n ≥ 360 days\t1.05\t0.839\t1.00\t0.994\t\n Triple therapy\t0.95\t0.844\t1.38\t0.613\t\n ≥ 90 days\t1.02\t0.951\t0.59\t0.607\t\n ≥ 180 days\t0.99\t0.983\t0.71\t0.735\t\n ≥ 360 days\t0.79\t0.588\tN/A\t0.297\t\nFEV1 forced expiratory volume in 1 second, CKD chronic kidney disease, LAMA long-acting muscarinic antagonists, LABA long-acting beta2-agonists, ICS inhaled corticosteroids\n\np < 0.05\n\np < 0.001\n\n\n\nIn COPD patients using bronchodilators in multivariate analysis, CVD, CKD and history of frequent exacerbations were independent risk factors for cardiovascular events (Fig. 1). The increased risk of adverse cardiovascular events with LAMA use noted in univariate analysis, notably not significant in multivariate analysis. Of the comorbidities, CVD (OR, 5.77; p < 0.001) and CKD (OR, 2.02; p = 0.001) were the major comorbidities associated with adverse cardiovascular events in COPD patients using inhaled long-acting bronchodilators. Moreover, for COPD patients with both CKD and CVD, the risk of adverse cardiovascular events increased to 6.32-fold over that of those with neither comorbidity. In the remaining COPD patients, the risk of adverse cardiovascular events increased 1.02-fold over that of those without CKD for each 1 mL/min decrease in renal creatinine clearance.\nFig. 1 Multivariate analysis of clinical characteristics associated with adverse cardiovascular events. BMI, body mass index; FEV1, forced expiratory volume in 1 second; DM, diabetes mellitus; CVD, cardiovascular disease; CKD, chronic kidney disease; LAMA, long-acting muscarinic antagonists; LABA, long-acting beta2-agonists; ICS, inhaled corticosteroids; CI: confidence interval. p < 0.001. p < 0.05\n\n\n\nTo further clarify the impact of major comorbidities, including cardiovascular disease and chronic kidney disease, as well as different inhaled therapies on the cardiovascular events in COPD patients, we compared the incidence and the risk of events between patient with or without major comorbidities stratified by five different inhaled bronchodilator combinations. In Table 3, the risk of cardiovascular effects was significantly higher among those with CVD or CKD than those without respectively, regardless of the type of bronchodilators for COPD patients.\nTable 3 The overall incidence of cardiovascular events and stroke in COPD patients with cardiovascular disease and chronic kidney disease\n\n\tCardiovascular events, n (%)\tOdds ratio\tp\tStrokes, n (%)\tOdds ratio\tp\t\nLAMA\t\n With CVD (n = 317)\t60 (18.9)\t6.23\t< 0.001\t9 (2.8)\t12.92\t0.002\t\n Without (n = 443)\t16 (3.6)\t\t\t1 (0.2)\t\t\t\n With CKD (n = 178)\t36 (20.2)\t3.08\t< 0.001*\t2 (1.1)\t0.72\t0.673\t\n Without (n = 512)\t39 (7.6)\t\t\t8 (1.6)\t\t\t\nLABA\t\n With CVD (n = 78)\t13 (16.7)\t16.4\t0.001\t0 (0.0)\t\t\t\n Without (n = 83)\t1 (1.2)\t\t\t0 (0.0)\t\t\t\n With CKD (n = 39)\t7 (17.9)\t3.34\t0.027\t0 (0.0)\t\t\t\n Without (n = 114)\t7 (6.1)\t\t\t0 (0.0)\t\t\t\nLABA/LAMA\t\n With CVD (n = 183)\t33 (18.0)\t5.89\t< 0.001\t4 (2.2)\t2.46\t0.287\t\n Without (n = 222)\t8 (3.6)\t\t\t2 (0.9)\t\t\t\n With CKD (n = 102)\t23 (22.5)\t4.30\t< 0.001\t3 (2.9)\t2.68\t0.215\t\n Without (n = 268)\t17 (6.3)\t\t\t3 (1.1)\t\t\t\nICS/LABA\t\n With CVD (n = 236)\t30 (12.7)\t15.39\t< 0.001\t3 (1.3)\tN/A\t0.043\t\n Without (n = 320)\t3 (0.9)\t\t\t0 (0.0)\t\t\t\n With CKD (n = 114)\t17 (14.9)\t4.09\t< 0.001*\t0 (0.0)\tN/A\t0.332\t\n Without (n = 365)\t15 (4.1)\t\t\t3 (0.8)\t\t\t\nTriple therapy\t\n With CVD (n = 110)\t13 (11.8)\t4.38\t0.015\t3 (2.7)\tN/A\t0.095\t\n Without (n = 101)\t3 (3.0)\t\t\t0 (0.0)\t\t\t\n With CKD (n = 55)\t8 (14.5)\t2.85\t0.040\t1 (1.8)\t1.30\t0.833\t\n Without (n = 142)\t8 (5.6)\t\t\t2 (1.4)\t\t\t\nCVD cardiovascular disease, CKD chronic kidney disease, LAMA long-acting muscarinic antagonists, LABA long-acting beta2-agonists, ICS inhaled corticosteroids\n\np < 0.05\n\n** p < 0.001\n\n\n\nChronic kidney disease predicts risk of mortality in COPD patients with multimorbidity using long- acting bronchodilators\nEighty-seven of 1565 COPD patients died during this study period. Among them, 21.8% patients (19 of 87) had cardiovascular-related mortality and 73.6% patients (64 of 87) had respiratory-related mortality. The overall causes of death were listed in Table 4. Multivariate analysis showed that CKD (OR, 2.45; p = 0.001), CVD (OR, 1.73; p = 0.048) and history of frequent exacerbations (OR, 4.33; p < 0.001), lung cancer (OR, 27.24; p < 0.001) were independent risk factors associated with increased mortality in COPD patients using bronchodilators. However, the risk of death decreased in COPD patients with ICS/LABA use (OR, 0.32; p = 0.001) (Table 5a). Of the respiratory-related mortality, history of frequent exacerbations (OR, 4.61; p < 0.001), lung cancer (OR, 35.79; p < 0.001) were the independent risk factors to increase respiratory-related mortality in COPD patients using bronchodilators (Table 5b). Of the cardiovascular-related mortality, CKD (OR, 4.87; p = 0.002) was the independent risk factor to increase cardiovascular-related mortality significantly in COPD patients using bronchodilators (Table 5c).\nTable 4 Causes of death among COPD patients\n\nMortality causes\tN (%)\t\nTotal\t87\t\nCardiovascular-related\t19\t\n Cardiac arrest\t7 (8.0)\t\n Acute decompensated heart failure\t6 (6.9)\t\n Acute myocardial infarction\t3 (3.4)\t\n Cerebral vascular stroke\t3 (3.4)\t\nRespiratory-related\t64\t\n Pneumonia with respiratory failure\t38 (43.7)\t\n COPD acute exacerbation\t26 (29.9)\t\nSepsis\t4\t\n\nTable 5 Multivariate analysis of clinical characteristics associated with (a) all-causes mortality, (b) respiratory-related mortality, and (c) cardiovascular-related mortality, in COPD patients\n\n\tOR\t95% CI\tP value\t\n(a) All-causes mortality\t\nMale\t0.79\t0.37\t1.67\t0.532\t\nAge > 65\t1.52\t0.70\t3.28\t0.292\t\nSmoking\t0.87\t0.50\t1.53\t0.634\t\nBMI > 27\t0.53\t0.26\t1.07\t0.077\t\nFEV1 < 50%\t1.66\t0.96\t2.88\t0.070\t\nDM\t0.70\t0.36\t1.37\t0.297\t\nHyperlipidemia\t0.58\t0.22\t1.58\t0.289\t\nCVD\t1.73\t1.00\t2.97\t0.048\t\nCKD\t2.45\t1.45\t4.14\t0.001\t\nLAMA\t1.00\t0.59\t1.70\t0.994\t\nICS/LABA\t0.32\t0.17\t0.63\t0.001\t\nHistory of exacerbations in the previous year\t\n 1\t1.43\t0.78\t2.63\t0.243\t\n > 2\t4.33\t2.20\t8.50\t< 0.001\t\nMalignancy\t\n Lung cancer\t27.24\t12.16\t61.04\t< 0.001\t\n Other cancer\t19.39\t7.85\t47.87\t< 0.001\t\n(b) Respiratory-related mortality\t\nMale\t0.83\t0.34\t1.98\t0.667\t\nAge > 65\t1.19\t0.52\t2.70\t0.681\t\nSmoking\t0.80\t0.42\t1.52\t0.491\t\nBMI > 27\t0.48\t0.20\t1.15\t0.100\t\nFEV1 < 50%\t1.82\t0.97\t3.41\t0.060\t\nDM\t0.75\t0.35\t1.62\t0.466\t\nHyperlipidemia\t0.53\t0.16\t1.73\t0.295\t\nCVD\t1.64\t0.88\t3.06\t0.116\t\nCKD\t1.52\t0.82\t2.82\t0.185\t\nLAMA\t1.11\t0.61\t2.03\t0.739\t\nICS/LABA\t0.40\t0.19\t0.83\t0.014\t\nHistory of exacerbations in the previous year\t\n 1\t2.03\t1.03\t4.00\t0.041\t\n > 2\t4.61\t2.14\t9.93\t< 0.001\t\nMalignancy\t\n Lung cancer\t35.79\t15.65\t81.82\t< 0.001\t\n Other cancer\t11.72\t4.27\t32.17\t< 0.001\t\n(c) Cardiovascular-related mortality\t\nMale\t0.79\t0.19\t3.33\t0.745\t\nAge > 65\t3.06\t0.38\t24.76\t0.294\t\nSmoking\t1.11\t0.39\t3.14\t0.849\t\nBMI > 27\t0.85\t0.26\t2.79\t0.793\t\nFEV1 < 50%\t1.40\t0.49\t4.00\t0.527\t\nDM\t0.49\t0.14\t1.71\t0.265\t\nHyperlipidemia\t1.14\t0.23\t5.70\t0.869\t\nCVD\t2.99\t0.98\t9.10\t0.053\t\nCKD\t4.87\t1.75\t13.55\t0.002\t\nLAMA\t0.93\t0.34\t2.56\t0.889\t\nICS/LABA\t0.33\t0.09\t1.25\t0.103\t\nHistory of exacerbations in the previous year\t\n 1\t0.60\t0.16\t2.26\t0.451\t\n > 2\t2.01\t0.57\t7.12\t0.277\t\nMalignancy\t\n Lung cancer\t1.43\t0.17\t12.34\t0.742\t\n Other cancer\t10.33\t2.42\t44.03\t0.002\t\nBMI body mass index, FEV1 forced expiratory volume in 1 second, DM diabetes mellitus, CVD cardiovascular disease, CKD chronic kidney disease, LAMA long-acting muscarinic antagonists, LABA long-acting beta2-agonists, ICS inhaled corticosteroids, CI confidence interval\n\n* p < 0.001; *p < 0.05\n\n\n\nDiscussion\nOur findings demonstrated that comorbid CVD or CKD but not bronchodilator use were independent risk factors for cardiovascular events in COPD patients using long-acting inhaled bronchodilators. In COPD patients with CKD, the risk of adverse cardiovascular events increased 1.02-fold over that of patients with COPD alone for each 1 mL/min decrease in renal creatinine clearance. In COPD patients with both CKD and CVD, this risk enhanced to 6.32-fold over that of those with neither comorbidity, regardless of the type of inhaled long-acting bronchodilator used. Furthermore, we found that CKD was the only independent risk factor to predict cardiovascular-related mortality in COPD patients. This is the first study to raise the possibility that the increased risk of adverse cardiovascular events among COPD patients using inhaled bronchodilators results from CVD and/or CKD as their major comorbidities and history of frequent exacerbations, rather than from the use of inhaled medications themselves.\n\nWe observed that COPD patients who used LAMA had a higher risk for cardiovascular events in univariate analysis that was not statistically significant in multivariate analysis. In contrast, prior nested case-control studies by Wang et al. [9] and Gershon et al. [10] found that COPD patients newly prescribed LAMAs or LABAs were at higher risk of cardiovascular events, irrespective of prior CVD status. This discrepancy might attribute that their potential misclassification of patients with COPD by ICD codes in the National Health Insurance Research Database (without lung function confirmation) and the majority COPD patients in the cohort did not receive standard treatment (less than 15% of the patients with COPD who had cardiovascular events had been treated with long-acting bronchodilators, and the most of them used oral theophylline, beta-agonists, and an oral corticosteroid as the initial treatment) [9], which further increased cardiovascular side effects [23, 24].\n\nMany observational studies and meta-analyses have reported that increase cardiovascular risk in patients with COPD was associated with their use of long-acting bronchodilators [5, 19, 20, 25, 26], nevertheless, the randomized controlled trials failed to show an increased risk [16, 27, 28] and a recent study even demonstrated that a LAMA/LABA combination improves cardiac function in COPD patients with lung hyperinflation [29]. This discrepancy may be partially attributable to the fact that most clinical trails have excluded patients with severe or multiple comorbidities. One population-based study indicated that the risk of cardiovascular events after initiation of long-acting bronchodilators is 3.5-fold higher in patients with baseline CVD who are taking CVD medications [30]. Similarly, we also observed that COPD patients with baseline CVD had higher risk of cardiovascular effects than those without, regardless of treatment regimens for COPD. Further multivariate analysis demonstrated that patients with baseline CVD predicted the risk of adverse cardiovascular events. Although inhaled long-acting bronchodilators are recommended as maintenance therapy for stable COPD patients [1], clinicians should be cautious when prescribing these medications to patients with preexisting cardiovascular disease.\n\nRecent studies showed that CKD not only has a significantly higher prevalence in COPD patients than in healthy controls [31–33], but also an important risk factor for CVD [34], which may carry high risk of cardiovascular complications [35]. The finding is of concern because LABA and LAMA are both excreted in the urine, and the systemic exposure of LABA and LAMA would be higher in COPD patients with renal impairment than those with normal renal function [14, 36]. Thus, COPD patients with CKD receiving long-acting bronchodilators might lead to severe adverse cardiovascular effects after long-term exposure [15] and even lead to significantly higher risk of death compared to those without CKD [37–39]. Our findings documented that COPD patients comorbid CKD not only have higher risk of cardiovascular events and also predict the risk of cardiovascular-related mortality. However, this data highlights the need for further prospective studies to investigate the underlying mechanisms and potential interventions to improve outcomes in this population.\n\nComparative studies have failed to show a significant difference in the risk of mortality and serious adverse events between LAMA, LABA, and ICS/LABA [40, 41]. Nevertheless, a systematic review and meta-analysis demonstrated that LAMA use was associated with higher risk of overall and cardiovascular death compared with other inhaled medications and ICS/LABA use was associated with the lowest risk of overall death among all treatments [42]. Differently, our reports showed that COPD patients with CKD, CVD, history of frequent exacerbations and underlying malignancies were associated with high risk of all-cause mortality, and those treated with ICS/LABA were associated with better outcome. These results imply that clinicians should not only foucs on the selection of inhaled bronchodilators for COPD, but also target the extra-pulmonary comorbidities as treatable traits to improve outcomes in real-world practice [43].\n\nOur study has several limitations. First, our study population was extracted from only one medical center database, so the results may not be applicable to patients examined at other clinics. Second, not all the prescriptions of inhaled bronchodilators were regulated by guidelines and the data is based on retrospective chart review. Thus, the COPD treatment may not be standardized and the adherence rate of inhalers could not be assessed. Third, the observed association between cardiovascular events in patients with preexisting cardiovascular conditions and the initiation of inhaled bronchodilators does not imply cause and effect. Fourth, we did not include COPD patients with CVD who are not taking inhaled COPD therapies for further clarifying the effects of inhaled bronchodilators on patients with CVD, which is attributed to very few diagnosed COPD patients without receiving any standard inhaled long-acting bronchodilators, even they with CV comorbidity. Fifth, our cohort enrolled relatively higher percentage of nonsmoker COPD patients (49.1%), which could be explained by enrollment of patients with asthma and COPD overlapped (ACO) and our patients had long-term exposure to highest level of fine particulate matter (PM2.5) in Taiwan [44]. Sixth, nearly one-fourth of patients (n = 380, 24.3%) had inhaler switching during the follow-up period and were reclassified to different groups after inhaler switch. However, in the real-world data with retrospective nature, we could not avoid the impact of carryover effects without washout periods. Finally, we did not investigate the medications used to treat underlying comorbidities such as DM, hypertension, or hyperlipidemia, or oral drugs for COPD patients.\n\nConclusions\nThe risk of cardiovascular events was associated with COPD patients with preexisting CKD or CVD, and history of frequent exacerbations rather than associated with the use of inhaled bronchodilators. Clinicians should closely monitor COPD patients with preexisting CKD and CVD for adverse cardiovascular events while using inhaled long-acting bronchodilators.\n\nAbbreviations\nACOAsthma and COPD overlapped\n\nBMIBody mass index\n\nCcrCreatinine clearance rate\n\nCKDChronic kidney disease\n\nCOPDChronic obstructive pulmonary disease\n\nCVDCardiovascular diseases\n\nDMDiabetes mellitus\n\nFEV1Forced expiratory volume in one second\n\nFVCForced vital capacity\n\nICSInhaled corticosteroids\n\nLABALong-acting β2-agonists\n\nLAMALong-acting muscarinic antagonists\n\nOROdds ratio\n\nPMParticulate matter\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNot applicable\n\nAuthors’ contributions\nYFC, CHC, CYC, and CJY conceptualized and designed the study. YFC, YCC, CHC and CYC collected the data for the study. YFC, YCC, and CYC analyzed and interpreted the data. YFC and CYC drafted the manuscript. YFC and CYC revised the manuscript critically for important intellectual content. All of the authors have read and approved the manuscript.\n\nFunding\nNo funding was obtained for the research.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThe Research Ethics Committee of National Taiwan University Hospital approved the study protocol and waived informed consent given the retrospective nature of the study and the lack of patient safety concerns.\n\nConsent for publication\nNot applicable\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Global Initiative for Chronic Obstructive Lung Disease Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease 2017 \n2. Putcha N Puhan MA Hansel NN Drummond MB Boyd CM Impact of co-morbidities on self-rated health in self-reported COPD: an analysis of NHANES 2001–2008 COPD 2013 10 3 324 332 10.3109/15412555.2012.744963 23713595 \n3. Vanfleteren LE Spruit MA Groenen M Clusters of comorbidities based on validated objective measurements and systemic inflammation in patients with chronic obstructive pulmonary disease Am J Respir Crit Care Med 2013 187 7 728 735 10.1164/rccm.201209-1665OC 23392440 \n4. Worth H Chung KF Felser JM Cardio- and cerebrovascular safety of indacaterol vs formoterol, salmeterol,tiotropium and placebo in COPD Respir Med 2011 105 571 579 10.1016/j.rmed.2010.11.027 21227674 \n5. Salpeter SR Ormiston TM Salpeter EE Cardiovascular effects of beta-agonists inpatients with asthma and COPD: a meta-analysis Chest 2004 125 2309 2321 10.1378/chest.125.6.2309 15189956 \n6. Singh S Loke YK Enright P Pro-arrhythmic and pro-ischaemic effects of inhaled anticholinergic medications Thorax 2013 68 114 116 10.1136/thoraxjnl-2011-201275 22764216 \n7. Cazzola M Imperatore F Salzillo A Cardiac effects of formoterol and salmeterol in patients suffering from COPD with preexisting cardiac arrhythmias and hypoxemia Chest 1998 114 411 415 10.1378/chest.114.2.411 9726723 \n8. Lee CH Choi S Jang EJ Inhaled bronchodilators and the risk of tachyarrhythmias Int J Cardiol 2015 190 133 139 10.1016/j.ijcard.2015.04.129 25918066 \n9. Wang MT Liou JT Lin CW Association of Cardiovascular Risk with Inhaled Long-Acting Bronchodilators in patients with chronic obstructive pulmonary disease: a nested case-control study JAMA Intern Med 2018 178 2 229 238 10.1001/jamainternmed.2017.7720 29297057 \n10. Gershon A Croxford R Calzavara A To T Stanbrook MB Upshur R Stukel TA Cardiovascular safety of inhaled long-acting bronchodilators in individuals with chronic obstructive pulmonary disease JAMA Intern Med 2013 173 13 1175 1185 10.1001/jamainternmed.2013.1016 23689820 \n11. Gaddam S Gunukula SK Lohr JW Arora P Prevalence of chronic kidney disease in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis BMC Pulm Med 2016 16 158 10.1186/s12890-016-0315-0 27881110 \n12. Yoshizawa T Okada K Furuichi S Prevalence of chronic kidney diseases in patients with chronic obstructive pulmonary disease: assessment based on glomerular filtration rate estimated from creatinine and cystatin C levels Int J Chron Obstruct Pulmon Dis 2015 10 1283 1289 10.2147/COPD.S80673 26185434 \n13. Caillaud D Le Merre C Martinat Y Aguilaniu B Pavia D A dose-ranging study of tiotropium delivered via Respimat Soft Mist Inhaler or HandiHaler in COPD patients Int J Chron Obstruct Pulmon Dis 2007 2 4 559 565 18268929 \n14. Türck D Weber W Sigmund R Pharmacokinetics of intravenous, single-dosetiotropium in subjects with differentdegrees of renalimpairment J Clin Pharmacol 2004 44 2 163 172 10.1177/0091270003261315 14747425 \n15. Verhamme KM van Blijderveen N Sturkenboom MC Tiotropium and the risk of death in COPD N Engl J Med 2014 370 5 481 482 24476443 \n16. Wise RA Anzueto A Cotton D Tiotropium Respimat inhaler and the risk of death in COPD N Engl J Med 2013 369 16 1491 1501 10.1056/NEJMoa1303342 23992515 \n17. Wedzicha JA Banerji D Chapman KR Indacaterol-Glycopyrronium versus Salmeterol-Fluticasone for COPD N Engl J Med 2016 374 23 2222 2234 10.1056/NEJMoa1516385 27181606 \n18. Lipson DA Barnhart F Brealey N Once-daily single-inhaler triple versus dual therapy in patients with COPD N Engl J Med 2018 378 18 1671 1680 10.1056/NEJMoa1713901 29668352 \n19. Singh S Loke YK Furberg CD Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis JAMA 2008 300 1439 1450 10.1001/jama.300.12.1439 18812535 \n20. Singh S Loke YK Enright PL Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials BMJ 2011 342 d3215 10.1136/bmj.d3215 21672999 \n21. LaForce C Derom E Bothner U Kloer IM Trampisch M Buhl R5. Long-term safety of tiotropium/olodaterol Respimat® in patients with moderate-to-very severe COPD and renal impairment in the TONADO® studies Int J Chron Obstruct Pulmon Dis 2018 13 1819 1831 10.2147/COPD.S161489 29910611 \n22. Snyder S Pendergraph B Detection and evaluation of chronic kidney disease Am Fam Physician 2005 72 9 1723 1732 16300034 \n23. Campo G Pavasini R Biscaglia S Overview of the pharmacological challenges facing physicians in the management of patients with concomitant cardiovascular disease and chronic obstructive pulmonary disease Eur Heart J Cardiovasc Pharmacother 2015 1 3 205 211 10.1093/ehjcvp/pvv019 27533997 \n24. Hillas G Perlikos F Tsiligianni I Managing comorbidities in COPD Int J Chron Obstruct Pulmon Dis 2015 10 95 109 25609943 \n25. Au DH Curtis JR Every NR Association between inhaled beta-agonists and the risk of unstable angina and myocardial infarction Chest 2002 121 846 851 10.1378/chest.121.3.846 11888971 \n26. Dong YH Chang CH Gagne JJ Hsu CL Lai MS Comparative cardiovascular and cerebrovascular safety of inhaled long-acting bronchodilators in patients with chronic obstructive pulmonary disease: a population-based cohort study Pharmacotherapy 2016 36 1 26 37 10.1002/phar.1684 26799347 \n27. Calverley PM Anderson JA Celli B Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease N Engl J Med 2007 356 775 789 10.1056/NEJMoa063070 17314337 \n28. Tashkin DP, Celli B, Senn S et al.: a 4-year trial of tiotropium in chronic obstructive pulmonary disease. Expert Opin Pharmacother. 2009;10:719–722.\n29. Hohlfeld JM Vogel-Claussen J Biller H Effect of lung deflation with indacaterol plus glycopyrronium on ventricular filling in patients with hyperinflation and COPD (CLAIM): a double-blind, randomised, crossover, placebo-controlled, single-Centre trial Lancet Respir Med 2018 6 5 368 378 10.1016/S2213-2600(18)30054-7 29477448 \n30. Aljaafareh A Valle JR Lin YL Kuo YF Sharma G Risk of cardiovascular events after initiation of long-acting bronchodilators in patients with chronic obstructive lung disease: a population-based study SAGE Open Med 2016 4 2050312116671337 10.1177/2050312116671337 27757229 \n31. Gaddam S Gunukula SK Lohr JW Arora P Prevalence of chronic kidney disease in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis BMC Pulm Med 2016 16 1 158 10.1186/s12890-016-0315-0 27881110 \n32. Chen CY Liao KM Chronic Obstructive Pulmonary Disease is associated with risk of Chronic Kidney Disease: A Nationwide Case-Cohort Study Sci Rep 2016 6 25855 10.1038/srep25855 27166152 \n33. Mapel DW Marton JP Prevalence of renal and hepatobiliary disease, laboratory abnormalities, and potentially toxic medication exposures among persons with COPD Int J Chron Obstruct Pulmon Dis 2013 8 127 134 10.2147/COPD.S40123 23515180 \n34. Levey AS de Jong PE Coresh J The definition, classification, and prognosis of chronic kidney disease: a KDIGO controversies conference report Kidney Int 2011 80 1 17 28 10.1038/ki.2010.483 21150873 \n35. Di Lullo L House A Gorini A Chronic kidney disease and cardiovascular complications Heart Fail Rev 2015 20 3 259 272 10.1007/s10741-014-9460-9 25344016 \n36. Kunz C Luedtke D Unseld A Pharmacokinetics and safety of olodaterol administered with the Respimat soft mist inhaler in subjects with impaired hepatic or renal function Int J Chron Obstruct Pulmon Dis 2016 11 585 595 10.2147/COPD.S94234 27051282 \n37. Navaneethan SD Schold JD Huang H Mortality outcomes of patients with chronic kidney disease and chronic obstructive pulmonary disease Am J Nephrol 2016 43 1 39 46 10.1159/000444422 26891053 \n38. van Gestel YR Chonchol M Hoeks SE Association between chronic obstructive pulmonary disease and chronic kidney disease in vascular surgery patients Nephrol Dial Transplant 2009 24 9 2763 2767 10.1093/ndt/gfp171 19369691 \n39. Lai CC Wu CH Wang YH Wang CY Wu VC Chen L The association between COPD and outcomes of patients with advanced chronic kidney disease Int J Chron Obstruct Pulmon Dis 2018 13 2899 2905 10.2147/COPD.S174215 30271136 \n40. Gershon A Croxford R To T Comparison of inhaled long-acting β-agonist and anticholinergic effectiveness in older patients with chronic obstructive pulmonary disease: a cohort study Ann Intern Med 2011 154 583 592 10.7326/0003-4819-154-9-201105030-00003 21536937 \n41. Vogelmeier C Hederer B Glaab T Tiotropium versus salmeterol for the prevention of exacerbations of COPD N Engl J Med 2011 364 1093 1103 10.1056/NEJMoa1008378 21428765 \n42. Dong YH Lin HH Shau WY Wu YC Chang CH Lai MS Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials Thorax 2013 68 1 48 56 10.1136/thoraxjnl-2012-201926 23042705 \n43. Agusti A Bel E Thomas M Treatable traits: toward precision medicine of chronic airway diseases Eur Respir J 2016 47 2 410 419 10.1183/13993003.01359-2015 26828055 \n44. Lo WC Shie RH Chan CC Lin HH Burden of disease attributable to ambient fine particulate matter exposure in Taiwan J Formos Med Assoc 2017 116 32 40 10.1016/j.jfma.2015.12.007 26874373\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2466", "issue": "19(1)", "journal": "BMC pulmonary medicine", "keywords": "Cardiovascular disease; Cardiovascular events; Chronic kidney disease; Chronic obstructive pulmonary disease; Comorbidity; Long-acting bronchodilator", "medline_ta": "BMC Pulm Med", "mesh_terms": "D000280:Administration, Inhalation; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001993:Bronchodilator Agents; D002318:Cardiovascular Diseases; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive; D018570:Risk Assessment", "nlm_unique_id": "100968563", "other_id": null, "pages": "233", "pmc": null, "pmid": "31795986", "pubdate": "2019-12-03", "publication_types": "D016428:Journal Article", "references": "26874373;23515180;27181606;29668352;25344016;23392440;27757229;22764216;21227674;15189956;17507545;18268929;26891053;23992515;29477448;17314337;25609943;21672999;30271136;19284368;26799347;23689820;26828055;11888971;27533997;23042705;29297057;19369691;24476443;29910611;18812535;27051282;9726723;21536937;23713595;25918066;21428765;27166152;21150873;26185434;14747425;27881110;16300034", "title": "Major comorbidities lead to the risk of adverse cardiovascular events in chronic obstructive pulmonary disease patients using inhaled long-acting bronchodilators: a case-control study.", "title_normalized": "major comorbidities lead to the risk of adverse cardiovascular events in chronic obstructive pulmonary disease patients using inhaled long acting bronchodilators a case control study" }	[ { "companynumb": "TW-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-122628", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "TIOTROPIUM BROMIDE MONOHYDRATE" ...
{ "abstract": "In this case report, we describe a case of primary retroperitoneal neuroendocrine carcinoma. An 85- year-old man presented with a 3-week history of left back pain. Contrast-enhanced computed tomography showed an 8×5 cm mass to the left of the aorta and multiple hepatic metastases. Immunohistochemistry staining of the tumor cells showed positivity for the neuroendocrine marker synaptophysin and a very high Ki67 proliferation index. He was treated with carboplatin and etoposide. After 2 courses of chemotherapy, the mass had decreased in size, confirming that the treatment was effective. We plan to administer a total of 6 courses of chemotherapy.", "affiliations": "The Department of Urology, Shizuoka City Shimizu Hospital.;The Department of Urology, Shizuoka City Shimizu Hospital.;The Department of Urology, Shizuoka City Shimizu Hospital.", "authors": "Fukushima\|Mika\|M\|;Otaki\|Tatsuya\|T\|;Usui\|Yukio\|Y\|", "chemical_list": "D005047:Etoposide; D016190:Carboplatin", "country": "Japan", "delete": false, "doi": "10.14989/ActaUrolJap_67_9_423", "fulltext": null, "fulltext_license": null, "issn_linking": "0018-1994", "issue": "67(9)", "journal": "Hinyokika kiyo. Acta urologica Japonica", "keywords": null, "medline_ta": "Hinyokika Kiyo", "mesh_terms": "D000369:Aged, 80 and over; D016190:Carboplatin; D018278:Carcinoma, Neuroendocrine; D005047:Etoposide; D006801:Humans; D008297:Male; D012186:Retroperitoneal Neoplasms; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "0421145", "other_id": null, "pages": "423-426", "pmc": null, "pmid": "34610708", "pubdate": "2021-09", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "A Case of Primary Neuroendocrine Carcinoma of the Retroperitoneum.", "title_normalized": "a case of primary neuroendocrine carcinoma of the retroperitoneum" }	[ { "companynumb": "JP-NOVARTISPH-NVSJ2021JP021073", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ETOPOSIDE" }, "drugadditional": "3", ...
{ "abstract": "The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 72-year-old man with a 40-pack-year tobacco history developed a cough and decreased exercise tolerance. A chest x-ray demonstrated a right-upper-lobe opacity. Chest computed tomography (CT) scan revealed a 2.5-cm mass in the right upper lobe with multiple mediastinal lymph node disease ( Fig 1 ). A positron emission tomography (PET) scan confirmed the lung lesion and the mediastinal lymphadenopathy without distant metastases. Brain magnetic resonance imaging results were negative. The biopsy specimen revealed adenocarcinoma with no actionable mutations present. Cervical mediastinoscopy was positive for carcinoma in level 2, 3, 4R, and 7 lymph nodes; level 4L was negative. The patient's stage was T1bN2M0, stage IIIA. His medical history was significant for hyperlipidemia and hypothyroidism. He had smoked one pack a day for 40 years and had quit 15 years earlier. Physical examination was unrevealing, and the patient had an Eastern Cooperative Oncology Group performance status of 0. Because of the extent of lung cancer in the mediastinum, the patient's cancer was deemed inoperable, and he was referred for consideration of concurrent chemotherapy and radiation.", "affiliations": "Kenneth E. Rosenzweig and Jorge E. Gomez, Icahn School of Medicine at Mount Sinai, New York, NY.;Kenneth E. Rosenzweig and Jorge E. Gomez, Icahn School of Medicine at Mount Sinai, New York, NY.", "authors": "Rosenzweig\|Kenneth E\|KE\|;Gomez\|Jorge E\|JE\|", "chemical_list": "D000068437:Pemetrexed; D016190:Carboplatin", "country": "United States", "delete": false, "doi": "10.1200/JCO.2016.69.9678", "fulltext": null, "fulltext_license": null, "issn_linking": "0732-183X", "issue": "35(1)", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "keywords": null, "medline_ta": "J Clin Oncol", "mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D059248:Chemoradiotherapy; D000075202:Contraindications; D006801:Humans; D008175:Lung Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D000068437:Pemetrexed; D011013:Pneumonectomy; D011879:Radiotherapy Dosage; D050397:Radiotherapy, Intensity-Modulated", "nlm_unique_id": "8309333", "other_id": null, "pages": "6-10", "pmc": null, "pmid": "27870565", "pubdate": "2017-01", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Concurrent Chemotherapy and Radiation Therapy for Inoperable Locally Advanced Non-Small-Cell Lung Cancer.", "title_normalized": "concurrent chemotherapy and radiation therapy for inoperable locally advanced non small cell lung cancer" }	[ { "companynumb": "US-FRESENIUS KABI-FK201702403", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PEMETREXED" }, "drugadditional": null, ...
{ "abstract": "The aims of this review were to describe the case of a patient with debilitating neuroarthropathy of the ankles and feet and reveal a primary systemic (amyloid light chain, AL) amyloidosis and to review the relevant literature concerning the peripheral neuropathy and neuroarthropathy due to amyloidosis. We will emphasize the diagnostic pitfalls and discuss prognosis and treatments of both the peripheral neuropathy and the arthropathy related to AL amyloidosis. This is a descriptive case report of a patient with neuroarthropathy of the lower limbs due to AL amyloidosis. A review and discussion of relevant literature were conducted, based on a PubMed search from 1973 to December 2013. A 51-year-old female was diagnosed with AL amyloidosis after 20 months of investigation of small painful deformities of the feet. Chronic peripheral neuropathy occurs as a manifestation of AL amyloidosis in 25 % of cases. It may exceptionally be complicated by neuroarthropathy. In this case, the paucity of clinical and electrophysiological signs of the neuropathy delayed the diagnosis, leading to a severe arthropathy. The massive destruction of the joints dominated the clinical and the poor functional outcome. Diagnosis of AL amyloidosis should be considered in the presence of a mild peripheral neuropathy and a distal destructive and painless arthropathy. The two key diagnostic procedures are serum protein electrophoresis and nerve biopsy. Delay in treatment worsens the prognosis.", "affiliations": "Service de Rhumatologie/DAL, CHUV, Av. Pierre Decker 4, 1011, Lausanne, Switzerland.;Service de Neurologie/DNC, CHUV, Rue du Bugnon 46, 1011, Lausanne, Switzerland.;Service de Pathologie Clinique, Hôpitaux Universitaires de Genève, Rue Gabrielle-Perret-Gentil 4, 1211, Geneva 14, Switzerland.;Service d' Hématologie clinique et Thérapie cellulaire/CHU, Av. Martin Luther King 2, 87042, Limoges, France.;Service de Rhumatologie/DAL, CHUV, Av. Pierre Decker 4, 1011, Lausanne, Switzerland. pascal.zufferey@chuv.ch.", "authors": "Andrei\|Irina Adriana\|IA\|;Kuntzer\|Thierry\|T\|;Lobrinus\|Johannes Alexander\|JA\|;Jaccard\|Arnaud\|A\|;Zufferey\|Pascal\|P\|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1007/s10067-014-2782-0", "fulltext": null, "fulltext_license": null, "issn_linking": "0770-3198", "issue": "35(2)", "journal": "Clinical rheumatology", "keywords": "Amylosis; Charcot arthropathy; Diabetic foot; MRI; Nerve biopsy; Neuroarthropathy", "medline_ta": "Clin Rheumatol", "mesh_terms": "D000686:Amyloidosis; D005260:Female; D005534:Foot Diseases; D006801:Humans; D000075363:Immunoglobulin Light-chain Amyloidosis; D007592:Joint Diseases; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases", "nlm_unique_id": "8211469", "other_id": null, "pages": "535-9", "pmc": null, "pmid": "25227773", "pubdate": "2016-02", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "6353084;23040361;18930414;9552085;23605846;21868781;2847276;4633108;23189548;22361982;2513459;19727057;10319082;6270334;20215989;228587;21264900;9057805;2537065;946252;20570543;1258700;3580010", "title": "Neuroarthropathy of the foot revealing primary systemic amyloidosis: case report and literature review.", "title_normalized": "neuroarthropathy of the foot revealing primary systemic amyloidosis case report and literature review" }	[ { "companynumb": "PHHY2014CH121578", "fulfillexpeditecriteria": "1", "occurcountry": "CH", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ZOLEDRONIC ACID" }, "drugadditional": null, ...
{ "abstract": "Aim To describe a case of persistent sub-therapeutic posaconazole levels in setting of salvage chemotherapy for relapsed acute myeloid leukemia. Case details A 57-year-old male was admitted for the management of relapsed acute myeloid leukemia and ongoing pulmonary aspergillosis. While continuing on posaconazole tablet 300 mg daily, he received a course of salvage chemotherapy. The initial steady state posaconazole trough level was therapeutic at 0.84 mg/L (target >0.70 mg/L). However, after five days, the level had dropped to 0.40 mg/L, coinciding with hyperbilirubinemia and hypoalbuminemia. Bilirubin level peaked at 36 µm/L (normal high <20 µm/L), albumin levels were consistently low, averaging at 25 g/L (range 33-46 g/L). The patient had been compliant and there were no underlying gastrointestinal conditions identified which might have potentially affected posaconazole absorption. Outcome An increase in posaconazole dose failed to achieve target levels and treatment was changed to voriconazole. However, levels were surprisingly supra-therapeutic, resulting in side effects and substantial dose reduction was required. Conclusion Failure to achieve target posaconazole levels despite increased dosing may be attributed to factors other than impaired oral absorption. Enhanced metabolism and clearance could be associated with hypoalbuminemia and hyperbilirubinemia. Further case studies, including PK modelling, are required to confirm this effect.", "affiliations": "Department of Pharmacy, Alfred Hospital, Prahran, Australia.;Department of Pharmacy, Alfred Hospital, Prahran, Australia.;Department of Pharmacy, Alfred Hospital, Prahran, Australia.;Department of Pharmacy, Alfred Hospital, Prahran, Australia.", "authors": "Maleki\|Sam\|S\|;Corallo\|Carmela\|C\|;Coutsouvelis\|John\|J\|;Singh\|Jasmine\|J\|", "chemical_list": "D000935:Antifungal Agents; D013607:Tablets; D014230:Triazoles; C101425:posaconazole", "country": "England", "delete": false, "doi": "10.1177/1078155216673228", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-1552", "issue": "24(1)", "journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners", "keywords": "Posaconazole; hyperbilirubinemia; hypoalbuminemia; phase 2 metabolism; therapeutic drug monitoring", "medline_ta": "J Oncol Pharm Pract", "mesh_terms": "D000935:Antifungal Agents; D016903:Drug Monitoring; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D013607:Tablets; D014230:Triazoles", "nlm_unique_id": "9511372", "other_id": null, "pages": "63-66", "pmc": null, "pmid": "27824587", "pubdate": "2018-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Failure to achieve therapeutic levels with high-dose posaconazole tablets potentially due to enhanced clearance.", "title_normalized": "failure to achieve therapeutic levels with high dose posaconazole tablets potentially due to enhanced clearance" }	[ { "companynumb": "AU-PFIZER INC-2017547194", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CYTARABINE" }, "drugadditional": "3", ...
{ "abstract": "A 55-year-old female patient presented to the endocrine clinic with Grave's disease. She was initially treated with carbimazole. After an early relapse, a decision was made to proceed with radioactive iodine therapy. Four days after radioiodine administration, she presented to the emergency department with chest tightness and dyspnea due to heart failure. Biochemistry revealed thyrotoxicosis and significantly elevated Troponin-T. There was ST segment elevation on electrocardiography. However, coronary angiography was normal. Ventricular function was fully restored after 6 weeks of supportive medical management. A diagnosis of stress cardiomyopathy following radioactive iodine therapy was made. This is the second case reported in the literature so far to the best of our knowledge.\n\n\n\nStress cardiomyopathy in the context of radiation thyroiditis is a rare complication following radioiodine therapy.\n\nA degree of awareness is essential because the approach is multidisciplinary. Management is mainly supportive and cardiac dysfunction is completely reversible in most cases.\n\nThe pathogenesis of this condition remains unclear. Post-menopausal women and susceptible individuals appear to be pre-disposed.", "affiliations": "Colchester Hospital University NHS Foundation Trust, Colchester, UK;Colchester Hospital University NHS Foundation Trust, Colchester, UK;Colchester Hospital University NHS Foundation Trust, Colchester, UK;Colchester Hospital University NHS Foundation Trust, Colchester, UK", "authors": "Dimakopoulou\|Anastasia\|A\|;Vithian\|Karunakaran\|K\|;Gannon\|David\|D\|;Harkness\|Allan\|A\|", "chemical_list": null, "country": "England", "delete": false, "doi": null, "fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case Rep\nEndocrinol Diabetes Metab Case Rep\nEDM\nEndocrinology, Diabetes & Metabolism Case Reports\n2052-0573\nBioscientifica Ltd Bristol\n\n30367748\nEDM150053\n10.1530/EDM-15-0053\nAdult\nFemale\nWhite\nUnited Kingdom\nHeart\nThyroid\nThyroid\nTSH\nThyroxine (T4)\nGraves' disease\nTakotsubo cardiomyopathy\nThyrotoxicosis\nHyperthyroidism\nThyroiditis\nGoitre (multinodular)\nHeart Failure\nTachycardia\nSweating\nLips - Dry\nDyspnoea\nAngiography\nElectrocardiogram\nEchocardiogram\nTSH\nThyroid Function\nFt4\nFt3\nTroponin\nChest Auscultation\nRadionuclide Therapy\nRadioiodine\nCarbimazole\nPrednisolone\nGlucocorticoids\nRamipril\nCarvedilol\nAlpha-Blockers\nPropylthiouracil\nLevothyroxine\nCardiology\nUnusual Effects of Medical Treatment\nUnusual Effects of Medical Treatment\nStress cardiomyopathy (Takotsubo) following radioactive iodine therapy\nTakotsubo cardiomyopathy\nDimakopoulou Anastasia anastasia.dimakopoulou@nhs.net\n\nVithian Karunakaran 1\nGannon David 1\nHarkness Allan 1\n1 Whittington Hospital, London, UK\n2 Colchester Hospital University NHS Foundation Trust, Colchester, UK\n1 8 2015\n1 8 2015\n2015 15-005324 7 2015\n31 7 2015\n© 2015 The authors\n2015\nThe authors\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 Unported License.\nSummary\n\nA 55-year-old female patient presented to the endocrine clinic with Grave's disease. She was initially treated with carbimazole. After an early relapse, a decision was made to proceed with radioactive iodine therapy. Four days after radioiodine administration, she presented to the emergency department with chest tightness and dyspnea due to heart failure. Biochemistry revealed thyrotoxicosis and significantly elevated Troponin-T. There was ST segment elevation on electrocardiography. However, coronary angiography was normal. Ventricular function was fully restored after 6 weeks of supportive medical management. A diagnosis of stress cardiomyopathy following radioactive iodine therapy was made. This is the second case reported in the literature so far to the best of our knowledge.\n\nLearning points\n\nStress cardiomyopathy in the context of radiation thyroiditis is a rare complication following radioiodine therapy.\n\nA degree of awareness is essential because the approach is multidisciplinary. Management is mainly supportive and cardiac dysfunction is completely reversible in most cases.\n\nThe pathogenesis of this condition remains unclear. Post-menopausal women and susceptible individuals appear to be pre-disposed.\n\nPatient demographics\n\nAdult\nFemale\nWhite\nUnited Kingdom\nClinical overview\n\nHeart\nThyroid\nThyroid\nTSH\nThyroxine (T4)\nGraves' disease\nTakotsubo cardiomyopathy\nThyrotoxicosis\nHyperthyroidism\nThyroiditis\nGoitre (multinodular)\nDiagnosis & treatment\n\nHeart failure\nTachycardia\nSweating\nLips - dry\nDyspnoea\nAngiography\nElectrocardiogram\nEchocardiogram\nTSH\nThyroid function\nFT4\nFT3\nTroponin\nChest auscultation\nRadionuclide therapy\nRadioiodine\nCarbimazole\nPrednisolone\nGlucocorticoids\nRamipril\nCarvedilol\nAlpha-blockers\nPropylthiouracil\nLevothyroxine\nRelated disciplines\n\nCardiology\nPublication details\n\nUnusual effects of medical treatment\nAugust\n2015\n==== Body\nBackground\n\nStress cardiomyopathy after radioactive iodine therapy was originally reported in 2009 (1). We would like to report this case in order to increase awareness among endocrinologists, cardiologists and general medical physicians. Stress cardiomyopathy is a condition characterised by reversible left ventricular dysfunction. The precipitant is usually a highly stressful experience with significant sympathetic drive. Thyrotoxicosis in the context of radiation thyroiditis represents a state of increased adrenergic activity and can potentially lead to stress cardiomyopathy in pre-disposed individuals.\n\nCase presentation\n\nA 55-year-old female patient was assessed in the endocrine clinic with facial sweating and dry lips. She did not have palpitations, heat intolerance or other symptoms suggestive of hyperthyroidism. She had a multinodular goitre, which was confirmed on thyroid ultrasound. There were no signs of thyroid ophthalmopathy. Her initial presentation was consistent with subclinical hyperthyroidism. Nine months later, biochemical hyperthyroidism developed with a thyroid-stimulating hormone (TSH) of <0.01 mU/l, a free thyroxine (T4) of 42.2 pmol/l and free triiodothyronine (T3) of 18 pmol/l. Carbimazole was started and free T4 normalised. In an attempt to reduce the dose of carbimazole, her Grave's disease relapsed. After 12 months of antithyroid treatment, TSH became undetectable and free T4 increased to 32.8 pmol/l. Our patient was keen to proceed with radioactive iodine therapy. One month prior radioiodine, free T4 was within normal range at 19.6 pmol/l and the dose of carbimazole was 20 mg daily. Four days after radioactive iodine (400 MBq) administration, she presented to the emergency department with chest tightness and dyspnea.\n\nOn arrival to the emergency department, clinical examination revealed signs of heart failure. There were bilateral crackles on chest auscultation and electrocardiography was consistent with an acute coronary event. Biochemistry confirmed raised cardiac markers. Therefore, urgent transfer to the local cardiothoracic centre was scheduled for possible primary coronary intervention.\n\nInvestigation\n\nOriginal electrocardiography showed sinus tachycardia at 121 per min and borderline ST elevation in II/III leads (Fig. 1). Troponin-T was elevated at 438 ng/l (normal range <15 ng/l).Figure 1 ECG showing borderline ST elevation in II/III leads.\n\nThyroid function testing was consistent with undetectable TSH and free T4 of 77.7 pmol/l (Table 1).Table 1 Thyroid function testing\n\n\tPresentation\tInitiation of antithyroid medication\tEuthyroid in 9 months\tRelapse in 12 months\tEuthyroid 1 month before I131\tThyrotoxicosis 4 days after I131\tHypothyroid 3 months after after I131\t\nTSH (mU/l)\t<0.01\t<0.01\t<0.01\t<0.01\t<0.03\t<0.01\t2.18\t\nFT4 (pmol/l)\t18.6\t42.2\t18.2\t32.8\t19.6\t77.7\t6.2\t\nFT3 (pmol/l)\t\t18\t\t\t\t21.1\t\t\n\nCoronary angiography performed at the cardiothoracic centre was normal. Echocardiography showed focal apical akinesia of left ventricular (LV) segments, apical ballooning and regional wall motion abnormalities. Systolic function was impaired with an ejection fraction of 30–35% (Fig. 2).Figure 2 Takotsubo cardiomyopathy on echocardiogram – parasternal long axis on original presentation.\n\nOutcome and follow-up\n\nOur patient was treated with propylthiouracil, ramipril and carvedilol. She also completed a course of oral prednisolone for radiation thyroiditis, a painful inflammation of the thyroid gland that occurs after radioiodine therapy (2).\n\nSix weeks after the episode of radiation thyroiditis, echocardiography showed normal left ventricular function with ejection fraction of 55% (Fig. 3). Ramipril was stopped. Mayo's revised criteria were used to confirm the diagnosis of Takotsubo cardiomyopathy (3) (4): i) transient hypokinesis or dyskinesis of left ventricular mid segments with apical ballooning; ii) absence of obstructive coronary disease; iii) new ST segment elevation or T wave inversion on electrocardiography; and iv) absence of pheochromocytoma and myocarditis.Figure 3 Takotsubo cardiomyopathy resolved echocardiogram – parasternal long axis, 6 weeks after original presentation.\n\nThree months after radioiodine, TSH increased to 2.18 mU/l with free T4 of 6.2 pmol/l. l-T4 was successfully introduced. No further cardiology input is required.\n\nDiscussion\n\nStress cardiomyopathy is a rare complication of thyrotoxicosis, which may occur in the context of radiation thyroiditis. The latter affects 1% of patients receiving radioiodine therapy and lasts for a few weeks. Radiation thyroiditis is associated with transient destruction-mediated release of thyroid hormones and this can have a significant impact on cardiovascular physiology. The effects of T3, the active cellular form of thyroid hormone, lead to increased cardiac output in patients with hyperthyroidism resembling a state of increased adrenergic activity (5).\n\nThe diagnosis of stress induced cardiomyopathy was originally described in Japan (6). It is also called Takotsubo, meaning octopus trap which has a shape similar to the apical ballooning of the left ventricle. It has been linked with acute illness, emotional or physical stress (3). A number of hypotheses have been postulated for pathogenesis of the syndrome, including catecholamine excess. Hyperthyroidism in the context of radiation thyroiditis also mimics a state of adrenergic excess. Thyroid hormone is believed to act upon cardiac myocytes partially via upregulation of β-adrenergic receptors. However, the exact pathogenesis of the condition remains unclear (5) (7). Heart failure develops on the grounds of normal coronary angiography and medical treatment with diuretics, β blockers as well as angiotensin-converting–enzyme (ACE) inhibitors result in full resolution of symptoms (3).\n\nThe first case of takotsubo cardiomyopathy complicating radiation thyroiditis was reported in a 73-year-old man from the Netherlands with a toxic multinodular goitre (1). He was initially treated with radioiodine therapy. Five years later, hyperthyroidism recurred and a second dose of radioactive iodine was administered. Four days later, he presented with irritation and signs of heart failure. He was hyperthyroid. Electrocardiography and ventricular angiography confirmed apical ballooning consistent with takotsubo cardiomyopathy. He was managed supportively and improved markedly after 24 h. His cardiac function returned to normal after 7 weeks. Antithyroid medications were never used during the course of his thyroid disease. Although this patient was treated in a different country, clinical guidelines from the Royal College of Physicians recommend that patients with severe hyperthyroidism or elderly patients with signs of heart failure should be treated with an antithyroid drug to restore normal circulating thyroid hormone levels before radioiodine treatment (8). This way thyroid hormone stores get depleted and the risk of symptom exacerbation or thyroid storm after early radioactive iodine therapy is diminished.\n\nOur patient received a full 12-month treatment with carbimazole, but still developed stress-induced cardiomyopathy secondary to post-ablative thyrotoxicosis. Postmenopausal women seem to be more at risk (3). A single centre retrospective study conducted to find the association of thyroid profile with takotsubo cardiomyopathy has shown that 11.36% of patients presenting with the syndrome over a 6 year period were found to be hyperthyroid. A significantly higher number (34.61%) had a history of hypothyroidism. Precipitating stress was identified in only 24% patients (7). Risk factors for developing the syndrome require further evaluation.\n\nInpatient mortality from stress cardiomyopathy alone ranges from 0 to 8% and patients who survive the acute episode recover to normal cardiac function within one to 4 weeks (3). The Royal College of Physicians recommends that in the first 2 weeks following administration of radioiodine therapy, patients should be warned that exacerbation of thyrotoxic symptoms may be experienced. Prospective observational population-based studies have not shown excess mortality during follow up after radioiodine treatment which has resulted in hypothyroidism, and this is strongly supportive of its safety (9).\n\nFunding\n\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nDeclaration of interest\n\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nPatient consent\n\nWritten informed consent was obtained from the patient for publication of this case report.\n\nAuthor contribution statement\n\nCo-authors have contributed towards patient care, management and also towards writing and finalising the draft.\n==== Refs\nReferences\n\nVan de Donk NW America YG Zelissen PM & Hamer BJ 2009 Takotsubo cardiomyopathy following radioiodine therapy for toxic multinodular goitre. Netherlands Journal of Medicine 67 350–352.\nRoss DS 2011 Radioiodine therapy for hyperthyroidism. New England Journal of Medicine 364 542–550. (10.1056/NEJMct1007101)\nBybee KA Kara T Prasad A Lerman A Barsness GW Wright RS & Rihal CS 2004 Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Annals of Internal Medicine 141 858. 10.7326/0003-4819-141-11-200412070-00010)15583228\nRadhakrishnan A & Granato JE 2009 An association between Takotsubo cardiomyopathy and thyroid storm. Postgraduate Medicine 121 126–130. (10.3810/pgm.2009.05.2012)19491550\nKlein I & Ojamaa K 2001 Thyroid hormone and the cardiovascular system. New England Journal of Medicine 344 501–509. (10.1056/NEJM200105103441901)\nSato H, Taiteishi H & Uchida T. Takotsubo-type cardiomyopathy due to multivessel spasm. In Clinical Aspect of Myocardial Injury: From Ischemia to Heart Failure, p 56. Tokyo: Kagakuhyouronsha, 1990.\nAggarwal S Papani R & Gupta V 2015 Can thyroid break your heart? Role of thyroid in Takotsubo cardiomyopathy: a single center retrospective study. International Journal of Cardiology 184 545–546. (10.1016/j.ijcard.2015.02.058)25767013\nRoyal College of Physicians. Radioiodine in the management of benign thyroid disease: clinical guidelines. Report of a Working Party. London: RCP, 2007.\nBoelaert K Maisonneuve P Torlinska B & Franklyn JA 2013 Comparison of mortality in hyperthyroidism during periods of treatment with thionamides and after radioiodine. Journal of Clinical Endocrinology and Metabolism 98 1869–1882. (10.1210/jc.2012-3459)23543662\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2052-0573", "issue": "2015()", "journal": "Endocrinology, diabetes & metabolism case reports", "keywords": null, "medline_ta": "Endocrinol Diabetes Metab Case Rep", "mesh_terms": null, "nlm_unique_id": "101618943", "other_id": null, "pages": null, "pmc": null, "pmid": "30367748", "pubdate": "2015-08-01", "publication_types": "D002363:Case Reports", "references": "19915229;21306240;11172193;15583228;25767013;23543662;19491550", "title": "Stress cardiomyopathy (Takotsubo) following radioactive iodine therapy", "title_normalized": "stress cardiomyopathy takotsubo following radioactive iodine therapy" }	[ { "companynumb": "GB-MALLINCKRODT-T201504436", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "SODIUM IODIDE I-131" }, "drugadditional": nu...
{ "abstract": "Tumour necrosis factor (TNF)-α inhibitors are highly used in Romania for the treatment of autoimmune disorders, such as rheumatoid arthritis (RA), psoriasis, inflammatory bowel diseases, and ankylosing spondylitis. Biological therapy using TNF-α inhibitors is very effective but is associated with an increased risk of opportunistic infections, including active tuberculosis. Here, two cases are presented of patients with RA and psoriasis under biological therapy who developed very aggressive forms of disseminated tuberculosis, with a rapid progression to death. The authors conclude that patients undergoing biological therapy require thorough evaluation prior to initiating treatment, followed by continuous and rigorous monitoring by a multidisciplinary team during biological treatment, particularly in countries with a high incidence of tuberculosis.", "affiliations": "1 Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania.;1 Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania.;1 Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania.;1 Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania.;1 Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania.;1 Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania.;1 Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania.", "authors": "Dantes\|Elena\|E\|;Tofolean\|Doina Ecaterina\|DE\|;Fildan\|Ariadna Petronela\|AP\|;Craciun\|Liviu\|L\|;Dumea\|Elena\|E\|;Tofolean\|Ioan Tiberiu\|IT\|;Mazilu\|Laura\|L\|", "chemical_list": "D018501:Antirheumatic Agents; D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab", "country": "England", "delete": false, "doi": "10.1177/0300060518771273", "fulltext": "\n==== Front\nJ Int Med ResJ. Int. Med. ResIMRspimrThe Journal of International Medical Research0300-06051473-2300SAGE Publications Sage UK: London, England 2979208410.1177/030006051877127310.1177_0300060518771273Case ReportsLethal disseminated tuberculosis in patients under biological treatment – two clinical cases and a short review Dantes Elena 12Tofolean Doina Ecaterina 13Fildan Ariadna Petronela 14Craciun Liviu 13Dumea Elena 15Tofolean Ioan Tiberiu 16Mazilu Laura 17\n1 Faculty of Medicine, Ovidius University of Constanta, Constanta, Romania\n2 Pneumology Adults department I, Clinical Pulmonology Hospital of Constanta, Constanta, Romania\n3 Department of Pulmonology, Constanta County Clinical Emergency Hospital ‘St. Apostol Andrei’, Constanta, Romania\n4 Pneumology Adults department II, Clinical Pulmonology Hospital of Constanta, Constanta, Romania\n5 Infectious Diseases Adults department I, Clinical Infectious Diseases Hospital of Constanta, Constanta, Romania\n6 Department of Gastroenterology, Constanta County Clinical Emergency Hospital ‘St. Apostol Andrei’, Constanta, Romania\n7 Department of Oncology, Constanta County Clinical Emergency Hospital ‘St. Apostol Andrei’, Constanta, RomaniaDoina Ecaterina Tofolean, Faculty of Medicine, Ovidius University of Constanta, 1 University Alley, 900470, Constanta, Romania; Department of Pulmonology, Constanta County Clinical Emergency Hospital ‘St. Apostol Andrei’, 145 Tomis Boulevard, 900591, Constanta, Romania. Email: tofoleandoina@yahoo.com23 5 2018 7 2018 46 7 2961 2969 17 1 2018 26 3 2018 © The Author(s) 20182018SAGE PublicationsCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.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).Tumour necrosis factor (TNF)-α inhibitors are highly used in Romania for the treatment of autoimmune disorders, such as rheumatoid arthritis (RA), psoriasis, inflammatory bowel diseases, and ankylosing spondylitis. Biological therapy using TNF-α inhibitors is very effective but is associated with an increased risk of opportunistic infections, including active tuberculosis. Here, two cases are presented of patients with RA and psoriasis under biological therapy who developed very aggressive forms of disseminated tuberculosis, with a rapid progression to death. The authors conclude that patients undergoing biological therapy require thorough evaluation prior to initiating treatment, followed by continuous and rigorous monitoring by a multidisciplinary team during biological treatment, particularly in countries with a high incidence of tuberculosis.\n\nRheumatoid arthritispsoriasisTNF-α inhibitorslethal disseminated tuberculosis\n==== Body\nIntroduction\nThe use of tumour necrosis factor (TNF)-α inhibitor therapy in patients diagnosed with autoimmune diseases, such as rheumatoid arthritis (RA) and psoriasis, has proven highly effective in suppressing the pathologic inflammation responsible for specific symptoms and joint damage, but is associated with a decrease in host defence against opportunistic infections, including active tuberculosis (TB).1–4 All anti-TNF drugs are associated with an increased risk of TB reactivation in patients positive for latent TB infection, with a lower risk associated with etanercept,5,6 and a consistent number of cases have also been reported from countries with a low TB incidence (less than 20 per 100 000 population per year).7 Cases of tuberculosis have been described in patients with known RA even before starting biological therapy, particularly in countries with high incidence of TB.8 Only a few cases with rapid progression to death due to disseminated forms of TB have been reported to date, however.9,10 Romania has a relatively high incidence of TB (70 per 100 000 inhabitants),11 and like other countries, biological treatment is frequently used, thus, monitoring of the adverse effects of this therapy must be very rigorous, multidisciplinary, and well established in active national guidelines. The tuberculin skin test (Statens Serum Institut, Copenhagen, Denmark) and QuantiFERON-TB Gold in-tube assay (Cellestis Ltd, Carnegie, Victoria, Australia) are used in Romania to screen for latent TB infection.\n\nHere, two cases are presented of patients with RA and psoriasis, treated using biological therapy, who developed very aggressive forms of disseminated tuberculosis. These cases are presented due to the unusual clinical features, unexpected severity, and fast progression to death.\n\nCase reports\nApproval to publish the present findings was provided by the Ethics committee of the Clinical Pneumology Hospital of Constanta (Case 1) and the Ethics committee of the Clinical Infectious Diseases Hospital of Constanta (Case 2) and each patient provided written informed consent on admission to hospital.\n\nCase 1\nA 72-year-old female patient was admitted to the First Internal Medicine Department of Constanta County Clinical Emergency Hospital in December 2015, for fever, chills, severe asthenia, productive cough, polyarthralgia, with symptomatology that had worsened over the previous 3 days. Medical history revealed arterial hypertension dating from 2010 and stage III seropositive RA since November 2004. The patient’s RA had been initially treated with 15 mg methotrexate, oral, weekly and anti-inflammatory drugs (500 mg naproxen with 20 mg esomeprazole as gastric protection, both oral, twice daily). From June 2015, because of highly active disease (Disease Activity Score 28 for Rheumatoid Arthritis using C-reactive protein [DAS28-CRP], 7.79), 40 mg adalimumab, subcutaneous, every other week, was added to the regimen. Before the initiation of adalimumab, chest X-ray was normal, tuberculin skin test (Statens Serum Institut) and QuantiFERON-TB Gold in-tube test (Cellestis) were negative, and enzyme-linked immunosorbent assay for human immunodeficiency virus (HIV) was negative. Following six months of adalimumab therapy, the patient was admitted into the hospital in a conscious state with normal body mass index (BMI, 21.1 kg/m2), fever (38.6 °C), joints with specific deformities only, normal lung examination, SpO2 of 97%, blood pressure at 120/70 mmHg, heart rate of 100 beats per min, and an enlarged abdomen with ascites. Biological tests showed normal white blood cell (WBC) count (5.910 x 103 cells/µl), mild chronic inflammatory anaemia (haemoglobin, 9.6 g/dl; haematocrit, 30.1 %) and systemic inflammatory syndrome (erythrocyte sedimentation rate [ESR], 36 mm/h; fibrinogen, 512 mg/dl). Bacteriological examination of blood culture was sterile and sputum samples were negative for pyogenic bacteria, fungi, and acid-fast bacillus. Standard chest X-ray (Figure 1) showed multiple micronodular and nodular pale opacities, disseminated in both lungs. The investigations were extended using thoracic computed tomography (CT) and revealed a bronchopneumonic aspect, mediastinal lymphadenopathy (between 12 and 20 mm), and straight lymph node calcifications (Figure 2). Antibiotic and antifungal treatment was initiated, comprising 1 g ceftazidinum twice daily and 400 mg/250 ml moxifloxacin once daily, plus 200 mg fluconazole once daily, all administered intravenously (i.v.). On day 4 of treatment, ceftazidinum was replaced with 1 g meropenem i.v., three times daily, and the treatment continued for a further 10 days, while previous treatment remained the same for the entire treatment duration. This treatment regimen was without good patient progression. Abdominal ultrasound, performed on the first day of hospitalization and repeated on day 5 due to poor patient progression, indicated splenomegaly with heterogeneous structure and multiple hypoechogenic formations, and gross ascites, confirmed by abdominal CT (Figure 3). Exploratory paracentesis revealed the presence of an exudate with protein (3.7 g/dl), lactate dehydrogenase (864 U/l), and increased adenosine deaminase (ADA; 93 U/l). At this hospitalization, the repeated QuantiFERON-TB Gold test was positive. Due to the risk of TB infection secondary to biological therapy, enforced by the patient’s lung images and ADA value, a complete range of bacteriological tests were performed. Microscopic examination of sputum was negative for acid-fast bacilli. The rapid detection of Mycobacterium tuberculosis in liquid culture from sputum specimens and ascites liquid (tested using the BD BACTEC™ MGIT™ automated mycobacterial detection system; Becton Dickinson, Sparks, MD, USA), which were both positive after 14 days of liquid culture, confirmed the diagnosis of disseminated secondary tuberculosis, with multiple organ involvement (pulmonary, peritoneal and possibly splenic). Consequently, the patient was transferred to the Pulmonology Department, Constanta County Clinical Emergency Hospital, to undergo appropriate treatment. Due to corroboration between clinical and paraclinical factors, treatment against TB had been initiated prior to having bacteriological confirmation from sputum and ascites samples in solid culture on Lowenstein-Jensen medium, which became positive after 40 days (positive culture with 1–30 colonies of M. tuberculosis, antigen MPT64 positive, fully sensitive to all TB drugs, in sputum and [++] in ascites liquid). The first standard regime of treatment, in accordance with the National Programme for Prevention, Monitoring and Control of Tuberculosis,11 was initiated with: 5 mg/kg/day isoniazid, 10 mg/kg/day rifampicin, 30 mg/kg/day pyrazinamide and 25 mg/kg/day ethambutol, all intravenous, in perfusion (approximately 30–40 min per drug), all administrated in the morning. In addition, 250 mg pyridoxine, and 20 mg esomeprazole, both oral, daily, were added. Progression was quickly and constantly unfavourable, with additional complications: upper digestive bleeding (exteriorized by haematemesis) and multiple organ failures (respiratory, kidney and liver). The patient finally died following 7 days of standard TB treatment and 21 days of hospitalization, despite all medical efforts. The family did not consent to an autopsy.\n\nFigure 1. Chest X-ray from a 72-year old female patient with rheumatoid arthritis, obtained following 6 months of treatment with 40 mg/day adalimumab, every 2 weeks: X-ray shows multiple pale nodular opacities disseminated bilaterally, particularly in the upper two thirds of the thorax\n\nFigure 2. Thoracic computed tomography (CT) image from a 72-year old female patient with rheumatoid arthritis, obtained following 6 months of treatment with 40 mg/day adalimumab, every 2 weeks: CT image shows bronchopneumonic aspect, mediastinal lymphadenopathies between 12 and 20 mm, and straight lymph node calcifications\n\nFigure 3. Abdominal computed tomography (CT) image from a 72-year old female patient with rheumatoid arthritis, obtained following 6 months of treatment with 40 mg/day adalimumab, every 2 weeks: CT image shows ascites, and a heterogeneous spleen with multiple hypoechogenic formations\n\nCase 2\nA 65-year-old female patient was admitted to the Cardiology Department of Constanta County Clinical Emergency Hospital in February 2016, for headache, dizziness and thoracic pain with suspicion of acute myocardial infarction. This patient presented with a history of essential stage III arterial hypertension (with very high additional risk) since 2002, diabetes mellitus with nephroangiopathy and polyneuropathy treated with oral antidiabetes medications since 2006, and severe chronic psoriasis since 2009. In the previous three months the patient had received treatment for severe psoriasis with psoriatic arthritis (Psoriasis Area and Severity Index score, 23.2) comprising an anti-TNF-α agent: three doses of 5 mg/kg infliximab, i.v. (at weeks 0, 2, and 6; last dose received in December 2016), according to an approved RA protocol.12 Physical examination did not reveal pathological signs. Biological tests were without significant or specific abnormalities: normal haemogram, fibrinogen, alanine transaminase, aspartate aminotransferase, creatine kinase-muscle/brain, creatinine, and urea, but elevated ESR (68 mm/h), blood glucose (195 mg/dl) and troponin level (199.2 µg/l). Myocardial infarction was excluded, but the patient’s general condition deteriorated during hospitalization, the level of consciousness decreased, and fever with signs of meningeal irritation appeared five days following hospital admission. She was diagnosed with acute meningoencephalitis with a Glasgow coma scale score of 6 and was admitted to the Intensive Care Unit. Analyses of cerebrospinal fluid (CSF) revealed: intense positive Pandy’s reaction (++++), 235 cells/µl (85% polymorphonuclear leukocytes and 15% lymphocytes), increased albumin (132 mg/dl), hypoglycorrhachia (glucose, 0.31 g/l) and hypochlorrhachia (chloride, 9.20 µmol/l [6.35 g/dl]). Bacteriological examination showed the CSF to be positive for acid-fast bacillus (Ziehl-Neelsen staining), positive for TB nucleic acid using GeneXpert (Cepheid, Sunnyvale, CA, USA) with no detection of rifampin resistance, and positive for M. tuberculosis in liquid culture, tested using the BD BACTEC™ MGIT™ system. Chest X-ray showed a miliary TB pattern (not shown). The patient was confirmed as a new case of disseminated TB in a patient recently treated with infliximab for psoriasis. Specific anti-TB chemotherapy with four first-line drugs, as in the previous case (5 mg/kg/day isoniazid, 10 mg/kg/day rifampicin, 30 mg/kg/day pyrazinamide and 25 mg/kg/day ethambutol), oral administration, was started. Three days following initiation of treatment for TB, the patient presented upper digestive haemorrhage exteriorized by melena. Despite all aggressive treatment, the patient died with cardiorespiratory failure after 16 days of hospitalization.\n\nDiscussion\nIncidence of RA in Romania is approximately 1% of the general population, and incidence of psoriasis is approximately 2%.12 In these population groups, the prevalence of latent TB infection remains unknown. In patients diagnosed with RA and psoriasis, TNF-α blockers are initiated only in patients who are unresponsive to conventional treatment, and after careful exclusion of latent TB infection.2,3,12,13 Romanian guidelines stipulate that prior to administration of biological treatment, the patient should follow an algorithm to identify latent TB infection, and chemoprophylactic treatment should be administered for 9 months in patients who have a positive tuberculin skin test, (tuberculin skin test, ≥ 10 mm, and without signs of active disease).11 Despite pretreatment evaluation, it is well known that the use of TNF-α inhibitor therapy is associated with an increased risk of active TB.12–15 The current report presents the cases of two female patients, both over 65 years old, with a long history of RA and psoriatic arthritis, who were diagnosed with TB after starting biological treatment, despite both being confirmed negative for latent TB infection prior to initiation of treatment. Neither of the cases had been recently exposed to TB, making it difficult to support an exogenous reinfection mechanism for TB. The possibility of a false-negative tuberculin skin test and negative QuantiFERON-TB Gold assay need to be taken into consideration, due to immunosuppression caused by disease or chronic anterior immunosuppressive therapy,16,17 making the reactivation of post-primary TB lesions more feasible. Moreover, use of the tuberculin skin test is more controversial for a patient with psoriasis due to the possibility of over-diagnosis or ambiguous results.18 Despite the fact that in many national guidelines the tuberculin skin test remains the first-line tool to screen for latent TB infection in patients with psoriasis, it is recommended that the QuantiFERON-TB Gold test is also performed, either before or on the same day as the Mantoux test, to increase the accuracy of diagnosis.18 Unusual clinical features in adults with disseminated pulmonary and extrapulmonary TB (peritoneal and meningitis), may delay diagnosis for 5 to 15 days, leading to an increased risk of mortality (authors’ personal experience). In Romania, meningitis is more frequently observed as a complication of primary TB in infants and is a very rare complication in adults.19 Knowing the paucibacillary character of serositis, the present authors consider that the positive acid-fast bacillus smear for CSF (case 2) and positive GeneXpert and liquid culture for M. tuberculosis for ascites (case 1) reflect the severity of the disease. Published studies report a positive rate for acid-fast bacillus smear in TB meningitis of between 37 and 58%.20,21 For both cases reported in the current study, death was considered to be related to disseminated TB, and it is unclear whether the occurrence of superior digestive haemorrhage aggravated the patients’ prognosis. The anti-TB treatment cannot be directly associated with this haemorrhage complication, as administration was intravenous in case 1, and the complication preceded the start of treatment in case 2.\n\nMedical professionals should be aware of the unusual pattern of TB in patients undergoing biological treatment.22 For example, extrapulmonary or disseminated tuberculosis are more frequently observed in patients treated with TNF-α inhibitors.7,23 A review of 70 cases of TB that developed after treatment with infliximab showed an increased proportion of extrapulmonary TB (56% versus 18%) and disseminated diseases (18% versus 2%), when associated with a severe immunosuppression status (including HIV positivity).22 The four deaths out of 70 patients in this study were related to TB,22 however, in patients receiving biological treatment, very few deaths related to TB have been reported in the literature.9,10\n\nThe number of TB cases has been reported in the literature to be higher for infliximab than adalimumab,22,24 however, two studies (one French and one English) reported that the incidence of TB was higher for adalimumab.5,6 The interval from starting anti-TNF-α treatment until TB onset was 6 months in the present first case (treated with adalimumab), which was shorter than in a published study reporting median time to TB onset of 18.5 months for 11 patients treated with adalimumab,6 and was more comparable with timeframes reported for patients treated with infliximab.3,22,25 Clinical deterioration despite specific anti-TB treatment has been reported in cases of RA treated with adalimumab, due to a paradoxical reaction involving the lungs, with acute respiratory failure attributed to the recurrence of disease in the absence of biological treatment.23,26,27 The onset of paradoxical reaction is considered one month after TB diagnosis and treatment.23,27 In the present cases, it is difficult to maintain that death was attributed to a paradoxical reaction, because it occurred soon after starting the anti-TB treatment (7 days for case 1, and 3 days for case 2), but after 4 weeks from the last dose of adalimumab and 8 weeks from the last dose of infliximab. Unfortunately, procalcitonin level, a possible diagnostic and prognosis marker for paradoxical reaction,23 was not tested in either case. The moment of restarting therapy with TNF-α inhibitors during or following the end of anti-TB treatment differs between guidelines. It is possible to restart after 2 months,28 but it is mandatory to pay close attention to TB evolution during follow-up.29\n\nIn conclusion, because of the high endemic value of TB in Romania,30 and given the severe forms presented by these cases, there is ongoing discussion as to whether or not chemoprophylaxis with isoniazid should be provided in all cases before anti TNF-α treatment, even if the first screening excludes latent TB infection. In addition, old age, female sex, long history of autoimmune disease, and association of other comorbidities, such as diabetes, digestive haemorrhage, and HIV infection, could be risk factors for developing disseminated and lethal forms of TB during biological treatment with infliximab and adalimumab. Etanercept may be a more beneficial anti-TNF-α treatment given its relatively low incidence rate of TB, for patients in which this therapy is mandatory.31\n\nIn cases at high risk of TB reactivation, the choice of a non-anti-TNF targeted biologic is advisable.31\n\nDeclaration of conflicting interest\nThe authors declare that there are no conflicts of interest.\n\nFunding\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 Ehlers S. \nRole of tumor necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF. \nAnn Rheum Dis \n2003 ; \n62 (Suppl 2 ): ii37 –ii42 .14532147 \n2 Schuna AA Megeff C. \nNew drugs for the treatment of rheumatoid arthritis. \nAm J Health Syst Pharm \n2000 ; \n57 : 225 –234 .10674776 \n3 Galloway JB Hyrich KL Mercer LK et al \nAnti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. \nRheumatology (Oxford) \n2011 ; \n50 : 124 –131 .20675706 \n4 Xie X Li F Chen JW et al \nRisk of tuberculosis infection in anti-TNF-a biological therapy: from bench to bedside. \nJ Microbiol Immunol Infect \n2014 ; \n47 : 268 –274 .23727394 \n5 Tubach F Salmon D Ravaud P et al \nRisk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: the three-year prospective French Research Axed on Tolerance of Biotherapies registry. \nArthritis Rheum \n2009 ; \n60 : 1884 –1894 .19565495 \n6 Dixon WG Hyrich KL Watson KD et al \nDrug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR). \nAnn Rheum Dis \n2010 ; \n69 : 522 –528 .19854715 \n7 Cantini F Nannini C Niccoli L et al \nRisk of tuberculosis reactivation in patients with rheumatoid arthritis, ankylosing spondylitis, and psoriatic arthritis receiving non-anti-TNF-targeted biologics . Mediators Inflamm \n2017 ; \n8909834 .\n8 Arghir OC Niţu M Trenchea M et al \nProgressive intraparenchymal lung nodules dissemination in a heavy smoker and seropositive rheumatoid arthritis suspected of tuberculosis relapse . Rom J Morphol Embryol \n2013 ; \n54 : 659 –663 .24068421 \n9 Hama M Yamazaki Y Kosaka M et al \nFulminant pulmonary tuberculosis by infliximab in patient with rheumatoid arthritis. \nMycobact Dis \n2016 ; \n6 : 206 . doi:10.4172/2161-1068.1000206.\n10 Moyer TM Groh B. \nDisseminated tuberculosis after treatment with infliximab . Hospital Physician \n2006 ; \n42 : 47 –51 .\n11 Arghir OC Chiotan DI Cioran NV , et al . Methodological guide to implementing the national program for prevention, monitoring and control of tuberculosis, 21 September 2015. Issued by the Ministry of Health. Official Monitor no. 748, 7 October 2015 [In Romanian]. \n12 Order MS - CNAS no. 1463/1036/2016 amending and supplementing Annex no. 1 to MS-CNAS Order no. 1301/500/2008 for the approval of the therapeutic protocols on the prescription of drugs corresponding to the frequent international names listed in the list of frequent international names corresponding to the drugs that insured persons have access to, with or without personal contribution, based on their prescription. http://amfms.ro/ordinul-mscnas-146310362016-privind-modificarea-si-completarea-anexei-nr-i-la-ordinul-13015002008-pentru-aprobarea-protocoalelor-terapeutice/ [In Romanian].\n13 Ledingham J Deighton C. \nUpdate on the British Society for Rheumatology guidelines for prescribing TNFα blockers in adults with rheumatoid arthritis (update of previous guidelines of April 2001) . Rheumatology (Oxford) \n2005 ; \n44 : 157 –163 .15637039 \n14 Centers for Disease Control and Prevention (CDC) . \nTuberculosis associated with blocking agents against tumor necrosis factor-alpha, California, 2002–2003 . MMWR Morb Mortal Wkly Rep \n2004 ; \n53 ; 683 –686 .15295313 \n15 Gardam MA Keystone EC Menzies R et al \nAnti-tumour necrosis factor agents and tuberculosis risk: mechanisms of action and clinical management. \nLancet Infect Dis \n2003 ; \n3 : 148 –155 .12614731 \n16 Keystone EC Papp KA Wobeser W. \nChallenges in diagnosing latent tuberculosis infection in patients treated with tumor necrosis factor antagonists. \nJ Rheumatol \n2011 ; \n38 : 1234 –1243 .21459944 \n17 Coaccioli S Di Cato L Marioli D et al \nImpaired cutaneous cell-mediated immunity in newly diagnosed rheumatoid arthritis . Panminerva Med \n2000 ; \n42 : 263 –266 .11294089 \n18 Balato N Di Constanzo L Ayala F et al \nPsoriatic disease and tuberculosis nowadays. \nClin Dev Immunol \n2012 ; \n2012 : 747204 .22645622 \n19 Leonard JM. Central nervous system tuberculosis. UpToDate\nhttps://www.uptodate.com/contents/central-nervous-system-tuberculosis#! (2018, accessed 29 April 2017)\n20 Kennedy DH Fallon RJ. \nTuberculous meningitis. \nJAMA \n1979 ; \n241 : 264 –268 .102806 \n21 Thwaites GE Chau TT Farrar JJ. \nImproving the bacteriological diagnosis of tuberculous meningitis. \nJ Clin Microbiol \n2004 ; \n42 : 378 –379 .14715783 \n22 Keane J Gershon S Wise RP et al \nTuberculosis associated with infliximab, a tumor necrosis factor alpha–neutralizing agent \nN Engl J Med \n2001 ; \n345 : 1098 –1104 .11596589 \n23 Wallis RS van Vuuren C Potgieter S. \nAdalimumab treatment of life-threatening tuberculosis. \nClin Infect Dis \n2009 ; \n48 : 1429 –1432 .19364287 \n24 Seong SS Choi CB Woo JH et al \nIncidence of tuberculosis in Korean patients with rheumatoid arthritis (RA): effects of RA itself and of tumor necrosis factor blockers . J Rheumatol \n2007 ; \n34 : 706 –711 .17309133 \n25 Brassard P Kezouh A Suissa S. \nAntirheumatic drugs and the risk of tuberculosis. \nClin Infect Dis \n2006 ; \n43 : 717 –722 .16912945 \n26 Salgado E Gomez-Reino JJ. \nThe risk of tuberculosis in patient treated with TNF antagonists. \nExpert Rev Clin Immunol \n2011 ; \n7 : 329 –340 .21595599 \n27 Garcia Vidal C Rodriguez Fernández S Martinez Lacasa J et al \nParadoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis. \nClin Infect Dis \n2005 ; \n40 : 756 –759 .15714425 \n28 Aslanidis S Pyrpasopoulou A Douma S et al \nIs it safe to readminister tumor necrosis factor alpha antagonists following tuberculosis flare? \nArthritis Rheum \n2008 ; \n58 : 327 –328 .18163500 \n29 Perlmutter A Mittal A Menter A. \nTuberculosis and tumour necrosis factor-alpha inhibitor therapy: a report of three cases in patients with psoriasis. Comprehensive screening and therapeutic guidelines for clinicians. \nBr J Dermatol \n2009 ; \n160 : 8 –15 .19016693 \n30 Nitu FM Olteanu M Streba CT et al \nTuberculosis and its particularities in Romania and worldwide. \nRom J Morphol Embryol \n2017 ; 58: \n385 –392. 28730222 \n31 Cantini F Nannini C Niccoli L et al \nGuidance for the management of patients with latent tuberculosis infection requiring biologic therapy in rheumatology and dermatology clinical practice. \nAutoimmun Rev \n2015 ; \n14 : 503 –509 .25617816\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "0300-0605", "issue": "46(7)", "journal": "The Journal of international medical research", "keywords": "Rheumatoid arthritis; TNF-α inhibitors; lethal disseminated tuberculosis; psoriasis", "medline_ta": "J Int Med Res", "mesh_terms": "D000068879:Adalimumab; D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D001688:Biological Products; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D000069285:Infliximab; D011565:Psoriasis; D014376:Tuberculosis; D014409:Tumor Necrosis Factor-alpha", "nlm_unique_id": "0346411", "other_id": null, "pages": "2961-2969", "pmc": null, "pmid": "29792084", "pubdate": "2018-07", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": "24068421;18163500;28730222;15295313;14715783;28659665;10674776;16912945;11294089;21459944;19364287;25617816;15637039;15714425;21595599;12614731;11596589;22645622;19016693;19854715;20675706;19565495;23727394;17309133;102806;14532147", "title": "Lethal disseminated tuberculosis in patients under biological treatment - two clinical cases and a short review.", "title_normalized": "lethal disseminated tuberculosis in patients under biological treatment two clinical cases and a short review" }	[ { "companynumb": "RO-FRESENIUS KABI-FK201809345", "fulfillexpeditecriteria": "1", "occurcountry": "RO", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null,...
{ "abstract": "Dextromethorphan (DXM) in combination with antihistamines and/or pseudoephedrine is widely available as an over-the-counter remedy commonly used for relief of colds and cough. In supratherapeutic amounts, DXM can be extremely activating. These cough preparations have been adopted by many young users of recreational drugs for their psychoactive effects. When used in amounts exceeding those recommended, this practice, known as \"robotripping,\" may result in a manic toxidrome of psychomotor agitation, hostility, grandiose behavior, hallucinations, paranoia, and panic. A case illustration of this phenomenon is described and implications of this phenomenon discussed. There are few reports associating DXM use with bipolar symptomatology.", "affiliations": "From the Department of Psychiatric Medicine, Brody School of Medicine, East Carolina University, Greenville, NC.", "authors": "Stanciu\|Cornel N\|CN\|;Penders\|Thomas M\|TM\|", "chemical_list": "D000996:Antitussive Agents; D004366:Nonprescription Drugs; D003915:Dextromethorphan", "country": "United States", "delete": false, "doi": "10.1097/ADM.0000000000000104", "fulltext": null, "fulltext_license": null, "issn_linking": "1932-0620", "issue": "9(2)", "journal": "Journal of addiction medicine", "keywords": null, "medline_ta": "J Addict Med", "mesh_terms": "D000996:Antitussive Agents; D001714:Bipolar Disorder; D003915:Dextromethorphan; D005260:Female; D006801:Humans; D004366:Nonprescription Drugs; D055815:Young Adult", "nlm_unique_id": "101306759", "other_id": null, "pages": "159-60", "pmc": null, "pmid": "25622122", "pubdate": "2015", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Mania after misuse of dextromethorphan: a case report and brief review of \"robotripping\".", "title_normalized": "mania after misuse of dextromethorphan a case report and brief review of robotripping" }	[ { "companynumb": "US-PFIZER INC-2015465044", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN\\CHLORPHENIRAMINE MALEATE" }, "...
{ "abstract": "As lenalidomide becomes increasingly established for upfront treatment of multiple myeloma, patients refractory to this drug represent a population with an unmet need. The combination of pomalidomide, bortezomib, and dexamethasone has shown promising results in phase 1/2 trials of patients with relapsed or refractory multiple myeloma. We aimed to assess the efficacy and safety of this triplet regimen in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.\n\n\n\nWe did a randomised, open-label, phase 3 trial at 133 hospitals and research centres in 21 countries. We enrolled patients (aged ≥18 years) with a diagnosis of multiple myeloma and measurable disease, an Eastern Cooperative Oncology Group performance status of 0-2, who received one to three previous regimens, including a lenalidomide-containing regimen for at least two consecutive cycles. We randomly assigned patients (1:1) to bortezomib and dexamethasone with or without pomalidomide using a permutated blocked design in blocks of four, stratified according to age, number of previous regimens, and concentration of β2 microglobulin at screening. Bortezomib (1·3 mg/m2) was administered intravenously until protocol amendment 1 then either intravenously or subcutaneously on days 1, 4, 8, and 11 for the first eight cycles and subsequently on days 1 and 8. Dexamethasone (20 mg [10 mg if age >75 years]) was administered orally on the same days as bortezomib and the day after. Patients allocated pomalidomide received 4 mg orally on days 1-14. Treatment cycles were every 21 days. The primary endpoint was progression-free survival in the intention-to-treat population, as assessed by an independent review committee. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered at ClinicalTrials.gov, number NCT01734928; patients are no longer being enrolled.\n\n\n\nBetween Jan 7, 2013, and May 15, 2017, 559 patients were enrolled. 281 patients were assigned pomalidomide, bortezomib, and dexamethasone and 278 were allocated bortezomib and dexamethasone. Median follow-up was 15·9 months (IQR 9·9-21·7). Pomalidomide, bortezomib, and dexamethasone significantly improved progression-free survival compared with bortezomib and dexamethasone (median 11·20 months [95% CI 9·66-13·73] vs 7·10 months [5·88-8·48]; hazard ratio 0·61, 95% CI 0·49-0·77; p<0·0001). 278 patients received at least one dose of pomalidomide, bortezomib, and dexamethasone and 270 patients received at least one dose of bortezomib and dexamethasone, and these patients were included in safety assessments. The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (116 [42%] of 278 patients vs 23 [9%] of 270 patients; nine [3%] vs no patients had febrile neutropenia), infections (86 [31%] vs 48 [18%]), and thrombocytopenia (76 [27%] vs 79 [29%]). Serious adverse events were reported in 159 (57%) of 278 patients versus 114 (42%) of 270 patients. Eight deaths were related to treatment; six (2%) were recorded in patients who received pomalidomide, bortezomib, and dexamethasone (pneumonia [n=2], unknown cause [n=2], cardiac arrest [n=1], cardiorespiratory arrest [n=1]) and two (1%) were reported in patients who received bortezomib and dexamethasone (pneumonia [n=1], hepatic encephalopathy [n=1]).\n\n\n\nPatients with relapsed or refractory multiple myeloma who previously received lenalidomide had significantly improved progression-free survival when treated with pomalidomide, bortezomib, and dexamethasone compared with bortezomib and dexamethasone. Adverse events accorded with the individual profiles of pomalidomide, bortezomib, and dexamethasone. This study supports use of pomalidomide, bortezomib, and dexamethasone as a treatment option in patients with relapsed or refractory multiple myeloma who previously received lenalidomide.\n\n\n\nCelgene.", "affiliations": "Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. Electronic address: paul_richardson@dfci.harvard.edu.;Institut Català d'Oncologia and Institut Josep Carreras, Hospital Germans Trias i Pujol, Barcelona, Spain.;Ankara University, Ankara, Turkey.;Università degli studi di Perugia, Perugia, Italy.;Azienda Ospedaliera Papa Giovanni XXIII, Unità Operativa di Ematologia, Bergamo, Italy.;Oslo Myeloma Center, Oslo University Hospital, Oslo, Norway; K G Jebsen Center for B Cell Malignancies, University of Oslo, Oslo, Norway.;East Kent Hospitals University NHS Foundation Trust, Kent and Canterbury Hospital, Canterbury, UK.;Department of Oncology, Hematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.;Dalhousie University and Queen Elizabeth II Health Sciences Centre, Halifax, NS, Canada.;University of Lille, Centre Hospitalier Universitaire Lille, Service des Maladies du Sang, Lille, France.;Clinica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.;National Hospital Organization Okayama Medical Center, Okayama, Japan.;Department of Haematology, Mater Misericordiae University Hospital, Dublin, Ireland; Cancer Trials Ireland, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.;Erasmus MC Cancer Institute, Rotterdam, Netherlands.;Medical University of Lodz, Lodz, Poland.;Pirogov Russian National Research Medical University, Moscow, Russia.;Department of Hematology, King's College London, London, UK.;Celgene Corporation, Summit, NJ, USA.;Celgene Corporation, Summit, NJ, USA.;Celgene International, Boudry, Switzerland.;Celgene International, Boudry, Switzerland.;Celgene International, Boudry, Switzerland.;Celgene Corporation, Summit, NJ, USA.;Jerome Lipper Multiple Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.;National and Kapodistrian University of Athens, Athens, Greece.", "authors": "Richardson\|Paul G\|PG\|;Oriol\|Albert\|A\|;Beksac\|Meral\|M\|;Liberati\|Anna Marina\|AM\|;Galli\|Monica\|M\|;Schjesvold\|Fredrik\|F\|;Lindsay\|Jindriska\|J\|;Weisel\|Katja\|K\|;White\|Darrell\|D\|;Facon\|Thierry\|T\|;San Miguel\|Jesus\|J\|;Sunami\|Kazutaka\|K\|;O'Gorman\|Peter\|P\|;Sonneveld\|Pieter\|P\|;Robak\|Pawel\|P\|;Semochkin\|Sergey\|S\|;Schey\|Steve\|S\|;Yu\|Xin\|X\|;Doerr\|Thomas\|T\|;Bensmaine\|Amine\|A\|;Biyukov\|Tsvetan\|T\|;Peluso\|Teresa\|T\|;Zaki\|Mohamed\|M\|;Anderson\|Kenneth\|K\|;Dimopoulos\|Meletios\|M\|;\|\|\|", "chemical_list": "D013792:Thalidomide; D000069286:Bortezomib; D003907:Dexamethasone; C467566:pomalidomide; D000077269:Lenalidomide", "country": "England", "delete": false, "doi": "10.1016/S1470-2045(19)30152-4", "fulltext": null, "fulltext_license": null, "issn_linking": "1470-2045", "issue": "20(6)", "journal": "The Lancet. Oncology", "keywords": null, "medline_ta": "Lancet Oncol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000069286:Bortezomib; D003907:Dexamethasone; D019008:Drug Resistance, Neoplasm; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D016879:Salvage Therapy; D015996:Survival Rate; D013792:Thalidomide; D055815:Young Adult", "nlm_unique_id": "100957246", "other_id": null, "pages": "781-794", "pmc": null, "pmid": "31097405", "pubdate": "2019-06", "publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial.", "title_normalized": "pomalidomide bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide optimismm a randomised open label phase 3 trial" }	[ { "companynumb": "US-TAKEDA-2019TUS032067", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "POMALIDOMIDE" }, "drugadditional": "3", ...
{ "abstract": "Chemotherapy during a viable pregnancy may be associated with adverse perinatal outcomes. We conducted a prospective cohort study to examine the perinatal outcomes of babies born following in utero exposure to chemotherapy in Australia and New Zealand. Over 18 months we identified 24 births, of >400 g and/or >20-weeks' gestation, to women diagnosed with breast cancer in the first or second trimesters. Eighteen babies were exposed in utero to chemotherapy. Chemotherapy commenced at a median of 20 weeks gestation, for a mean duration of 10 weeks. Twelve exposed infants were born preterm with 11 by induced labour or pre-labour caesarean section. There were no perinatal deaths or congenital malformations. Our findings show that breast cancer diagnosed during mid-pregnancy is often treated with chemotherapy. Other than induced preterm births, there were no serious adverse perinatal outcomes.", "affiliations": "Faculty of Health, University of Technology Sydney, Sydney, NSW, Australia.;The Kids Cancer Centre, Sydney Children's Hospital, Sydney, NSW, Australia.;Faculty of Health and Medical Sciences, Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, WA, Australia.;Department of Newborn Care, Royal Hospital for Women, Sydney, Australia.;Faculty of Health, University of Technology Sydney, Sydney, NSW, Australia.;Faculty of Health, University of Technology Sydney, Sydney, NSW, Australia.;Faculty of Health, University of Technology Sydney, Sydney, NSW, Australia. E.Sullivan@newcastle.edu.au.", "authors": "Safi\|Nadom\|N\|;Anazodo\|Antoinette\|A\|;Dickinson\|Jan E\|JE\|;Lui\|Kei\|K\|;Wang\|Alex Y\|AY\|;Li\|Zhuoyang\|Z\|;Sullivan\|Elizabeth A\|EA\|", "chemical_list": "D013629:Tamoxifen; D000077143:Docetaxel; D004317:Doxorubicin; D003520:Cyclophosphamide; D016190:Carboplatin; D000068878:Trastuzumab; D017239:Paclitaxel", "country": "England", "delete": false, "doi": "10.1038/s41416-019-0563-x", "fulltext": "\n==== Front\nBr J Cancer\nBr J Cancer\nBritish Journal of Cancer\n0007-0920\n1532-1827\nNature Publishing Group UK London\n\n31488880\n563\n10.1038/s41416-019-0563-x\nBrief Communication\nIn utero exposure to breast cancer treatment: a population-based perinatal outcome study\nSafi Nadom 1\nAnazodo Antoinette 23\nDickinson Jan E. 4\nLui Kei 56\nWang Alex Y. 1\nLi Zhuoyang 1\nSullivan Elizabeth A. +61 2 49854355 E.Sullivan@newcastle.edu.au\n\n17\n1 0000 0004 1936 7611 grid.117476.2 Faculty of Health, University of Technology Sydney, Sydney, NSW Australia\n2 0000 0004 0640 6474 grid.430417.5 The Kids Cancer Centre, Sydney Children’s Hospital, Sydney, NSW Australia\n3 grid.415193.b Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, Sydney, NSW Australia\n4 0000 0004 1936 7910 grid.1012.2 Faculty of Health and Medical Sciences, Division of Obstetrics and Gynaecology, The University of Western Australia, Perth, WA Australia\n5 0000 0004 0640 3740 grid.416139.8 Department of Newborn Care, Royal Hospital for Women, Sydney, Australia\n6 0000 0004 4902 0432 grid.1005.4 School of Women’s and Child’s Health, University of New South Wales, Sydney, Australia\n7 0000 0000 8831 109X grid.266842.c Faculty of Health and Medicine, University of Newcastle, Callaghan, NSW Australia\n6 9 2019\n15 10 2019\n121 8 719721\n5 4 2019\n16 8 2019\n© Cancer Research UK 2019\nhttps://creativecommons.org/licenses/by/4.0/ This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).\nChemotherapy during a viable pregnancy may be associated with adverse perinatal outcomes. We conducted a prospective cohort study to examine the perinatal outcomes of babies born following in utero exposure to chemotherapy in Australia and New Zealand. Over 18 months we identified 24 births, of >400 g and/or >20-weeks’ gestation, to women diagnosed with breast cancer in the first or second trimesters. Eighteen babies were exposed in utero to chemotherapy. Chemotherapy commenced at a median of 20 weeks gestation, for a mean duration of 10 weeks. Twelve exposed infants were born preterm with 11 by induced labour or pre-labour caesarean section. There were no perinatal deaths or congenital malformations. Our findings show that breast cancer diagnosed during mid-pregnancy is often treated with chemotherapy. Other than induced preterm births, there were no serious adverse perinatal outcomes.\n\nSubject terms\n\nEpidemiology\nOutcomes research\nCancer epidemiology\nhttps://doi.org/10.13039/501100001026 National Breast Cancer Foundation (NBCF) NC-12-38 Sullivan Elizabeth A. issue-copyright-statement© Cancer Research UK 2019\n==== Body\npmcBackground\n\nThe management of cancer diagnosed during pregnancy poses unique challenges in optimising maternal and infant outcomes. One of these challenges is choosing the optimal treatment regimen to balance the benefit to the women and the potential risks of adverse outcomes for the foetus.1 Timing of treatment initiation is also challenging, especially if cancer diagnosis is early in the first trimester as foetal exposure to chemotherapy during the period of organogenesis has been associated with an increased risk of congenital malformations.2,3\n\nThis study describes the perinatal outcomes of babies of women diagnosed with breast cancer during the first or second trimesters of pregnancy by whether exposed to in utero systemic chemotherapy or not.\n\nMethods\n\nA population-based prospective cohort study design was conducted in Australia and New Zealand using the Australasian Maternity Outcomes Surveillance System (AMOSS).4 We identified babies born to women with a confirmed diagnosis of breast cancer during pregnancy through monthly surveillance between January 2013 and June 2014. Eligible births included live or stillborn babies of at least 400 g or 20 weeks gestation whether exposed to chemotherapy or not. Data were collected on maternal and cancer care, and perinatal outcomes.\n\nPerinatal outcomes included: stillbirth, neonatal death, major congenital malformations, preterm birth (<37 completed weeks of gestation), low birthweight (<2,500 grams) and small for gestational age (birthweight <10th percentile for gestational age).5\n\nChi-square, Fisher’s exact test, Fisher-Freeman-Halton test, and independent sample t-test were used to investigate the difference in outcomes of babies stratified by in utero exposure to chemotherapy.\n\nResults\n\nOf the 24 babies born to women diagnosed with breast cancer during the first and second trimesters of pregnancy, 18 (75%) were exposed to chemotherapy, and six were not (detailed in Supplementary Table 1). Demographic and treatment characteristics of the 24 women are shown in Supplementary Tables 1 and 2.\n\nThe types of systemic chemotherapeutic agents used during the pregnancies are listed in Supplementary Table 3. The median gestational age at first in utero exposure was 20 weeks (range 13–31). Fourteen (77.8%) of the 18 babies had their first exposure in the second trimester and four (22.2%) in the third trimester. All 18 babies were exposed to a minimum of two therapeutic agents with a mean duration of exposure of 10.4 ± 5.8 weeks. All babies were exposed to alkylating agents; either nitrogen mustard (Cyclophosphamide) or platinum compounds (Carboplatin), 16 (88.9%) were exposed to anthracyclines (Doxorubicin or Epirubicin), 10 (55.6%) to taxanes (Paclitaxel or Docetaxel) and 1 (5.6%) to Fluorouracil.\n\nThe mean gestational age at birth for the 18 chemotherapy exposed babies was 35.7 ± 2 weeks, significantly lower than that for the six non-exposed babies (mean 38.8 ± 1.5 weeks) (P = 0.002) (Table 1). There were no stillbirths, diagnosed congenital malformations or neonatal deaths in any of the 24 babies. The need for resuscitation was seen in the two babies exposed to Tamoxifen combined systemic therapy (Cyclophosphamide, Doxorubicin and Docetaxel and Tamoxifen; and Paclitaxel, Carboplatin and Tamoxifen). The former was female born following induction at 36 weeks, birthweight 2480 g Apgar score at 5 min of 8 and resuscitated with a continuous positive airway pressure (CPAP) mask, however, discharged home without the need for admission to neonatal intensive care (NICU) or Special Care Nursery (SCN). The latter was a boy delivered at 34 weeks by CS (birthweight 2240 g, Apgar score at 5 min of 8) and required resuscitation with a continuous positive airway pressure (CPAP) mask and admission to the SCN.Table 1 Perinatal outcomes amongst the 24 babies\n\n\tExposed\tNon-exposed\tP value\t\n(n = 18)\t(n = 6)\t\nLive births\t18 (100)\t6 (100)\tNA\t\nNeonatal deathsa\t0 (0)\t0 (0)\tNA\t\nPreterm (<37 weeks)\t\n Yes\t12 (66.7)\t0 (0)\t0.014\t\n <32 weeks\t1 (5.6)\t0 (0)\t\n 33– < 37 weeks\t11 (61.1)\t0 (0)\t\n No\t6 (33.3)\t6 (100)\t\t\nSmall for gestational age\t2 (11.1)\t0 (0)\t1.000\t\nLow birthweight (<2500 g)\t9 (50)\t0 (0)\t0.052\t\nResuscitation\t\n Yes\t6 (33.3)\t0 (0)\t0.277\t\n Neopuff or CPAP mask only\t3 (16.7)\t0 (0)\t\n Oxygen\t1 (5.6)\t0 (0)\t\n Neopuff or CPAP mask + Suction + Oxygen\t2 (11.1)\t0 (0)\t\n No\t12 (66.7)\t6 (100)\t\nRespiratory support\t\n Yesb\t1 (5.6)\t0 (0)\t1.000\t\n No\t16 (88.9)\t6 (100)\t\n Not known\t1 (5.6)\t0 (0)\t\nApgar score (5 min)\t\n 8\t5 (27.8)\t0 (0)\t0.348\t\n 9\t10 (55.6)\t5 (83.3)\t\n 10\t3 (16.7)\t1 (16.7)\t\nAdmission to NICU/SCN\t9 (50)\t1 (16.7)\t0.341\t\nBreastfeeding initiated\t\n Yes\t6 (33.3)\t5 (83.3)\t0.061\t\n No\t12 (66.7)\t1 (16.7)\t\naDuring hospital stay only\n\nbCPAP mask only\n\nNeopuff Infant T-Piece Resuscitator\n\nCPAP Continuous Positive Airways Pressure\n\nA third baby exposed to Trastuzumab, Docetaxel and Cyclophosphamide was born vaginally following induction at 36 weeks (birthweight 2380 g; Apgar score of 10) and was admitted to SCN with mild respiratory distress before being discharged home on day 4.\n\nTen of the babies were exposed to Taxanes in addition to other chemotherapeutic agents. However, their perinatal outcomes did not significantly differ from those who had exposed to non-Taxane chemotherapy (Supplementary Table 4).\n\nDiscussion\n\nIn this analysis, we examined the effect of in utero exposure to chemotherapy on perinatal outcomes. As expected, the gestation at diagnosis influenced the decision on the timing of chemotherapy and the non-use of radiotherapy during pregnancy. All cases in our study whether exposed to chemotherapy or not were diagnosed in the first or second trimesters. The other factors influencing management decisions are the grading and staging of breast cancer. Of note, none of the non-exposed babies’ mothers had distant metastasis and none had a preterm birth.\n\nIt is recognised that management decisions are often a delicate balance in considering the treatment impacts on both the maternal and foetal health during the pregnancy. In this study, apart from preterm birth, there were no serious adverse perinatal outcomes in the 18 babies exposed to chemotherapy nor in the six non-exposed babies. There was no perinatal death or congenital malformations.\n\nThe majority of exposed babies were exposed to cyclophosphamide and doxorubicin, with one baby exposed to trastuzumab and two others to tamoxifen. This is consistent with the other studies in which the babies were mainly exposed to a combination of cyclophosphamide and doxorubicin.6–9\n\nTamoxifen is contraindicated during pregnancy.10 The two babies who were exposed to tamoxifen in our study were born without congenital malformations. However, due to the small number of babies exposed to tamoxifen in our study, we were unable to recommend the use of tamoxifen during pregnancy.\n\nTrastuzumab is contraindicated during pregnancy, as it has been associated with oligohydramnios and renal impairment in the foetus.11 We were unable to confirm this association as in our study only one baby was exposed to trastuzumab in the third trimester.\n\nIn agreement with other studies,2 our results show a significantly higher rate of preterm births among babies exposed to systemic therapy during pregnancy compared to the non-exposed babies (12 out of 18 vs 0 out of 6).\n\nMorbidities in neonates (low birthweight and admission to NICU/SCN) in our study were directly linked to preterm birth. Similar to the previous studies,2,9 the leading cause of preterm birth amongst the exposed group in our study is iatrogenic to facilitate maternal systemic chemotherapy postpartum (supplementary fig. 1).\n\nThere is a growing evidence on the safety of exposure to anthracyclines containing regimens after the first trimester; however, it is limited for the other chemotherapeutic agents and the non-chemotherapy systemic treatment. There is a need for standardised information on the maternal-foetal exposure and outcomes of chemotherapy and other systemic anticancer agents use in pregnancy that is collated internationally into a database for use in informing clinical practice and research worldwide.\n\nA major strength of this cohort study is its population-design of all cases in Australia and New Zealand during the study period. Limitations include the rarity of the condition, the low uptake of chemotherapy during pregnancy and the follow-up period being restricted to the perinatal period.\n\nConclusion\n\nOur study provides assurance that there were no congenital abnormalities or perinatal deaths among the 18 babies exposed to at least two different chemotherapy agents during pregnancy. The directionality of our findings is consistent with the two largest studies in the international literature, particularly regarding preterm birth.6,7 Larger observational studies are needed to provide better information on in utero exposure and outcomes following chemotherapy to inform gestational breast cancer management.\n\nSupplementary information\n\nSupplementary materials\n\nSupplementary information\n\nSupplementary information is available for this paper at 10.1038/s41416-019-0563-x.\n\nAcknowledgements\n\nWe gratefully acknowledge Professor Christobel Saunders for her review of the manuscript and expertise in breast cancer management. This research is supported by an Australian Government Research Training Program Scholarship. We gratefully acknowledge AMOSS data collectors and participating hospitals for providing the data.\n\nAuthor contributions\n\nAll authors were involved in the conception and design of the study and data interpretation. N.S. drafted the paper and performed data analysis. A.W., Z.L. were involved in the data analysis and N.S., A.W., Z.L. and E.A.S. in data interpretation. All authors critically revised the paper and approved it for submission.\n\nCompeting interests\n\nThe authors declare no competing interests.\n\nEthics approval and consent to participate\n\nEthics approval for our study was granted by the NSW Population and Health Services Research Ethics Committee (HREC/09/CIPHS/21), and multiple Human Research Ethics Committees across Australia. Multi-Regional Ethics Committee approval (MEC/09/73/EXP) was granted in New Zealand.\n\nFunding\n\nThis study is funded by the National Breast Cancer Foundation, Australia (Ref: NC-12-38).\n\nData availability\n\nData will be available from the corresponding author on reasonable request.\n\nPublisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThese authors contributed equally: Jan E. Dickinson, Kei Lui\n==== Refs\nReferences\n\n1. Morice P Uzan C Uzan S Cancer in pregnancy: a challenging conflict of interest Lancet 2012 379 495 496 10.1016/S0140-6736(11)61814-X 22325648\n2. Amant F Van Calsteren K Halaska MJ Gziri MM Hui W Lagae L Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: an observational study Lancet Oncol. 2012 13 256 264 10.1016/S1470-2045(11)70363-1 22326925\n3. Albright CM Wenstrom KD Malignancies in pregnancy Best Pract. Res. Clin. Obstet. Gynaecol. 2016 33 2 18 10.1016/j.bpobgyn.2015.10.004 26542928\n4. AMOSS. Australasian Maternity Outcomes Surveillance System Annual Report 2010–2011.https://npesu.unsw.edu.au/surveillance/australasian-maternityoutcomes-surveillance-system-annual-report-2010%E2%80%932011. Accessed 22 August, 2019.\n5. Australian Institute of Health and Welfare. Australia’s mothers and babies 2015—in brief. Perinatal statistics series no. 33. Cat no. PER 91. (AIHW, Canberra, 2017)\n6. Amant F Vandenbroucke T Verheecke M Fumagalli M Halaska MJ Boere I Pediatric outcome after maternal cancer diagnosed during pregnancy N Engl J Med 2015 373 1824 1834 10.1056/NEJMoa1508913 26415085\n7. Cardonick EH Gringlas MB Hunter K Greenspan J Development of children born to mothers with cancer during pregnancy: comparing in utero chemotherapy-exposed children with nonexposed controls Am J Obstet Gynecol 2015 212 658.e651 658 10.1016/j.ajog.2015.01.036 25434835\n8. Hahn KM Johnson PH Gordon N Kuerer H Middleton L Ramirez M Treatment of pregnant breast cancer patients and outcomes of children exposed to chemotherapy in utero Cancer 2006 107 1219 1226 10.1002/cncr.22081 16894524\n9. Loibl S Han SN von Minckwitz G Bontenbal M Ring A Giermek J Treatment of breast cancer during pregnancy: an observational study Lancet Oncol 2012 13 887 896 10.1016/S1470-2045(12)70261-9 22902483\n10. Peccatori FA Lambertini M Scarfone G Del Pup L Codacci-Pisanelli G Biology, staging, and treatment of breast cancer during pregnancy: reassessing the evidences Cancer Biol Med 2018 15 6 13 10.20892/j.issn.2095-3941.2017.0146 29545964\n11. Shachar SS Gallagher K McGuire K Zagar TM Faso A Muss HB Multidisciplinary management of breast cancer during pregnancy Oncologist 2017 22 324 334 10.1634/theoncologist.2016-0208 28232597\n\n", "fulltext_license": "CC BY", "issn_linking": "0007-0920", "issue": "121(8)", "journal": "British journal of cancer", "keywords": null, "medline_ta": "Br J Cancer", "mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001315:Australia; D001943:Breast Neoplasms; D016190:Carboplatin; D016022:Case-Control Studies; D002585:Cesarean Section; D015331:Cohort Studies; D000013:Congenital Abnormalities; D045422:Continuous Positive Airway Pressure; D003520:Cyclophosphamide; D000077143:Docetaxel; D004317:Doxorubicin; D005260:Female; D005865:Gestational Age; D006801:Humans; D007230:Infant, Low Birth Weight; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D007751:Labor, Induced; D009520:New Zealand; D017239:Paclitaxel; D066087:Perinatal Death; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011261:Pregnancy Trimester, First; D011262:Pregnancy Trimester, Second; D047928:Premature Birth; D011446:Prospective Studies; D012127:Respiratory Distress Syndrome, Newborn; D050497:Stillbirth; D013629:Tamoxifen; D000068878:Trastuzumab", "nlm_unique_id": "0370635", "other_id": null, "pages": "719-721", "pmc": null, "pmid": "31488880", "pubdate": "2019-10", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": "26542928;26415085;22902483;28232597;22325648;25434835;22326925;16894524;29545964", "title": "In utero exposure to breast cancer treatment: a population-based perinatal outcome study.", "title_normalized": "in utero exposure to breast cancer treatment a population based perinatal outcome study" }	[ { "companynumb": "AU-PFIZER INC-2020256341", "fulfillexpeditecriteria": "1", "occurcountry": "AU", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DOCETAXEL" }, "drugadditional": "3", ...
{ "abstract": "Not all causes of subcutaneous emphysema are attributable to necrotizing fasciitis. Consider other causes of subcutaneous emphysema in the differential diagnosis.", "affiliations": "Department of Anesthesiology UZ Brussel Brussel Belgium.;Department of Radiology UZ Brussel Brussel Belgium.;Department of Radiology UZ Brussel Brussel Belgium.;Department of Radiology UZ Brussel Brussel Belgium.", "authors": "Tosi\|Maurizio\|M\|https://orcid.org/0000-0001-7518-8675;Al-Awa\|Alexandre\|A\|https://orcid.org/0000-0003-3549-3274;Raeymaeckers\|Steven\|S\|https://orcid.org/0000-0003-0822-1919;De Mey\|Johan\|J\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1002/ccr3.4831", "fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.4831\nCCR34831\nCase Report\nCase Reports\nSubcutaneous emphysema of the extremities: Be wary of necrotizing fasciitis, but also consider occult rupture or perforation\nTOSI et al.\nTosi Maurizio https://orcid.org/0000-0001-7518-8675\n1 maurizio.tosi@uzbrussel.be\n\nAl‐Awa Alexandre https://orcid.org/0000-0003-3549-3274\n2\nRaeymaeckers Steven https://orcid.org/0000-0003-0822-1919\n2\nDe Mey Johan 2\n1 Department of Anesthesiology UZ Brussel Brussel Belgium\n2 Department of Radiology UZ Brussel Brussel Belgium\n* Correspondence\nMaurizio Tosi, Department of Anesthesiology, UZ Brussel, Laarbeeklaan 101, 1090 Jette, Belgium.\nEmail: maurizio.tosi@uzbrussel.be\n\n21 9 2021\n9 2021\n9 9 10.1002/ccr3.v9.9 e0483118 8 2021\n13 3 2021\n30 8 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ 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.\n\nAbstract\n\nNot all causes of subcutaneous emphysema are attributable to necrotizing fasciitis. Consider other causes of subcutaneous emphysema in the differential diagnosis.\n\nNot all causes of subcutaneous emphysema are attributable to necrotizing fasciitis. Consider other causes of subcutaneous emphysema in the differential diagnosis.\n\nintestinal perforation\nnecrotizing fasciitis\noccult rupture\nsoft tissue infection\nsubcutaneous emphysema\nsource-schema-version-number2.0\ncover-dateSeptember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:22.09.2021\nTosiM, Al‐AwaA, RaeymaeckersS, De MeyJ. Subcutaneous emphysema of the extremities: Be wary of necrotizing fasciitis, but also consider occult rupture or perforation. Clin Case Rep. 2021;9 :e04831. 10.1002/ccr3.4831\n\nFunding information\n\nNone\n==== Body\npmc1 CASE\n\nSubcutaneous emphysema of the extremities can be associated with necrotizing fasciitis but can also be caused by local spreading of air. If the lower extremity is affected, an intestinal rupture should be explored. The diagnosis of a retroperitoneal perforation is usually impeded by a lack of signs of peritoneal irritation.\n\nA 69‐year‐old male patient presented at the ER with fever and an infectious and inflammatory bloodwork. The patient was previously diagnosed with a rectal carcinoma in 2016 (T3N2M0), for which he had undergone neoadjuvant radiochemotherapy and robot‐assisted resection of the rectum. In 2018, a solitary metastatic lung lesion was diagnosed, for which the patient underwent a left upper lobectomy. Recently, a new solitary metastatic liver lesion was diagnosed. For this, the patient was started on chemotherapy (FOLFOX/bevacizumab) for two months. The patient now presented with persistent pain in the gluteal region for several days, local redness with calor, and swelling in the right buttock was seen with an abrasive wound on the skin (Figure 1). The diagnosis of erysipelas was withheld, and the patient was admitted to the hospital and started on IV flucloxacillin. Oxycodone was given for the pain. The next day, the patient developed a progressive swelling of the ipsilateral upper leg with subcutaneous emphysema. The edema had spread to the level of the knee, and necrotizing fasciitis was suspected. The attending dermatologist then switched the antibiotic treatment to broad‐spectrum antibiotics using a combination of amoxicillin/clavulanic acid and clindamycin. The dermatologist also ordered a contrast‐enhanced CT of the leg to confirm the presence and the extent of collections. Axial slices through the upper leg demonstrate the diffuse presence of air, both subcutaneous and dissecting the muscles (Figure 2). This free air extends up to the buttocks and into the retroperitoneum where the radiologist suspected a rectum perforation (Figure 3). No collections were present in the upper leg, so the diagnosis of necrotizing fasciitis seemed less likely. The abdominal surgeons performed an emergency laparoscopy, confirming the presence of a rectum perforation. The surgeons performed a resection, draining a localized collection. A protective loop colostomy was constructed. Over the next 6 days, three other surgical procedures with debridement of the gluteal region were performed. Wound swab specimens were found to be positive, with a rich mixed culture of aerobic (predominately Escherichia coli) and anaerobic (Bacteroides) bacteria. Broad‐spectrum antibiotics were continued. The patient eventually developed profound neutropenia and thrombocytopenia, probably attributed to the combination of chemotherapy and sepsis. The patient was admitted to the ICU in reverse isolation, and platelets were administered to combat the thrombocytopenia. Ten days after the initial laparoscopy, the patient was returned to the ward. Vacuum‐assisted closure was installed to aid the healing process of the wound. The patient remained in the hospital for the treatment of the gluteal wound for another three months while continuing the remainder of his chemotherapy, eventually being treated with a gluteal graft. After this procedure, the patient could be discharged in reasonable health.\n\nFIGURE 1 Swollen aspect and redness of the inflamed right buttock as present at initial presentation. The diagnosis of erysipelas was withheld\n\nFIGURE 2 Contrast‐enhanced CT of the upper leg, axial plane. Diffuse presence of air in the soft tissues, both subcutaneous and dissecting the muscles of the posterior compartment\n\nFIGURE 3 Contrast‐enhanced CT of the upper leg, sagittal plane. The air extends upward into the soft tissues of the buttocks and continues into the retroperitoneum, where a rectal perforation is suspected (arrow)\n\n2 DISCUSSION\n\nNecrotizing fasciitis is a surgical emergency. Risk factors include poor immune function as can be found in patients with diabetes or cancer. Obesity, alcoholism, intravenous drug use, and peripheral artery disease are also associated risk factors. Early detection and aggressive surgical intervention are crucial to reduce patient mortality and morbidity.1 Not all cases of subcutaneous emphysema, however, are attributable to necrotizing fasciitis. It is a well‐known fact that subcutaneous emphysema can occur in the upper extremities due to an underlying pneumothorax or even a tracheal or esophageal rupture.2, 3 Free air in the retroperitoneum resulting from bowel perforation can also spread extra‐abdominally.4 When subcutaneous emphysema is located in the upper portion of the lower extremity, an intestinal source should be explored.5 Subcutaneous emphysema of the leg has been previously described in cases of perforated diverticulitis,6 perforation of the colon due to underlying carcinoma7 and also in a case of perforated appendicitis.8 Perforation of the rectum is frequently observed in malignant diseases: perforation can be spontaneous as a result of tumor progression or iatrogenic as a result of endoscopic procedures or radiotherapy. The diagnosis of retroperitoneal perforation is usually impeded by lack of signs of peritoneal irritation.9 Exploration of the thigh can be avoided if the abdominal pathology is promptly managed.10 In our described case, the pathology was probably already insidiously present for days at least. In this case, the condition of the wounds required repeated debridement procedures, prolonged VAC treatment and eventually even skin grafting. In summary, it is important to consider other causes of subcutaneous emphysema of the extremities in the differential diagnosis to allow for swift and appropriate medical therapy.\n\nCONFLICT OF INTEREST\n\nNone declared.\n\nAUTHOR CONTRIBUTIONS\n\nMT authored and revised the text and researched the literature. AA coauthored the text. JDM supervised and approved the article. SR authored and revised the text, made the images, and supervised the article.\n\nETHICAL APPROVAL\n\nNo approval was warranted.\n\nCONSENT\n\nInformed consent was obtained from the patient included in the manuscript.\n\nACKNOWLEDGEMENTS\n\nNone.\n\nDATA AVAILABILITY STATEMENT\n\nData available on request from the authors.\n==== Refs\nREFERENCES\n\n1 de TullioD, RossiC, BolzonS, ScagliariniL, OcchionorelliS. Necrotizing fasciitis: a surgical emergency. Updates Surg. 2010;62 (2 ):83‐87. 10.1007/s13304-010-0019-6 20845008\n2 HiroseK, VisserBC. Images in clinical medicine. Massive subcutaneous emphysema after tracheal perforation. N Engl J Med. 2004;351 (3 ):e2. 10.1056/ENEJMicm030421 15254295\n3 SriramKB, JersmannH. Pneumothorax, pneumomediastinum and subcutaneous emphysema following closed percutaneous pleural biopsy: a case report. Cases J. 2008;1 (1 ):274. 10.1186/1757-1626-1-274 18950521\n4 SalduaNS, FellarsTA, CoveyDC. Case report: Bowel perforation presenting as subcutaneous emphysema of the thigh. Clin Orthop Relat Res. 2010;468 (2 ):619‐623. 10.1007/s11999-009-1015-3 19653051\n5 LeeK‐B, MoonE‐S, JungS‐T, SeoH‐Y. Subcutaneous emphysema mimicking gas gangrene following perforation of the rectum: a case report. J Korean Med Sci. 2004;19 (5 ):756‐758. 10.3346/jkms.2004.19.5.756 15483358\n6 HaiartDC, StevensonP, HartleyRC. Leg pain: an uncommon presentation of perforated diverticular disease. J R Coll Surg Edinb. 1989;34 (1 ):17‐20.2709351\n7 GallagherE, WeingartenM, SwirskyM. Carcinoma of colon appearing as subcutaneous emphysema of lower extremity. N Y State J Med. 1982;82 (2 ):219‐221.6952090\n8 TomasoaNB, UlteeJM, VrouenraetsBC. Retroperitoneal abscess and extensive subcutaneous emphysema in perforated appendicitis: a case report. Acta Chir Belg. 2008;108 (4 ):457‐459. 10.1080/00015458.2008.11680263 18807603\n9 WelchJP, DonaldsonGA. Perforative carcinoma of colon and rectum. Ann Surg. 1974;180 (5 ):734‐740. 10.1097/00000658-197411000-00005 4423043\n10 MekhailP, SaklaniA, PhilobosM, MasoudAG. Thigh subcutaneous emphysema: is that a clear indication for thigh exploration? J Surg Case Rep. 2011;2011 (2 ):1. 10.1093/jscr/2011.2.1\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "2050-0904", "issue": "9(9)", "journal": "Clinical case reports", "keywords": "intestinal perforation; necrotizing fasciitis; occult rupture; soft tissue infection; subcutaneous emphysema", "medline_ta": "Clin Case Rep", "mesh_terms": null, "nlm_unique_id": "101620385", "other_id": null, "pages": "e04831", "pmc": null, "pmid": "34584708", "pubdate": "2021-09", "publication_types": "D002363:Case Reports", "references": "15254295;6952090;4423043;18950521;15483358;2709351;18807603;20845008;19653051;24950556", "title": "Subcutaneous emphysema of the extremities: Be wary of necrotizing fasciitis, but also consider occult rupture or perforation.", "title_normalized": "subcutaneous emphysema of the extremities be wary of necrotizing fasciitis but also consider occult rupture or perforation" }	[ { "companynumb": "BE-TEVA-2021-BE-1993001", "fulfillexpeditecriteria": "1", "occurcountry": "BE", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "FLUOROURACIL" }, "drugadditional": null, ...
{ "abstract": "OBJECTIVE\nTo compare associations between individual antidepressants and newborn outcomes.\n\n\nMETHODS\nRetrospective cohort study.\n\n\nMETHODS\nDeliveries in a large, US medical system.\n\n\nMETHODS\nWomen who received at least one antidepressant prescription 3 months prior to conception through delivery.\n\n\nMETHODS\nEligible women had maternal characteristics and newborn outcomes extracted from medical record data. Exposure was defined by the timing of the prescription during pregnancy.\n\n\nMETHODS\nNewborn outcomes (any adaptation syndrome, neonatal intensive care unit (NICU) admission) were analyzed for each antidepressant and compared using standard statistics and multivariable regression compared to exposure to bupropion. Odds of outcomes based on timing of exposure were also explored.\n\n\nRESULTS\nA total of 3,694 women were analyzed. Rates of any adaptation syndrome (p < 0.001), NICU admission (p < 0.001), and transient tachypnea of newborn (TTN) (p = 0.006) were significantly different between drugs. Infants exposed to duloxetine had the highest rates of NICU admissions (39.6%) and adaptation syndromes (15.1%). Venlafaxine-exposed infants had the highest rates of TTN (18.2%). Controlling for maternal age, race, insurance, and gestational age at delivery, early pregnancy antidepressant exposure was associated with adaptation syndrome and NICU admission for both duloxetine (adjusted odds ratio (aOR) 2.31 [95% Confidence Interval (CI) 1.11-4.80] and aOR 2.47 [95% CI 1.40-4.34], respectively) and escitalopram (aOR 1.72 [95% CI 1.09-2.70] and aOR 1.64 [95% CI 1.21-2.22], respectively). Exposure in the third trimester was associated with any adaptation syndrome for citalopram, duloxetine, escitalopram, fluoxetine, sertraline, and venlafaxine and NICU admission for bupropion, citalopram, duloxetine, escitalopram, and fluoxetine.\n\n\nCONCLUSIONS\nDuloxetine and escitalopram appear to have the strongest associations with any adaptation syndrome and NICU admission whereas bupropion and sertraline tended to have among the lowest risks of these outcomes. These results can help providers and patients discuss choice of individual antidepressant drugs during pregnancy.", "affiliations": "Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Regenstrief Institute, Indianapolis, Indiana, USA.;Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana, USA.;Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana, USA.", "authors": "Marks\|Claire\|C\|;Silvola\|Rebecca\|R\|;Teal\|Evgennia\|E\|;Quinney\|Sara K\|SK\|;Haas\|David M\|DM\|https://orcid.org/0000-0002-8379-0743", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1002/phar.2628", "fulltext": null, "fulltext_license": null, "issn_linking": "0277-0008", "issue": "41(11)", "journal": "Pharmacotherapy", "keywords": "abstinence syndrome; antidepressants; exposure; newborn outcomes; pregnancy", "medline_ta": "Pharmacotherapy", "mesh_terms": null, "nlm_unique_id": "8111305", "other_id": null, "pages": "907-914", "pmc": null, "pmid": "34587291", "pubdate": "2021-11", "publication_types": "D016428:Journal Article", "references": "19701065;26613360;23240634;9400006;32777011;17671283;32357982;19185342;11750180;15361919;10405881;17375980;10122097", "title": "Comparing newborn outcomes after prenatal exposure to individual antidepressants: A retrospective cohort study.", "title_normalized": "comparing newborn outcomes after prenatal exposure to individual antidepressants a retrospective cohort study" }	[ { "companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-06346", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VENLAFAXINE HYDROCHLORIDE" }, ...
{ "abstract": "OBJECTIVE\nTo conduct a dose-escalation trial of rituximab in patients with chronic lymphocytic leukemia (CLL) to define the maximum-tolerated dose (MTD), to evaluate first-dose reactions in patients with high circulating lymphocyte counts, and to assess the efficacy at higher versus lower doses.\n\n\nMETHODS\nFifty patients with CLL (n = 40) or other mature B-cell lymphoid leukemias (n = 10) were treated with four weekly infusions of rituximab. The first dose was 375 mg/m(2) for all patients; dose- escalation began with dose 2 but was held constant for each patient. Escalated doses were from 500 to 2,250 mg/m(2).\n\n\nRESULTS\nToxicity with the first dose (375 mg/m(2)) was noted in 94% of patients but was grade 1 or 2 in most, predominantly fever and chills. Six patients (12%) experienced severe toxicity with the first dose, including fever, chills, dyspnea, and hypoxia in all six patients, hypotension in five, and hypertension in one. Toxicity on subsequent doses was minimal until a dose of 2,250 mg/m(2) was achieved. Eight (67%) of 12 patients had grade 2 toxicity, including fever, chills, nausea, and malaise, although no patient had grade 3 or 4 toxicity. Severe toxicity with the first dose was significantly more common in patients with other B-cell leukemias, occurring in five (50%) of 10 patients versus one (2%) of 40 patients with CLL (P <.001). The overall response rate was 40%; all responses in patients with CLL were partial remissions. Response rates were 36% in CLL and 60% in other B-cell lymphoid leukemias. Response was correlated with dose: 22% for patients treated at 500 to 825 mg/m(2), 43% for those treated at 1,000 to 1,500 mg/m(2), and 75% for those treated at the highest dose of 2,250 mg/m(2) (P =.007). The median time to disease progression was 8 months. Myelosuppression and infections were uncommon.\n\n\nCONCLUSIONS\nRituximab has significant activity in patients with CLL at the higher dose levels. Severe first-dose reactions were uncommon in patients with CLL, even with high circulating lymphocyte counts, but were frequent in patients with other mature B-cell leukemias in which CD20 surface expression is increased. Efficacy of rituximab was also significant in this group of patients.", "affiliations": "Leukemia Department, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA.", "authors": "O'Brien\|S M\|SM\|;Kantarjian\|H\|H\|;Thomas\|D A\|DA\|;Giles\|F J\|FJ\|;Freireich\|E J\|EJ\|;Cortes\|J\|J\|;Lerner\|S\|S\|;Keating\|M J\|MJ\|", "chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab", "country": "United States", "delete": false, "doi": "10.1200/JCO.2001.19.8.2165", "fulltext": null, "fulltext_license": null, "issn_linking": "0732-183X", "issue": "19(8)", "journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology", "keywords": null, "medline_ta": "J Clin Oncol", "mesh_terms": "D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D023341:Chills; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004417:Dyspnea; D005260:Female; D005334:Fever; D006801:Humans; D000860:Hypoxia; D007262:Infusions, Intravenous; D015448:Leukemia, B-Cell; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D000069283:Rituximab; D016896:Treatment Outcome", "nlm_unique_id": "8309333", "other_id": null, "pages": "2165-70", "pmc": null, "pmid": "11304768", "pubdate": "2001-04-15", "publication_types": "D016430:Clinical Trial; D017426:Clinical Trial, Phase I; D016428:Journal Article", "references": null, "title": "Rituximab dose-escalation trial in chronic lymphocytic leukemia.", "title_normalized": "rituximab dose escalation trial in chronic lymphocytic leukemia" }	[ { "companynumb": "US-ROCHE-1853675", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, "...
{ "abstract": "Stress fractures of the proximal tibia metaphysis are rare in the elderly. We present a case of a 65-year old male who developed sequential proximal tibia stress fractures associated with prolonged usage of methotrexate and prednisolone within a span of 18 months. Magnetic Resonance Imaging revealed an incomplete stress fracture involving the medial proximal tibial region. The patient was treated with stemmed total knee arthroplasty (TKA) bilaterally. Stress fractures should be considered in patients with atypical knee pain who have a history of methotrexate and prednisolone usage. TKA is an effective treatment in stress fractures of the proximal tibia.", "affiliations": "Department of Orthopaedic Surgery, Tan Tock Seng Hospital, Singapore.;Department of Orthopaedic Surgery, Tan Tock Seng Hospital, Singapore.", "authors": "Tan\|Tjl\|T\|;Ho\|Wls\|W\|", "chemical_list": null, "country": "Malaysia", "delete": false, "doi": "10.5704/MOJ.1511.010", "fulltext": "\n==== Front\nMalays Orthop JMalays Orthop JmojMalaysian Orthopaedic Journal1985-25332232-111XMalaysian Orthopaedic Association Kuala Lumpur 10.5704/MOJ.1511.010Case ReportSequential Proximal Tibial Stress Fractures associated with Prolonged usage of Methotrexate and Corticosteroids: A Case Report Tan TJL MBBS (UK)Ho WLS MBBS (NUS)Department of Orthopaedic Surgery, Tan Tock Seng Hospital, SingaporeTeo YH FRCS Orth (Ed)Department of Orthopaedic Surgery, Tan Tock Seng Hospital, Singapore Email: Lester.Tan@mohh.com.sg11 2015 9 3 65 67 1 7 2015 1 10 2015 © 2015 Malaysian Orthopaedic Association (MOA). All Rights Reserved2015This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Stress fractures of the proximal tibia metaphysis are rare in the elderly. We present a case of a 65-year old male who developed sequential proximal tibia stress fractures associated with prolonged usage of methotrexate and prednisolone within a span of 18 months. Magnetic Resonance Imaging revealed an incomplete stress fracture involving the medial proximal tibial region. The patient was treated with stemmed total knee arthroplasty (TKA) bilaterally. Stress fractures should be considered in patients with atypical knee pain who have a history of methotrexate and prednisolone usage. TKA is an effective treatment in stress fractures of the proximal tibia.\n\nTibial stress fracturetotal knee arthroplastymethotrexate osteopathy\n==== Body\nIntroduction\nStress fractures can be caused by either abnormal repetitive stresses placed on normal bone, or by normal stresses placed on abnormal bone1. Causes of abnormal bone include osteoporosis, inflammatory conditions such as rheumatoid arthritis as well as prolonged usage of medications such as corticosteroids and methotrexate. Prolonged methotrexate usage has been postulated to induce bone changes and predispose patients to stress fractures2–4. Whilst proximal tibial stress fractures have been associated with moderate to severe osteoarthritis of the knee, the association with mild osteoarthritis remains rare5. We describe a rare case of sequential proximal tibia stress fractures in a male patient on long-term methotrexate and prednisolone with mild osteoarthritis of the knees. The authors have obtained the patient’s informed written consent for print and electronic publication of the case report.\n\nCase Report\nA 65 year-old man presented with a 3-month history of left knee pain after hiking. The patient had a known history of psoriasis for which he was treated with 15mg/week of oral methotrexate for the last four years. He also had a history of gout for which he was on 4mg of oral prednisolone daily, with colchicine for acute exacerbations. The patient developed a mechanical left knee pain after an episode of prolonged walking. There was no history of trauma. The patient was able to ambulate without aid, with complete resolution of pain on rest. Clinical examination revealed a left knee range of motion of 0 to 130º, with no effusion, palpable tenderness or warmth. Radiographs revealed a lucent line in the medial tibial plateau, suspicious of a stress fracture. Magnetic Resonance Imaging (MRI) (Figure 1.), confirmed the diagnosis of an incomplete proximal tibial stress fracture.\n\nFig. 1 (A) Weight bearing X-ray of the left knee showing lucency over medial proximal tibia. (B) MRI of the left knee revealing a fracture of the medial aspect of the tibial plateau.\n\nThe patient was treated non-surgically with a knee ranger brace and advised to reduce loading on the affected limb. However, the patient returned seven months later complaining of persistent pain. Repeat radiograph (Figure 2.) showed progressive collapse of the medial tibial plateau. In view of the progressive deformity and pain, the patient underwent a computer-navigation assisted left TKA. A stemmed tibia implant was used to compensate for the loss of medial support. Post-operatively, the patient achieved a good range of movement from 0-120º. Knee Society Scores and Knee Society Function Scores improved from 59 to 94, and 60 to 100 respectively at three months.\n\nFig. 2 Weight bearing radiograph of the left knee showing progressive varus collapse of the medial tibial plateau.\n\nThe patient returned 18 months later complaining of similar pain in the right knee. There was no history of trauma. Clinical examination revealed right knee range of motion of 0 to 130º, with no palpable tenderness. Radiographs and subsequent MRI revealed a right proximal tibial stress fracture. (Figure 3). Lower limb extremity radiographs did not demonstrate any significant varus/valgus malalignment. (Figure 4A-B.) A bone mineral densitometry utilizing dual energy x-ray absorptiometry (DEXA) revealed osteoporosis, with a Z score of -3.8 (Lumbar) and -3.2 (Proximal femur). At that point, he was not on any osteoporosis treatment. Calcium and vitamin D levels were normal.\n\nFig. 3 (A) Weight bearing X-ray of the right knee showing lucency over medial proximal tibia. (B) MRI of the right knee revealing a fracture of the medial aspect of the tibial plateau.\n\nFig. 4 Long lower extremity radiograph showing minimal mal-alignment of the right knee with left total knee arthroplasty.\n\nComputer-assisted navigation TKA of the right knee was performed. (Figure 5). Post-operatively, the patient achieved a good range of movement from 0-120º. Knee Society Scores and Knee Society Function Scores improved from 54 to 80, and 30 to 100 respectively at 3 months. The patient was started on strontium ranelate for osteoporosis. The patient was reviewed two years after surgery and remained well.\n\nFig. 5 Post-operative antero-posterior (AP) X-ray of the right knee showing a total knee arthroplasty with stemmed tibial implant.\n\nDiscussion\nProximal tibia stress fractures may occur on the background of osteoarthritis, due to the inherent mal alignment of the knee joint. However, it is rare for stress fractures of the proximal tibia to occur in cases of mild osteoarthritis of the knee, where there is minimal mal alignment. In our case, we believe that the stress fractures occurred in association with methotrexate osteopathy due to prolonged usage of methotrexate (MTX). MTX is an anti-metabolite that inhibits RNA and DNA synthesis3. MTX is postulated to affect osteoblastic activity and may enhance osteoclastic bone resorption. Prolonged usage of MTX can result in osteopathy4. In addition, our patient was on long-term prednisolone, which may have contributed to osteoporosis. MTX and prednisolone usage may account for a weakened bone in our patient, predisposing the proximal tibia to stress fracture on the background of a mild osteoarthritis.\n\nPatients with stress fractures of the proximal tibia may present without any preceding event of trauma. Often, they present with sudden onset of pain aggravated by activity and relieved by rest6. On physical examination, they may be an effusion and pain on palpation. Plain radiographs can reveal abnormalities such as a sclerotic band or lucency but these changes can be subtle, especially in acute stress fractures. Osteophyte formation may obscure bony changes6. Magnetic Resonance Imaging (MRI) can be used to confirm the diagnosis and has the added advantage of being able to evaluate both the osseous structures and soft tissues in the knee. This may be important when considering arthroplasty as a form of treatment.\n\nTreatment options for proximal tibia stress fractures can be surgical or non-surgical. Non-surgical modalities include a period of offloading, complete non-weight bearing or partial weight bearing. This may be complemented by immobilization in either a cast or a brace to protect the fracture site. Stress fractures can often heal after a period of reduced activity. However, complications of such treatment include non-union, mal-union or varus collapse of the tibial plateau, which can worsen the mal-alignment, leading to increased pain. Surgery is indicated if patients present with worsening pain and deformity. Arthroplasty can treat the underlying arthritis, correct deformity and provide immediate stability. Mal alignment can be corrected and abnormal stresses on the tibia can be relieved. In our patient, we opted for computer navigation to improve accuracy of bone cuts and correction of deformity. A stemmed tibial implant can reduce stresses and provide additional stability.\n\nConclusion\nProlonged usage of methotrexate and corticosteroids can predispose patients to stress fractures. In such patients who present with persistent knee pain, the diagnosis of stress fracture should be considered. Magnetic resonance imaging can be utilized to confirm diagnosis. Total knee arthroplasty is an effective treatment option that reduces pain, corrects deformity and allows for immediate post-operative ambulation.\n==== Refs\nReferences\n1 Devas M Stress Fractures Edinburgh, London and New York Churchill Livingstone 1975 \n2 Singwe M Le Gars L Karneff A Prier A Kaplan G Rev - Rheum Engl Ed 1998 Jul-Sep 65(7-9) 508 10 \n3 Stevens H Jacobs JW Van Rijk PP De Klerk JM Methotrexate osteopathy demonstrated by technetium-99m HDP bone scintigraphy Clin Nucl Med 2001 26 389 91 11317015 \n4 Ragab AH Frech RS Vietti TJ Osteoporotic fractures secondary to methotrexate therapy of acute leukemia in remission Cancer 1970 25 580 5 5264439 \n5 Nabors ED Kremchek TE Burke DW Stress fracture of the proximal tibia associated with severe osteoarthritis Am J Knee Surg 1995 8 4 141 3 8590126\n\n", "fulltext_license": "CC BY", "issn_linking": "1985-2533", "issue": "9(3)", "journal": "Malaysian orthopaedic journal", "keywords": "Tibial stress fracture; methotrexate osteopathy; total knee arthroplasty", "medline_ta": "Malays Orthop J", "mesh_terms": null, "nlm_unique_id": "101564672", "other_id": null, "pages": "65-67", "pmc": null, "pmid": "28611915", "pubdate": "2015-11", "publication_types": "D002363:Case Reports", "references": "11317015;5264439;8590126;9785399", "title": "Sequential Proximal Tibial Stress Fractures associated with Prolonged usage of Methotrexate and Corticosteroids: A Case Report.", "title_normalized": "sequential proximal tibial stress fractures associated with prolonged usage of methotrexate and corticosteroids a case report" }	[ { "companynumb": "SG-FRESENIUS KABI-FK201600610", "fulfillexpeditecriteria": "1", "occurcountry": "SG", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null,...
{ "abstract": "Immune checkpoint inhibitors (ICIs) are new agents that are efficacious in a variety of cancers. However, they are associated with immune-related adverse events due to activated immune system. Among them, checkpoint inhibitor pneumonitis (CIP) deserves more special attentions, because diagnosis and therapy are still challengeable. camrelizumab is a programmed cell death 1 (PD-1) inhibitor that was developed by Jiangsu Hengrui Medicine Co. CIP that is induced by camrelizumab was rarely reported. We described a case that a patient developed CIP 12 days later after one dose of camrelizumab. A 60-year-old man with advanced esophageal squamous cell carcinoma received 6 cycles of Tislelizumab/placebo, capecitabine and cisplatin first. Owing to the poor control of the disease, the patient used Nimotuzumab and docetaxel on April 3, 2020 and April 24, 2020, respectively. Later, he obtained the combination of 200 mg of camrelizumab and 140 mg of docetaxel regimen for once on May 14, 2020. After 12 days, he was diagnosed with CIP in Outpatient. Multiple ground glass opacities were revealed in bilateral lungs from routine CT examination. After giving 40 mg of prednisolone orally once a day, his CIP improved. Meanwhile, camrelizumab was not used again. Teaching point: same as other PD-1 inhibitors, camrelizumab can also cause immune-related pneumonitis. Close observation, regular CT examination and timely corticosteroids intervention are essential.", "affiliations": "Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China.;Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China.;Department of Pharmacy, Beijing Friendship Hospital, Capital Medical University, Beijing, China.", "authors": "Li\|Ling\|L\|;Lou\|Anqi\|A\|;Yu\|Junxian\|J\|", "chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000082082:Immune Checkpoint Inhibitors; C000707970:tislelizumab; C000631724:camrelizumab", "country": "China", "delete": false, "doi": "10.21037/apm-21-23", "fulltext": null, "fulltext_license": null, "issn_linking": "2224-5820", "issue": "10(7)", "journal": "Annals of palliative medicine", "keywords": "Checkpoint inhibitor pneumonitis (CIP); anti-programmed cell death (PD-1) blockade; camrelizumab; case report; immune-related pneumonitis (IMP)", "medline_ta": "Ann Palliat Med", "mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008297:Male; D008875:Middle Aged; D011014:Pneumonia", "nlm_unique_id": "101585484", "other_id": null, "pages": "8460-8466", "pmc": null, "pmid": "34044548", "pubdate": "2021-07", "publication_types": "D002363:Case Reports; D016454:Review", "references": null, "title": "Immune checkpoint inhibitor-related pneumonitis induced by camrelizumab: a case report and review of literature.", "title_normalized": "immune checkpoint inhibitor related pneumonitis induced by camrelizumab a case report and review of literature" }	[ { "companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-300198", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CISPLATIN" }, "druga...
{ "abstract": "Purpose: Patients with relapsed/refractory acute lymphocytic leukemia (R/R ALL) have a poor prognosis. Chimeric antigen receptor-modified T cells against CD19 (CART19) have displayed anti-leukemia activities. However, data from systemic trials in Chinese patients are limited.Experimental Design: T cells transduced with CD19-directed CAR lentiviral vectors were infused in patients with R/R ALL under fludarabine- and cyclophosphamide-based lymphodepletion. The postinfusion responses, toxicities, expansion, and persistence of CART19s in enrolled patients were observed and monitored.Results: We enrolled 15 patients with R/R ALL. The median transduction efficiency of CART19s was 33%. In vitro cytotoxicity assays were conducted and showed prominent antileukemia activities with CART19s. The patients received CART19s infusion at doses of 1.1 × 106/kg to 9.8 × 106/kg. Twelve patients achieved complete remission 1 month after CART19s infusion. CART19s expanded and persisted in peripheral blood and bone marrow. At 150 days, the overall survival rate and leukemia-free survival rate were 65.5% and 37.8%, respectively. The cumulative incidence of relapse and the nonrelapse mortality rate were 54.5% and 7.7%, respectively. Four patients underwent subsequent haploidentical hematopoietic stem cell transplantation. In this trial, 10 patients experienced cytokine release syndrome (CRS). Grade 3 CRS developed in 40% of patients and was associated with a higher disease burden on day -1 and a higher number of previous relapses.Conclusions: This trial demonstrated potent antileukemia activities of CART19s in Chinese patients with R/R ALL. Disease relapse remained the main obstacle. However, patients with a high risk of relapse after CART19s might benefit from subsequent haploidentical hematopoietic stem cell transplantation. Clin Cancer Res; 23(13); 3297-306. ©2016 AACR.", "affiliations": "Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Innovative Cellular Therapeutics Co., Ltd (formerly SiDanSai Biotechnology Co., Ltd), Shanghai, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Innovative Cellular Therapeutics Co., Ltd (formerly SiDanSai Biotechnology Co., Ltd), Shanghai, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Department of Hematology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Innovative Cellular Therapeutics Co., Ltd (formerly SiDanSai Biotechnology Co., Ltd), Shanghai, China.;Department of Blood Transfusion, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Clinical Research Center, Zhejiang Provincial People's Hospital, Hangzhou, China.;Institute of Hematology, School of Medicine, Zhejiang University, Hangzhou, China.;Innovative Cellular Therapeutics Co., Ltd (formerly SiDanSai Biotechnology Co., Ltd), Shanghai, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.;Innovative Cellular Therapeutics Co., Ltd (formerly SiDanSai Biotechnology Co., Ltd), Shanghai, China. huanghe@zju.edu.cn Xiaolei@sidansai.com.;Bone Marrow Transplantation Center, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China. huanghe@zju.edu.cn Xiaolei@sidansai.com.", "authors": "Hu\|Yongxian\|Y\|;Wu\|Zhao\|Z\|;Luo\|Yi\|Y\|;Shi\|Jimin\|J\|;Yu\|Jian\|J\|;Pu\|Chengfei\|C\|;Liang\|Zuyu\|Z\|;Wei\|Guoqing\|G\|;Cui\|Qu\|Q\|;Sun\|Jie\|J\|;Jiang\|Jing\|J\|;Xie\|Jue\|J\|;Tan\|Yamin\|Y\|;Ni\|Wanmao\|W\|;Tu\|Jifang\|J\|;Wang\|Jinping\|J\|;Jin\|Aiyun\|A\|;Zhang\|Hao\|H\|;Cai\|Zhen\|Z\|;Xiao\|Lei\|L\|;Huang\|He\|H\|", "chemical_list": "D018941:Antigens, CD19; C000604811:CD19 molecule, human; D011948:Receptors, Antigen, T-Cell", "country": "United States", "delete": false, "doi": "10.1158/1078-0432.CCR-16-1799", "fulltext": null, "fulltext_license": null, "issn_linking": "1078-0432", "issue": "23(13)", "journal": "Clinical cancer research : an official journal of the American Association for Cancer Research", "keywords": null, "medline_ta": "Clin Cancer Res", "mesh_terms": "D000328:Adult; D018941:Antigens, CD19; D002681:China; D018572:Disease-Free Survival; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011948:Receptors, Antigen, T-Cell; D012008:Recurrence; D012074:Remission Induction; D013601:T-Lymphocytes", "nlm_unique_id": "9502500", "other_id": null, "pages": "3297-3306", "pmc": null, "pmid": "28039267", "pubdate": "2017-07-01", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Potent Anti-leukemia Activities of Chimeric Antigen Receptor-Modified T Cells against CD19 in Chinese Patients with Relapsed/Refractory Acute Lymphocytic Leukemia.", "title_normalized": "potent anti leukemia activities of chimeric antigen receptor modified t cells against cd19 in chinese patients with relapsed refractory acute lymphocytic leukemia" }	[ { "companynumb": "CN-SA-2017SA133007", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": null, ...
{ "abstract": "Adding the selective BCL-2 inhibitor venetoclax to reduced intensity conditioning (RIC) chemotherapy (fludarabine and busulfan, FluBu2) may enhance anti-leukemic cytotoxicity and thereby reduce the risk of post-transplant relapse. This phase 1 study investigated the recommended phase 2 (RP2D) of venetoclax, a BCL-2 selective inhibitor, when added to FluBu2 in adult patients with high risk acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and MDS/myeloproliferative neoplasms (MPN) undergoing transplant. Patients received dose-escalated venetoclax (200-400 mg daily starting day -8 for 6-7 doses) in combination with fludarabine 30 mg/m2/day for four doses and busulfan 0.8 mg/kg twice daily for eight doses on day -5 to -2 (FluBu2). Transplant related-toxicity was evaluated from the first venetoclax dose on day -8 to +28. Twenty-two patients were treated. At study entry, 5 MDS and MDS/MPN patients had 5-10% marrow blasts and 18/22 (82%) had a persistent detectable mutation. Grade 3 adverse events included mucositis, diarrhea and liver transaminitis (N=3 each). Neutrophil/platelet recovery and acute/chronic GVHD rates were similar to standard FluBu2. No DLTs were observed. The RP2D of venetoclax was 400 mg daily for 7 doses. With a median follow-up of 14.7 months (8.6-24.8 months), median overall survival was not reached, and progression free survival was 12.2 months (95% CI: 6.0 months, not estimable). In high risk AML, MDS, and MDS/MPN patients, adding venetoclax to FluBu2 was feasible and safe. To further address relapse risk, assessment of maintenance therapy after venetoclax plus FluBu2 transplant is on-going. This study was registered at clinicaltrials.gov as #NCT03613532.", "affiliations": "Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Brigham and Women's Hospital, Boston, Massachusetts, United States.;Dana Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana- Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana Farber / Harvard Medical School, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Brigham and Women's Hospital, Boston, Massachusetts, United States.;Brigham and Women's Hospital, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.;Dana-Farber Cancer Institute, Boston, Massachusetts, United States.", "authors": "Garcia\|Jacqueline S\|JS\|0000-0003-2118-6302;Kim\|Haesook T\|HT\|;Murdock\|H Moses\|HM\|0000-0003-4098-8968;Cutler\|Corey S\|CS\|;Brock\|Jennifer\|J\|;Gooptu\|Mahasweta\|M\|;Ho\|Vincent T\|VT\|;Koreth\|John\|J\|;Nikiforow\|Sarah\|S\|;Romee\|Rizwan\|R\|;Shapiro\|Roman M\|RM\|;Loschi\|Fiona\|F\|;Ryan\|Jeremy Adam\|JA\|0000-0002-3327-1283;Fell\|Geoffrey\|G\|;Karp\|Hannah Q\|HQ\|;Lucas\|Fabienne\|F\|0000-0002-4388-0349;Kim\|Annette S\|AS\|0000-0002-8699-2439;Potter\|Danielle Sinead\|DS\|;Mashaka\|Thelma\|T\|;Stone\|Richard M\|RM\|;DeAngelo\|Daniel J\|DJ\|0000-0001-7865-2306;Letai\|Anthony\|A\|;Lindsley\|R Coleman\|RC\|0000-0001-9822-806X;Soiffer\|Robert J\|RJ\|;Antin\|Joseph H\|JH\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1182/bloodadvances.2021005566", "fulltext": null, "fulltext_license": null, "issn_linking": "2473-9529", "issue": null, "journal": "Blood advances", "keywords": null, "medline_ta": "Blood Adv", "mesh_terms": null, "nlm_unique_id": "101698425", "other_id": null, "pages": null, "pmc": null, "pmid": "34614506", "pubdate": "2021-10-06", "publication_types": "D016428:Journal Article", "references": null, "title": "Adding venetoclax to fludarabine/busulfan RIC transplant for high risk MDS and AML is feasible, safe, and active.", "title_normalized": "adding venetoclax to fludarabine busulfan ric transplant for high risk mds and aml is feasible safe and active" }	[ { "companynumb": "US-OTSUKA-2021_038650", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSULFAN" }, "drugadditional": "3", "dr...
{ "abstract": "A 5-year-old girl developed severe proteinuria and microscopic hematuria 17 months after allogeneic bone marrow transplantation (BMT) for chronic myeloid leukemia. These nephrotic symptoms occurred during cyclosporin tapering, in the absence of other signs of chronic graft-versus-host disease (GVHD). A renal biopsy revealed focal segmental glomerulosclerosis. After methylprednisolone therapy, the proteinuria gradually decreased. The altered or disordered immune regulation that occurred after BMT may have resulted in the development of nephrotic syndrome.", "affiliations": "Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan.", "authors": "Chien\|Y H\|YH\|;Lin\|K H\|KH\|;Lee\|T Y\|TY\|;Lu\|M Y\|MY\|;Tsau\|Y K\|YK\|", "chemical_list": null, "country": "Singapore", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0929-6646", "issue": "99(6)", "journal": "Journal of the Formosan Medical Association = Taiwan yi zhi", "keywords": null, "medline_ta": "J Formos Med Assoc", "mesh_terms": "D016026:Bone Marrow Transplantation; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease; D006801:Humans; D009404:Nephrotic Syndrome", "nlm_unique_id": "9214933", "other_id": null, "pages": "503-6", "pmc": null, "pmid": "10925558", "pubdate": "2000-06", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Nephrotic syndrome in a bone marrow transplant recipient without chronic graft-versus-host disease.", "title_normalized": "nephrotic syndrome in a bone marrow transplant recipient without chronic graft versus host disease" }	[ { "companynumb": "PHHY2010TW25671", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "BUSULFAN" }, "drugadditional": "3", "drugadmi...
{ "abstract": "Lung cancers have various acquired resistance mechanisms that lead to treatment failure and disease progression, including secondary epidermal growth factor receptor (EGFR) exon 20 T790 M mutations, EGFR downstream or bypass pathway activation, and histologic transformation from adenocarcinoma to small cell carcinoma, squamous cell carcinoma, or sarcomatoid carcinoma.\n\n\n\nThis study compared the pathological and immunohistochemical characteristics before and after sarcomatoid transformation. Six advanced cases of lung adenocarcinoma that developed sarcomatoid transformation after treatment were collected.\n\n\n\nFive cases had classic EGFR mutations and one had a ROS1 rearrangement. The interval from initial diagnosis to sarcomatoid transformation ranged from 9 to 88 mo (median of 31.5 mo). The median survival after sarcomatoid transformation was 2.5 mo (1-16 mo). Before sarcomatoid transformation, all cases demonstrated typical adenocarcinoma features, including acinar, micropapillary, or solid/cribriform patterns, negative or weak focal vimentin staining, and strong E-cadherin expression. Histologic features of sarcomatoid transformation included giant cell features (6/6), loose cellular cohesion (6/6), strong staining for vimentin (6/6), decreased or lost E-cadherin expression (5/6), and high PD-L1 expression (5/6; one case demonstrated high PD-L1 staining at initial diagnosis). High MET expression and MET copy number gain (two samples with high polysomy and three with true amplification) were observed in five cases with EGFR mutation treated with tyrosine kinase inhibitors (TKI). One case exhibited MET amplification prior to the start of TKI treatment.\n\n\n\nSarcomatoid transformation is a type of lung cancer histologic evolution with a poor prognosis and a high proportion of cases with aberrant MET activation and PD-L1 expression.", "affiliations": "Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan; Graduate Institute of Pathology, National Taiwan University College of Medicine, Taipei, Taiwan.;Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: mwlin@ntu.edu.tw.;Department of Pathology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. Electronic address: yihsuan65@gmail.com.", "authors": "Hsieh\|Min-Shu\|MS\|;Lin\|Mong-Wei\|MW\|;Lee\|Yi-Hsuan\|YH\|", "chemical_list": "D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met", "country": "Ireland", "delete": false, "doi": "10.1016/j.lungcan.2019.08.029", "fulltext": null, "fulltext_license": null, "issn_linking": "0169-5002", "issue": "137()", "journal": "Lung cancer (Amsterdam, Netherlands)", "keywords": "Drug resistance; Lung cancer; MET; Sarcomatoid carcinoma", "medline_ta": "Lung Cancer", "mesh_terms": "D000077192:Adenocarcinoma of Lung; D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; D002296:Carcinosarcoma; D002471:Cell Transformation, Neoplastic; D005260:Female; D005500:Follow-Up Studies; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D019859:Proto-Oncogene Proteins c-met", "nlm_unique_id": "8800805", "other_id": null, "pages": "76-84", "pmc": null, "pmid": "31561203", "pubdate": "2019-11", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Lung adenocarcinoma with sarcomatoid transformation after tyrosine kinase inhibitor treatment and chemotherapy.", "title_normalized": "lung adenocarcinoma with sarcomatoid transformation after tyrosine kinase inhibitor treatment and chemotherapy" }	[ { "companynumb": "TW-ASTELLAS-2019US041737", "fulfillexpeditecriteria": "1", "occurcountry": "TW", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "ERLOTINIB" }, "drugadditional": "3", ...
{ "abstract": "The occurrence of two or more primary malignant neoplasms in the same person is rare. We report a case report of a 45-year-old woman with triple malignancy involving breast, ovary, and uterine vault managed at our center for 5 years. Our patient presented as a postoperated case of two primary malignant neoplasms of carcinoma, breast and ovary. For carcinoma ovary, she underwent adjuvant chemotherapy and interval cytoreductive surgery. For carcinoma breast, she received adjuvant locoregional radiotherapy and chemotherapy. After 42 months, the patient was diagnosed with squamous cell carcinoma vault, for which she received pelvic radiotherapy. She is on regular follow-up. Our patient had two synchronous and one metachronous malignancy. She was diagnosed with carcinoma uterine vault when she was in regular follow-up, and the two previous primaries were controlled. This emphasizes the importance of a regular follow-up and the need of a meticulous workup for early diagnosis and prompt management of any metachronous malignancy.", "affiliations": "Department of Radiotherapy, J. N. Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.;Department of Obstetrics and Gynaecology, J. N. Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.;Department of Radiotherapy, J. N. Medical College and Hospital, Aligarh Muslim University, Aligarh, Uttar Pradesh, India.", "authors": "Alam\|Mohammad Shadab\|MS\|;Perween\|Roshan\|R\|;Siddiqui\|Shahid Ali\|SA\|", "chemical_list": null, "country": "India", "delete": false, "doi": "10.4103/0973-1482.220419", "fulltext": null, "fulltext_license": null, "issn_linking": "1998-4138", "issue": "13(6)", "journal": "Journal of cancer research and therapeutics", "keywords": null, "medline_ta": "J Cancer Res Ther", "mesh_terms": "D001943:Breast Neoplasms; D065426:Cytoreduction Surgical Procedures; D005260:Female; D006801:Humans; D008875:Middle Aged; D016609:Neoplasms, Second Primary; D010051:Ovarian Neoplasms; D014594:Uterine Neoplasms", "nlm_unique_id": "101249598", "other_id": null, "pages": "1059-1061", "pmc": null, "pmid": "29237978", "pubdate": "2017", "publication_types": "D002363:Case Reports; D016422:Letter", "references": null, "title": "Triple malignancy involving breast, ovary, and uterine vault: A case report and literature review.", "title_normalized": "triple malignancy involving breast ovary and uterine vault a case report and literature review" }	[ { "companynumb": "IN-CIPLA LTD.-2018IN00766", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "d...
{ "abstract": "In this work, we present a case of deteriorative acne that occurred during methylprednisolone and danazol treatment of idiopathic thrombocytopenic purpura (ITP). Treatment of the patient with a combination of 5-aminolevulinic acid photodynamic therapy (ALA-PDT) and isotretinoin was satisfactory, though the patient had platelets as low as 4-10 × 109/L during treatment. We consider that the combination of oral isotretinoin and ALA-PDT was effective in this patient may be due to the synergetic effect of these treatments. To the best of our knowledge, no such cases have been reported.", "affiliations": "Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Dermatology, Beijing ChuiYangLiu Hospital, Beijing, 100022, China.;Department of Dermatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Electronic address: wangtaopumch@126.com.", "authors": "Hao\|Jianchun\|J\|;Wang\|Tao\|T\|", "chemical_list": "D004965:Estrogen Antagonists; D005938:Glucocorticoids; D017319:Photosensitizing Agents; D000622:Aminolevulinic Acid; D015474:Isotretinoin; D003613:Danazol; D008775:Methylprednisolone", "country": "Netherlands", "delete": false, "doi": "10.1016/j.pdpdt.2019.101630", "fulltext": null, "fulltext_license": null, "issn_linking": "1572-1000", "issue": "29()", "journal": "Photodiagnosis and photodynamic therapy", "keywords": "5-Aminolevulinic acid photodynamic therapy (ALA-PDT); Drug-induced acne fulminans; Isotretinoin", "medline_ta": "Photodiagnosis Photodyn Ther", "mesh_terms": "D000152:Acne Vulgaris; D000284:Administration, Oral; D000328:Adult; D000622:Aminolevulinic Acid; D003613:Danazol; D004359:Drug Therapy, Combination; D004965:Estrogen Antagonists; D005938:Glucocorticoids; D006801:Humans; D015474:Isotretinoin; D008297:Male; D008775:Methylprednisolone; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D016553:Purpura, Thrombocytopenic, Idiopathic", "nlm_unique_id": "101226123", "other_id": null, "pages": "101630", "pmc": null, "pmid": "31870898", "pubdate": "2020-03", "publication_types": "D002363:Case Reports", "references": null, "title": "5-Aminolevulinic acid photodynamic therapy and isotretinoin for treatment of drug-induced acne fulminans in a patient with idiopathic thrombocytopenic purpura.", "title_normalized": "5 aminolevulinic acid photodynamic therapy and isotretinoin for treatment of drug induced acne fulminans in a patient with idiopathic thrombocytopenic purpura" }	[ { "companynumb": "CN-SGP-000003", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DANAZOL" }, "drugadditional": "3", "drugadminis...
{ "abstract": "BACKGROUND\nEverolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), and sunitinib, an oral inhibitor of vascular endothelial growth factor (VEGF)/platelet-derived growth factor receptor tyrosine kinase signaling, have both been shown to provide clinical benefit in patients with advanced renal cell carcinoma (RCC). We sought to determine the safety and efficacy of combination therapy with these agents in patients with advanced RCC.\n\n\nMETHODS\nWe conducted a phase 1b dose escalation trial of sunitinib and everolimus in patients with advanced metastatic RCC. Prior nephrectomy was required, and prior radiation or chemotherapy other than VEGF/mTOR-based therapies was permitted. The primary end point was to determine the maximum tolerated dose/recommended phase 2 dose.\n\n\nRESULTS\nA total of 4 out of a planned 30 subjects were enrolled onto this study (M:F = 2:2; mean age 52 years, 50% with Karnofsky performance status < 80). The first 3 patients were enrolled onto a 4 + 2 dosing schedule of daily sunitinib 50 mg and weekly everolimus 30 mg. Mean time receiving drug was 99 days. One partial response was seen. Toxicities included mucositis, thrombocytopenia, anemia, fatigue, dehydration, and hypoglycemia. Because of multiple grade 3 to 4 toxicities, the protocol was amended to 2 + 1 dosing of sunitinib 37.5 mg and daily everolimus 5 mg. The first patient on this schedule died from multiorgan failure with septic shock after 1 cycle of treatment. Subsequently, the study was closed. Pharmacokinetic results inconclusively suggest that toxicities could be attributed to the drug exposure.\n\n\nCONCLUSIONS\nCombined use of everolimus and sunitinib in the treatment of metastatic RCC was not well tolerated in this small cohort.", "affiliations": "Duke University Medical Center, Durham, NC.;Duke Clinical Research Institute, Durham, NC.;Duke University, Durham, NC.;Duke University Medical Center, Durham, NC.;Duke Clinical Research Institute, Durham, NC.;Duke University Medical Center, Durham, NC. Electronic address: daniel.geoge@duke.edu.", "authors": "Kanesvaran\|Ravindran\|R\|;Watt\|Kevin\|K\|;Turnbull\|James D\|JD\|;Armstrong\|Andrew J\|AJ\|;Wolkowiez\|Michael Cohen\|MC\|;George\|Daniel J\|DJ\|", "chemical_list": "D007211:Indoles; D011758:Pyrroles; D000068338:Everolimus; D000077210:Sunitinib", "country": "United States", "delete": false, "doi": "10.1016/j.clgc.2014.12.011", "fulltext": null, "fulltext_license": null, "issn_linking": "1558-7673", "issue": "13(4)", "journal": "Clinical genitourinary cancer", "keywords": "Combination; Kidney cancer; Metastatic; VEGF TKI; mTOR inhibitor", "medline_ta": "Clin Genitourin Cancer", "mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002292:Carcinoma, Renal Cell; D000068338:Everolimus; D005260:Female; D006801:Humans; D007211:Indoles; D007680:Kidney Neoplasms; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011758:Pyrroles; D000077210:Sunitinib; D016896:Treatment Outcome", "nlm_unique_id": "101260955", "other_id": null, "pages": "319-327", "pmc": null, "pmid": "26174223", "pubdate": "2015-08", "publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013487:Research Support, U.S. Gov't, P.H.S.", "references": "17215529;17215530;17538086;18332470;18256322;17805538;18653228;19213664;20100962;20215359;20368558;19967539;21898375;11266932;11719728;8668925;9833985;10220493;16314617;16916320;17041096", "title": "A Single-Arm Phase 1b Study of Everolimus and Sunitinib in Patients With Advanced Renal Cell Carcinoma.", "title_normalized": "a single arm phase 1b study of everolimus and sunitinib in patients with advanced renal cell carcinoma" }	[ { "companynumb": "PHHY2015US091100", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "EVEROLIMUS" }, "drugadditional": null, "drug...
{ "abstract": "BACKGROUND\nPharmacological treatment plays a major role in the management of advanced, persistent or recurrent uterine leiomyosarcoma (LMS), whereas its usefulness in the adjuvant setting is still debated. A thorough literature search was undertaken using the Pubmed databases. Systematic reviews and controlled trials on medical treatment of uterine LMS were collected and critically analyzed. Other study types were secondarily considered when pertinent.\n\n\nMETHODS\nDoxorubicin (DOX), ifosfamide and dacarbazine have been long used in the treatment of this malignancy. Novel active agents are represented by gemcitabine, docetaxel, trabectedin, pazopanib and aromatase inhibitors, whereas the role of eribulin, bevacizumab, aflibercept and mammalian target of rapamycin inhibitors is still investigational.\n\n\nCONCLUSIONS\nDOX alone, gemcitabine alone, DOX + dacarbazine and gemcitabine + docetaxel may be treatment options for first-line and second-line therapies. However, the clinical benefit of the combination chemotherapy versus single-agent chemotherapy is still debated. Trabectedin is a promising agent for recurrent uterine LMS, able to obtain a prolonged disease control, with 3-month and 6-month progression-free survival rates exceeding 50 and 30%, respectively, and with sometimes unexpectedly durable responses. Pazopanib is the only approved targeted therapy. Hormone therapy with aromatase inhibitors may be a therapeutic option in heavily treated patients with slowly progressive, steroid receptor-positive tumors. Whenever possible, women with recurrent uterine LMS should be encouraged to enter well-designed clinical trials aimed to detect novel active agents.", "affiliations": "University of Pisa, Division of Gynecology and Obstetrics, Department of Experimental and Clinical Medicine , Via Roma 56, Pisa, 56127 , Italy +39 50 992609 ; +39 50 992354 ; a.gadducci@med.unipi.it.", "authors": "Gadducci\|Angiolo\|A\|;Guerrieri\|Maria Elena\|ME\|", "chemical_list": "D000970:Antineoplastic Agents; D015507:Drugs, Investigational", "country": "England", "delete": false, "doi": "10.1517/14656566.2015.985205", "fulltext": null, "fulltext_license": null, "issn_linking": "1465-6566", "issue": "16(3)", "journal": "Expert opinion on pharmacotherapy", "keywords": "aromatase inhibitors; chemotherapy; docetaxel; doxorubicin; gemcitabine; mammalian target of rapamycin inhibitors; pazopanib; trabectedin; uterine leiomyosarcoma", "medline_ta": "Expert Opin Pharmacother", "mesh_terms": "D000970:Antineoplastic Agents; D018572:Disease-Free Survival; D015507:Drugs, Investigational; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma; D009364:Neoplasm Recurrence, Local; D014594:Uterine Neoplasms", "nlm_unique_id": "100897346", "other_id": null, "pages": "335-46", "pmc": null, "pmid": "25418060", "pubdate": "2015-02", "publication_types": "D016428:Journal Article; D016454:Review", "references": null, "title": "Pharmacological treatment for uterine leiomyosarcomas.", "title_normalized": "pharmacological treatment for uterine leiomyosarcomas" }	[ { "companynumb": "US-CIPLA LTD.-2014US02940", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE" }, "d...
{ "abstract": "Multidrug-resistant organisms cause significant morbidity and mortality. Infections due to resistant gram-negative bacilli are increasingly being reported. For years, carbapenem antibiotics have been successfully used to treat infections due to resistant Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae, including those producing extended spectrum β-lactamases, a subset of β-lactamase enzymes that confer broad resistance to penicillins and cephalosporins. More recently, carbapenem-resistant Enterobacteriaceae have emerged as pathogenic organisms, which confer broad resistance to most β-lactam antibiotics including 'last-line' carbapenems. However, different types of carbapenemases confer diverse spectra of antibiotic resistance. Here, we describe the case of an 84-year-old lady on peritoneal dialysis (PD) for 3 years who, on developing carbapenem-resistant Klebsiella pneumoniae PD peritonitis, was successfully treated with colistin, an antimicrobial agent first used in the 1950s.", "affiliations": "Renal Services, North Shore Hospital, Waitematā District Health Board, Auckland, New Zealand.;Infectious Diseases, North Shore Hospital, Waitematā District Health Board, Auckland, New Zealand.;Renal Services, North Shore Hospital, Waitematā District Health Board, Auckland, New Zealand.;Renal Services, North Shore Hospital, Waitematā District Health Board, Auckland, New Zealand.", "authors": "O'Riordan\|Joanne\|J\|;Bhally\|Hasan S\|HS\|;Salmon\|Andrew Hj\|AH\|;de Zoysa\|Janak R\|JR\|", "chemical_list": "D000900:Anti-Bacterial Agents; D003091:Colistin", "country": "United States", "delete": false, "doi": "10.1177/0896860819879879", "fulltext": null, "fulltext_license": null, "issn_linking": "0896-8608", "issue": "40(1)", "journal": "Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis", "keywords": "Carbapenem-resistant enterobacteriaceae; colistin; peritoneal dialysis", "medline_ta": "Perit Dial Int", "mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D000073182:Carbapenem-Resistant Enterobacteriaceae; D003091:Colistin; D004756:Enterobacteriaceae Infections; D005260:Female; D006801:Humans; D007676:Kidney Failure, Chronic; D010530:Peritoneal Dialysis; D010538:Peritonitis", "nlm_unique_id": "8904033", "other_id": null, "pages": "100-102", "pmc": null, "pmid": "32063148", "pubdate": "2020-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Successful treatment of carbapenemase producing Enterobacteriaceae peritonitis: 'Old therapy for a new bug'.", "title_normalized": "successful treatment of carbapenemase producing enterobacteriaceae peritonitis old therapy for a new bug" }	[ { "companynumb": "NZ-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-240233", "fulfillexpeditecriteria": "1", "occurcountry": "NZ", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "MEROPENEM" }, "druga...
{ "abstract": "A 43-year-old woman was first admitted to the ophthalmology clinic with the complaint of a mass compressing the right eye. Based on clinical and laboratory examinations she was diagnosed as having marginal zone lymphoma (MZL) of the right lacrimal gland in addition to hepatitis C virus (HCV) infection. After the treatment for HCV infection with pegylated interferon plus ribavirin, a radiographic response of the MZL was obtained; she remains in remission through thirty months of clinical follow-up. In this case, the treatment of HCV infection led to regression of MZL suggesting the necessity of testing for HCV infection and treatment of the HCV infection should be highly considered in all HCV-positive patients with MZL's.", "affiliations": "Department of Gastroenterology, Adnan Menderes University, School of Medicine, Turkey.", "authors": "Coskun\|Adil\|A\|;Yukselen\|Ozden\|O\|;Yukselen\|Vahit\|V\|;Karaoglu\|A Onder\|AO\|", "chemical_list": "D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; C417083:peginterferon alfa-2b", "country": "Japan", "delete": false, "doi": "10.2169/internalmedicine.52.0450", "fulltext": null, "fulltext_license": null, "issn_linking": "0918-2918", "issue": "52(23)", "journal": "Internal medicine (Tokyo, Japan)", "keywords": null, "medline_ta": "Intern Med", "mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D005134:Eye Neoplasms; D005260:Female; D019698:Hepatitis C, Chronic; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007765:Lacrimal Apparatus; D018442:Lymphoma, B-Cell, Marginal Zone; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012074:Remission Induction; D012254:Ribavirin; D014057:Tomography, X-Ray Computed", "nlm_unique_id": "9204241", "other_id": null, "pages": "2615-8", "pmc": null, "pmid": "24292750", "pubdate": "2013", "publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review", "references": null, "title": "Lacrimal gland marginal zone lymphoma: regression after treatment of chronic hepatitis C virus infection: case report and review of the literature.", "title_normalized": "lacrimal gland marginal zone lymphoma regression after treatment of chronic hepatitis c virus infection case report and review of the literature" }	[ { "companynumb": "PHHY2015TR059732", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "PEGINTERFERON ALFA-2B" }, "drugadditional": null, ...
{ "abstract": "BACKGROUND\nSimilar autoimmune processes (defective T-cell function) take place during the pathogenesis of aplastic anemia (AA) and Graves' disease (GD). Antithyroid drugs used for the management of GD may induce AA and GD may occur following treatment of severe aplastic anemia (SAA).\n\n\nMETHODS\nClinical and laboratory investigations were performed for an 11-year-and-2-month-old girl who was referred for bilateral exophthalmus and abnormal thyroid function tests. She had been diagnosed as having severe acquired AA at the age of 8 years and had been treated with allogenic hematopoietic stem cell transplantation from her healthy human leukocyte antigen-matched sibling donor. Clinical examination revealed a weight of 32.6 kg (-0.88 standard deviation [SD] score); height, 145.7 cm (-0.14 SD score); body mass index 15.5 kg/m2 (-1.01 SD score); heart rate, 110/min; blood pressure, 128/74 mmHg; bilateral exophthalmos and an enlarged thyroid gland. The laboratory workup showed hemoglobin of 11.1 g/dL; white blood cells, 7500/mL; platelets, 172,000/mL; free thyroxine (FT4), 4.80 ng/dL (normal, 0.5-1.51); free triiodothyronine (FT3), 17.7 pg/mL (normal, 2.5-3.9); thyrotropin (TSH), 0.015 mIU/mL (normal, 0.38-5.3); antithyroglobulin peroxidase (TPO) antibody, 61.7 IU/mL (normal, 0-9); antithyroglobulin (TG) antibody, <0.9 IU/mL (normal, 0-4) and thyrotropin (TSH) receptor antibodies 14 U/L (normal, 0-1). Doppler ultrasonography showed diffuse enlargement of the thyroid gland and increased vascularity. She was treated with methimazole (0.6 mg/kg/day). L-thyroxine treatment was also needed (50 μg/day). Thrombocytopenia developed during follow-up. A thyroidectomy was performed for definitive treatment at the 14th month of treatment.\n\n\nCONCLUSIONS\nThe association of hyperthyroidism and AA in the pediatric age group is rare. The long-term use of antithyroid drugs and radioactive iodine should be avoided due to their hematologic toxic side effects.", "affiliations": "Department of Pediatric Endocrinology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey.;Department of Pediatric Endocrinology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey.;Department of Pediatric Hematology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey.;Department of Pediatric Endocrinology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey.;Department of Pediatric Endocrinology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey.;Department of Pediatric Hematology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey.;Department of Pediatric Endocrinology, Dokuz Eylul University, Faculty of Medicine, Izmir, Turkey.", "authors": "Paketçi\|Ahu\|A\|;Demir\|Korcan\|K\|;Tüfekçi\|Özlem\|Ö\|;Acar\|Sezer\|S\|;Abacı\|Ayhan\|A\|;Yılmaz\|Şebnem\|Ş\|;Böber\|Ece\|E\|", "chemical_list": null, "country": "Germany", "delete": false, "doi": "10.1515/jpem-2017-0358", "fulltext": null, "fulltext_license": null, "issn_linking": "0334-018X", "issue": "31(5)", "journal": "Journal of pediatric endocrinology & metabolism : JPEM", "keywords": "Graves’ disease; allogenic hematopoietic stem cell transplantation; hyperthyroidism; severe aplastic anemia", "medline_ta": "J Pediatr Endocrinol Metab", "mesh_terms": "D000741:Anemia, Aplastic; D002648:Child; D005260:Female; D006111:Graves Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D011379:Prognosis; D013960:Thyroid Function Tests; D014184:Transplantation, Homologous", "nlm_unique_id": "9508900", "other_id": null, "pages": "589-593", "pmc": null, "pmid": "29708883", "pubdate": "2018-04-25", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Graves' disease following allogenic hematopoietic stem cell transplantation for severe aplastic anemia: case report and literature review.", "title_normalized": "graves disease following allogenic hematopoietic stem cell transplantation for severe aplastic anemia case report and literature review" }	[ { "companynumb": "TR-SA-2018SA142070", "fulfillexpeditecriteria": "1", "occurcountry": "TR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "...
{ "abstract": "OBJECTIVE\nThis study aimed to evaluate the long-term effectiveness and safety of the first anti-tumor necrosis factor α therapy (TNFi) and to identify the associated factors of drug discontinuation in patients with spondyloarthritis.\n\n\nMETHODS\nThis was a medical records review study. Patients with spondyloarthritis who were prescribed the first TNFi between December 2009 and October 2014 in the Rheumatic Disease Prior Authorization registry were enrolled. Baseline clinical data were retrieved. The Cox proportional hazards model was used to identify factors associated with discontinuation of drugs.\n\n\nRESULTS\nAmong 138 patients, 97 had ankylosing spondylitis (AS), and 41 had psoriatic arthritis (PsA). The effectiveness of TNFi in AS and PsA was 55% to 59% at 4 months and 75% to 96% at 3 years, as measured by a 50% decrease in the Bath Ankylosing Spondylitis Disease Activity Index from baseline. For PsA with peripheral arthritis, improvement of the joint count by 50% was observed in 61.8% of patients at 4 months and 100% at 3 years. Survival from TNFi was 63% for AS and 56% for PsA at 3 years. For AS, the factors associated with good response leading to discontinuation of TNFi were baseline patient global assessment 3 to 6/10 (hazard ratio [HR], 6.3) and the use of leflunomide (HR, 6.0) and infliximab (HR, 4.8). A good response (38.5%) was the most common cause of discontinuation of the first TNFi, followed by toxicity (28.2%), nonadherence (20.5%), and lack of effectiveness (12.8%).\n\n\nCONCLUSIONS\nAnkylosing spondylitis and PsA responded well to TNFi during the 3-year follow-up. The retention rate was approximately 60% for AS and PsA. A good response to the first TNFi was the most common reason for discontinuation.", "affiliations": "Division of Rheumatology, Department of Medicine, Faculty of Medicine, Chulalongkorn University.;Division of Rheumatology, Department of Internal Medicine, Phramongkutklao Hospital and College of Medicine.;Division of Allergy Immunology and Rheumatology, Department of Internal Medicine, Faculty of Medicine, Ramathibodi Hospital, Mahidol University.;Rheumatology Unit, Department of Medicine, Rajavithi Hospital, Ministry of Public Health, Bangkok.;Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Prince of Songkla University, Songkla.;Division of Rheumatology, Department of Internal Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, Thailand.", "authors": "Chiowchanwisawakit\|Praveena\|P\|;Katchamart\|Wanruchada\|W\|;Osiri\|Manathip\|M\|;Narongroeknawin\|Pongthorn\|P\|;Chevaisrakul\|Parawee\|P\|;Kitumnuaypong\|Tasanee\|T\|;Siripaitoon\|Boonjing\|B\|;Louthrenoo\|Worawit\|W\|", "chemical_list": "D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept", "country": "United States", "delete": false, "doi": "10.1097/RHU.0000000000000741", "fulltext": null, "fulltext_license": null, "issn_linking": "1076-1608", "issue": "25(1)", "journal": "Journal of clinical rheumatology : practical reports on rheumatic & musculoskeletal diseases", "keywords": null, "medline_ta": "J Clin Rheumatol", "mesh_terms": "D000328:Adult; D000368:Aged; D018501:Antirheumatic Agents; D004334:Drug Administration Schedule; D000068800:Etanercept; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D016016:Proportional Hazards Models; D012042:Registries; D012189:Retrospective Studies; D025241:Spondylarthritis; D013785:Thailand; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha; D028761:Withholding Treatment", "nlm_unique_id": "9518034", "other_id": null, "pages": "9-15", "pmc": null, "pmid": "29517554", "pubdate": "2019-01", "publication_types": "D016428:Journal Article", "references": null, "title": "Effectiveness and Drug Survival of Anti-Tumor Necrosis Factor α Therapies in Patients With Spondyloarthritis: Analysis From the Thai Rheumatic Disease Prior Authorization Registry.", "title_normalized": "effectiveness and drug survival of anti tumor necrosis factor therapies in patients with spondyloarthritis analysis from the thai rheumatic disease prior authorization registry" }	[ { "companynumb": "TH-JNJFOC-20190133274", "fulfillexpeditecriteria": "1", "occurcountry": "TH", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, ...
{ "abstract": "A subcorneal pustular dermatosis and a vesicobullous eruption with the clinical ad histologic features of localized bullous pemphigoid(BP) were observed in a 44-year-old woman with morphea and a recent history of phenytoin sodium-induced toxic epidermal necrolysis. Localized BP is rare and has been previously described in association with other cutaneous disorders. The coexistence of localized BP, morphea, and subcorneal pustulosis suggests that immunologic factors may play a role in all three conditions.", "affiliations": null, "authors": "Bernstein\|J E\|JE\|;Medenica\|M\|M\|;Soltani\|K\|K\|", "chemical_list": null, "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0003-987X", "issue": "117(11)", "journal": "Archives of dermatology", "keywords": null, "medline_ta": "Arch Dermatol", "mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D010391:Pemphigoid, Bullous; D012594:Scleroderma, Localized; D012867:Skin; D012871:Skin Diseases; D012872:Skin Diseases, Vesiculobullous; D013262:Stevens-Johnson Syndrome; D013492:Suppuration", "nlm_unique_id": "0372433", "other_id": null, "pages": "725-7", "pmc": null, "pmid": "7032424", "pubdate": "1981-11", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Coexistence of localized bullous pemphigoid, morphea, and subcorneal pustulosis.", "title_normalized": "coexistence of localized bullous pemphigoid morphea and subcorneal pustulosis" }	[ { "companynumb": "US-PFIZER INC-2016522549", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PHENYTOIN SODIUM" }, "drugadditional": "1", ...
{ "abstract": "Relapse remains the leading cause of death in patients with acute myeloid leukaemia (AML). Relatively few new chemotherapy agents have been proven to be effective in this population. We report on a Phase 2 clinical trial using the novel combination of 2-chlorodeoxyadenosine (2-CDA) (8 mg/m² per d x 5 d) plus idarubicin (Ida) (10 mg/m² per d x 3 d). The study involved 109 paediatric patients with AML at first relapse, of whom 104 were available for analysis. The overall response rate was 51% (complete response [CR] + partial response) with a CR rate of 46%. 2-year event-free survival (EFS) and overall survival (OS) were 20% and 26%. The only significant variable in determining response, EFS and OS was duration of initial remission, with patients who had an initial remission >1 year having much worse outcomes overall (response rate 74% vs. 25%, EFS 8% vs. 37% and OS of 16% vs. 39%, P < 0.01 for all). There was an acceptable toxicity profile with one neurological event and no cardiac events observed. The most common grade 3-4 toxicities observed were neutropenia (59%) and thrombocytopenia (68%). This study demonstrated that the novel combination of 2-CDA/Ida was effective and should be considered for incorporation in front line therapy for children with AML.", "affiliations": "Maine Children's Cancer Program, Portland, ME, USA. chales1@mmc.org", "authors": "Chaleff\|Stanley\|S\|;Hurwitz\|Craig A\|CA\|;Chang\|Myron\|M\|;Dahl\|Gary\|G\|;Alonzo\|Todd A\|TA\|;Weinstein\|Howard\|H\|", "chemical_list": "C020967:2-chlorodiazepam; D001569:Benzodiazepines; D003975:Diazepam; D015255:Idarubicin", "country": "England", "delete": false, "doi": "10.1111/j.1365-2141.2011.08976.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0007-1048", "issue": "156(5)", "journal": "British journal of haematology", "keywords": null, "medline_ta": "Br J Haematol", "mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001569:Benzodiazepines; D002648:Child; D003975:Diazepam; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D015255:Idarubicin; D015470:Leukemia, Myeloid, Acute; D008297:Male; D012008:Recurrence; D055815:Young Adult", "nlm_unique_id": "0372544", "other_id": null, "pages": "649-55", "pmc": null, "pmid": "22512017", "pubdate": "2012-03", "publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article", "references": null, "title": "Phase II study of 2-chlorodeoxyadenosine plus idarubicin for children with acute myeloid leukaemia in first relapse: a paediatric oncology group study.", "title_normalized": "phase ii study of 2 chlorodeoxyadenosine plus idarubicin for children with acute myeloid leukaemia in first relapse a paediatric oncology group study" }	[ { "companynumb": "US-MYLANLABS-2016M1058234", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLADRIBINE" }, "drugadditional": "3", ...
{ "abstract": "Restricting oncology and hematology medications to outpatient infusion centers may be considered when infrequent administration is required, a low risk of serious adverse effects exists, or when prompt amelioration of a condition is not expected. At the University of California, San Diego (UCSD), we created a new formulary status for medications designated \"formulary, outpatient-restricted use only.\" This designation could optimize payer reimbursement, as well as improve patient comfort, by negating the need for inpatient admission. When the inpatient administration of a restricted medication is requested at UCSD, there ensues a loosely defined review process involving an informal conversation between the requesting prescriber and the oncology pharmacy and therapeutics (P&T) chair. Patient outcomes associated with this formulary status and informal request process are limited. The purpose of this study is to describe the use of formulary, outpatient-restricted oncology and hematology medications in the inpatient setting at a single-center, academic, and comprehensive cancer center.\nA retrospective chart review was conducted between January 1, 2015 and May 1, 2017. The primary outcome was to determine the percentage of formulary, outpatient-restricted oncology or hematology medications that were administered in the inpatient setting and continued to the outpatient setting. Secondary outcomes included overall survival, hospice enrollment, disease progression status, level of evidence supporting the medication usage, and cost.\nTwenty-three patients and 24 outpatient-restricted medications met the inclusion criteria. Thirteen (54%) medications were continued upon discharge and eight (33%) were not continued in the outpatient setting. Five of those eight medications were discontinued as a result of patient death.\nIn this single-center study, approximately one-third of the outpatient-restricted medications were not continued upon discharge. The findings suggest that our informal approval process could result in the suboptimal use of formulary outpatient-restricted medications for oncology and hematology indications. A more formalized request process might lead to the more effective utilization of these medications.", "affiliations": null, "authors": "Lau\|Kimberly M\|KM\|;Derry\|Katrina\|K\|;Dalton\|Ashley\|A\|;Martino\|Janine\|J\|", "chemical_list": null, "country": "United States", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "1052-1372", "issue": "44(8)", "journal": "P & T : a peer-reviewed journal for formulary management", "keywords": "costs; formulary; hematology; oncology; restricted", "medline_ta": "P T", "mesh_terms": null, "nlm_unique_id": "9015516", "other_id": null, "pages": "481-496", "pmc": null, "pmid": "31447536", "pubdate": "2019-08", "publication_types": "D016428:Journal Article", "references": "10387975;12887472;18242413;18589893;18593684;18688053;22024309;22454421;22614995;23943887;24607553;24756457;25399551;25482145;25482239;25976743;27345636;27416912;27557302;28579726;29915640;8879893", "title": "Outcomes of Inpatient Administration of Restricted Antineoplastic Medications at a Large Academic Medical Institution.", "title_normalized": "outcomes of inpatient administration of restricted antineoplastic medications at a large academic medical institution" }	[ { "companynumb": "US-AMGEN-USASP2019185343", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ROMIPLOSTIM" }, "drugadditional": null, ...
{ "abstract": "Interstitial lung disease (ILD) is a serious and potentially fatal adverse event in lung cancer therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a novel, solvent-free formulation of paclitaxel (PTX). Although the incidence of nab-PTX-induced ILD is not clear, it is generally considered that this formulation presents a similar risk of developing ILD as PTX. Here, we report 3 patients who developed severe ILD following treatment with nab-PTX. We draw attention to the risk of developing drug-induced ILD following nab-PTX treatment, and highlight that this novel formulation might therefore not be as safe as PTX with respect to the development of ILD.", "affiliations": "First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.;First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.;First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.;First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.;First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.;First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.;First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.;First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.;First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.;First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.;First Department of Internal Medicine, Kansai Medical University, Hirakata, Japan.", "authors": "Nakatani\|Yuki\|Y\|;Nakaya\|Aya\|A\|;Kurata\|Takayasu\|T\|;Yokoi\|Takashi\|T\|;Takeyasu\|Yuki\|Y\|;Niki\|Maiko\|M\|;Kibata\|Kayoko\|K\|;Satsutani\|Naoko\|N\|;Ogata\|Makoto\|M\|;Miyara\|Takayuki\|T\|;Nomura\|Shosaku\|S\|", "chemical_list": null, "country": "Switzerland", "delete": false, "doi": "10.1159/000479148", "fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000479148cro-0010-0683Case ReportInterstitial Lung Disease Following Single-Agent Nanoparticle Albumin-Bound Paclitaxel Treatment in Patients with Advanced Non-Small Cell Lung Cancer Nakatani Yuki Nakaya Aya Kurata Takayasu Yokoi Takashi Takeyasu Yuki Niki Maiko Kibata Kayoko Satsutani Naoko Ogata Makoto Miyara Takayuki Nomura Shosaku First Department of Internal Medicine, Kansai Medical University, Hirakata, JapanAya Nakaya, First Department of Internal Medicine, Kansai Medical University, 2-5-1, Shin-machi, Hirakata, Osaka 573-1010 (Japan), E-Mail nakaya1016@yahoo.co.jpMay-Aug 2017 4 8 2017 4 8 2017 10 2 683 688 3 7 2017 3 7 2017 Copyright © 2017 by S. Karger AG, Basel2017This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Interstitial lung disease (ILD) is a serious and potentially fatal adverse event in lung cancer therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a novel, solvent-free formulation of paclitaxel (PTX). Although the incidence of nab-PTX-induced ILD is not clear, it is generally considered that this formulation presents a similar risk of developing ILD as PTX. Here, we report 3 patients who developed severe ILD following treatment with nab-PTX. We draw attention to the risk of developing drug-induced ILD following nab-PTX treatment, and highlight that this novel formulation might therefore not be as safe as PTX with respect to the development of ILD.\n\nKeywords\nInterstitial lung diseaseNanoparticle albumin-bound paclitaxelNon-small cell lung cancerSingle-agent treatment\n==== Body\nIntroduction\nNanoparticle albumin-bound paclitaxel (nab-PTX) is an albumin-bound formulation of paclitaxel (PTX). In first-line therapy for patients with advanced non-small cell lung cancer (NSCLC), nab-PTX in combination with other platinum reagents showed significant efficacy in improving patients' prognosis as well as reducing toxicity profiles [1, 2, 3]. PTX-induced interstitial lung disease (ILD) occurs in approximately 1% of treated patients [4, 5]; thus, PTX is considered relatively safety with respect to the risk of developing drug-induced ILD. Although the incidence of nab-PTX-induced ILD is not clear, it is generally thought that this formulation presents a similar risk of developing ILD as PTX.\n\nTo date, only one study has evaluated the development of nab-PTX-induced ILD in clinical trials [6]. Here, we present case reports of 3 patients who developed severe ILD following treatment with nab-PTX. Our reports highlight the risk of developing drug-induced ILD following nab-PTX therapy and indicate that this novel formulation might therefore not be as safe as PTX with respect to the development of ILD.\n\nCase Reports\nCase 1\nA 71-year-old male ex-smoker, who was diagnosed with stage IV NSCLC (adenocarcinoma), received a platinum-based doublet regimen (carboplatin, pemetrexed, and bevacizumab) as initial chemotherapy until progression. nab-PTX (100 mg/m2) was subsequently used as a second-line regimen. On day 23 of the second cycle of nab-PTX treatment, he developed grade 1 fever and grade 3 dyspnea. Computed tomography (CT) scanning revealed hyperplasia of interlobular septa, nodular shadows, and ground glass opacity, which suggested a pattern of hypersensitivity pneumonia (Fig. 1). There was no elevation of tumor markers and the size of the target lesion was stable. Cultures of sputum, blood, and mycobacterium were all negative. The results of serological testing for Candida antigen and Aspergillus antigen were negative. (1→3)β-D-glucan was not elevated. Although all infectious disease tests were negative, and antibiotics were started prophylactically (tazobactam/piperacillin 13.5 g/day). Serum KL-6 level was 985 U/mL. Since the respiratory condition had deteriorated, bronchoscopy could not be performed. Clinically, we diagnosed nab-PTX-induced ILD. The drug lymphocyte stimulation test (DLST) was not conducted. Steroid treatment (prednisolone 0.5 mg/kg) was immediately initiated and the ILD symptoms quickly improved. Then steroid treatment was decreased. As there was no alternative anticancer agent for lung cancer, a minimum dose for the remainder of nab-PTX treatment was started. We explained the risk of exacerbation of ILD and obtained the patient's consent. nab-PTX treatment was continued for two further cycles until progression, and the ILD was not exacerbated during the remaining treatment.\n\nCase 2\nA 74-year-old male ex-smoker, who was diagnosed with stage IV NSCLC (squamous carcinoma), received a platinum-based doublet regimen (carboplatin, tegafur/gimeracil/oteracil) as initial chemotherapy and nab-PTX (100 mg/m2) as a second-line regimen. On day 24 of the first cycle of nab-PTX, he developed grade 1 fever and grade 3 dyspnea. There was no elevation of tumor markers and the size of the target lesion was stable. Cultures of sputum, blood, and mycobacterium were all negative. The results of serological testing for Candida antigen and Aspergillus antigen were negative. (1→3)β-D-glucan was not elevated. Although all infectious disease tests were negative, antibiotics were started prophylactically (meropenem 3 g/day). Serum KL-6 level was 334 U/ml. Since the respiratory condition had deteriorated, bronchoscopy could not be performed. CT scanning showed scattered ground glass opacity and hyperplasia of bronchovascular bundles, which suggested a pattern of hypersensitivity pneumonia (Fig. 2). Clinically, we diagnosed nab-PTX-induced ILD. DLST was not conducted. He was immediately given steroid treatment (prednisolone 0.5 mg/kg). ILD improved and steroid treatment was decreased to a maintenance level. As there was no alternative anticancer agent for lung cancer, a minimum dose of nab-PTX treatment was started. We explained the risk of exacerbation of ILD and obtained patient's consent. nab-PTX was continued for two further cycles until progression. During the remaining nab-PTX treatment, the patient's ILD did not worsen.\n\nCase 3\nA 59-year-old male ex-smoker, whose disease had relapsed following surgery for stage IIIB NSCLC (adenocarcinoma), was treated with a platinum-based doublet regimen (cisplatin and vinorelbine) and concurrent radiation therapy as a first-line regimen, followed by another platinum-based doublet regimen (carboplatin, pemetrexed, and bevacizumab); nab-PTX was subsequently given as a third-line regimen. On day 24 of the second cycle of nab-PTX therapy, the patient developed grade 1 fever and grade 3 dyspnea. CT scanning revealed consolidation with an air bronchogram and interlobular ground glass opacity, which suggested a pattern of organizing pneumonia (Fig. 3). There was no elevation of tumor markers and the size of the target lesion was stable. Cultures of sputum, blood, and mycobacterium were all negative. The results of serological testing for Candida antigen and Aspergillus antigen were negative. (1→3)β-D-glucan was not elevated. Although all infectious disease tests were negative, antibiotics were started prophylactically (tazobactam/piperacillin 13.5 g/day). Since the respiratory condition had deteriorated, bronchoscopy could not be performed. Clinically, we diagnosed nab-PTX-induced ILD. DLST was not conducted. Steroid treatment (prednisolone 0.5 mg/kg) was immediately initiated, and ILD temporarily improved. nab-PTX treatment was discontinued and a minimum dose of steroid was maintained; however, the patient's condition worsened and he developed infectious pneumonia. Despite steroid pulse therapy, the patient died of respiratory failure approximately 6 months after developing ILD.\n\nDiscussion\nILD is a serious and potentially fatal condition associated with lung cancer therapy and its development has been associated with treatment with several anti-cancer agents. Given that PTX-induced ILD occurs in approximately 1% of treated patients [4, 5], this drug is considered to present a low risk of development of ILD. nab-PTX is a novel, solvent-free formulation of PTX that shows significant efficacy in improving patients' prognosis, with a reduced toxicity profile, when administered in combination with carboplatin. However, the risk of developing ILD following nab-PTX treatment remains largely unknown.\n\nNo incidence of ILD was reported as an adverse event in the largest phase III clinical trial of nab-PTX in patients with NSCLC conducted to date [1]. Furthermore, a phase I/II study of nab-PTX as a first-line single agent did not report any adverse events related to ILD [7]. Two phase II studies have investigated nab-PTX as a second-line regimen [6, 8]. In one of the phase II studies, 2 patients developed ILD but neither case was fatal. According to our case reports, although the number of cases was too small to be conclusive, male gender and ex-smoker status might represent risk factors for developing ILD. One patient underwent radiation therapy, although the relevance of a relationship between radiation therapy and the onset of ILD is unclear. Furthermore, an investigation of the risk of administering nab-PTX therapy to lung cancer patients with a history of ILD would be beneficial.\n\nThe present study was limited in size and data were collected retrospectively. Additionally, no bronchoalveolar lavage or lung biopsy were performed to confirm ILD. Each pattern was evaluated using only CT.\n\nAlthough the incidence of ILD is relatively low, it might be premature to consider nab-PTX as having a similar safety profile to PTX with respect to the development of this condition. Therefore, further studies to investigate the relationship between nab-PTX and ILD are warranted.\n\nStatement of Ethics\nThe material in the manuscript has been acquired according to modern ethical standards and written informed consent of the patients has been obtained.\n\nDisclosure Statement\nNone of the authors have any conflict of interest to declare.\n\nAuthor Contributions\nAll authors contributed equally to the literature search, data collection (including figures), and manuscript writing.\n\nFig. 1 Plain chest computed tomography of case 1. Hyperplasia of interlobular septa, nodular shadows, and ground glass opacity, which suggest a pattern of hypersensitivity pneumonia.\n\nFig. 2 Plain chest computed tomography of case 2. Scattered ground glass opacity and hyperplasia of bronchovascular bundles, which suggest a pattern of hypersensitivity pneumonia.\n\nFig. 3 Plain chest computed tomography of case 3. Consolidation with an air bronchogram and interlobular ground glass opacity, which suggest a pattern of organizing pneumonia.\n==== Refs\nReferences\n1 Socinski MA Bondarenko I Karaseva NA Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial J Clin Oncol 2012 30 2055 2062 22547591 \n2 Socinski MA Okamoto I Hon JK Safety and efficacy analysis by histology of weekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer Ann Oncol 2013 24 2390 2396 23842283 \n3 Fang Y Wang L Xia GH Shi MQ Clinical investigation of efficacy of albumin bound paclitaxel plus platinum compounds as first-line chemotherapy for stage III/IV squamous non-small cell lung cancer Asian Pac J Cancer Prev 2014 15 7453 7457 25227858 \n4 Khan A McNally D Tutschka PJ Bilgrami S Phase II trial of weekly paclitaxel in previously untreated advanced non-small-cell lung cancer Oncology 2003 65 224 228 14657596 \n5 Yasuda K Igishi T Kawasaki Y Yamamoto M Kato K Matsumoto S Kotani M Sako T Shigeoka Y Sugitani A Histuda Y Shimizu E Paclitaxel-induced acute bilateral pneumonitis Ann Pharmacother 1997 31 1471 1474 9416383 \n6 Sakata S Saeki S Okamoto I Phase II trial of weekly nab-paclitaxel for previously treated advanced non-small cell lung cancer: Kumamoto thoracic oncology study group (KTOSG) trial 1301 Lung Cancer 2016 99 41 45 27565912 \n7 Rizvi NA Riely GJ Azzoli CG Phase I/II trial of weekly intravenous 130-nm albumin-bound paclitaxel as initial chemotherapy in patients with stage IV non-small-cell lung cancer J Clin Oncol 2008 26 639 643 18235124 \n8 Hu W Zhang Z A phase II clinical study of using nab-paclitaxel as second-line chemotherapy for Chinese patients with advanced non-small cell lung cancer Med Oncol 2015 32 177\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "1662-6575", "issue": "10(2)", "journal": "Case reports in oncology", "keywords": "Interstitial lung disease; Nanoparticle albumin-bound paclitaxel; Non-small cell lung cancer; Single-agent treatment", "medline_ta": "Case Rep Oncol", "mesh_terms": null, "nlm_unique_id": "101517601", "other_id": null, "pages": "683-688", "pmc": null, "pmid": "28878650", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "27565912;25944796;14657596;18235124;25227858;22547591;23842283", "title": "Interstitial Lung Disease Following Single-Agent Nanoparticle Albumin-Bound Paclitaxel Treatment in Patients with Advanced Non-Small Cell Lung Cancer.", "title_normalized": "interstitial lung disease following single agent nanoparticle albumin bound paclitaxel treatment in patients with advanced non small cell lung cancer" }	[ { "companynumb": "JP-PFIZER INC-2017366087", "fulfillexpeditecriteria": "1", "occurcountry": "JP", "patient": { "drug": [ { "actiondrug": "2", "activesubstance": { "activesubstancename": "PACLITAXEL" }, "drugadditional": "1", ...
{ "abstract": "Candida infections are common diseases in immunocompromised patients. A 19-year-old boy with liver transplantation, necrotic skin lesion, jaundice, dyspnea, and ascites was admitted to Namazi Hospital, Shiraz, southern Iran. The mycological examination for the skin lesion was requested. The skin sample was cultured on Sabouraud dextrose agar and evaluated by direct microscopic smear. Identification of isolated yeast was performed with RFLP-PCR. In direct smear, pseudohyphae, blastopores and yeasts were observed. Candida species was isolated from the media and identified as Candida albicans by molecular method. He died before starting any treatments. A skin lesion may present as the only sign of a systemic fungal infection in immunocompromised people. Careful attention and follow up are therefore recommended.", "affiliations": "Prof. Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.;Prof. Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.;Department of Organ Transplant Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.;Prof. Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.", "authors": "Badiee\|P\|P\|;Jafarian\|H\|H\|;Malek-Hosseini\|S A\|SA\|;Ghasemmi\|F\|F\|", "chemical_list": null, "country": "Iran", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "2008-6482", "issue": "10(1)", "journal": "International journal of organ transplantation medicine", "keywords": "Candida albicans; Fungal infection; Liver transplantation", "medline_ta": "Int J Organ Transplant Med", "mesh_terms": null, "nlm_unique_id": "101535773", "other_id": null, "pages": "46-50", "pmc": null, "pmid": "30891169", "pubdate": "2019", "publication_types": "D002363:Case Reports", "references": "11817966;12490804;17136699;17617057;19168950;19923491;21143834;21345708;21655823;23315320;23470036;29157206;29487735;7890937", "title": "Severe Cutaneous Candidiasis in a Liver Transplant Patient.", "title_normalized": "severe cutaneous candidiasis in a liver transplant patient" }	[ { "companynumb": "IR-FRESENIUS KABI-FK201905514", "fulfillexpeditecriteria": "1", "occurcountry": "IR", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "HYDROCORTISONE" }, "drugadditional": nul...
{ "abstract": "Pemphigus vulgaris is an autoimmune disease characterized by the formation of suprabasal intra-epidermal blisters on the skin and mucosal surfaces. Infectious diseases are the main cause of death in patients with pemphigus due to the disrupture of the physiological skin barrier, immune dysregulation, and the use of immunosuppressive medications leaving the patient prone to acquire opportunistic infections. We report the case of a 67-year-old woman diagnosed with pemphigus vulgaris, who was irregularly taking prednisone and mycophenolate mofetil. She was hospitalized because of a 1-month history of watery diarrhea and oral ulcers. Unfortunately, the patient died suddenly on the ward. The autopsy revealed a bilateral saddle pulmonary embolism, Gram-positive cocci bronchopneumonia, and gastrointestinal cytomegalovirus infection, causing extensive gastrointestinal mucosal ulcers.", "affiliations": "Autopsy Division - Anatomic Pathology Department - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP - Brazil.;Department of Dermatology - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP - Brazil.;Department of Dermatology - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP - Brazil.;Emergency Department - Hospital das Clínicas - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP - Brazil.;Department of Dermatology - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP - Brazil.;Department of Dermatology - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP - Brazil.;Autopsy Division - Anatomic Pathology Department - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP - Brazil.", "authors": "Oliveira\|Luiza Barbosa\|LB\|;Maruta\|Celina Wakisaka\|CW\|;Miyamoto\|Denise\|D\|;Salvadori\|Fernanda Aburesi\|FA\|;Santi\|Claudia Giuli\|CG\|;Aoki\|Valeria\|V\|;Duarte-Neto\|Amaro Nunes\|AN\|", "chemical_list": null, "country": "Brazil", "delete": false, "doi": "10.4322/acr.2017.008", "fulltext": "\n==== Front\nAutops Case RepAutops Case RepAutopsy & Case Reports2236-1960São Paulo, SP: Universidade de São Paulo, Hospital Universitário autopsy-07-0102310.4322/acr.2017.008Article / Autopsy Case ReportGastrointestinal cytomegalovirus disease in a patient with pemphigus vulgaris treated with corticosteroid and mycophenolate mofetil Gastrointestinal cytomegalovirus disease in a patient with pemphigus vulgaris treated with corticosteroid and mycophenolate mofetilOliveira LB, Maruta CW, Miyamoto D, et al.Oliveira Luiza Barbosa aMaruta Celina Wakisaka bMiyamoto Denise bSalvadori Fernanda Aburesi cSanti Claudia Giuli bAoki Valeria bDuarte-Neto Amaro Nunes aca Autopsy Division - Anatomic Pathology Department - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP – Brazil.b Department of Dermatology - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP – Brazil.c Emergency Department - Hospital das Clínicas - Faculty of Medicine - Universidade de São Paulo, São Paulo/SP – Brazil.Conflict of interest: None\n\nCorrespondence \nAmaro Nunes Duarte-Neto \nDepartamento de Patologia - Faculdade de Medicina - Universidade de São Paulo (USP) \nAvenida Dr. Arnaldo, 455 – Cerqueira Cesar – São Paulo/SP – Brazil \nCEP: 01246-903 \nPhone: +55 (11) 98546-4225 \namaro.ndneto@hc.fm.usp.br30 3 2017 Jan-Mar 2017 7 1 23 30 23 1 2017 01 3 2017 Autopsy and Case Reports. ISSN 2236-1960. Copyright © 2017.2017Autopsy and Case ReportsThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium provided the article is properly cited.Pemphigus vulgaris is an autoimmune disease characterized by the formation of suprabasal intra-epidermal blisters on the skin and mucosal surfaces. Infectious diseases are the main cause of death in patients with pemphigus due to the disrupture of the physiological skin barrier, immune dysregulation, and the use of immunosuppressive medications leaving the patient prone to acquire opportunistic infections. We report the case of a 67-year-old woman diagnosed with pemphigus vulgaris, who was irregularly taking prednisone and mycophenolate mofetil. She was hospitalized because of a 1-month history of watery diarrhea and oral ulcers. Unfortunately, the patient died suddenly on the ward. The autopsy revealed a bilateral saddle pulmonary embolism, Gram-positive cocci bronchopneumonia, and gastrointestinal cytomegalovirus infection, causing extensive gastrointestinal mucosal ulcers.\n\nKeywords\nAutopsyCytomegalovirusOpportunistic InfectionsPemphigus\n==== Body\nCASE REPORT\nA 67-year-old woman sought the emergency department complaining of a 1-month history of watery diarrhea without mucus or blood, followed by the appearance of lesions in the oral cavity with odynophagia over the last 2 weeks. Despite 10 days of treatment with metronidazole in an outpatient clinic due to the presence of Blastocystis hominis in the stool examination, diarrhea persisted.\n\nThe patient had a medical history of pemphigus vulgaris and recurrent episodes of severe major depression. After histopathological confirmation of pemphigus vulgaris, which was initially diagnosed more than 10 years ago, the patient had been followed-up in the dermatologic clinic. Over the last 7 years, she had been hospitalized several times to compensate the pemphigus and the depression. It should be added that she was used to inducing self-scarification of her skin lesions, and had significant problems with treatment compliance (i.e. she did not attend the appointments and refused to properly treat her psychiatric condition). At the time of her last hospitalization, she was irregularly using prednisone 60 mg/day and mycophenolate mofetil (MMF) 3 g/day.\n\nIn the emergency room, the physical examination revealed an emaciated patient with erosions covered by hematic crusts on the face, without signs of secondary infection. She also had an ulcer on the dorsal surface of the tongue and some erosions covered with a whitish exudate on the oral mucosa. Due to the diagnostic hypothesis of oral and esophageal candidiasis, the patient was treated with fluconazole with partial relief of the odynophagia. Abnormal laboratory findings included normocytic and normochromic anemia, lymphopenia (530 cells/mm3 (reference value [RV]: 900-3400 cells/mm3), mildly elevated pancreatic enzymes (amylase and lipase), and leukocyturia. Based on the urinalysis result, ciprofloxacin was prescribed; and a urine culture further identified negative-coagulase Staphylococcus sp. The chest x-ray was normal.\n\nOn the fourth day of hospitalization, an upper digestive endoscopy evidenced extensive erosive esophagitis, and gastric antral erosions; biopsies were performed. The pathological report was released post mortem. After 6 days of hospitalization, the patient had a sudden cardiac arrest in pulseless electrical activity, and our rapid response team (“blue code”) attempted resuscitation. Unfortunately, the patient did not respond to the standard resuscitation maneuvers. An autopsy was performed with the consent of her relatives.\n\nAUTOPSY FINDINGS\nThe corpse weighed 42.0 kg and measured 1.60 m (body mass index = 16.4 kg/m2). The ectoscopy revealed an emaciated female corpse. Erosions with fibrin-hematic crusts were observed bilaterally on the malar skin (Figure 1).\n\nFigure 1 Pemphigus vulgaris facial lesions: erosions with fibrin-hematic crusts on the malar region.\nAt the opening of the cavities, no abnormalities were found. There was an organized thrombus in the right atrium extending to the tricuspid valve (Figure 2A). The right lung weighed 744.0 g (mean RV = 450 g) and the left weighed 686.0 g (mRV = 375 g). Both lungs had a massive saddle pulmonary embolism, which extended to the peripheral branches. The cut surface of the lungs showed marked congestion, draining a foamy, pinkish liquid when compressed, with firm consistency in the basal regions (Figure 2B). At microscopy, the lung parenchyma had extensive areas of bronchopneumonia caused by Gram-positive cocci associated with diffuse alveolar damage (congestion, alveolar edema and hemorrhage, and hyaline membranes) and numerous arterial thrombi (Figure 2C, D).\n\nFigure 2 A - Gross examination of the heart showing an organized thrombus in the right atrium (arrow); B - Saddle pulmonary thromboembolism in the right lung (arrow); C - Micrography of the lungs showing suppurative bronchopneumonia (arrow) associated with colonies of cocci (arrowhead) (H&E, 55X); D - Gram-positive cocci in the areas of suppurative pneumonia (arrows) (Brown-Brenn, 400X).\nAn extensive ulcer, measuring 2.5 cm in diameter, was found on the tongue’s dorsal surface (Figure 3A), which histopathologically corresponded to an ischemic ulcer with ongoing regeneration, neutrophilic inflammatory infiltrate, granulation tissue, and reepithelization (Figure 3B). Within the surrounding areas of the ulcer there were multiple inflammatory, stromal, and endothelial cells presenting cytomegaly and intranuclear eosinophilic inclusion, surrounded by a clear halo, which was consistent with cytomegalovirus infection (Figure 3B).\n\nFigure 3 A - Gross examination of the tongue depicting an ulcer on the dorsum (arrow); B - Micrography of the tongue showing mucosal ulcer with endothelial cells exhibiting cytomegalic cytopathic effect (arrow and inset) (H&E, 300X); C - Macroscopic examination of the colonic mucosa exhibiting small ulcers (arrows); D - Micrography of the colon showing a positive immunohistochemistry reaction for cytomegalovirus (CMV) antigens, detecting cytomegalic endothelial (arrow) and inflammatory (arrow head) cells in a colonic ulcer, with nuclear staining (mouse anti-CMV cocktail of DDG9 and CCH2, Diagnostic BioSystems, 400X).\nThe esophagus presented several small erosions, and the stomach had ulcers with punctuated hemorrhages measuring less than 1.0 cm in diameter. The colonic mucosa was covered by multiple fibrinous plates measuring from 0.7 cm to 2.0 cm in diameter, intermingled with scattered ulcerations measuring on the average of 0.5 cm in diameter, from the cecum to the descendent colon (Figure 3C). The microscopic examination of the gastrointestinal ulcers showed similar findings as the tongue: mucosal ulcers with neutrophilic inflammatory infiltrate, granulation tissue, and endothelial cytomegalic inclusion, stromal, and inflammatory cells. Immunohistochemistry (mouse anti-cytomegalovirus [CMV] cocktail of DDG9 and CCH2, Diagnostic BioSystems, Pleasanton, CA, USA) was performed and all gastrointestinal lesions stained positively for cytomegalovirus in the nuclear inclusions of the cytomegalic cells (Figure 3D).\n\nAdditional findings of the autopsy included multiple organ damage due to septic shock, such as discrete lymphomononuclear myocarditis, nutmeg liver, splenitis, and acute tubular necrosis.\n\nDISCUSSION\nTaken together, the clinical and autopsy findings described in the present report can be interpreted as a patient with pemphigus vulgaris (the underlying cause of death) and recurrent major depression, under chronic immunosuppression secondary to prednisone and MMF. Tapering off the immunosuppressive therapy was not possible as the patient remained with active pemphigus vulgaris lesions due to treatment non-compliance. As a consequence, she acquired two infections: (i) cytomegalovirus infection reactivation, producing diffuse lesions in the gastrointestinal tract, with prolonged symptomatic diarrhea and odynophagia before her death; and (ii) nosocomial pneumonia due to Gram-positive cocci (an autopsy finding, not clinically suspected). Both infections certainly induced to prothrombotic state, leading to a massive pulmonary embolism, which was the immediate cause of her death.1-3 The malnutrition observed at her physical exam was probably synergistic with the drug-induced immunosuppression, corroborated by the anorexia caused by reduced food intake due to painful oral lesions,4 and lymphopenia, which was evidenced in her first complete blood count at this final hospitalization.5-7\n\nPemphigus vulgaris is an autoimmune disease characterized by the formation of suprabasal intra-epidermal blisters on the skin and mucosal surfaces, due to the destruction of the epithelial desmosomes by autoantibodies.8 Until the 1950s, the 5-year mortality related to pemphigus vulgaris was 100%.9 Mortality decreased to 25-45% with the use of systemic corticosteroids but adverse effects, such as diabetes, osteoporosis, dyslipidemia, and cataracts, led to the introduction of immunosuppressants as steroid-sparing agents.10,11 Death rates improved to 5-10% with adjuvant immunosuppression, but the risk of opportunistic infections increased.11,12\n\nInfectious diseases are the main cause of death in patients with pemphigus.13-15 Few studies are published on the autopsies of patients with autoimmune bullous disorders concerning the pathology of their death. To the best of our knowledge, in 1984 Aki et al.16 performed the study with the largest number of patients including 18 autopsied cases. Among them, 10 had pemphigus vulgaris and 8 had pemphigus foliaceus. In the group with pemphigus vulgaris, nine deaths were attributed to infectious diseases related to immunosuppressive therapy, such as disseminated strongyloidiasis (two cases), military tuberculosis (two cases), pneumonia (three cases), sepsis related to Gram-positive cocci, and colitis (one case).16 Other isolated autopsy case reports showed bronchiolitis obliterans17 and lymphomatoid granulomatosis18 as causes of death in patients with pemphigus vulgaris.\n\nCMV is a common human pathogen, and a member of the Herpesviridae family. Estimates of the worldwide prevalence of CMV infection range from 40% to 100%, with greater indexes in underdeveloped or developing countries due to higher population density.19 CMV transmission occurs through “close contact”, saliva, urine, sexual contact, and vertical transmission (the latter usually during early childhood). A Brazilian study conducted in Caieiras, a city in the northern area of the São Paulo State, showed that 90% of the infants had maternal antibodies against CMV.20 The immunocompetent hosts most commonly have an asymptomatic infection, and some develop a mononucleosis-like syndrome. The congenital cytomegalovirus infection occurs when a pregnant woman transmits the virus vertically to the fetus. After an acute phase, the CMV can establish a latent infection into the host cells that can reactivate under systemic immunosuppression (AIDS, post-transplantation, post-chemotherapy, and the use of steroids and other immunosuppressive drugs).21 The immunocompromised host with CMV disease can develop lesions in almost all organ systems, but mainly in the gastrointestinal tract (esophagitis, gastritis, colitis, ulcers, and perforations), the lungs (pneumonitis), the liver (hepatitis), the eyes (retinitis) and the nervous system (encephalitis and myelitis). Gastrointestinal CMV disease, with superficial mucosal lesions, can be diagnosed when the CMV nuclear inclusions are only seen in the epithelial cells (owl’s eye aspect) in a tissue sample. The invasive and systemic CMV disease is evidenced when the pathologist detects cytomegalic endothelial cells–with the typical nuclear inclusion–obliterating the vascular lumen, causing ischemic necrosis and ulceration of the gastrointestinal mucosa. Epithelial and stromal cells are also affected.22,23 The clinical manifestations include fever, malaise, weight loss, abdominal pain, diarrhea (watery or bloody), dysphagia, odynophagia, anemia, leucopenia, and viremia.24\n\nCMV infection has been described among patients with pemphigus vulgaris under steroid therapy associated or not with azathioprine or rituximab, causing asymptomatic erythematous gastritis,25 gastric ulcers,22 or skin lesions.23 In a prospective cohort study of patients with pemphigus vulgaris, Leshem et al.12 found an incidence of 8.1% (14/172 patients) of opportunistic infections (OI) within the first year of follow-up. Two patients had fatal CMV disease: one had cutaneous and lung CMV infections, and the other presented systemic CMV. Advanced age and possibly diabetes were associated with an increased risk for OI among patients with pemphigus in this study.12\n\nIt should be emphasized that autoimmune bullous disorders can be superinfected or colonized by the herpes simplex virus (HSV).26 Besides HSV, which is the most common virus infection described,26-30 herpes virus 8 (HHV-8) may cause localized lesions of Kaposi sarcoma in areas previously treated with corticosteroid infiltrations,31 multifocal lesions,32 or skin colonization with uncertain clinical significance.33 CMV is described as causing skin superinfection or disseminated disease in some reports.12,23,34 The Herpesviridae virus superinfection must be suspected when there are bullous or ulcerative lesions refractory to immunosuppressive treatment. Diagnosis confirmation relies on histopathological or immunohistochemical analysis of skin samples, and through a polymerase chain reaction to detect CMV-DNA in blood samples (viremia).12,30,35,36 Our case illustrates how an infection can be detrimental to a patient with autoimmune bullous disorder. Despite proper diagnostic and therapeutic measures towards the patient’s complaints and clinical conditions, she had a fatal outcome due to a saddle pulmonary thromboembolism. Epidemiological data provide evidence of the association between acute infections and thromboembolic events, including deep vein thrombosis and pulmonary embolism. The risk of thrombotic events increases more than 2-fold within a period of 2 weeks to 3 months after either community or nosocomial infections of the respiratory and urinary tracts, blood, abdomen, skin, or soft tissues, and Gram-positive bacterial infections.1,2 An autopsy-based study conducted at King’s College Hospital (London, UK) found that among 110 patients with fatal pulmonary embolism associated with well-defined clinical conditions, 26 (23.6%) had infections–predominantly in the respiratory tract–during the 6 weeks prior to death.3 The reasons why an infection predisposes to a prothrombotic state are still not fully understood, but endothelial damage by virus or bacterial infections, dehydration, and white-cell activation have been implicated.37,38 In the current case, CMV gastrointestinal infection and nosocomial pneumonia were the determinants for the patient’s death. The suppurative pneumonia identified at the autopsy was probably not clinically diagnosed because the patient was receiving immunosuppressive drugs, and oral ciprofloxacin for urinary infection and diarrhea, which could mask the signs and symptoms of the respiratory infection.\n\nPatients with bullous autoimmune disorders exhibit a higher infectious risk related to the disrupture of the physiological skin barrier, leading to colonization and infection with bacteria and other microorganisms, immune dysregulation, and the use of immunosuppressive medications.15,39 Infections are one of the main adverse effects of steroids, as they downregulate the innate and cell-mediated adaptive immune responses against intracellular microorganisms.5 MMF inhibits the purine nucleotide synthesis, an essential pathway to lymphocytes proliferation. Therapeutic regimens, including MMF, are associated with an increased likelihood of CMV disease among kidney transplant recipients.6\n\nAs a secondary preventive measure to infections, physicians must be aware of the signs and symptoms of infection, especially OI, caused by a myriad of agents (such as CMV), to provide early diagnosis and adequate treatment to the patients under immunosuppressive therapy.\n\nA recent evidence-based guideline on the screening for infectious diseases in patients with autoimmune bullous dermatoses, recommends testing patients for Mycobacterium tuberculosis, and hepatitis B and C viruses, before prescribing rituximab treatment.14 On the other hand, doctors must educate their patients to avoid colonization and infection of their skin (proper hand washing, nail cleaning, and avoiding any physical contact with other patients) and recognize early signs and symptoms of infection to seek health assistance for rapid diagnosis and treatment.36 In addition, patient compliance to the medical prescription and follow-up appointments must be actively persuaded to prevent misuse of medications and consequent prolonged immunosuppression, which can lead to a fatal outcome, such as the one we have described here.\n\nACKNOWLEDGEMENTS\nThe authors would like to thank Mrs. Deryn Pompeia and Mr. Reginaldo Silva do Nascimento for their technical assistance in the preparation of this manuscript.\n\nOliveira LB, Maruta CW, Miyamoto D, et al. Gastrointestinal cytomegalovirus disease in a patient with pemphigus vulgaris treated with corticosteroid and mycophenolate mofetil. Autopsy Case Rep [Internet]. 2017;7(1):23-30. http://dx.doi.org/10.4322/acr.2017.008\n\nFinancial support: None\n==== Refs\nREFERENCES\n1 Smeeth L , Cook C , Thomas S , Hall AJ , Hubbard R , Vallance P \nRisk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting . Lancet . 2006 ;367 (9516 ):1075 -9 . PMid: http://dx.doi.org/10.1016/S0140-6736(06)68474-2. 16581406 \n2 Schmidt M , Horvath-Puho E , Thomsen RW , Smeeth L , Sørensen HT \nAcute infections and venous thromboembolism . J Intern Med . 2012 ;271 (6 ):608 -18 . PMid: http://dx.doi.org/10.1111/j.1365-2796.2011.02473.x. 22026462 \n3 Alikhan R , Peters F , Wilmott R , Cohen AT \nFatal pulmonary embolism in hospitalized patients: a necropsy review . J Clin Pathol . 2004 ;57 (12 ):1254 -7 . PMid: http://dx.doi.org/10.1136/jcp.2003.013581. 15563663 \n4 Knudson RM , Kalaaji AN , Bruce AJ \nThe management of mucous membrane pemphigoid and pemphigus . Dermatol Ther (Heidelb) . 2010 ;23 (3 ):268 -80 . PMid: http://dx.doi.org/10.1111/j.1529-8019.2010.01323.x. 20597945 \n5 Migita K , Arai T , Ishizuka N , et al \nRates of serious intracellular infections in autoimmune disease patients receiving initial glucocorticoid therapy . PLoS One . 2013 ;8 (11 ):e78699 . PMid: http://dx.doi.org/10.1371/journal.pone.0078699. 24260127 \n6 Song ATWS , Abdala E , Bonazzi PR , Bacchella T , Machado MC \nDoes mycophenolate mofetil increase the risk of cytomegalovirus infection in solid organ transplant recipients?: a mini review . Braz J Infect Dis . 2006 ;10 (2 ):132 -8 . PMid: http://dx.doi.org/10.1590/S1413-86702006000200011. 16878265 \n7 Santos JI \nNutrition, infection, and immunocompetence . Infect Dis Clin North Am . 1994 ;8 (1 ):243 -67 . PMid:8021446 \n8 Ben Lagha N , Poulesquen V , Roujeau JC , Alantar A , Maman L \nPemphigus vulgaris: a case-based update . J Can Dent Assoc . 2005 ;71 (9 ):667 -72 . PMid:16271165 \n9 Mimouni D , Bar H , Gdalevich M , Katzenelson V , David M \nPemphigus: analysis of epidemiological factors in 155 patients . J Eur Acad Dermatol Venereol . 2008 ;22 (10 ):1232 -5 . PMid: http://dx.doi.org/10.1111/j.1468-3083.2008.02786.x. 18482324 \n10 Bystryn JC , Steinman NM \nThe adjuvant therapy of pemphigus: an update . Arch Dermatol . 1996 ;132 (2 ):203 -12 . PMid: http://dx.doi.org/10.1001/archderm.1996.03890260105016. 8629830 \n11 Stanley JR \nTherapy of pemphigus vulgaris . Arch Dermatol . 1999 ;135 (1 ):76 -8 . PMid: http://dx.doi.org/10.1001/archderm.135.1.76. 9923786 \n12 Leshem YA , Gdalevich M , Ziv M , David M , Hodak E , Mimouni D \nOpportunistic infections in patients with pemphigus . J Am Acad Dermatol . 2014 ;71 (2 ):284 -92 . PMid: http://dx.doi.org/10.1016/j.jaad.2014.03.020. 24815564 \n13 Chams-Davatchi C , Valikhani M , Daneshpazhooh M , et al \nPemphigus: analysis of 1209 cases . Int J Dermatol . 2005 ;44 (6 ):470 -6 . PMid: http://dx.doi.org/10.1111/j.1365-4632.2004.02501.x. 15941433 \n14 Keith PJ , Wetter DA , Wilson JW , Lehman JS \nEvidence-based guidelines for laboratory screening for infectious diseases before initiation of systemic immunosuppressive agents in patients with autoimmune bullous dermatoses . Br J Dermatol . 2014 ;171 (6 ):1307 -17 . PMid: http://dx.doi.org/10.1111/bjd.13355. 25130049 \n15 Lehman JS , Khunger M , Lohse CM \nInfection in autoimmune bullous diseases: a retrospective comparative study . J Dermatol . 2013 ;40 (8 ):613 -9 . PMid: http://dx.doi.org/10.1111/1346-8138.12175. 23772962 \n16 Aki HE , Sotto MN , Sampaio SA \nPost-mortem evaluation in endemic pemphigus foliaceus and pemphigus vulgaris . Med Cutan Ibero Lat Am . 1984 ;12 (2 ):151 -7 . PMid:6374324 \n17 Saito K , Morita M , Enomoto K \nBronchiolitis obliterans with pemphigus vulgaris and Castleman’s disease of hyaline-vascular type: an autopsy case analyzed by computer-aided 3-D reconstruction of the airway lesions . Hum Pathol . 1997 ;28 (11 ):1310 -2 . PMid: http://dx.doi.org/10.1016/S0046-8177(97)90208-2. 9385940 \n18 Jauregui HO \nLymphomatoid granulomatosis after immunosuppression for pemphigus . Arch Dermatol . 1978 ;114 (7 ):1052 -5 . PMid: http://dx.doi.org/10.1001/archderm.1978.01640190040014. 686725 \n19 Jong MD , Galasso GJ , Gazzard B , et al \nSummary of the II International Symposium on Cytomegalovirus . Antiviral Res . 1998 ;39 (3 ):141 -62 . PMid: http://dx.doi.org/10.1016/S0166-3542(98)00044-8. 9833956 \n20 Almeida LNB , Azevedo RS , Amaku M , Massad E \nCytomegalovirus seroepidemiology in an urban community of São Paulo, Brazil . Rev Saude Publica . 2001 ;35 (2 ):124 -9 . PMid: http://dx.doi.org/10.1590/S0034-89102001000200004. 11359197 \n21 Goodgame RW \nGastrointestinal cytomegalovirus disease . Ann Intern Med . 1993 ;119 (9 ):924 -35 . PMid: http://dx.doi.org/10.7326/0003-4819-119-9-199311010-00010. 8215005 \n22 Orton DI , Orteu CH , Rustin MHA \nCytomegalovirus-associated gastric ulcer in an immunosuppressed patient with pemphigus vulgaris . Clin Exp Dermatol . 2001 ;26 (2 ):170 -2 . PMid: http://dx.doi.org/10.1046/j.1365-2230.2001.00787.x. 11298108 \n23 Chiu H-Y , Chang C-Y , Hsiao C-H , Wang LF \nConcurrent cytomegalovirus and herpes simplex virus infection in pemphigus vulgaris treated with rituximab and prednisolone . Acta Derm Venereol . 2013 ;93 (2 ):200 -1 . PMid: http://dx.doi.org/10.2340/00015555-1429. 22948546 \n24 Buckner FS , Pomeroy C \nCytomegalovirus disease of the gastrointestinal tract in patients without AIDS . Clin Infect Dis . 1993 ;17 (4 ):644 -56 . PMid: http://dx.doi.org/10.1093/clinids/17.4.644. 8268345 \n25 Hokama A , Taira K , Yamamoto Y , et al \nCytomegalovirus gastritis . World J Gastrointest Endosc . 2010 ;2 (11 ):379 -80 . PMid: http://dx.doi.org/10.4253/wjge.v2.i11.379. 21173917 \n26 Oliveira-Baptista D , Janini MER , Fernandes NC , Santos N \nLaboratory diagnosis of herpesvirus infections in patients with pemphigus vulgaris lesions . Intervirology . 2013 ;56 (4 ):231 -6 . PMid: http://dx.doi.org/10.1159/000349889. 23735576 \n27 Feldmeyer L , Trüeb RM , French LE , Hafner J \nPitfall: pemphigus herpeticatus should not be confounded with resistant pemphigus vulgaris . J Dermatolog Treat . 2010 ;21 (5 ):311 -3 . PMid: http://dx.doi.org/10.3109/09546630903287452. 19895326 \n28 Marzano AV , Tourlaki A , Merlo V , Spinelli D , Venegoni L , Crosti C \nHerpes simplex virus infection and pemphigus . Int J Immunopathol Pharmacol . 2009 ;22 (3 ):781 -6 . PMid: http://dx.doi.org/10.1177/039463200902200324. 19822095 \n29 Nikkels AF , Delvenne P , Herfs M , Pierard GE \nOccult herpes simplex virus colonization of bullous dermatitides . Am J Clin Dermatol . 2008 ;9 (3 ):163 -8 . PMid: http://dx.doi.org/10.2165/00128071-200809030-00004. 18429645 \n30 Brandão ML , Fernandes NC , Batista DP , Santos N \nRefractory pemphigus vulgaris associated with herpes infection: case report and review . Rev Inst Med Trop Sao Paulo . 2011 ;53 (2 ):113 -7 . PMid: http://dx.doi.org/10.1590/S0036-46652011000200010. 21537760 \n31 Avalos-Peralta P , Herrera A , Ríos-Martín JJ , Pérez-Bernal AM , Moreno-Ramírez D , Camacho F \nLocalized Kaposi’s sarcoma in a patient with pemphigus vulgaris . J Eur Acad Dermatol Venereol . 2006 ;20 (1 ):79 -83 . PMid: http://dx.doi.org/10.1111/j.1468-3083.2005.01348.x. 16405614 \n32 Halpern SM , Parslew R , Cerio R , Kirby JT , Sharpe GR \nKaposi’s sarcoma associated with immunosuppression for bullous pemphigoid . Br J Dermatol . 1997 ;137 (1 ):140 -3 . PMid: http://dx.doi.org/10.1111/j.1365-2133.1997.tb03718.x. 9274643 \n33 Meibodi NT , Nahidi Y , Mahmoudi M , et al \nEvaluation of coexistence of the human herpesvirus type 8 (HHV-8) infection and pemphigus . Int J Dermatol . 2010 ;49 (7 ):780 -3 . PMid: http://dx.doi.org/10.1111/j.1365-4632.2009.04398.x. 20618497 \n34 Casals DS , Nunes EA , Maruta CW , et al \nDisseminated cytomegalovirus disease as a cause of prolonged fever in a bullous pemphigoid patient under systemic steroid therapy . J Dermatol . 2003 ;30 (4 ):332 -6 . PMid: http://dx.doi.org/10.1111/j.1346-8138.2003.tb00396.x. 12707471 \n35 Gee SN , Velez NF , Sepehr A , Burgin S \nTwo distinct viral infections complicating pemphigus foliaceus . Dermatol Online J . 2012 ;18 (1 ):3 . PMid:22301040 \n36 Lehman JS , Murrell DF , Camilleri MJ , Kalaaji AN \nInfection and infection prevention in patients treated with immunosuppressive medications for autoimmune bullous disorders . Dermatol Clin . 2011 ;29 (4 ):591 -8 . PMid: http://dx.doi.org/10.1016/j.det.2011.06.021. 21925003 \n37 Opal SM , Cohen J \nClinical gram-positive sepsis: does it fundamentally differ from gram-negative bacterial sepsis? \nCrit Care Med . 1999 ;27 (8 ):1608 -16 . PMid: http://dx.doi.org/10.1097/00003246-199908000-00039. 10470773 \n38 Visseren FL , Bouwman JJ , Bouter KP , Diepersloot RJ , de Groot PH , Erkelens DW \nProcoagulant activity of endothelial cells after infection with respiratory viruses . Thromb Haemost . 2000 ;84 (2 ):319 -24 . PMid:10959707 \n39 Maddur MS , Vani J , Lacroix-Desmazes S , Kaveri S , Bayry J \nAutoimmunity as a predisposition for infectious diseases . PLoS Pathog . 2010 ;6 (11 ):e1001077 . PMid: http://dx.doi.org/10.1371/journal.ppat.1001077. 21079687\n\n", "fulltext_license": "CC BY-NC", "issn_linking": "2236-1960", "issue": "7(1)", "journal": "Autopsy & case reports", "keywords": "Autopsy; Cytomegalovirus; Opportunistic Infections; Pemphigus", "medline_ta": "Autops Case Rep", "mesh_terms": null, "nlm_unique_id": "101640070", "other_id": null, "pages": "23-30", "pmc": null, "pmid": "28536684", "pubdate": "2017", "publication_types": "D002363:Case Reports", "references": "20597945;24815564;8215005;20618497;18482324;18429645;16878265;23735576;15941433;11298108;24260127;21079687;22026462;9923786;22301040;9385940;8629830;16405614;21173917;21537760;10470773;12707471;21925003;686725;9833956;16271165;19822095;22948546;19895326;16581406;8268345;9274643;15563663;11359197;10959707;8021446;23772962;25130049;6374324", "title": "Gastrointestinal cytomegalovirus disease in a patient with pemphigus vulgaris treated with corticosteroid and mycophenolate mofetil.", "title_normalized": "gastrointestinal cytomegalovirus disease in a patient with pemphigus vulgaris treated with corticosteroid and mycophenolate mofetil" }	[ { "companynumb": "BR-ACCORD-052254", "fulfillexpeditecriteria": "1", "occurcountry": "BR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "MYCOPHENOLIC ACID" }, "drugadditional": null, ...
{ "abstract": "A Caucasian man in early 80s was seen in Gastroenterology Clinic, following, referral from the Endocrinology Clinic for concerns for CT Abdomen requested for tiredness and weight loss of three kilograms. The patient also had microcytic picture with low MCV and Ferritin and hypomagnesemia. The CT suggested gross circumferential thickening of the wall of stomach with advice for invasive investigations to further characterise the CT findings. The Endoscopy suggested grossly enlarged rugae in the stomach, and enlarged gastric polyps. Patient was assured no new sinister abnormality. Treatment challenges to consider were to stop acid suppression by prescribing Proton Pump Inhibitors (PPIs) which would lead to stomach ulcers, or to continue with PPIs with sequalae of worsening of hypertrophic gastric folds, enlarged gastric polyps and hypomagnesemia. It would be necessary to consider risk versus benefits in either situation to determine an appropriate treatment plan in the long term. With background of Zollinger-Ellison Syndrome and MEN1 with heterozygous mutation with gastrinoma of the duodenum, and frailty he was advised to continue with Proton Pump Inhibitors with twice weekly correction of Magnesium infusions, and Iron tablets following Multi-disciplinary meeting.", "affiliations": "Dr. Mansoor Zafar, MBBS, MRCP (UK). Gastroenterology and General Internal Medicine Specialty Registrar, Conquest Hospital. East Sussex Healthcare, NHS Trust. TN37 7RD, UK.;Dr. Tila Muhammad, MBBS, FCPS (Pakistan), MRCP (UK). Consultant Gastroenterology, Conquest Hospital. East Sussex Healthcare, NHS Trust. TN37 7RD, UK.;Dr. Najam us Saher, Consultant and Assistant Professor, Department of Dermatology, Aga Khan University Hospital, Karachi, Pakistan. 74800.;Dr. Muhammad Toqeer, MBBS, FCPS (Pakistan), MRCP (UK). Consultant Gastroenterology. Conquest Hospital. East Sussex Healthcare, NHS Trust. TN37 7RD, UK.", "authors": "Zafar\|Mansoor\|M\|;Muhammad\|Tila\|T\|;Saher\|Najam Us\|NU\|;Toqeer\|Muhammad\|M\|", "chemical_list": null, "country": "Pakistan", "delete": false, "doi": "10.12669/pjms.37.4.3984", "fulltext": "\n==== Front\nPak J Med Sci\nPak J Med Sci\nPakistan Journal of Medical Sciences\n1682-024X\n1681-715X\nProfessional Medical Publications Pakistan\n\nPJMS-37-1237\n10.12669/pjms.37.4.3984\nCase Report\nHypertrophic Gastric folds with Hypomagnesemia, linking the dots\nZafar Mansoor 1\nMuhammad Tila 2\nSaher Najam us 3\nToqeer Muhammad 4\n1 Dr. Mansoor Zafar, MBBS, MRCP (UK). Gastroenterology and General Internal Medicine Specialty Registrar, Conquest Hospital. East Sussex Healthcare, NHS Trust. TN37 7RD, UK\n2 Dr. Tila Muhammad, MBBS, FCPS (Pakistan), MRCP (UK). Consultant Gastroenterology, Conquest Hospital. East Sussex Healthcare, NHS Trust. TN37 7RD, UK\n3 Dr. Najam us Saher, Consultant and Assistant Professor, Department of Dermatology, Aga Khan University Hospital, Karachi, Pakistan. 74800\n4 Dr. Muhammad Toqeer, MBBS, FCPS (Pakistan), MRCP (UK). Consultant Gastroenterology. Conquest Hospital. East Sussex Healthcare, NHS Trust. TN37 7RD, UK\nCorrespondence: Dr. Mansoor Zafar, MBBS, MRCP (UK), Gastroenterology and General Internal Medicine Specialty Registrar, Conquest Hospital, East Sussex Healthcare, NHS Trust, TN37 7RD, UK. E-mail: 1mansoorzafar@gmail.com\nJul-Aug 2021\n37 4 12371240\n08 12 2020\n10 2 2021\n12 4 2021\nCopyright: © Pakistan Journal of Medical Sciences\n2021\nhttps://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nA Caucasian man in early 80s was seen in Gastroenterology Clinic, following, referral from the Endocrinology Clinic for concerns for CT Abdomen requested for tiredness and weight loss of three kilograms. The patient also had microcytic picture with low MCV and Ferritin and hypomagnesemia. The CT suggested gross circumferential thickening of the wall of stomach with advice for invasive investigations to further characterise the CT findings. The Endoscopy suggested grossly enlarged rugae in the stomach, and enlarged gastric polyps. Patient was assured no new sinister abnormality.\n\nTreatment challenges to consider were to stop acid suppression by prescribing Proton Pump Inhibitors (PPIs) which would lead to stomach ulcers, or to continue with PPIs with sequalae of worsening of hypertrophic gastric folds, enlarged gastric polyps and hypomagnesemia. It would be necessary to consider risk versus benefits in either situation to determine an appropriate treatment plan in the long term.\n\nWith background of Zollinger-Ellison Syndrome and MEN1 with heterozygous mutation with gastrinoma of the duodenum, and frailty he was advised to continue with Proton Pump Inhibitors with twice weekly correction of Magnesium infusions, and Iron tablets following Multi-disciplinary meeting.\n\nOesophago-gastroduodenoscopy (OGD)\nHypertrophic Gastric Polyps\nHypomagnesemia\nZollinger-Ellison Syndrome\nMultiple Endocrine Neoplasia type 1 (MEN1)\nProton Pump Inhibitors (PPIs)\n==== Body\nCASE REPORT\n\nA Caucasian man in early 80s was seen in Gastroenterology Clinic referred from the Endocrinology clinic for concerns over the CT-Abdomen findings, requested for complaint of tiredness, fatigue, weight loss of three kilograms, microcytic picture with low MCV and Ferritin, hypomagnesemia.\n\nHe was approached remotely by the Tertiary hospital after his father and another sibling were managed for complex renal stones, and genetic testing confirmed Multiple Endocrine Neoplasia Type-1 (MEN1) in them. Following he underwent Parathyroidectomy fifty-five years ago and again twenty-five years ago, for hypercalcemia.\n\nHe has a complex past history of MEN I, with heterozygous mutation, Zollinger-Ellison Syndrome secondary to Gastrinoma of the duodenum diagnosed more than 20 years ago with no previous abdominal surgery, bilateral adrenal adenomas asymptomatic, stable psoriasis and, hypertension. Other comorbidities include, pulmonary embolism and persistent hypomagnesaemia on twice weekly magnesium infusions, and Omeprazole 20 mg, three times a day for more than forty years, as prescribed by the tertiary centre. He was later referred to the local district general hospital for periodic follow up due to frailty. His family history with one son who had tested negative for MEN, and another child not willing to get investigated. Non-smoker, with Alcohol only socially less than 21 units/ week, lives with wife.\n\nClinical Examination\n\nSuggested normal scaphoid abdomen, with stable phase psoriatic patches along both elbows. Pulse 69, BP 170/96, Weight 66 kg (recent visit) and 69.1 kg (six months ago). It was concluded that patient needed further work-up to clarify CT findings.\n\nInvestigations:\n\nElectrolytes\n\nSerum Magnesium 0.38, Serum Inorganic Phosphate 1.14 mmol/l, Serum Sodium 129 mmol/l, Serum Potassium 4.9 mmol/l, Corrected Calcium 2.56 mmol/l.\n\nHormonal Profile\n\nSerum FSH 21.3* IU/L, Serum LSH 7.2 IU/L, Plasma Gastrin 224* pmol/l, Plasma Vasointestinal Peptide <4, Plasma Pancreatic Polypeptide 85 pmol/l, Plasma Chromogranin B 106 pmol/l, Plasma Chromogranin A 64* pmol/l, Serum Parathormone 45 ng/l (15-65), Plasma Calcitonin <3, Plasma Glucagon 10 pmol/l, Plasma Somatostatin 23 pmol/l, Serum IGF-1 23.4, Serum Human Growth Hormone 8.64 ug/l, Serum Testosterone 25.46 nmol/l.\n\nHaematinics\n\nFerritin 33, Folate 9.2, Vitamin B12 499, MCV 79.7, Haemoglobin 126, Platelet Count 178.\n\nCT Abdomen:\n\nPancreas compressed/displaced by a grossly enlarged gastric chamber which appeared to correspond to a circumferential thickening of the wall of the stomach of uncertain aetiology.\n\nSubtle locules of air noted within the periphery of the gastric chamber, of uncertain significance with presumption of related to air between presumably grossly hypertrophic rugae or, much less likely, a concomitant longstanding bezoar. (Fig.1, 2).\n\nFig.1 Computerised Tomogram (CT) -Abdomen; Coronal view, grossly enlarged Stomach.\n\nFig.2 Computerised Tomogram. Transverse CT view, grossly enlarged stomach, pancreatic atrophy.\n\nOral Gastro-Duodenoscopy:\n\nSignificant hypertrophy of gastric folds in the fundus large gastric polyps. (Fig. 3, 4).\n\nFig.3 OGD; Antral view with hypertrophic Gastric Folds and Large Gastric Polyps.\n\nFig.4 OGD; Stomach in Retro flexion. The thickening seen on the CT secondary to enlarged folds and huge fundic gland polyps secondary to chronic PPI use.\n\nTreatment:\n\nThe case was discussed in Gastroenterology Multi-Disciplinary Meeting.\n\nConsidering the frailty, it was decided that patient need to be managed conservatively with PPIs, and periodic twice weekly 24 mmol Magnesium infusions.\n\nHis corrected Calcium levels to date have been in normal range.\n\nOutcome and Follow up:\n\nPatient was assured of no sinister pathology. He was advised periodic clinic review in Gastroenterology Clinic, with 24 mmol Magnesium infusions on regular basis twice in a week, with continuation of Omeprazole 20 mg three times a day, and Ferrous Gluconate 210 mg once daily. He reported resolution of symptoms of tiredness, and happy with the conservative management.\n\nDISCUSSION\n\nZollinger-Ellison Syndrome is neuro-endocrine functional tumours predominantly of either Pancreatic or Duodenal Origin. Incidence remains 0.2-2 per 1000000 annually.1 They are associated with increase Gastrin Secretion, with associated stomach ulcers, diarrhoea and other sequalae. Most patents are diagnosed in age group 20 to 50 and most of them are Men. Surprisingly 80% of cases are sporadic2, however, up to 30% of cases are in association with MEN1, as our patient.3 The Pancreatic Origin is more likely to metastasize; however, duodenal origin runs a relatively benign course, with less likelihood of being spread to liver at the time of presentation, size usually is < 1 cm and usually multiple and more likely to occur in the first part of duodenum, as in our patient.2,3 Rarely, they may arise from stomach, liver, bile duct, lymphatic channels along mesentery or pancreatic region, ovary, and even more rarely in heart, lungs-in association with small cell lung cancer.4\n\nIn a patient managed conservatively with PPIs on long term basis, for duodenal origin of Zollinger-Ellison Syndrome, there are multiple side-effects reported. The common side effects include: Hyponatremia, Clostridium difficile enteritis, and Interstitial Nephritis.\n\nKomorowski et al have elaborated the importance of snare biopsy for surveillance to rule out Gastric Cancers.5 Kuiper EJ et al, have found more predisposition to Helicobacter pylori infection with long term use of PPIs6 and more incidence of Atrophic Gastritis and Gastric polyps with prolong use of PPIs.7\n\nThe National Institute of Diabetes and Digestive and Kidney Disease (NIDDK), gives online info for patients, general population and healthcare providers towards symptomatology, and management of the patients with Zollinger-Ellison Syndrome in particular in association with MEN1 8. National Organisation for Rare Disorders also has helpful info available.9\n\nLearning Points:\n\nUnderstanding of side-effects of long-term use of PPIs is important to clinically co-relate, with side effects.\n\nEndoscopic viewing is important to clarify ambiguity by the scans, to rule out stomach cancer.\n\nThere are frail patients with Zollinger-Ellison Syndrome, associated with MEN1, that can be managed conservatively.\n\nAuthors’ Contribution:\n\nMZ: Clinically evaluated the patient, designed the case report, prepared the manuscript and is responsible for clinical integrity of the study.\n\nTM: Clinically involved in the care of the patient.\n\nNS: Reviewed the manuscript for intellectual input.\n\nMT: Involved in the overall care of the patient, and reviewed the manuscript for intellectual input.\n==== Refs\nREFERENCES\n\n1 Metz DC Jensen RT Gastrointestinal neuroendocrine tumors:pancreatic endocrine tumors Gastroenterology 2008 135 5 1469 1492 doi:10.1053/j.gastro.2008.05.047 18703061\n2 Berna MJ Annibale B Marignani M Luong TV Corleto V Pace A A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome:identification of risk factors J Clin Endocrinol Metab 2008 93 5 1582 91 doi:10.1210/jc.2007-2279 18270260\n3 Norton JA Neuroendocrine tumors of the pancreas and duodenum Curr Probl Surg 1994 31 2 77 156 doi:10.1016/0011-3840(94)90079-5 7904550\n4 Norton JA Alexander HR Fraker DL Venzon DJ Gibril F Jensen RT Possible primary lymph node gastrinoma:occurrence, natural history, and predictive factors:a prospective study Ann Surg 2003 237 5 650 657 discussion 7-9 doi:10.1097/01.SLA.0000064375.51939.48 12724631\n5 Komorowski RA Caya JG Geenen JE The morphologic spectrum of large gastric folds:utility of the snare biopsy Gastrointest Endosc 1986 32 3 190 192 doi:10.1016/s0016-5107(86)71802-6 3721138\n6 Kuipers EJ Uyterlinde AM Peña AS Hazenberg HJ Bloemena E Lindeman J Increase of Helicobacter pylori-associated corpus gastritis during acid suppressive therapy:implications for long-term safety Am J Gastroenterol 1995 90 9 1401 1406 doi:10.3748/wjgv6.i3.311 7661157\n7 Kuipers EJ Lundell L Klinkenberg-Knol EC Havu N Festen HP Liedman B Atrophic gastritis and Helicobacter pylori infection in patients with reflux esophagitis treated with omeprazole or fundoplication N Engl J Med 1996 334 16 1018 1022 doi:10.1056/NEJM199604183341603 8598839\n8 Zollinger-Ellison Syndrome National Institute of Diabetes and Digestive and Kidney Disease (NIDDK) https://www.niddk.nih.gov/health-information/digestive-diseases/zollinger-ellison-syndrome [December 2013]\n9 Gastritis, Giant Hypertrophic;National Organisation for Rare Disorders (NORD) [https://rarediseases.org/rare-diseases/gastritis-giant-hypertrophic/] [Years Published 1986 1994,2002 2004]\n\n", "fulltext_license": "CC BY", "issn_linking": "1681-715X", "issue": "37(4)", "journal": "Pakistan journal of medical sciences", "keywords": "Hypertrophic Gastric Polyps; Hypomagnesemia; Multiple Endocrine Neoplasia type 1 (MEN1); Oesophago-gastroduodenoscopy (OGD); Proton Pump Inhibitors (PPIs); Zollinger-Ellison Syndrome", "medline_ta": "Pak J Med Sci", "mesh_terms": null, "nlm_unique_id": "100913117", "other_id": null, "pages": "1237-1240", "pmc": null, "pmid": "34290814", "pubdate": "2021", "publication_types": "D002363:Case Reports", "references": "18270260;3721138;7661157;18703061;8598839;7904550;12724631", "title": "Hypertrophic Gastric folds with Hypomagnesemia, linking the dots.", "title_normalized": "hypertrophic gastric folds with hypomagnesemia linking the dots" }	[ { "companynumb": "GB-MYLANLABS-2021M1087851", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "4", "activesubstance": { "activesubstancename": "OMEPRAZOLE" }, "drugadditional": null, ...
{ "abstract": "Chronic granulomatous disease (CGD) can be cured by allogeneic hemopoietic stem cell transplantation (HSCT). Complications include graft failure, graft-versus-host disease (GVHD), infection, and transplant-related mortality; therefore, reduced-intensity conditioning regimens are being used to improve outcomes. In this retrospective study, the aim was to determine the outcome of treosulfan-based conditioning in HSCT for pediatric patients with CGD. The following data were collected: risk features pre-HSCT, additional conditioning agents, donor type and stem cell source, toxicity, engraftment, GVHD, chimerism, viral reactivation, post-HSCT complications, length of follow-up, and outcome. Seventy patients (median age, 107 months; interquartile range [IQR], 46-232 months) from 16 centers worldwide were transplanted between 2006 and 2015. Ninety-one percent had high-risk features. Fifty-seven HLA-matched donors, 12 HLA-mismatched donors, and 1 CD3(+)TCR αβ/CD19 depleted parental haploidentical transplants were performed. No major toxicity was reported. Median times to neutrophil and platelet engraftment were 17 (IQR, 15-35) and 16 (IQR, 13-50) days. At a median follow-up of 34 months (IQR, 13-102 months), the overall survival was 91.4%, and event-free survival was 81.4%. The cumulative incidence of acute grade III-IV GVHD was 12%. Nine patients developed chronic GVHD. When split cell chimerism was available, 95% or more myeloid donor chimerism was documented in 80% of surviving patients. Secondary graft failure occurred in 12% of patients. Treosulfan-containing conditioning regimens can be used safely in HSCT for children with CGD and high-risk clinical features, achieving excellent survival with high myeloid chimerism. Further studies are needed to compare with other regimens and evaluate the long-term outcome, particularly on fertility.", "affiliations": "Department of Paediatric Immunology, Great North Children´s Hospital, Newcastle Upon Tyne, United Kingdom;;Hannover Medical School, Hannover, Germany;;Paediatric Bone Marrow Transplant, Great Ormond Street Hospital, London, United Kingdom;;Fred Hutchinson Cancer Research Center, Seattle, WA; The University of Washington School of Medicine, Seattle, WA;;Department of Pediatrics, University Medical Center Ulm, Ulm, Germany;;Paediatric Bone Marrow Transplantation Schiehallion Unit, Royal Hospital for Sick Children, Glasgow, United Kingdom;;Paediatric Bone Marrow Transplantation Schiehallion Unit, Royal Hospital for Sick Children, Glasgow, United Kingdom;;Department of Pediatric Hematology and Oncology, Teaching Hospital Motol, Prague, Czech Republic;;Department of Pediatric Hematology and Oncology, Teaching Hospital Motol, Prague, Czech Republic;;Pediatric Haematology/Oncology, University Medical Centre, Freiburg, Germany;;Rambam Hospital, Haifa, Israel;;Wroclaw Medical University, Wroclaw, Poland;;Medical College of Wisconsin, Milwaukee, WI;;Fred Hutchinson Cancer Research Center, Seattle, WA; The University of Washington School of Medicine, Seattle, WA;;Lady Cilento Children's Hospital, Brisbane, Australia;;Department of Microbiology and Immunology, Department of Pediatrics, University Hospitals Leuven, KU Leuven, Leuven, Belgium;;University Medical Center Hamburg-Eppendorf, Hamburg, Germany;;University of Medical Sciences, Poznan, Poland;;San Raffaele Telethon Institute for Gene Therapy, Pediatric Immunohematology and Bone Marrow Transplantation Unit, San Raffaele Scientific Institute, Milan, Italy; and.;Paediatric Bone Marrow Transplant, Great Ormond Street Hospital, London, United Kingdom;;Hannover Medical School, Hannover, Germany;;Department of Paediatric Immunology, Great North Children´s Hospital, Newcastle Upon Tyne, United Kingdom; Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.;Department of Paediatric Immunology, Great North Children´s Hospital, Newcastle Upon Tyne, United Kingdom; Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.", "authors": "Morillo-Gutierrez\|Beatriz\|B\|;Beier\|Rita\|R\|;Rao\|Kanchan\|K\|;Burroughs\|Lauri\|L\|;Schulz\|Ansgar\|A\|;Ewins\|Anna-Maria\|AM\|;Gibson\|Brenda\|B\|;Sedlacek\|Petr\|P\|;Krol\|Ladislav\|L\|;Strahm\|Brigitte\|B\|;Zaidman\|Irina\|I\|;Kalwak\|Krzysztof\|K\|;Talano\|Julie-An\|JA\|;Woolfrey\|Ann\|A\|;Fraser\|Chris\|C\|;Meyts\|Isabelle\|I\|;Müller\|Ingo\|I\|;Wachowiak\|Jacek\|J\|;Bernardo\|Maria Ester\|ME\|;Veys\|Paul\|P\|;Sykora\|Karl-Walter\|KW\|;Gennery\|Andrew R\|AR\|;Slatter\|Mary\|M\|", "chemical_list": "C018404:treosulfan; D002066:Busulfan", "country": "United States", "delete": false, "doi": "10.1182/blood-2016-03-704015", "fulltext": null, "fulltext_license": null, "issn_linking": "0006-4971", "issue": "128(3)", "journal": "Blood", "keywords": null, "medline_ta": "Blood", "mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D064591:Allografts; D001792:Blood Platelets; D002066:Busulfan; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006085:Graft Survival; D006086:Graft vs Host Disease; D006105:Granulomatous Disease, Chronic; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D009504:Neutrophils; D015996:Survival Rate; D019172:Transplantation Conditioning", "nlm_unique_id": "7603509", "other_id": null, "pages": "440-8", "pmc": null, "pmid": "27216217", "pubdate": "2016-07-21", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't", "references": "18503990;25614174;19866337;15367433;24747172;22390490;20493396;25175046;21195301;25537876;25196857;11259721;24161820;25231927;18410635;12393596;25264161;21325599;23637873;19222467;26259076;26644451;23011479;23870668;25974284", "title": "Treosulfan-based conditioning for allogeneic HSCT in children with chronic granulomatous disease: a multicenter experience.", "title_normalized": "treosulfan based conditioning for allogeneic hsct in children with chronic granulomatous disease a multicenter experience" }	[ { "companynumb": "GB-MYLANLABS-2016M1039958", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "FLUDARABINE PHOSPHATE" }, "drugadditional": "...
{ "abstract": "Opsoclonus-myoclonus syndrome (OMS) may be associated with ANNA-1 (anti-Hu) autoantibodies. The standard treatment with IVIG, steroids, and anti-CD20 monoclonal antibody may fail, and optimal therapy is unknown. A patient developed OMS with high-titer ANNA-1 following recovery from neuroblastoma. She failed standard therapy and had only transient response to rituximab. Treatment with the humanized anti-CD20 monoclonal antibody ofatumumab combined with methotrexate resulted in transient neurologic improvement and decrease of ANNA-1. This suggests that ofatumumab combined with methotrexate should further be considered OMS patients, particularly in refractory disease.", "affiliations": "Department of Internal Medicine and Pediatrics, University of Minnesota, Minneapolis, Minnesota.", "authors": "Ketterl\|Tyler G\|TG\|;Messinger\|Yoav H\|YH\|;Niess\|Dawn R\|DR\|;Gilles\|Elizabeth\|E\|;Engel\|William Keith\|WK\|;Perkins\|Joanna L\|JL\|", "chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001323:Autoantibodies; D001324:Autoantigens; D051959:ELAV Proteins; C527517:ofatumumab; D008727:Methotrexate", "country": "United States", "delete": false, "doi": "10.1002/pbc.24646", "fulltext": null, "fulltext_license": null, "issn_linking": "1545-5009", "issue": "60(12)", "journal": "Pediatric blood & cancer", "keywords": "neuroblastoma; ofatumumab; opsoclonus-myoclonus syndrome; rituximab", "medline_ta": "Pediatr Blood Cancer", "mesh_terms": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001323:Autoantibodies; D001324:Autoantigens; D051959:ELAV Proteins; D005260:Female; D006801:Humans; D007223:Infant; D008479:Mediastinal Neoplasms; D008727:Methotrexate; D009447:Neuroblastoma; D053578:Opsoclonus-Myoclonus Syndrome", "nlm_unique_id": "101186624", "other_id": null, "pages": "E163-5", "pmc": null, "pmid": "23813921", "pubdate": "2013-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Ofatumumab for refractory opsoclonus-myoclonus syndrome following treatment of neuroblastoma.", "title_normalized": "ofatumumab for refractory opsoclonus myoclonus syndrome following treatment of neuroblastoma" }	[ { "companynumb": "US-GLAXOSMITHKLINE-B1023437A", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "CYCLOPHOSPHAMIDE" }, "drugadditional": nul...
{ "abstract": "A 51-year-old male patient presented to the emergency room with an anterior ST-elevation myocardial infarction. After a loading dose of both ticagrelor and aspirin, the patient underwent primary-PCI on the left anterior descending coronary artery with stent implantation. After successful revascularization, medical therapy included beta-blockers, statins, and angiotensin II receptor antagonists. Two days later, ivabradine was also administered in order to reduce heart rate at target, but the patient developed a severe symptomatic bradycardia and sinus arrest, even requiring administration of both atropine and adrenaline. Ivabradine and ticagrelor have been then suspended and this latter changed with prasugrel. Any other similar event was not reported during the following days. This clinical case raised concerns about the safety of the combination of beta-blockers and ivabradine in patients treated with ticagrelor, particularly during the acute phase of an acute coronary syndrome. These two latter drugs, in particular, might interact with the same receptor. In fact, ivabradine directly modulates the If-channel which is also modulated by the cyclic adenosine monophosphate levels. These latter have been shown to increase after ticagrelor assumption via inhibition of adenosine uptake by erythrocytes. Further studies are warrant to better clarify the safety of this association.", "affiliations": "Division of Cardiology, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy ; Division of Cardiology, P.O. Di Venere, Via Ospedale di Venere, No. 1, 70131 Bari, Italy.;Division of Cardiology, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy.;Division of Cardiology, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy.;Division of Cardiology, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy.;Division of Cardiology, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy.;Division of Cardiology, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy.", "authors": "Di Serafino\|Luigi\|L\|;Rotolo\|Francesco Luigi\|FL\|;Boggi\|Augusto\|A\|;Colantonio\|Riccardo\|R\|;Serdoz\|Roberto\|R\|;Monti\|Francesco\|F\|", "chemical_list": null, "country": "United States", "delete": false, "doi": "10.1155/2014/932595", "fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi Publishing Corporation 10.1155/2014/932595Case ReportPotential Additive Effects of Ticagrelor, Ivabradine, and Carvedilol on Sinus Node Di Serafino Luigi \n1\n\n2\nRotolo Francesco Luigi \n1\nBoggi Augusto \n1\nColantonio Riccardo \n1\nSerdoz Roberto \n1\nMonti Francesco \n1\n1Division of Cardiology, Ospedale San Pietro Fatebenefratelli, 00189 Rome, Italy2Division of Cardiology, P.O. Di Venere, Via Ospedale di Venere, No. 1, 70131 Bari, ItalyLuigi Di Serafino: luigidiserafino@msn.comAcademic Editor: Antonio de Padua Mansur\n\n2014 29 9 2014 2014 93259522 7 2014 9 9 2014 Copyright © 2014 Luigi Di Serafino et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 51-year-old male patient presented to the emergency room with an anterior ST-elevation myocardial infarction. After a loading dose of both ticagrelor and aspirin, the patient underwent primary-PCI on the left anterior descending coronary artery with stent implantation. After successful revascularization, medical therapy included beta-blockers, statins, and angiotensin II receptor antagonists. Two days later, ivabradine was also administered in order to reduce heart rate at target, but the patient developed a severe symptomatic bradycardia and sinus arrest, even requiring administration of both atropine and adrenaline. Ivabradine and ticagrelor have been then suspended and this latter changed with prasugrel. Any other similar event was not reported during the following days. This clinical case raised concerns about the safety of the combination of beta-blockers and ivabradine in patients treated with ticagrelor, particularly during the acute phase of an acute coronary syndrome. These two latter drugs, in particular, might interact with the same receptor. In fact, ivabradine directly modulates the If-channel which is also modulated by the cyclic adenosine monophosphate levels. These latter have been shown to increase after ticagrelor assumption via inhibition of adenosine uptake by erythrocytes. Further studies are warrant to better clarify the safety of this association.\n==== Body\n1. Background\nCoronary artery disease (CAD) is the leading cause of death worldwide. Acute coronary syndromes (ACS) are responsible for a large number of cardiac-related hospital admissions. Nowadays, mortality and morbidity of patients presenting with ACS have improved as a result of the cumulative effect of multiple interventions. The management of ACS in fact has been revolutionized by contemporary therapies and strategies of care. Although coronary interventions play a critical role, medical therapy continues to retain a central place and recently several newer agents have been proposed. The purpose of this clinical case is to describe the unexpected potential additive effect of the combination of currently used drugs in the management of patients presenting with ACS.\n\n2. Case Presentation\nA 51-year-old male patient, with a history of hypertension and hyperlipidemia, presented to the emergency department with an anterior ST-elevation myocardial infarction (Figure 1(a)). A loading dose of both ticagrelor (180 mg) and aspirin (ASA, 250 mg i.v.) was administered and the patient sent to the cath-lab for primary percutaneous coronary intervention (PCI) on the left anterior descending coronary artery (Figures 1(b)-1(c)). After revascularization, medical therapy included beta-blockers (carvedilol 6.25 mg b.i.d.), statins (atorvastatin 80 mg), and angiotensin II receptor antagonists (telmisartan 80 mg). Dual antiplatelet therapy was continued with ticagrelor (90 mg b.i.d.) and ASA (100 mg). At the echocardiography, performed the day after the revascularization, the ejection fraction was critically reduced (EF: 25%) with akinesia of the anteroseptal wall. Titration of carvedilol was performed during the following two days without significantly reducing the heart rate at target (90 bpm with 12.5 mg carvedilol b.i.d.). Ivabradine was then administered at 5 mg b.i.d. Few hours after the first dose, the patient presented with severe symptomatic bradycardia (Figure 1(d)) and sinus arrest. Atropine and adrenaline i.v. were administered and both ivabradine and ticagrelor suspended and this latter changed with prasugrel. Any other similar event was not reported during the following days and the national competent authority was finally informed.\n\n3. Discussion\nHigh heart rate is an independent predictor of all-cause and cardiovascular mortality in coronary artery disease (CAD) patients [1]. Ivabradine, by inhibiting the sinus node “funny-current” (If), reduces heart rate without significantly affecting myocardial contractility. Normally, in cardiac pacemaker cells, If-channel is dually modulated by voltage and cyclic adenosine monophosphate (cAMP). This latter directly binds to If-channels increasing their open probability (Figure 2(a)) [2]. The safety and efficacy of ivabradine in patients with CAD have been demonstrated in several trials, and the combination with beta-blockers has also been shown to improve clinical outcome in a subset of patients [3]. However, there are no large data examining the use of ivabradine in the acute coronary syndromes and the RIVIERA study is currently expected to recruit more than 1200 patients with non-ST elevation myocardial infarction [4].\n\nIn this setting, platelet activation and subsequent aggregation play a dominant role and consequently they represent the key therapeutic targets in the management of ACS. Prasugrel and ticagrelor are currently the preferred ADP-receptor blockers since it has been shown in large trials that these drugs have higher efficacy as compared with clopidogrel [5]. In particular, in the platelet inhibition and patient outcomes (PLATO) trial, ticagrelor reduced both the composite primary endpoint (cardiovascular death, non-fatal MI, or stroke) and the cardiovascular mortality in patients with ACS [5]. However, ticagrelor may cause transient dyspnea at the onset of therapy and may also be associated with asymptomatic bradycardia in the first week of therapy [6]. Multiple hypotheses have been raised concerning the mechanism by which ticagrelor precipitates bradyarrhythmias. The first potential mechanism is that P2Y12 inhibition may directly affect cardiac conduction, but the off-target effects of ticagrelor are most likely related to the occurrence of bradyarrhythmic events. Ticagrelor, in fact, has been shown to increase adenosine concentration via inhibition of adenosine uptake by erythrocytes, probably through the inhibition of the sodium-independent equilibrative nucleoside transporters [6]. The effect of adenosine on the heart rate is well known. This is based on a direct and indirect activation of cardiac adenosine receptor 1 (A1ARs). Direct A1AR signaling effects are mediated by the activation of a potassium current through an inward rectifier potassium channel (IKAdo) which leads to the hyperpolarization of the sinus node cells as well as cells of the atrioventricular node (AV node) [7–9]. Indirect effects of adenosine signaling on the heart rate may involve the ability of the A1AR of lowering intracellular cAMP levels (Figure 2(b)), thereby limiting the activation of the If-channel [10]. Nevertheless, bradyarrhythmic events associated with ticagrelor have been reported as occurring most frequently in the acute phase of the ACS without any clinical consequence. By the way, the combination of ticagrelor and ivabradine has not been directly investigated and their association with beta-blockers might potentially result in clinically significant bradyarrhythmic events.\n\nIn our case, it is possible that the direct effect of ivabradine on If-channels has been unintentionally enhanced by the off-target effects of ticagrelor.\n\n4. Conclusions\nThe above presented clinical case raised concerns about the safety of the combination of ivabradine and beta-blockers in patients treated with ticagrelor, particularly during the acute phase of an acute coronary syndrome. Further studies are warrant to better clarify the safety of this association.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publishing of this paper.\n\nFigure 1 Figure 2\n==== Refs\n1 Diaz A Bourassa MG Guertin M-C Tardif J-C Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease European Heart Journal 2005 26 10 967 974 2-s2.0-18844368814 15774493 \n2 DiFrancesco D Tortora P Direct activation of cardiac pacemaker channels by intracellular cyclic AMP Nature 1991 351 6322 145 147 2-s2.0-0025782740 1709448 \n3 Fox K Ford I Steg PG Tendera M Ferrari R Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial The Lancet 2008 372 9641 807 816 2-s2.0-50649109186 \n4 Dominguez-Rodriguez A Fard SS Abreu-Gonzalez P Randomised, double-blind, placebo-controlled trial of ivabradine in patients with acute coronary syndrome: effects of the I(f) current inhibitor ivabradine on reduction of inflammation markers in patients with acute coronary syndrome—riviera trial study design and rationale Cardiovascular Drugs and Therapy 2009 23 3 243 247 2-s2.0-67649090226 19229603 \n5 Wallentin L Becker RC Budaj A Ticagrelor versus clopidogrel in patients with acute coronary syndromes The New England Journal of Medicine 2009 361 11 1045 1057 2-s2.0-70149101223 19717846 \n6 Cannon CP Husted S Harrington RA Safety, tolerability, and initial efficacy of AZD6140, the first reversible oral adenosine diphosphate receptor antagonist, compared with clopidogrel, in patients with non-st-segment elevation acute coronary syndrome: primary results of the DISPERSE-2 trial Journal of the American College of Cardiology 2007 50 19 1844 1851 2-s2.0-35548995394 17980250 \n7 West GA Belardinelli L Correlation of sinus slowing and hyperpolarization caused by adenosine in sinus node Pflugers Archiv European Journal of Physiology 1985 403 1 75 81 2-s2.0-0021985508 3982962 \n8 Belardinelli L Shryock JC Song Y Wang D Srinivas M Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes The FASEB Journal 1995 9 5 359 365 2-s2.0-0028910425 7896004 \n9 Belardinelli L Giles WR West A Ionic mechanisms of adenosine actions in pacemaker cells from rabbit heart The Journal of Physiology 1988 405 615 633 2-s2.0-0023780277 2855644 \n10 Olsson RA Pearson JD Cardiovascular purinoceptors Physiological Reviews 1990 70 3 761 845 2-s2.0-0025326815 2194223\n\n", "fulltext_license": "CC BY", "issn_linking": "2090-6404", "issue": "2014()", "journal": "Case reports in cardiology", "keywords": null, "medline_ta": "Case Rep Cardiol", "mesh_terms": null, "nlm_unique_id": "101576452", "other_id": null, "pages": "932595", "pmc": null, "pmid": "25328715", "pubdate": "2014", "publication_types": "D016428:Journal Article", "references": "7896004;2855644;1709448;17980250;2194223;18757088;3982962;19717846;15774493;19229603", "title": "Potential additive effects of ticagrelor, ivabradine, and carvedilol on sinus node.", "title_normalized": "potential additive effects of ticagrelor ivabradine and carvedilol on sinus node" }	[ { "companynumb": "PHHY2014IT164129", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "TICAGRELOR" }, "drugadditional": null, "drug...
{ "abstract": "BACKGROUND\nPituitary tumor apoplexy (PTA) is a rare clinical syndrome which requires urgent diagnosis and treatment due to its life-threatening consequences. Management of undiagnosed pituitary tumor before pregnancy is a problem during pregnancy.\nWe reported a case with PTA which was not diagnosed before pregnancy presenting with vomiting associated with hyponatremia during the third trimester. After supplying the sodium the patient presented with dysarthria and hemiplegia.\nMRI examination showed PTA accompanied with extrapontine myelinolysis (EPM).\n\n\nMETHODS\nThe patient was given hydrocortisone according to the symptoms gradually to taper off dose, at the same times oral levothyroxine therapy (25μg/day) was given.\n\n\nRESULTS\nThe patient delivered a healthy baby via cesarean section at hospital at 38 + 1 week of gestation. We performed MRI examination regularly and the tumor regressed significantly 8 months postpartum.\n\n\nCONCLUSIONS\nWe reported a case as PTA associated with EPM. Headache during pregnancy is often nonspecific, so careful medical history inquiry is very important.", "affiliations": "Department of Obstetrics and Gynecology.;Department of Radiology.;Department of Obstetrics and Gynecology.;Department of Obstetrics and Gynecology.;Department of neurology.;Department of endocrinology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu, China.;Department of Obstetrics and Gynecology.;Department of Radiology.", "authors": "Ye\|Wenfeng\|W\|;Huang\|Wenjie\|W\|;Chen\|Linlin\|L\|;Yao\|Changfang\|C\|;Sheng\|Shiying\|S\|;Liu\|Zhengyu\|Z\|;Xue\|Chunyan\|C\|;Xing\|Wei\|W\|0000-0003-2140-2685", "chemical_list": "D012964:Sodium; D013974:Thyroxine; D006854:Hydrocortisone", "country": "United States", "delete": false, "doi": "10.1097/MD.0000000000025075", "fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\nMD-D-20-12096\n10.1097/MD.0000000000025075\n25075\n5600\nResearch Article\nClinical Case Report\nPituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy\nA case report\nYe Wenfeng MD a\nHuang Wenjie MD b\nChen Linlin MD a\nYao Changfang MD a\nSheng Shiying MD c\nLiu Zhengyu MD d\nXue Chunyan MD a\nhttp://orcid.org/0000-0003-2140-2685\nXing Wei MD, PhD b∗\nSaranathan. Maya\na Department of Obstetrics and Gynecology\nb Department of Radiology\nc Department of neurology\nd Department of endocrinology, The Third Affiliated Hospital, Soochow University, Changzhou, Jiangsu, China.\n∗ Correspondence: Wei Xing, Department of Radiology, The Third Affiliated Hospital of Soochow University, Changzhou 213003, Jiangsu, China (e-mail: suzhxingwei@126.com).\n12 3 2021\n12 3 2021\n100 10 e2507514 12 2020\n12 2 2021\n15 2 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nThis is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0\n\nAbstract\n\nRationale:\n\nPituitary tumor apoplexy (PTA) is a rare clinical syndrome which requires urgent diagnosis and treatment due to its life-threatening consequences. Management of undiagnosed pituitary tumor before pregnancy is a problem during pregnancy.\n\nPatient concerns:\n\nWe reported a case with PTA which was not diagnosed before pregnancy presenting with vomiting associated with hyponatremia during the third trimester. After supplying the sodium the patient presented with dysarthria and hemiplegia.\n\nDiagnoses:\n\nMRI examination showed PTA accompanied with extrapontine myelinolysis (EPM).\n\nInterventions:\n\nThe patient was given hydrocortisone according to the symptoms gradually to taper off dose, at the same times oral levothyroxine therapy (25μg/day) was given.\n\nOutcomes:\n\nThe patient delivered a healthy baby via cesarean section at hospital at 38 + 1 week of gestation. We performed MRI examination regularly and the tumor regressed significantly 8 months postpartum.\n\nLessons:\n\nWe reported a case as PTA associated with EPM. Headache during pregnancy is often nonspecific, so careful medical history inquiry is very important.\n\nKeywords\n\nextrapontine myelinolysis\nhyponatremia\npituitary tumor apoplexy\npregnancy\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nPituitary tumor apoplexy (PTA) is a rare clinical syndrome with an estimated prevalence of 6.2 cases per 100,000 persons, which requires urgent diagnosis and treatment due to its life-threatening consequences.[1] Management of undiagnosed pituitary tumors before pregnancy is a problem during pregnancy and faces some safety issues including potential tumor growth and apoplexy which are very low and will be confronted with a major concern by the clinical doctors.[2] Pregnancy is one of the risk factors for pituitary apoplexy (PA) because the enlarged size of the pituitary gland, increased blood flow in the gland and increased hormones which stimulate the gland and pituitary tumor.[3,4] The PA occurrence rate during pregnancy is rare so that the diagnosis and treatment is sometimes neglected or delayed.\n\nPTA is characterized by some acute clinical syndrome including headache, nausea, vomiting, visual abnormity, and/or decreased consciousness because of the result of a pituitary tumor infarction or hemorrhage.[5] Nausea and vomiting, as one of the most common symptoms of PTA, is very common during pregnancy and it does not get much attention from the patients and clinicians. Vomiting could cause pregnant women to develop severe electrolyte disorders, among which hypokalemia and hyponatremia occur most frequently. Hyponatremia refers to the serum sodium concentration less than 135 mmol/L, which is one of the most common kinds of water and salt imbalance in clinical practice, accounting for most of hospitalized patients. Hyponatremia can increase the complexity of symptoms and lead to misdiagnosis by the clinicians. There are different treatment principles about of hyponatremia of different degree, and inappropriate treatment such as rapid correction of hyponatraemia in patients may cause demyelination disease of nerve permeability.[6,7] Central pontine myelinolysis (CPM) and extrapontine myelinolysis (EMP) belong to osmotic demyelination syndrome (ODS) which can be caused in the treatment of hyponatremia associated with poor prognosis.[8] The patients with ODS present differently, including acute paralysis, dysarthria and dysphagia.\n\nWe report a case with PTA who was not diagnosed before pregnancy presenting with vomiting associated with hyponatremia during the third trimester. After supplying the sodium the patient presented with dysarthria and hemiplegia, MRI examination showed PTA accompanied with EPM and the patient was managed conservatively with a successful outcome. We performed MRI examination regularly and the tumor regressed significantly 8 months postpartum.\n\n2 Case report\n\nA 24-year-old woman with a history of vomiting for 3 days was admitted at emergency ward during the 32th week on December 11th, 2018. She complained that she had a history of low fever without measuring body temperature, no abdominal pain, no diarrhea and other discomfort and she did not take it seriously at first because she thought it was common flue or upper respiratory tract infection. But 1 day before, she began to vomit severely associated with fatigue.\n\nUrgent blood arterial gas analysis for the patient showed that serum sodium concentration as high as 111.6 mmol/L, chlorine as 91.3 mmol/L, plasmatic osmolality as 226 m Osm 226/kg. Blood electrolyte test showed that serum sodium concentration was as 116.7 mmol/L, chlorine concentration as 87.3 mmol/L and potassium as 4.52 mmol/L in emergency ward. The patient was given 3% NaCl 400 ml by intravenous infusion. The next day, blood electrolyte retest showed that serum sodium concentration was 126.0 mmol/L (Table 1), so 3% NaCl 400 ml was given by intravenous infusion in the morning again. The patient developed aphasia and hemiplegia with no movement of the right limb in the afternoon suddenly, so she was admitted to the obstetric department for further treatment.\n\nTable 1 Clinical detailed results of blood biochemistry measurements.\n\nvalue\tDate\tResult (mmol/l)\tnormal range\tAnnotation\t\nOsmolality\t2018-12-11\t226 Osm/kg\t280–310mOsm/kg\t3%Nacl 400 ml was given\t\n\t2018-12-13\t252 Osm/kg\t\t\t\n\t2018-12-13\t280 Osm/kg\t\t\t\nSodium\t2018-12-11\t116.7g mmol/l\t137–147 mmol/l\t3%Nacl 400 ml was given\t\n\t2018-12-12\t126 mmol/l\t\t3%Nacl 400 ml was given\t\n\t2018-12-13\t132.7 mmol/l\t\t\t\n\t2019-01-01\t135.8 mmol/l\t\t\t\n\t2019-01-15\t132.8 mmol/l\t\t\t\nPotassium\t2018-12-11\t4.52 mmol/l\t3.5–5.3 mmol/l\t\t\n\t2018-12-12\t4.67 mmol/l\t\t\t\n\t2018-12-13\t4.49 mmol/l\t\t\t\n\t2019-01-01\t4.4 mmol/l\t\t\t\n\t2019-01-15\t3.6 mmol/l\t\t\t\nChloride\t2018-12-11\t87.3 mmol/l\t98–110 mmol/l\t3%Nacl 400 ml was given\t\n\t2018-12-12\t101.6 mmol/l\t\t3%Nacl 400 ml was given\t\n\t2018-12-13\t107.7 mmol/l\t\t\t\n\t2019-01-01\t105.7 mmol/l\t\t\t\n\t2019-01-15\t105 mmol/l\t\t\t\nFibrinogen\t2018-12-13\t6.76 g/l\t2–4 g/l\tHeparin was given\t\n\t2018-12-15\t3.77 g/l\t\t\t\n\nAfter admission at the obstetric department, she was afebrile with 36.6°C on examination, with a heart rate of 101bpm and blood pressure of 122/77 mm Hg. Physical examination revealed that the patient's right nasolabial groove became shallow and her tongue extended to the right direction. Her visual field detection was normal. She was retarded with aphasia associated with hemiplegia in right arms and legs. Her right upper limb power was grade 0/5, right lower limb power was grade 3/5 and the left limb power was 4/5. Her pain sensitivity was lower in the right than that in the left. All her deep tendon reflexes were positive. Her plantar response was positive in the right. The rest of her physical examination was unremarkable. Obstetrical examinations showed a gravid uterus at around 32 weeks of gestation with normal fetal heart rate.\n\nAn emergency cerebral magnetic resonance imaging (MRI) was performed and a sellar abnormal signal with size about 15 × 14 × 14 mm was revealed, which indicated the PTA. Abnormal signals in corpus callosum, bilateral basal ganglia, and centrum semiovale were seen. There were no obvious abnormalities in magnetic resonance angiography and venography (Fig. 1). Immediate laboratory testing revealed as follow: PH 7.31, blood oxygen saturation 98.8%, CO2 partial pressure 23.10 mm Hg, plasmatic osmolality 252 Osm 226/kg, blood glucose 2.8 mmol/l, lactic acid <1 mmol/L by blood arterial gas analysis. Blood routine showed hemoglobin of 11.5 mg/dl, PLT of 248 × 109/L. Biochemistry test showed Na of 131.6 mmol/L, CO2 of 12.3 mmol/L, BUN of 1.0 mmol/L, creatinine of 45U mol/L, blood amylase of 63μ/L, blood lipase of 119μ/L, fibrinogen of 6.01 g/L (Table 1).\n\nFigure 1 Brain Magnetic resonance imaging of the patient. (A) sagittal T1-weighted images shows a sellar and suprasellar high signal with the size of 15mm × 14mm × 14 mm, in which stratification was demonstrated, (B) coronal FLAIR images shows the high signal appeared as an hourglass, (C) axial T2-weighted images shows hyperintensity in bilateral basal ganglia region and corpus callosum, (D) (E) axial DWI images shows hyperintensity in corpus callosum and bilateral centrum semiovale (picture A–E, during 32 + 1 gestational week on December 12th,2018), (F) (G) shows the size of sellar and suprasellar high signal is reduced to 13mm × 12mm × 13 mm, compared with the previous examination (picture 1, 2),(H) shows the lesion in corpus callosum was slightly smaller, compared with picture 3,(I) (J) the signal of the lesion in corpus callosum and bilateral centrum semiovale was weaker, compared with picture 4, 5 (picture F–J, on December 20th,2018), (K)(L)shows the size of sellar and suprasellar high signal was reduced to 10mm × 11mm × 12 mm, (M)shows the abnormally high signal in bilateral basal ganglia region basically disappeared (picture K–M, on January 18th,2019), (N)(O)(P)shows the size of sellar and suprasellar high signal was further reduced to 8mm × 5mm × 9mm (on April 27th,2019),(Q)(R)contrast enhanced images shows the pituitary gland was almost normal in size, with homogeneous enhancement after enhancement, and pituitary stem was slightly shifted to the left, (S) coronal T2-weighed images shows the pituitary gland appeared as heterogeneous signal (on September 24th,2019).\n\nFurther hormonal examination results after admission were as follows: plasma prolactin (PRL) level of 104.71 ng/ml (3.34–26.72 ng/ml), TSH level of 1.49 mIU/ml (0.3–5.5 mIU/ml), fT4 level of 11.26 pmol/L (11.46–23.17 pmol/L), fT3 level of 3.25 pmol/L (2.8–7.1 pmol/L), ACTH level (8AM) of 9.53 pg/ml (6–40 pg/ml), ACTH level (4PM) of 7.12 pg/ml (3–30 pg/ml), and cortisol level (8AM):15.46 μg/dl (6.7–22.8), cortisol level (4PM) of >61.4 μg/dl (0–10 μg/dl), growth hormone of 0.65 ng/ml (0.06–5ng/ml) (Table 2). High cortisol level of 4PM was associated with hydrocortisone taking.\n\nTable 2 Clinical detailed results of hormonal measurements.\n\nvalue\tDate\tResult (mmol/l)\tnormal range\tAnnotation\t\nTSH\t2018-12-13\t1.49 UIU/ml\t0.3–5.5 UIU/ml\t2019-01-23 delivery\t\n\t2018-12-18\t3.03 UIU/ml\t\t\t\n\t2019-01-08\t3.67 UIU/ml\t\t\t\n\t2019-01-25\t6.97 UIU/ml\t\t\t\n\t2019-02-13\t1.39 UIU/ml\t\t\t\n\t2019-09-18\t4.06 UIU/ml\t\t\t\n\t2019-11-17\t2.88 UIU/ml\t\t\t\nFT4\t2018-12-13\t11.26 pmol/l\t11.46–23.17pmol/l\t\t\n\t2018-12-18\t11.68 pmol/l\t\t\t\n\t2019-01-08\t12.5pmol/l\t\t\t\n\t2019-01-25\t13.09 pmol/l\t\t\t\n\t2019-02-13\t14.99 pmol/l\t\t\t\n\t2019-09-18\t11.7 pmol/l\t12–22 pmol/l\t\t\n\t2019-11-17\t11.57 pmol/l\t\t\t\nFT3\t2018-12-13\t3.25 pmol/l\t2.8–7.1pmol/l\t\t\n\t2018-12-18\t3.11 pmol/l\t\t\t\n\t2019-01-08\t3.27 pmol/l\t\t\t\n\t2019-01-25\t3.03 pmol/l\t\t\t\n\t2019-02-13\t4.6 pmol/l\t\t\t\n\t2019-09-18\t4.46 pmol/l\t3.1–6.8pmol/l\t\t\n\t2019-11-17\t4.22 pmol/l\t\t\t\nCortisol\t2018-12-14\t8AM:15.46μg/dl\t6.7–22.8 μg/dl\tCortisol 4PM (2018-12-14) after hydrocortisone using\t\n\t2018-12-14\t4PM:>61.4μg/dl\t0–10 μg/dl\t\t\n\t2019-01-25\t8AM:8.87μg/dl\t6.7–22.8 μg/dl\t\t\n\t2019-01-25\t4PM:5.58μg/dl\t0-10 μg/dl\t\t\n\t2019-09-18\t8AM:7.37μg/dl\t6.7–22.8 μg/dl\t\t\n\t2019-09-18\t4PM:2.2μg/dl\t0–10 μg/dl\t\t\nACTH\t2018-12-14\t8AM:9.53 pg/ml\t6–40 pg/ml\t\t\n\t2018-12-14\t4PM:7.12 pg/ml\t3–30 pg/ml\t\t\n\t2019-01-26\t8AM:16.6 pg/ml\t6–40 pg/ml\t\t\n\t2019-01-26\t4PM:7.36 pg/ml\t3–30 pg/ml\t\t\n\t2019-09-18\t8AM:19.95pg/ml\t6–40 pg/ml\t\t\n\t2019-09-18\t4PM:11.66pg/ml\t3–30 pg/ml\t\t\nProlactin\t2018-12-13\t104.71 ng/ml\t3.34–26.72 ng/ml\tPostpartum no breastfeeding\t\n\t2018-12-18\t108.40 ng/ml\t\t\t\n\t2019-01-25\t110.55 ng/ml\t\t\t\n\t2019-02-13\t59.06 ng/ml\t\t\t\n\t2019-07-19\t50.76 ng/ml\t\t\t\n\t2019-09-18\t48.80 ng/ml\t\t\t\n\t2020-01-17\t44.59 ng/ml\t\t\t\nGrowth hormone\t2018-12-13\t0.65 ng/ml\t0.06–5 ng/ml\t\t\n\t2019-02-13\t0.06 ng/ml\t\t\t\n\t2019-09-18\t0.87 ng/ml\t\t\t\nInsulin-like growth factor\t2019-02-13\t195.5 ng/ml\t60–350 ng/ml\t\t\n\t2019-09-18\t176 ng/ml\t\t\t\n\nA multidisciplinary team was organized including neurology, neurosurgery, endocrinology, ICU and obstetric department. PA with pituitary insufficiency were considered which caused hyponatremia and sodium supplied rapidly for EPM induction with hemiplegia and aphasia. The patient was given hydrocortisone according to the symptoms gradually to taper off dose, at the same times oral levothyroxine therapy (25μg/day) was given. The symptoms improved after 2 days and the patient could speak and recovered the movement of limbs. Her medical history was got which included that she had been irregular menstruation from the menarche at 14-year-old. In 2 years before pregnancy (August 23, 2016) she had taken hormone test and results were nearly normal. After that she had not gone to the hospital until she was pregnancy. She complained severe headache for the entire pregnancy and got the drug for painkiller at the early pregnancy. After taking medications, her symptoms did not improve and because of worrying about the outcomes of drugs on fetal, so she stopped the drug. After using hydrocortisone and levothyroxine, the symptoms including headache and vomiting disappear, MRI after 8 days at admission showed that abnormal signal in the splenium of the corpus callosum, bilateral basal ganglia, and centrum semiovale were weaker significantly. She delivered a healthy baby via cesarean section at hospital at 38 + 1 week of gestation (January 23, 2019). The baby birth weight was 2850 grams. The Apgar score was 9’ and 9’at first and fifth minutes, respectively. The blood volume during operation was 1000 ml. The patient did not have breastfeeding after delivery.\n\nPostpartum, the patient did not have headache and vomiting except her irregular menstruation. The pituitary tumor was significantly regressive by MRI (Fig. 1). Meanwhile the blood hormone examination showed that PRL was decreased gradually of 44.59ng/ml (January 17, 2020). Thyroid function tests, serum cortisol, ACTH, growth hormone, and IGF-1 level showed normally. This study was approved by the Ethics Committee of Soochow University. The patient agreed to authorize us to share the figures and the experiences during the treatment procedure in our department. Informed consent was obtained.\n\n3 Discuss\n\nGestational pituitary tumor apoplexy is a rare disease. Considering the situation of lack of consensus, it is difficult to manage the PA cases. So, every patient should be assessed and managed carefully. Especially for some cases with pituitary tumor which was not found before pregnancy it is difficult for timely treatment.\n\n4 Clinical signs and diagnosis\n\nPA occurs in patients which are asymptomatic previously in 60% to 80% of cases.[9] The main symptoms of PTA include headache, nausea, visual impairment among which headache occurs in 95% of cases and vomiting in 69% of that.[10,11] Due to the atypical symptoms, misdiagnosis is often caused and serious clinical complications are resulted in.[12]\n\nBefore pregnancy most of the patients with pituitary tumor have the history of irregular menstruation because of the elevated sexual hormones such as prolactin. Headache is one of the most common symptoms of PTA during pregnancy. Our patient complained of headache, but there was no effect after taking painkiller drugs. This symptom provided us with certain signals, but the clinician did not pay enough attention to it, because headache is common during pregnancy, associated with emotion such as stress, lack of sleep, depression, and malnutrition. In addition pregnant women themselves often fear that drugs for painkiller might affect the fetus, so simple headaches are not taken seriously.[13] Vomiting is one of the symptoms of PTA during pregnancy. The case complained of vomiting for 3 days, but emergency department only routinely conducted blood electrolyte examination, and immediately gave a large amount of sodium supplement treatment after the discovery of hyponatremia. Only the patient had symptoms with aphasia and hemiplegia on the next day, the attention was aroused by the clinicians. Similarly there are many reasons for simple vomiting during pregnancy and clinicians often pay more attention to electrolyte disorders than the reason of hyperemesis. The symptoms including headache and vomiting are caused by the increased intracranial pressure due to PTA and meningeal irritation.[9,10]\n\nMRI examination is necessary for the diagnosis of PA and EPM. The precise mechanism underlying EPM and CPM remains elusive. It involves a patient with hyponatremia, in whom compensatory cellular expansion offsets the reduced plasma osmotic pressure. Thereafter, any rapid change in osmosis in the opposite direction, usually caused by hypertonic fluid, causes the swollen cells to shrink, leading to osmotic demyelination. The mechanism of cellular expansion relies upon the generation of osmoses such as taurine, glycine, glutamine, sorbitol, and inositol.[14] Our patient was given the rapid sodium treatment to correct hyponatremia which resulted in transient hemiplegia and aphasia. MRI examination may reveal abnormal signal, which could be considered the acute cerebral infarction if not combined with clinical history or lack of understanding of EMP and may lead to misdiagnosis of clinical doctors.\n\nTraditional CPM was thought as pathological features about pons base symmetrical demyelination of nerve fibers, later it was found that outside parts of the pons also could appear the same change, known as the EPM. Generally, both of them have a history of rapid correction of hyponatremia. EPM without CPM was rare, which could result in misdiagnosis. The hallmark of EPM has the striking T2 signal abnormalities with lesions most commonly occurrence in the cerebellum, the lateral geniculate body, the external and extreme capsule, basal ganglia, thalamus, gray-white junction of the cerebral cortex, and the hippocampi.[15] Although rare, lesions have been described in the spinal cord, amygdala, anterior commissure, optic tracts, and the subthalamic nuclei.[6,8]\n\n5 Treatment\n\nManagement of PA has 2 choices: surgery and conservative medication. When pregnancy is confirmed, most of the women with pre-existing pituitary tumor choose to stop dopamine agonist generally,[16] although the knowledge about pregnancy outcomes for women who have become pregnant while taking bromocriptine or cabergoline is widening. Large adenoma size, pregnancy, and cessation of cabergoline could lead to PA. There are no clear guidelines for the management of PA during pregnancy. In the case of prolactioma and non-stroke symptomatic tumor growth, most of them are recommended reactivating dopamine agonist as first-line therapy, as this is generally considered to be less risky to the mother and fetus than surgical intervention. Half of the patients were treated conservatively with pituitary hormone replacement therapy when necessary, few cases were treated with dopamine agonists.[17,18]\n\nThere are no randomized controlled trials comparing the effects of surgical and conservative treatment in pregnant women with PA. However, surgery seems appropriate for patients who fail to respond to conservative treatment or cannot tolerate dopamine agonists.[16] Neurosurgical intervention should be considered in cases with persistent visual field defects or deteriorating level of consciousness. If operation, it is emphasized that surgical excision should be performed by experienced neurosurgeons, not by on-call surgeons.\n\nThe main conservative treatment with PTA during pregnancy is to provide fluid and electrolyte balance and high dose glucocorticoid for emergency condition. Glucocorticoid is the most commonly used hormonal drug. In addition, if combined with thyroid insufficiency and adrenal insufficiency, it can be supplemented according to the examination results and clinical symptoms. About the CPM and EPM caused by fast natrium replenishment, sodium supplementation must be controlled. After the treatment, the symptoms of aphasia and hemiplegia of this case were rapidly improved and the effect of conservative treatment was obvious. Hypopituitarism is an important complication of apoplexy including hypothyroidism, hypoadrenalism and hyperprolactinaemia and may be missed if not carefully investigated.[5] Therefore, clinicians must pay attention to the occurrence of hypophysis dysfunction and give related hormone therapy in time.\n\n6 Prognosis\n\nThe risk of pituitary tumor development will increase during pregnancy. The prognosis of PA during pregnancy depends on the timely diagnosis and clinical management. In general, early symptoms such as headache and vomiting should be pay attention. Careful medical history inquiry by the clinician, timely physical examination, MRI application and hormone replacement therapy as soon as possible can significantly improve the therapeutic effect.\n\n7 Conclusion\n\nIn general, in the case of pregnancy, the diagnosis of PTA can be challenging and confused with other complex situations, such as preeclampsia. MRI is one of the most sensitive examination, revealing to confirm diagnosis of PTA and/or necrosis of part of adrenocorticotropic hormone deficiency and adrenal insufficiency. If not treated, it is a potentially life-threatening disease for both mother and fetus. Headache during pregnancy is often nonspecific, so it is easy to be omitted by clinicians. Therefore, careful medical history inquiry is very important. The patients need to be re-evaluated if chronic headaches do not ease. A multidisciplinary team consisting of neurology, neurosurgery, endocrinology, ICU, and obstetric department is important in deciding the optimal treatment. At the same time, maternal desires should be taking into consideration.\n\nAuthor contributions\n\nConceptualization: Wenfeng Ye, Linlin Chen.\n\nData curation: Shiying Sheng, Zhengyu Liu.\n\nInvestigation: Wenfeng Ye, Linlin Chen, Changfang Yao, Chunyan Xue.\n\nProject administration: Wenfeng Ye, Chunyan Xue, Wei Xing.\n\nSupervision: Wei Xing.\n\nValidation: Changfang Yao, Shiying Sheng, Zhengyu Liu, Chunyan Xue, Wei Xing.\n\nVisualization: Wenjie Huang, Linlin Chen, Changfang Yao, Zhengyu Liu, Wei Xing.\n\nWriting – original draft: Wenfeng Ye, Wenjie Huang.\n\nWriting – review & editing: Wei Xing.\n\nAbbreviations: CPM = central pontine myelinolysis, EPM = extrapontine myelinolysis, MRI = magnetic resonance imaging, ODS = osmotic demyelination syndrome, PA = pituitary apoplex, PTA = pituitary tumor apoplex.\n\nHow to cite this article: Ye W, Huang W, Chen L, Yao C, Sheng S, Liu Z, Xue C, Xing W. Pituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy: a case report. Medicine. 2021;100:10(e25075).\n\nWY and WH contributed equally to this work.\n\nThe authors have no conflicts of interests to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n\n[1] Fernandez A Karavitaki N Wass JAH . Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol 2010;72 :377–82.\n[2] Molitch ME . Prolactinoma in pregnancy [J]. Best practice & research. Clin Endocrinol Metabol 2011;25 :885–96.\n[3] Bi WL Dunn IF Laws ER Jr . Pituitary apoplexy. Endocrine 2015;48 :69–75.25063308\n[4] Giritharan S Gnanalingham K Kearney T . Pituitary apoplexy - bespoke patient management allows good clinical outcome. Clin Endocrinol 2016;85 :415–22.\n[5] Randeva HS Schoebel J Byrne J . Classical pituitary apoplexy: clinical features, management and outcome. Clin Endocrinol 1999;51 :181–8.\n[6] Singh TD Fugate JE Rabinstein AA . Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol 2014;21 :1443–50.25220878\n[7] Abbott R Silber E Felber J . Osmotic demyelination syndrome. BMJ Clin Res Ed 2005;331 :829–30.\n[8] Alleman AM . Osmotic demyelination syndrome: central pontine myelinolysis and extrapontine myelinolysis. Sem Ultrasound CT MR 2014;35 :153–9.\n[9] Nawar RN AbdelMannan D Selman WR . Pituitary tumor apoplexy: a review. J Intens Care Med 2008;23 :75–90.\n[10] Murad-Kejbou S Eggenberger E . Pituitary apoplexy: evaluation, management, and prognosis. Curr Opin Ophthalmol 2009;20 :456–61.19809320\n[11] Bills DC Meyer FB Laws ER Jr . A retrospective analysis of pituitary apoplexy. Neurosurgery 1993;33 :602–9.8232799\n[12] Lambert K Rees K Seed PT . Macroprolactinomas and nonfunctioning pituitary adenomas and pregnancy outcomes. Obstetrics gynecol 2017;129 :185–94.\n[13] Negro A Delaruelle Z Ivanova TA . Headache and pregnancy: a systematic review. J Headache Pain 2017;18 :106–106.29052046\n[14] Lien YH Shapiro JI Chan L . Study of brain electrolytes and organic osmolytes during correction of chronic hyponatremia. Implications for the pathogenesis of central pontine myelinolysis. J Clin Invest 1991;88 :303–9.2056123\n[15] Juergenson I Zappini F Fiaschi A . Teaching neuroimages: neuroradiologic findings in pontine and extrapontine myelinolysis: clue for the pathogenesis. Neurology 2012;78 :e1–2.22201117\n[16] Melmed S Casanueva FF Hoffman AR . Diagnosis and treatment of hyperprolactinemia: an endocrine society clinical practice guideline. J Clin Endocrinol Metabol 2011;96 :273–88.\n[17] Motivala S Gologorsky Y Kostandinov J . Pituitary disorders during pregnancy. Endocrinol Metabol Clin N Am 2011;40 :827–36.\n[18] Molitch ME . Prolactinomas and pregnancy. Clin Endocrinol 2010;73 :147–8.\n\n", "fulltext_license": "CC BY", "issn_linking": "0025-7974", "issue": "100(10)", "journal": "Medicine", "keywords": null, "medline_ta": "Medicine (Baltimore)", "mesh_terms": "D002585:Cesarean Section; D004359:Drug Therapy, Combination; D004401:Dysarthria; D005260:Female; D006261:Headache; D006429:Hemiplegia; D006801:Humans; D006854:Hydrocortisone; D007010:Hyponatremia; D008279:Magnetic Resonance Imaging; D017590:Myelinolysis, Central Pontine; D010899:Pituitary Apoplexy; D010902:Pituitary Gland; D010911:Pituitary Neoplasms; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011263:Pregnancy Trimester, Third; D012964:Sodium; D013974:Thyroxine; D016896:Treatment Outcome; D014839:Vomiting; D055815:Young Adult", "nlm_unique_id": "2985248R", "other_id": null, "pages": "e25075", "pmc": null, "pmid": "33725898", "pubdate": "2021-03-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Pituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy: A case report.", "title_normalized": "pituitary tumor apoplexy associated with extrapontine myelinolysis during pregnancy a case report" }	[ { "companynumb": "CN-B.BRAUN MEDICAL INC.-2110041", "fulfillexpeditecriteria": "1", "occurcountry": "CN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "SODIUM CHLORIDE" }, "drugadditional": ...
{ "abstract": "In pregnant women, magnesium sulfate infusions are a treatment commonly used for preeclampsia and as a tocolytic agent. In this case report, a 33-year-old woman at 26 weeks of gestation received intravenous magnesium sulfate in Ringer's lactate solution and corticosteroids for preterm uterine contractions without preeclampsia. She developed polyuria of more than 18L in 48 hours, with urine chemistries documenting that magnesium sulfate contributed 30% of the solute in this massive isosthenuric diuresis. Therefore, magnesium sulfate should be added to the common solutes, glucose, sodium chloride, urea, and mannitol, as a cause of solute diureses.", "affiliations": "Division of Nephrology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA. Electronic address: rbrown@bidmc.harvard.edu.", "authors": "Brown\|Robert S\|RS\|", "chemical_list": "D007552:Isotonic Solutions; D000077325:Ringer's Lactate; D008278:Magnesium Sulfate; D001623:Betamethasone", "country": "United States", "delete": false, "doi": "10.1053/j.ajkd.2016.09.028", "fulltext": null, "fulltext_license": null, "issn_linking": "0272-6386", "issue": "69(4)", "journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation", "keywords": "Solute diuresis; case report; magnesium sulfate; polyuria; pregnancy; preterm labor; tocolytic agent; urine chemistry; urine output", "medline_ta": "Am J Kidney Dis", "mesh_terms": "D000328:Adult; D001623:Betamethasone; D004231:Diuresis; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D007273:Injections, Intramuscular; D007552:Isotonic Solutions; D008278:Magnesium Sulfate; D007752:Obstetric Labor, Premature; D011141:Polyuria; D011247:Pregnancy; D012008:Recurrence; D000077325:Ringer's Lactate", "nlm_unique_id": "8110075", "other_id": null, "pages": "550-551", "pmc": null, "pmid": "28049556", "pubdate": "2017-04", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Magnesium Sulfate: Another Cause of a Solute Diuresis.", "title_normalized": "magnesium sulfate another cause of a solute diuresis" }	[ { "companynumb": "US-009507513-1704USA013609", "fulfillexpeditecriteria": "2", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "PROGESTERONE" }, "drugadditional": null, ...
{ "abstract": "BACKGROUND\nPotential additive effects of polypharmacy are rarely considered in adverse events of geriatric patients living in long-term care facilities. Our aim, therefore, was to identify adverse events in this setting and to assess plausible concomitant drug causes.\n\n\nMETHODS\nA cross-sectional observational study was performed in three facilities as follows: (i) adverse event identification: we structurally identified adverse events using nurses' interviews and chart review. (ii) Analysis of the concomitantly administered drugs per patient was performed in two ways: (ii.a) a review of summary of product characteristics for listed adverse drug reactions to identify possible causing drugs and (ii.b) a causality assessment according to Naranjo algorithm.\n\n\nRESULTS\n(i) We found 424 adverse events with a median of 4 per patient (range 1-14) in 103 of the 104 enrolled patients (99%). (ii.a) We identified a median of 3 drugs (range 0-11) with actually occurring adverse events listed as an adverse drug reaction in the summary of product characteristics. (ii.b) Causality was classified in 198 (46.9%) of adverse events as \"doubtful,\" in 218 (51.2%) as \"possible,\" in 7 (1.7%) as \"probable,\" and in 1 (0.2%) adverse event as a \"definitive\" cause of the administered drugs. In 340 (80.2%) of all identified adverse events several drugs simultaneously reached the highest respective Naranjo score.\n\n\nCONCLUSIONS\nPatients in long-term facilities frequently suffer from many adverse events. Concomitantly administered drugs have to be frequently considered as plausible causes for adverse events. These additive effects of drugs should be more focused in patient care and research.", "affiliations": "Drug Safety Center, University Hospital of Leipzig, Leipzig University, Brüderstr. 32, 04103, Leipzig, Germany.;Drug Safety Center, University Hospital of Leipzig, Leipzig University, Brüderstr. 32, 04103, Leipzig, Germany.;Dept. of General Practice, Medical Faculty, University of Leipzig, Philipp-Rosenthal-Str. 55, 04103, Leipzig, Germany.;Sana Geriatric Hospital Zwenkau, Pestalozzistr. 9, 04442, Zwenkau, Germany.;Drug Safety Center, University Hospital of Leipzig, Leipzig University, Brüderstr. 32, 04103, Leipzig, Germany. thilo.bertsche@uni-leipzig.de.;Drug Safety Center, University Hospital of Leipzig, Leipzig University, Brüderstr. 32, 04103, Leipzig, Germany.", "authors": "Lexow\|Monika\|M\|;Wernecke\|Kathrin\|K\|http://orcid.org/0000-0002-2944-7282;Schmid\|Gordian L\|GL\|;Sultzer\|Ralf\|R\|;Bertsche\|Thilo\|T\|http://orcid.org/0000-0002-4930-6655;Schiek\|Susanne\|S\|http://orcid.org/0000-0001-8194-7180", "chemical_list": null, "country": "Austria", "delete": false, "doi": "10.1007/s00508-020-01750-6", "fulltext": "\n==== Front\nWien Klin Wochenschr\nWien Klin Wochenschr\nWiener Klinische Wochenschrift\n0043-5325\n1613-7671\nSpringer Vienna Vienna\n\n33090261\n1750\n10.1007/s00508-020-01750-6\nOriginal Article\nConsidering additive effects of polypharmacy\nAnalysis of adverse events in geriatric patients in long-term care facilities\nLexow Monika monika.lexow@uni-leipzig.de\n\n12\nhttp://orcid.org/0000-0002-2944-7282\nWernecke Kathrin kathrin.wernecke@uni-leipzig.de\n\n12\nSchmid Gordian L. MD gordian.schmid@posteo.de\n\n3\nSultzer Ralf MD ralf.sultzer@sana.de\n\n4\nhttp://orcid.org/0000-0002-4930-6655\nBertsche Thilo PhD thilo.bertsche@uni-leipzig.de\n\n12\nhttp://orcid.org/0000-0001-8194-7180\nSchiek Susanne PhD susanne.schiek@uni-leipzig.de\n\n12\n1 grid.9647.c 0000 0004 7669 9786 Drug Safety Center, University Hospital of Leipzig, Leipzig University, Brüderstr. 32, 04103 Leipzig, Germany\n2 grid.9647.c 0000 0004 7669 9786 Dept. of Clinical Pharmacy, Leipzig University, Brüderstr. 32, 04103 Leipzig, Germany\n3 grid.9647.c 0000 0004 7669 9786 Dept. of General Practice, Medical Faculty, University of Leipzig, Philipp-Rosenthal-Str. 55, 04103 Leipzig, Germany\n4 Sana Geriatric Hospital Zwenkau, Pestalozzistr. 9, 04442 Zwenkau, Germany\n22 10 2020\n22 10 2020\n2021\n133 15-16 816824\n10 6 2020\n23 9 2020\n© The Author(s) 2020\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nBackground\n\nPotential additive effects of polypharmacy are rarely considered in adverse events of geriatric patients living in long-term care facilities. Our aim, therefore, was to identify adverse events in this setting and to assess plausible concomitant drug causes.\n\nMethods\n\nA cross-sectional observational study was performed in three facilities as follows: (i) adverse event identification: we structurally identified adverse events using nurses’ interviews and chart review. (ii) Analysis of the concomitantly administered drugs per patient was performed in two ways: (ii.a) a review of summary of product characteristics for listed adverse drug reactions to identify possible causing drugs and (ii.b) a causality assessment according to Naranjo algorithm.\n\nResults\n\n(i) We found 424 adverse events with a median of 4 per patient (range 1–14) in 103 of the 104 enrolled patients (99%). (ii.a) We identified a median of 3 drugs (range 0–11) with actually occurring adverse events listed as an adverse drug reaction in the summary of product characteristics. (ii.b) Causality was classified in 198 (46.9%) of adverse events as “doubtful,” in 218 (51.2%) as “possible,” in 7 (1.7%) as “probable,” and in 1 (0.2%) adverse event as a “definitive” cause of the administered drugs. In 340 (80.2%) of all identified adverse events several drugs simultaneously reached the highest respective Naranjo score.\n\nConclusion\n\nPatients in long-term facilities frequently suffer from many adverse events. Concomitantly administered drugs have to be frequently considered as plausible causes for adverse events. These additive effects of drugs should be more focused in patient care and research.\n\nKeywords\n\nNursing homes\nSide effects\nAged\nAdverse drug reactions\nNaranjo algorithm\nUniversität Leipzig (1039)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© Springer-Verlag GmbH Austria, part of Springer Nature 2021\n==== Body\nIntroduction\n\nGeriatric patients in long-term care (LTC) facilities are multimorbid and, therefore, suffer from many (non)specific symptoms and geriatric syndromes [1]. Disease-related symptoms should be distinguished from adverse drug reactions (ADR) that result from drug therapy [2]. The latter can lead to hospital admissions and have a considerable impact on morbidity and mortality with high costs in the health care system [3–5]. Polypharmacy makes a significant contribution to the clinical consequences deriving from ADRs in geriatric patients [6]. For this reason, a structured analysis of adverse events (AE) and drug-related causes in these patients is of high interest for routine care.\n\nDistinguishing whether an observed AE was caused by a disease (i.e. symptom) or by a drug (ADR) poses a challenge for healthcare professionals [7, 8]. The correct attribution is required for appropriate treatment strategies but can result only from structured detection, analysis and classification. Geriatric patients are frequently cognitively impaired or suffer from speech or hearing disorders. Hence, information provided by the patients is often insufficient. In LTC facilities, therefore, chart documentation and nurses’ interviews are the most valuable sources for AE detection [9, 10]. So far, no specific method exists to analyze and classify AE in LTC facility residents with polypharmacy. The Naranjo algorithm has previously been used for causality assessment in this collective [11, 12]. It allows a detailed assessment of every detected AE and every single administered drug. This algorithm provides further information on drug-related causes when combined with established methods for patient safety, such as drug-drug interactions and potentially inappropriate medications [13].\n\nCausality scores like the Naranjo score, however, do not consider simultaneously contributing drugs. For some ADRs, it has been shown that the number of specific drugs causes their clinical manifestations. For example, patients are exposed to an increased risk of falling when they take two or more drugs which increase the risk of falling [14]. Concerning anticholinergic ADRs, it is common to calculate an anticholinergic burden to quantify the risk for an adverse outcome [15]. Little is known, however, about additive drug effects in other events. Therefore, data about potential additive effects in this vulnerable patient collective are of great interest for routine care.\n\nThe aim of this study was to identify AEs occurring in LTC facility patients and to assess plausible concomitant drug causes.\n\nPatients, material and methods\n\nDefinitions\n\nWe defined an AE as an outcome that occurs while a patient is taking a drug, but is not or not necessarily attributable to it and an ADR as an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product [16]. We used the term drug not only for the effective substance but for the whole product prescribed in the medication chart of the patient. A drug therefore could contain more than one active substance. We considered all drugs administered to the patient during the acquisition period. Continuous and on-demand medications were assessed separately because the temporal relationship between AE and administration of the drug could be different in that case.\n\nParticipants and setting\n\nWe conducted a cross-sectional observation study in three LTC facilities in Germany. After written informed consent of the residents or their legal representative and the responsible general practitioner, residents in the participating LTC facilities were enrolled in the study. We included residents of facilities with different ownerships (welfare, municipal or private associations) to approach a representative sample of 100 residents. Inclusion criteria were: informed consent, age ≥65 years, long-term/chronic medicines ≥3 and multimorbidity with ≥3 comorbidities at the time of recruitment, more than 8 weeks stay in the LTC facility, and a life expectancy of more than 6 months according to nurses’ present information. The study was conducted over a time period of 10 months.\n\nStudy design and data collection\n\nWe conducted a structured analysis of AEs.\n\n(i) AE identification\n\nWe used two complement sources of information for our structured data collection: Firstly, an interview about individual AEs with nurses involved in daily care and, secondly, a review of residents’ records (electronic and chart documentation, laboratory values) for documented events and their temporal occurrence. To ensure standardized identification of AEs, a checklist of events was applied to both methods. The listed events comprised the most relevant AEs or ADRs for geriatric patients and LTC residents based on the literature [17–19]: blackened stool, bleeding/hematoma, confusion/disorientation, constipation, depression/anxiety, diarrhea, dizziness/vertigo, dry mouth, ear disorders, eye disorders, falls, hallucination, hyperglycemia/hypoglycemia, hyperhidrosis, hyperkalemia/hypokalemia, hypernatremia/hyponatremia, nausea, pain, restlessness, skin disorders/pruritus, insomnia, urinary incontinence, vomiting (in alphabetical order). Additional relevant reported or documented events were collected as well. We considered reported and documented symptoms during a time period of the prior 30 days (considered as 1 resident month) for new and continuous symptoms. Data collection was performed at two measurement points per patient at intervals of 6–8 weeks by two clinical pharmacists. All detected AEs and the corresponding system organ class were classified based on the common terminology criteria for adverse events (CTCAE) [20].\n\n(iia) Review of summary of product characteristics\n\nWe systematically collected data from the medical charts (continuous drugs, on demand drugs and their frequency of use, date of first administration). We checked all summaries of product characteristics (SmPCs) of the actually administered drugs for listed ADRs. A drug would be considered as “potentially causing” if the listed ADR in the SmPC represented a synonym for the detected AE or possibly caused it (e.g. dizziness in cases of falls). For the analysis of additive effects, we counted the number of potentially causing drugs. Prescribed drugs were characterized by their code in the anatomical therapeutic chemical classification system (ATC code).\n\n(iib) Causality assessment according to the Naranjo algorithm\n\nWe used the Naranjo algorithm for causality assessment. All further relevant information, such as the duration of the AE, underlying diseases, clinical consequences (e.g. from hospital report), laboratory values, and patient-specific conditions were collected and used to determine the Naranjo score. The most likely associated drugs were the ones that reached the highest Naranjo score concerning the single analyzed AE. Naranjo distinguishes between definitive with a total score ≥9, probable with 5 < total score < 8, possible with 1 < total score < 4 and doubtful with a total score ≤ 0 [21, 22].\n\nInconclusive evaluations in all steps (i, ii.a, and ii.b) were discussed and finalized by mutual agreement in an expert panel. This panel consisted of four experienced clinical pharmacists.\n\nStatistical analysis\n\nTo ensure comparable patient parameters between the three LTC facilities independent of the allocation to a single facility, main patient parameters were statistically analyzed. For this purpose, a Kruskal Wallis test with pairwise comparison was performed. Analyzed parameters were age, gender, number of diagnoses and number of continuous and on demand drugs, as well as the number of AEs in the patients and the maximum Naranjo score per patient. The data analysis was performed using IBM SPSS Statistics Version 25.0 (IBM Corporation, Armonk, NY, USA) and Microsoft Office Excel 2013 (Microsoft Corporation, Redmond, WA, USA). P-values ≤ 0.05 were considered as statistically significant.\n\nResults\n\nPatient characteristics\n\nIn the participating parts of the LTC facilities, 182 patients were potentially available for the study and 154 met the inclusion criteria. From these, 104 patients or their legal guardian gave their informed consent as well as their responsible physician and were enrolled in the study. Patients were mostly female (72.1%) and in median 86 (range: 66–101) years old (Table 1). Patients did not differ between the three LTC facilities according to the following parameters: age (p = 0.311), gender (p = 0.684), number of diagnoses (p = 0.070) and number of continuous (p = 0.629) and on demand drugs (p = 0.911).Table 1 Characteristics of patients included in the study with frequency of documented diagnoses, main ATC classes and main active substances\n\nCharacteristics\tValue\t\nPatients, total, n\t104\t\nPatients in facility of welfare ownership, n (%)\t34 (32.7%)\t\nPatients in facility of municipal ownership, n (%)\t30 (28.8%)\t\nPatients in facility of ownership by private association, n (%)\t40 (38.5%)\t\nFemale, n (%)\t75 (72.1%)\t\nLength of residence (months), median (Q25/Q75; min–max)\t31 (12/63; 1–414)\t\nAge (years), median (Q25/Q75; min–max)\t86 (78/90; 66–101)\t\nDocumented diagnoses, median (Q25/Q75; min–max)\t15 (10/21; 3–35)\t\nNo. of continuous drugs, median (Q25/Q75; min–max)\t8 (6/10; 2–18)\t\nNo. of on demand medication, median (Q25/Q75; min–max)\t2 (1/3; 1–6)\t\nDocumented diagnosisa\t\nHypertension, n (%)\t82 (78.8%)\t\nDementia, n (%)\t69 (66.3%)\t\nDiabetes, n (%)\t41 (39.4%)\t\nHeart failure, n (%)\t32 (30.8%)\t\nAtrial fibrillation, n (%)\t32 (30.8%)\t\nRenal failure, n (%)\t24 (23.1%)\t\nOsteoporosis, n (%)\t19 (18.3%)\t\nStroke, n (%)\t17 (16.3%)\t\nMain ATC classesb\t\nC (cardiovascular system), n (%)\t236 (28.7%)\t\nN (nervous system), n (%)\t216 (26.3%)\t\nA (alimentary tract and metabolism), n (%)\t164 (20.0%)\t\nB (blood and blood-forming organs), n (%)\t68 (8.3%)\t\nH (systemic hormonal preparations, excluding sex hormones and insulins), n (%)\t27 (3.3%)\t\nMain active substancesb\t\nTorasemide, n (%)\t47 (5.7%)\t\nPantoprazole, n (%)\t40 (4.9%)\t\nRamipril, n (%)\t35 (4.3%)\t\nAcetylsalicylic acid, n (%)\t33 (4.0%)\t\nMetoprolol, n (%)\t23 (2.8%)\t\nATC anatomical therapeutic chemical/defined daily dose classification, Q25/Q75 first and third quartile\n\naOrder is based on the most relevant diagnoses found in literature data to geriatric patients\n\nbAccording to the documented continuous drugs\n\n(i) AE identification\n\nFrom a total of 104 patients, at least 1 AE was identified in 103 (99.0%). We identified 424 AEs, with a detected median of 4 (Q25/Q75: 2/5, range 1–14) AEs per patient, which equals 2.05 AEs per resident month. The identified AEs and the number of affected patients are shown in Table 2. The system organ classes renal and urinary disorder (87 patients), gastrointestinal disorder (43 patients), skin and subcutaneous tissue disorders (37 patients) were most common in our patient collective. Altogether, 72 different AE categories were detected, 185 AEs were identified in the patient records and 195 AEs by the nurses’ interviews, with 44 AEs in concordance of both methods. We found a significant difference in the detected number of AEs between the observed LTC facilities (p = 0.020). Following the pairwise comparison, we only found differences between the municipal LTC facility with 3 (Q25/Q75: 2/4) AEs and the private LTC facility with a median of 4 (Q25/Q75: 3/6.25) AEs (p = 0.022).Table 2 Identified adverse evnts (n = 424) according to CTCAE and affected patients (n = 104)\n\nSystem organ class\tNumber of identified AEs,\nn (%)\tAffected patients, n (%)\tAE with number of affected patientsa (n)\t\nRenal and urinary disorders\t88 (20.8)\t87 (83.7)\tUrinary incontinence (87), urinary tract pain (1)\t\nGastrointestinal disorders\t55 (13.0)\t43 (41.3)\tConstipation (22), vomiting (16), diarrhea (10), blackened stools (3), nausea (2), lower gastrointestinal bleeding (1), periodontal disease (1)\t\nPsychiatric disorders\t55 (13.0)\t35 (33.7)\tConfusion (21), restlessness (12), defensive behavior (8), insomnia (5), depression (4), anxiety (2), hallucinations (1), personality change (1), psychiatric disorders—other specify (1)\t\nSkin and subcutaneous tissue disorders\t50 (11.8)\t37 (35.6)\tIntertrigo (9), dry skin (7), hyperhidrosis (7), skin ulceration (6), local redness (5), pruritus (4), purpura (4), skin and subcutaneous tissue disorders—other specify (3), skin induration (1), urticaria (2), alopecia (1), angioedema (1)\t\nMetabolism and nutritional disorders\t41 (9.7)\t27 (26.0)\tHyperglycemia (26), hypoglycemia (15)\t\nMusculoskeletal and connective tissue disorders\t40 (9.4)\t33 (31.7)\tArthralgia (14), pain in extremity (12), back pain (6), arthritis (4), musculoskeletal and connective tissue disorders—other specify (3), general muscle weakness (1)\t\nNervous system disorders\t39 (9.2)\t31 (29.8)\tDizziness (11), somnolence (10), headache (4), syncope (3), ataxia (2), cognitive disturbance (2), paresthesia (2), depressed level of consciousness (1), lethargy (1), neuralgia (1), seizure (1), spasticity (1)\t\nInjury, poisoning and procedural complications\t14 (3.3)\t14 (13.5)\tFall (14)\t\nVascular disorders\t11 (2.6)\t11 (10.6)\tHematoma (10), flushing (1)\t\nInfections and infestations\t8 (1.9)\t7 (6.7)\tSkin infection (4), vulval infection (2), conjunctivitis infective (1), stoma site infection (1)\t\nGeneral disorders and administration site conditions\t7 (1.7)\t7 (6.7)\tEdema limbs (3), pain (3), fatigue (1)\t\nRespiratory, thoracic and mediastinal disorders\t7 (1.7)\t6 (5.8)\tDyspnea (4), cough (1), epistaxis (1), respiratory, thoracic and mediastinal disorders—other specify (1)\t\nEar and labyrinth disorders\t3 (0.7)\t3 (2.9)\tHearing impaired (2), tinnitus (1)\t\nCardiac disorders\t2 (0.5)\t2 (1.9)\tChest pain—cardiac (1), palpitations (1)\t\nEye disorders\t2 (0.5)\t1 (1.0)\tBlurred vision (1), glaucoma (1)\t\nInvestigations\t2 (0.5)\t2 (1.9)\tWeight gain (1), weight loss (1)\t\nAE(s) adverse event(s), CTCAE common terminology criteria for adverse events\n\naMultiple categories per patient possible\n\n(ii.a) Review of summary of product characteristics\n\nTo analyze the concomitantly administered drugs, we assessed 3725 combinations of AEs and corresponding drugs. For this analysis five drug/AE pairs had to be excluded because no information from the SmPC was available (moisturizing eye drops, medical device). Considering every identified AE, patients had a median of 3 potentially causing drugs according to the SmPC, with a range from 0 to 11 drugs (Q25/Q75: 2/4; details in Fig. 1). The most frequently (n ≥ 10) detected AEs and the affected system organ classes are shown in Table 3. The ATC classes prescribed most often (C, N, A, B, H) were frequently among the potentially causing drugs for the most common system organ classes (Fig. 2).Fig. 1 Number of detected adverse events versus number of potentially causing drugs according Summary of Product Charactetistics. AE(s) adverse event(s), SmPC summary of products characteristics\n\nTable 3 Median number of potentially causing drugs according Summary of Product Charactersitics and corresponding Naranjo Score per patient (n = 104) for the most frequently detected (≥10) adverse events (AEs) and for their corresponding System organ classes (all 424 detected AE included)\n\nSystem organ class and\n... most frequent AE\tNumber (n)\tMedian number of potentially causing drugs per patient [range]\tMedian Naranjo score [range]\t\nRenal and urinary disorders\t88\t2 [0–5]\t0 [−1–2]\t\n... Urinary incontinence\t87\t2 [0–5]\t0 [−1–2]\t\nGastrointestinal disorders\t55\t5 [0–11]\t2 [0–4]\t\n... Constipation\t22\t5 [0–10]\t0 [0–3]\t\n... Vomiting\t16\t7.5 [2–10]\t2 [0–4]\t\n... Diarrhea\t10\t4.5 [2–11]\t3 [0–3]\t\nPsychiatric disorders\t55\t3 [0–7]\t0 [−1–9]\t\n... Confusion\t21\t3 [1–7]\t1 [0–8]\t\n... Restlessness\t12\t3 [0–4]\t0 [−1–3]\t\nMetabolism and nutrition disorders\t41\t3 [0–5]\t1 [0–5]\t\n... Hyperglycemia\t26\t3 [0–4]\t1 [0–1]\t\n... Hypoglycemia\t15\t3 [1–5]\t4 [2–5]\t\nMusculoskeletal and connective tissue disorders\t40\t3 [0–8]\t2 [−1–3]\t\n... Arthralgia\t14\t3 [0–6]\t1 [−1–3]\t\n... Pain in extremity\t12\t2 [1–8]\t2 [0–3]\t\nNervous system disorders\t39\t4 [0–10]\t1 [−1–7]\t\n... Dizziness\t11\t5 [1–10]\t2 [0–7]\t\n... Somnolence\t10\t4 [3–7]\t3 [0–5]\t\nInjury, poisoning and procedural complications\t14\t6 [3–11]\t2 [0–3]\t\n... Fall\t14\t6 [3–11]\t2 [0–3]\t\nVascular disorders\t11\t1 [0–3]\t1 [0–3]\t\n... Hematoma\t10\t1 [0–3]\t0.5 [0–2]\t\nAE(s) Adverse Event(s), SmPC Summary of product characteristics\n\nFig. 2 Potentially causing drugs according Summary of Product Characteristics differentiated into the ATC classes for the most frequently detected system organ classes. AE(s) adverse event(s), ATC anatomical therapeutic chemical/defined daily dose classification, CTCAE common criteria for the terminology of adverse events, SmPC summary of products characteristics. ATC classes: A: alimentary tract and metabolism, B: blood and blood forming organs, C: cardiovascular system, H: systemic hormonal preparations, excluding sex hormones and insulins, N: nervous system\n\n(ii.b) Causality assessment according to the Naranjo algorithm\n\nAll 3730 drug/AE pairs were included in the causality assessment. From the 424 identified AEs, 198 (46.9%) were classified as ADR with “doubtful”, 218 (51.2%) “possible”, 7 (1.7%) “probable”, and 1 (0.2%) “definitive” cause (Table 4). We found no significant differences in the maximum Naranjo scores per patient between the three LTC facilities (p = 0.964). On the basis of 424 detected AEs, only 1 drug in 84 AEs (19.8%) and several drugs in 340 AEs (80.2%) reached the highest score (Table 4). According to Naranjo these need to be considered as the most likely causing drug(s).Table 4 Results of the adverse event drug causality assessment according to the Naranjo algorithm\n\nNaranjo Score per AE\tIdentified AE [n]\tNumber of affected patientsa, [n]\tClassification\tIdentified AE per class, n (%)\tNumber of AE with one/several highest Naranjo drug(s) [n]\t\n−1\t22\t17\tDoubtful\t199 (46.9)\t38/161\t\n0\t177\t92\t\n1\t68\t48\tPossible\t217 (51.2)\t38/179\t\n2\t90\t51\t\n3\t41\t30\t\n4\t18\t18\t\n5\t3\t3\tProbable\t7 (1.7)\t7/0\t\n6\t2\t2\t\n7\t1\t1\t\n8\t1\t1\t\n9\t1\t1\tDefinitive\t1 (0.2)\t1/0\t\nAE(s) adverse event(s)\n\naSeveral AEs per patient possible\n\nThe probable and definitive ADRs were as follows: angioedema (severity grade according to CTCAE 4) induced by enalapril, urticaria (grade 2) induced by amoxicillin and clavulanic acid, hypoglycemia (grade 1) induced by insulin glargine, paresthesia (grade 2) induced by tapentadol and a complex case of occurring hallucinations (grade 3) in combination with confusion (grade 3), dizziness (grade 3) and somnolence (grade 3, in total 4 detected AEs) which were attributable to digitoxin (highest Naranjo score). In this case, the patient also received high doses of oxycodone and duloxetine. It can be seen as a mixed intoxication based on the hospital report. In the algorithm, digitoxin reached a one-point higher score than oxycodone/duloxetine because measurement of the increased blood level was available only for digitoxin.\n\nAll of the detected AEs and ADRs were managed adequately by the nurses, for example, by informing a physician or arranging a hospital admission for the affected patient. Thus, no further action was required due to this study.\n\nDiscussion\n\nIn our study we addressed AEs in geriatric patients living in LTC facilities. We assessed which type of AEs occurred and also investigated potential additive effects of polypharmacy. With nearly all (99%) patients affected by AEs, we demonstrated the relevance of this topic. We found the identified AEs potentially caused by up to 11 different administered drugs. The Naranjo algorithm showed at least possible drug causes in half of these AEs. Thereby, multiple drugs were equally likely involved 80% of the time. Our results point out that AEs should be systematically recorded in routine practice in LTC facilities. In order to prevent ADRs, additive effects need to be considered in any strategies developed.\n\nPrevalence of AE and ADR in LTC residents\n\nMore than half of our identified AEs could be associated with drug use. Our rate of probable and definitive ADRs was similar to other studies in the LTC setting (0.04 vs. up to 0.10 ADRs per observed resident month), although studies should be compared with caution [9, 23]. Nevertheless, the causality assessment leaves us with a high number of possible ADRs. Especially for AEs which were ongoing for a longer period, causality assessment was challenging in the routine setting. Information to evaluate the exact temporal connection between AE and drug use was frequently missing and therefore could have led to lower Naranjo scores. To resolve this problem, a regular and structured routine assessment of AEs and potentially causing drugs might increase the chance to identify ADRs and protect patients from the consequences.\n\nOur overall rate of identified AEs was higher than results seen in other studies (2.05 AEs vs 0.03–0.12 per observed resident month) [9, 23]. This indicates that we identified a noticeable amount of the general symptom burden of LTC residents that results from underlying diseases or age-related changes. This is consistent with the fact that incontinence, pain, sleep disorders and psychopathological symptoms are widely found in LTC residents [24]. Therefore, a regular routine AE assessment can support ADR detection as well as structured symptom evaluation.\n\nAdditive effects of polypharmacy\n\nThe suspected AE was listed as an ADR in the respective SmPC in a median of 3 and up to 11 administered drugs per patient. In 80% of all identified AEs, various drugs reached the highest Naranjo score simultaneously. This means that they were equally likely to cause the AE. This coincidence can increase the chance of AE occurrence independently from single causality scores. This result also raises the question whether ADRs resulting from additive effects have been underestimated. In cases with “probable” or “definitive” ADRs (Naranjo ≥5), we found results from only one drug with the highest Naranjo score; however, in four of these AEs, the drug with the highest Naranjo (digitoxin) was only part of a mixed intoxication with duloxetine and oxycodone based on the hospital report for the affected patient. In this case, the sole consideration of the causality assessment could mask an additive effect of at least 3 concomitantly given drugs. This shows that additive effects need to be considered in every detected AE independently from the single causality. Besides ADRs from well-known drug classes (e.g. vascular ADRs from drugs affecting blood and blood-forming organs), in a substantial amount of AEs, we found involvement of varying ATC-classes that are less familiar (e.g. nervous system ADRs in drugs affecting the cardiovascular system). This underlines the complexity of geriatric patient treatment and the need for interdisciplinary medication reviews that include an assessment of drug-related problems, such as drug-drug interactions, potentially inappropriate medication, as well as ADRs [25, 26]. In routine care, however, potential additive effects are often not taken into account. In particular, new and unclear symptoms could be misinterpreted as new diseases and sometimes even lead to prescribing cascades [27, 28].\n\nImplications for practice\n\nFirstly, our study shows the need for a good data base and a regular routine assessment of AEs that occur in LTC facilities. We found a very low concordance rate of only 10% between AEs detected in nurses’ interviews and those mentioned in the patient record analysis. This demonstrates the potential of information loss in LTC facilities due to heterogeneous and incomplete AE documentation [29]. It also indicates the potential of recall bias in the nurses. The identification of every occurring AE allows a better assessment of simultaneously occurring events. We found in our study, for example, a combination of vomiting and diarrhea that indicated an infection rather than an ADR. Furthermore, the information on patients’ current symptoms contributes to appropriate proposals for medication changes in cases of identified ADRs.\n\nSecondly, our results support the development of strategies with improved consideration of the additive effects of polypharmacy. Combining an AE assessment with structured medication reviews improves the drug cause analysis of AEs as well as the detection and interpretation of drug-related problems. Ongoing prospective evaluation of AEs and potential drug-related causes contributes to prevent patients from experiencing negative events. This process could be further accelerated by electronic assistance. Electronic documentation of AEs and computer-assisted signal detection of ADRs can support problem solving in a narrow timeframe since physicians and pharmacists are usually not permanently present in the LTC facilities [11, 30]. Database-supported comparison of the events with patients’ medication can assist pharmacists in a comprehensive medication review. Currently, such electronic solutions are rarely used in the LTC setting in Germany. They could also support future research by providing information on the additive effects of various combined drugs and underlying diseases.\n\nThirdly, our data suggest the need for improvement in interdisciplinary communication in LTC facilities. In interprofessional teams with nurses, pharmacists and physicians, systematic information about AEs, medication reviews and actual health conditions could be transmitted more effectively in patient-orientated practice.\n\nConclusion\n\nNearly every long-term care resident suffered from adverse events (AEs), with half of them at least possibly caused by drugs. In four fifths of these AEs, several concomitantly given drugs were equally associated causes. Therefore, potential additive effects need to be considered independently from single causality and should be more focused in further research. A routinely implemented structured search for AEs and additive effects of polypharmacy contributes to medication reviews and interdisciplinary collaboration and will help to meet the needs of this complex patient collective and to protect them from negative consequences.\n\nAcknowledgements\n\nWe thank all participating co-workers of the LTC facilities and the attending physicians for their support. Furthermore, we thank PhD Johanna Freyer for her assistance with the ethics approval and Katharine Worthington for language editing.\n\nFunding\n\nA co-worker of the study (Monika Lexow) was financially supported in part by the Lesmueller Foundation, Munich, Germany, the German Pharmacist Foundation, Berlin, Germany and the Pharmacist Foundation Westfalen-Lippe, Münster, Germany.\n\nAuthor Contribution\n\nConceptualization: Monika Lexow, Kathrin Wernecke, Ralf Sulzer, Thilo Bertsche, Susanne Schiek; methodology: Monika Lexow, Kathrin Wernecke, Thilo Bertsche, Susanne Schiek; formal analysis and investigation: Kathrin Wernecke, Susanne Schiek; investigation: Monika Lexow, Kathrin Wernecke; writing, original draft preparation: Monika Lexow, Kathrin Wernecke, Thilo Bertsche, Susanne Schiek; writing, review and editing: Monika Lexow, Kathrin Wernecke, Ralf Sultzer, Gordian L. Schmid, Thilo Bertsche, Susanne Schiek; visualization: Monika Lexow, Kathrin Wernecke, Susanne Schiek; supervision: Thilo Bertsche, Susanne Schiek; project administration: Monika Lexow; funding acquisition: Thilo Bertsche, Susanne Schiek.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL.\n\nCompliance with ethical guidelines\n\nConflict of interest\n\nM. Lexow, K. Wernecke, G.L. Schmid, R. Sultzer, T. Bertsche, and S. Schiek declare that they have no competing interests.\n\nEthical standards\n\nAll procedures performed in this study involving human participants were approved both by the ethics committee of the Faculty of Medicine of Leipzig University as well as the ethics committee of the State Chamber of Physicians of Saxony (reference: 231/13-ff and EK-allg-26/14-1) and have been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All participants gave their informed consent prior to inclusion in the study.\n\nThe authors M. Lexow and K. Wernecke contributed equally to the manuscript.\n\nThe authors T. Bertsche and S. Schiek contributed equally to the manuscript.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Gordon AL Franklin M Bradshaw L Logan P Elliott R Gladman JR Health status of UK care home residents: a cohort study Age Ageing 2014 43 1 97 103 10.1093/ageing/aft077 23864424\n2. Wierenga PC Buurman BM Parlevliet JL Association between acute geriatric syndromes and medication-related hospital admissions Drugs Aging 2012 29 8 691 699 22812539\n3. Chan M Nicklason F Vial JH Adverse drug events as a cause of hospital admission in the elderly Intern Med J 2001 31 4 199 205 10.1046/j.1445-5994.2001.00044.x 11456032\n4. Schneeweiss S Hasford J Göttler M Hoffmann A Riethling AK Avorn J Admissions caused by adverse drug events to internal medicine and emergency departments in hospitals: a longitudinal population-based study Eur J Clin Pharmacol 2002 58 4 285 291 10.1007/s00228-002-0467-0 12136375\n5. Kongkaew C Hann M Mandal J Risk factors for hospital admissions associated with adverse drug events Pharmacotherapy 2013 33 8 827 837 10.1002/phar.1287 23686895\n6. Field TS Gurwitz JH Avorn J Risk factors for adverse drug events among nursing home residents Arch Intern Med 2001 161 13 1629 1634 10.1001/archinte.161.13.1629 11434795\n7. Bäckström M Mjörndal T Dahlqvist R Spontaneous reporting of adverse drug reactions by nurses Pharmacoepidemiol Drug Saf 2002 11 8 647 650 10.1002/pds.753 12512239\n8. Hohl CM Robitaille C Lord V Emergency physician recognition of adverse drug-related events in elder patients presenting to an emergency department Acad Emerg Med 2005 12 3 197 205 10.1197/j.aem.2004.08.056 15741581\n9. Gurwitz JH Field TS Avorn J Incidence and preventability of adverse drug events in nursing homes Am J Med 2000 109 2 87 94 10.1016/S0002-9343(00)00451-4 10967148\n10. Morimoto T Gandhi TK Seger AC Hsieh TC Bates DW Adverse drug events and medication errors: detection and classification methods Qual Saf Health Care 2004 13 4 306 314 10.1136/qshc.2004.010611 15289635\n11. Handler SM Hanlon JT Perera S Assessing the performance characteristics of signals used by a clinical event monitor to detect adverse drug reactions in the nursing home AMIA Annu Symp Proc 2008 6 278 282\n12. Carnovale C Gentili M Fortino I The importance of monitoring adverse drug reactions in elderly patients: the results of a long-term pharmacovigilance programme Expert Opin Drug Saf 2016 15 2 131 139 10.1517/14740338.2016.1131816 26882049\n13. Lavan AH Gallagher P Predicting risk of adverse drug reactions in older adults Ther Adv Drug Saf 2016 7 1 11 22 10.1177/2042098615615472 26834959\n14. Schiek S Hildebrandt K Zube O Bertsche T Fall-risk-increasing adverse reactions-is there value in easily accessible drug information? A case-control study Eur J Clin Pharmacol 2019 75 6 849 857 10.1007/s00228-019-02628-x 30758518\n15. Salahudeen MS Duffull SB Nishtala PS Anticholinergic burden quantified by anticholinergic risk scales and adverse outcomes in older people: a systematic review BMC Geriatr 2015 15 31 10.1186/s12877-015-0029-9 25879993\n16. Edwards IR Aronson JK Adverse drug reactions: definitions, diagnosis, and management Lancet 2000 356 9237 1255 1259 10.1016/S0140-6736(00)02799-9 11072960\n17. Handler SM Hanlon JT Perera S Consensus list of signals to detect potential adverse drug reactions in nursing homes J Am Geriatr Soc 2008 56 5 808 815 10.1111/j.1532-5415.2008.01665.x 18363678\n18. Thürmann P, Jaehde U. Drug therapy safety in nursing homes: cross-sectional analysis and feasibility of a multidisciplinary approach. Final report federal ministry of health. 2011. https://www.bundesgesundheitsministerium.de/fileadmin/Dateien/5_Publikationen/Gesundheit/Berichte/Abschlussbericht_Arzneimitteltherapiesicherheit_in_Alten-_und_Pflegeheimen_Querschnittsanalyse_und_Machbarkeit_eines_multidisziplinaeren_Ansatzes.pdf. Accessed 20 Jan 2020.\n19. Härkänen M Kervinen M Ahonen J Voutilainen A Turunen H Vehviläinen-Julkunen K Patient-specific risk factors of adverse drug events in adult inpatients—evidence detected using the global trigger tool method J Clin Nurs 2015 24 3–4 582 591 10.1111/jocn.12714 25393838\n20. U.S. Department of Health and Human Services, National Institutes of Health, National Cancer Institute. Common terminology criteria for adverse events (CTCAE) version 4.03. 2010. https://www.eortc.be/services/doc/ctc/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. Accessed 20 Jan 2020.\n21. Naranjo CA Busto U Sellers EM A method for estimating the probability of adverse drug reactions Clin Pharmacol Ther 1981 30 2 239 245 10.1038/clpt.1981.154 7249508\n22. Agbabiaka TB Savović J Ernst E Methods for causality assessment of adverse drug reactions: a systematic review Drug Saf 2008 31 1 21 37 10.2165/00002018-200831010-00003 18095744\n23. Gurwitz JH Field TS Judge J The incidence of adverse drug events in two large academic long-term care facilities Am J Med 2005 118 3 251 258 10.1016/j.amjmed.2004.09.018 15745723\n24. Elseviers MM Vander Stichele RR Van Bortel L Drug utilization in Belgian nursing homes: impact of residents’ and institutional characteristics Pharmacoepidemiol Drug Saf 2010 19 10 1041 1048 10.1002/pds.1983 20564427\n25. Fog AF Kvalvaag G Engedal K Straand J Drug-related problems and changes in drug utilization after medication reviews in nursing homes in Oslo, Norway Scand J Prim Health Care 2017 35 4 329 335 10.1080/02813432.2017.1397246 29096573\n26. Halvorsen KH Stadeløkken T Garcia BH A stepwise pharmacist-led medication review service in interdisciplinary teams in rural nursing homes Pharmacy (Basel) 2019 7 4 148 10.3390/pharmacy7040148\n27. Rochon PA Gurwitz JH Optimising drug treatment for elderly people: the prescribing cascade BMJ 1997 315 7115 1096 1099 10.1136/bmj.315.7115.1096 9366745\n28. Davies EA O’Mahony MS Adverse drug reactions in special populations—the elderly Br J Clin Pharmacol 2015 80 4 796 807 10.1111/bcp.12596 25619317\n29. Ehrenberg A Ehnfors M The accuracy of patient records in Swedish nursing homes: congruence of record content and nurses’ and patients’ descriptions Scand J Caring Sci 2001 15 4 303 310 10.1046/j.1471-6712.2001.00044.x 12453171\n30. Forster AJ Jennings A Chow C Leeder C van Walraven C Supervised signal detection for adverse drug reactions in medication dispensing data Comput Methods Programs Biomed 2018 161 25 38 10.1016/j.cmpb.2018.03.021 29852965\n\n", "fulltext_license": "CC BY", "issn_linking": "0043-5325", "issue": "133(15-16)", "journal": "Wiener klinische Wochenschrift", "keywords": "Adverse drug reactions; Aged; Naranjo algorithm; Nursing homes; Side effects", "medline_ta": "Wien Klin Wochenschr", "mesh_terms": "D000368:Aged; D015984:Causality; D003430:Cross-Sectional Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D006801:Humans; D008134:Long-Term Care; D064887:Observational Studies as Topic; D019338:Polypharmacy", "nlm_unique_id": "21620870R", "other_id": null, "pages": "816-824", "pmc": null, "pmid": "33090261", "pubdate": "2021-08", "publication_types": "D016428:Journal Article; D016454:Review", "references": "29096573;10967148;25879993;18363678;12453171;22812539;30758518;11456032;15289635;11072960;26882049;15745723;25393838;7249508;9366745;23686895;15741581;18095744;20564427;11434795;26834959;31694298;25619317;29852965;12512239;18998853;12136375;23864424", "title": "Considering additive effects of polypharmacy : Analysis of adverse events in geriatric patients in long-term care facilities.", "title_normalized": "considering additive effects of polypharmacy analysis of adverse events in geriatric patients in long term care facilities" }	[ { "companynumb": "DE-Nuvo Pharmaceuticals Inc-2121821", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "OXYCODONE HYDROCHLORIDE" }, "drugad...
{ "abstract": "BACKGROUND\nCraniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage.\n\n\nMETHODS\nMISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, number NCT00224770.\n\n\nRESULTS\nBetween Feb 2, 2006, and April 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7-22.6] vs eight [14·8%, 6·6-27·1], p=0·542), 7 day mortality (zero [0%, 0-8·4] vs one [1·9%, 0·1-9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1-12·6] vs five [9·3%, 3·1-20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1-12·6] vs zero [0%, 0-6·6], p=0·438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22·2%; 95% CI 12·0-35·6] vs three [7·1%; 1·5-19·5]; p=0·051).\n\n\nCONCLUSIONS\nMIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage.\n\n\nBACKGROUND\nNational Institute of Neurological Disorders and Stroke, Genentech, and Codman.", "affiliations": "Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA. Electronic address: dhanley@jhmi.edu.;Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.;Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.;Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.;Emissary International, Austin, TX, USA.;Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.;Department of Neuroradiology, University of Maryland, Baltimore, MD, USA.;Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurology, Boston University, Boston, MA, USA.;Department of Neurology, Brain Injury Outcomes Coordinating Center, Johns Hopkins University, Baltimore, MD, USA.;Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.;Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.;Department of Biostatistics, School of Public Health, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurology, Virginia Commonwealth University, Richmond, VA, USA.;Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA, USA.;Department of Neurosurgery, University of Maryland, Baltimore, MD, USA.;Department of Neurosurgery, Stanford University, Palo Alto, CA, USA.;Department of Neurology, Stanford University, Palo Alto, CA, USA.;Department of Neurosurgery, University of Texas, San Antonio, TX, USA.;Department of Neurosurgery, Johns Hopkins University, Baltimore, MD, USA.;Department of Neurosurgery, University of Kansas, Kansas City, KS, USA.;Neurosurgery, Newcastle University, Newcastle upon Tyne, UK.;Neurosurgery, Newcastle University, Newcastle upon Tyne, UK.;National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.;Department of Neurology, University of California, Los Angeles, Los Angeles, CA, USA.;Department of Neurosurgery, University of California, Los Angeles, Los Angeles, CA, USA.;Department of Neurosurgery, University of Chicago, Chicago, IL, USA.;Department of Neurosurgery, University of Cincinnati, Cincinnati, OH, USA.", "authors": "Hanley\|Daniel F\|DF\|;Thompson\|Richard E\|RE\|;Muschelli\|John\|J\|;Rosenblum\|Michael\|M\|;McBee\|Nichol\|N\|;Lane\|Karen\|K\|;Bistran-Hall\|Amanda J\|AJ\|;Mayo\|Steven W\|SW\|;Keyl\|Penelope\|P\|;Gandhi\|Dheeraj\|D\|;Morgan\|Tim C\|TC\|;Ullman\|Natalie\|N\|;Mould\|W Andrew\|WA\|;Carhuapoma\|J Ricardo\|JR\|;Kase\|Carlos\|C\|;Ziai\|Wendy\|W\|;Thompson\|Carol B\|CB\|;Yenokyan\|Gayane\|G\|;Huang\|Emily\|E\|;Broaddus\|William C\|WC\|;Graham\|R Scott\|RS\|;Aldrich\|E Francois\|EF\|;Dodd\|Robert\|R\|;Wijman\|Cristanne\|C\|;Caron\|Jean-Louis\|JL\|;Huang\|Judy\|J\|;Camarata\|Paul\|P\|;Mendelow\|A David\|AD\|;Gregson\|Barbara\|B\|;Janis\|Scott\|S\|;Vespa\|Paul\|P\|;Martin\|Neil\|N\|;Awad\|Issam\|I\|;Zuccarello\|Mario\|M\|;\|\|\|", "chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator", "country": "England", "delete": false, "doi": "10.1016/S1474-4422(16)30234-4", "fulltext": "\n==== Front\n10113930930413Lancet NeurolLancet NeurolThe Lancet. Neurology1474-44221474-44652775155410.1016/S1474-4422(16)30234-4nihpa823825ArticleSafety and efficacy of minimally invasive surgery plus recombinant tissue plasminogen activator in intracerebral haemorrhage evacuation (MISTIE): a randomised, phase 2 trial Hanley Daniel F. Thompson Richard E. Muschelli John Rosenblum Michael McBee Nichol Lane Karen Bistran-Hall Amanda J. Mayo Steven W. Keyl Penelope Gandhi Dheeraj Morgan Tim C. Ullman Natalie Mould W. Andrew Carhuapoma J. Ricardo Kase Carlos Ziai Wendy Thompson Carol B. Yenokyan Gayane Huang Emily Broaddus William C. Graham R. Scott Aldrich E. Francois Dodd Robert Wijman Cristanne Caron Jean-Louis Huang Judy Camarata Paul Mendelow A. David Gregson Barbara Janis Scott Vespa Paul Martin Neil Awad Issam †Zuccarello Mario †for the MISTIE II Investigators* Department of Neurology, Brain Injury Outcomes (BIOS) Coordinating Center (Prof DF Hanley, MD, N McBee, MPH, K Lane, CMA, A Bistran-Hall, BS, P Keyl, PhD, T Morgan, MPH, N Ullman, MPH, WA Mould, BA, JR Carhuapoma, MD, W Ziai, MD) and Department of Neurosurgery (J Huang, MD) and Department of Biostatistics, School of Public Health (RE Thompson, PhD, J Muschelli, PhD, M Rosenblum, PhD, CB Thompson, MS, G Yenokyan, PhD, E Huang, PhDc); Johns Hopkins University, Baltimore, MD; Emissary International, LLC, Austin, TX (SW Mayo, PD); Department of Neuroradiology (D Gandhi, MD) and Department of Neurosurgery (EF Aldrich, MD), University of Maryland, Baltimore, MD; Department of Neurology, Boston University, Boston, MA (C Kase, MD); Department of Neurology (W Broaddus, MD) and Department of Neurosurgery (RS Graham, MD), Virginia Commonwealth University, Richmond, VA; Department of Neurology (C Wijman, MD) and Department of Neurosurgery (R Dodd, MD), Stanford University, Palo Alto, CA; Department of Neurosurgery, University of Texas, San Antonio, San Antonio, TX (JL Caron, MD); Department of Neurosurgery, University of Kansas, Kansas City, KS (P Camarata, MD); National Institutes of Health, National Institute of Neurological Disorders and Stroke, Bethesda, MD (S Janis, PhD); Department of Neurology (P Vespa, MD) and Department of Neurosurgery (N Martin, MD), University of California, Los Angeles, Los Angeles, CA; Department of Neurosurgery, University of Chicago, Chicago, IL (Prof I Awad, MD); Department of Neurosurgery, University of Cincinnati, Cincinnati, OH (Prof M Zuccarello, MD). Neurosurgery, Newcastle University, Newcastle upon Tyne, UK (A D Mendelow FRCS[SN], B Gregson PhD)Corresponding author: Prof Daniel F. Hanley, Acute Care Neurology, Johns Hopkins University, Division of Brain Injury Outcomes, 1550 Orleans Street, 3M50 South Baltimore, MD 21231, USA, dhanley@jhmi.edu* A complete list of investigators in the MISTIE II trial is provided in the Supplementary Appendix.\n\n† Contributed equally\n\n5 11 2016 11 10 2016 11 2016 01 11 2017 15 12 1228 1237 This manuscript version is made available under the CC BY-NC-ND 4.0 license.SUMMARY\nBackground\nCraniotomy, when evaluated in trials, does not improve outcome after intracerebral haemorrhage (ICH). Whether minimally invasive catheter evacuation followed by thrombolysis is safe and can achieve a good functional outcome by removing clot is unknown. We investigated safety and efficacy of alteplase with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage.\n\nMethods\nMISTIE was an international, randomized, open-label study and was done in 26 hospitals in the USA, Canada, the UK, and Germany. Patients (aged 18–80 years), with non-traumatic (spontaneous) ICH ≥20 mL were randomly allocated, centrally, to medical care or image-guided MIS plus rt-PA (0.3 mg or 1.0 mg every 8 hours for up to 9 doses) to remove clot using surgical aspiration followed with alteplase clot irrigation. The primary efficacy outcome was the adjusted dichotomized modified Rankin Scale (mRS) 0–3 vs 4–6 assessed at day 180 after symptom onset. Analysis was by intention to treat. (ClinicalTrials.gov number NCT00224770).\n\nFindings\nBetween February 2, 2006 and April 8, 2013, 96 subjects were randomized and completed follow-up: 54 received treatment and 42 medical care. Primary safety outcomes: mortality, symptomatic bleeding, brain infections, as well as withdrawal of care, did not differ between groups. Asymptomatic hemorrhages were more common in the surgical group (3 (7%) vs. 12 (22%) p= 0.05) producing a difference of 15.1% (95% CI: 1.5% to 28.6%). The estimated absolute benefit, i.e., the unadjusted difference in observed proportions of all subjects with mRS 0–3 (33% vs 21%) at 180 days comparing MISPA vs. medical control, is 0.109 [95%CI: −0.088, 0.294; p=0.26], and is 0.162 [95%CI: 0.003, 0.323; p=0.05] after adjustment for potential imbalances in baseline severity between study arms (primary efficacy outcome).\n\nInterpretation\nMIS+rt-PA appears safe with an apparent advantage of better functional outcome at 180 days. Increased asymptomatic bleeding is a major cautionary finding. The MISTIE trial results, if replicable, could produce a meaningful functional benefit adding surgical management as a therapeutic strategy for ICH.\n\nFunding\nNational Institute of Neurologic Disorders and Stroke, Genentech, and Codman.\n\nIntracerebral hemorrhageThrombolysisrt-PAClot aspirationMinimally Invasive SurgeryMISTIE\n==== Body\nIntroduction\nBrain haemorrhage affects more than 5 million people each year.1 It is the most severe form of stroke for which there is no evidence-based primary treatment.2–4 Well executed pragmatic trials of therapy used in routine practice have not shown that any treatment substantially reduces haematoma size and brain tissue damage, and improves functional outcome. In the STICH (Surgical Treatment for Intracerebral Hemorrhage) I and II trials, routine craniotomy did not show an alteration of functional outcomes.5,6 STICH I suggested clot removal may simplify and shorten overall medical care,5 and STICH II demonstrated a non-significant 5.6% decrease in mortality. Nonsurgical trials of aggressive, early haemostasis,7 showed some stabilisation of haematoma growth but no change in functional outcome. In the large INTERACT (Intensive Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial) II trial, early blood pressure (BP) lowering reduced clot growth by a small amount and led to a nonsignificant, 3.7%, gain in functional outcome.8 The MISTIE II trial was designed to assess alteplase (Alteplase, Genentech, South San Francisco, CA, USA) dose response (stage one) and whether minimally invasive surgery (MIS) followed by thrombolytic treatment is safe and reduces, and perhaps reverses, the burden of clot on tissue (stage two)9,10 and to provide preliminary functional outcome data.10–15\n\nMethods\nStudy Design\nMISTIE II was an international, multicenter (26 sites in the USA, Canada, UK, and Germany), randomized, phase 2 trial16 of image-guided,14 catheter-based13 removal of ICH ≥20 mL, measured by the ABC/2 method.17 All subjects were managed in an intensive care unit setting. Local institutional review board (or Ethics Committee) approval was obtained at each hospital.\n\nParticipants\nSubjects with non-traumatic (spontaneous) ICH attributed to cerebral small vessel disease and not due to a macrovascular cause such as an aneurysm or AVM were candidates for this trial. After obtaining written, informed consent, all patients age 18–80 years old with spontaneous, non-traumatic, supratentorial ICH ≥20mL, Glasgow Coma Scale (GCS) score ≤14 or NIH Stroke Scale (NIHSS) score ≥6, a historical modified Rankin Scale (mRS) score of 0 or 1, whose ICH remained the same size for ≥ 6hrs and who satisfied all other inclusion/exclusion criteria listed in the Supplemental Appendix (page 4) were randomized.\n\nRandomization and Blinding\nPatients were randomized by local site personnel using a central web-based enrollment system. The trial statistician employed a randomly generated number sequence to allocate patients to the surgical and medical groups. Patient allocation was stratified according to clot size with two schedules employed: one for ICH ≥20 mL and ≤40 mL; and one for ICH >40 mL as measured on the diagnostic CT. The trial had two pre-planned stages, which were managed by an independent data safety monitoring board (DSMB): a dose finding stage and a safety assessment stage. Stage one (dose finding) consisted of two doses (0.3mg and 1.0mg). A third dose, 3mg, was not investigated after a planned DSMB review. This decision decreased the sample size from 110 to 96 subjects. Subjects in stage 1 were randomized 3:1 to treatment (MIS plus the dose of rt-PA in that part) or medical management. In stage one only, blocks of 4 patients were employed within each randomization schedule to ensure a 3:1 assignment to treatment (MIS+rt-PA) versus control (medical management). After stage one enrollment and DSMB review were completed, a planned protocol amendment, occurred. This specified the use of alteplase at the selected 1 mg dose (based on safety profile and clot removal efficiency), use of a surgical oversight center (based on initial surgical performance) and addition of 365 day outcome assessments. This amendment was reviewed and approved by the DSMB and executive committee. Stage two remained stratified by size, used 1:1 randomization and evaluated the safety of treatment vs. medical management.\n\nThe first subject at every site was assigned to surgical management and served as a “credentialing subject” to document the surgeon’s ability to perform the surgical protocol. Once a surgeon was credentialed, subsequent eligible patients were randomized to MIS+rt-PA or medical management (stage one: 3:1; stage two: 1:1). The assignments were not masked because of surgical assignment in the protocol. The number randomized in stage one was 29 to MIS+rt-PA and 17 to medical management; the corresponding numbers in stage two are 25 to MIS+rt-PA and 25 to medical management. Unlike stage one participants (followed up to 180 days), stage two participants were followed up for 365 days. The site examiners performing the outcome assessments were masked to treatment assignment.\n\nProcedures\nStability Protocol\nThe risks of initial haematoma growth/instability were managed by use of a stability protocol combining normalization of coagulation parameters, BP management, and repeat computed tomography (CT) assessment of clot size, measured using the ABC/2 method. Six or more hours after the diagnostic CT, a stability CT was performed to ensure that the ICH clot had not expanded by >5 mL, providing image demonstration of a safe starting point for clot reduction therapy, defined as the absence of active bleeding before performing MIS+rt-PA. The CT could be repeated every six hours until the clot stabilized or just before the 48-hour eligibility window closed, whichever came first. In addition, a magnetic resonance image (MRI) or CT angiography (CTA) was required to rule out underlying pathology as the bleeding source; an angiogram was encouraged with equivocal findings on vascular pathology screening.17 An INR ≤1.3, a normal aPTT, and BP stability were required prior to randomization.18,19 After a protocol amendment, planned catheter insertion trajectories describing the skull entry site and the planned linear path to the hematoma target were shared by the site with the trial’s Surgical Center for joint review (stage two only).\n\nMIS Protocol\nIndividuals randomized to MIS+rt-PA were taken to the operating room and general anesthesia was induced. Image-guidance was used to place an introducer cannula within the middle two-thirds of the overall haematoma diameter, via a burr hole or twist drill opening. The introducer portion was then removed. Clot aspiration was performed using a 10 mL hand-held syringe until there was no longer any fluid component of the clot noted in the aspirate and/or until first resistance. A soft catheter was passed through a rigid, peel-away cannula into the residual haematoma, tunneled subcutaneously, and connected to a three-way stopcock and a closed drainage system. A postoperative CT was performed to confirm positioning of the soft catheter within, and stability of, the residual haematoma and catheter tract.\n\nThrombolysis Protocol\nThree or more hours after catheter placement, intraclot rt-PA administrations of 0.3 mg in 1 mL or 1.0 mg in 1 mL were given every 8 hours, for up to 9 doses, or until a trial-defined surgical performance requirement was reached. All doses were followed by a 3 mL flush of preservative-free normal saline. After each assigned dose, the system was closed for 1 hour to allow drug-clot interaction, and then reopened to allow for gravitational drainage. Trial-defined surgical performance requirements were reduction of clot to either 20% of the volume measured on the stability CT prior to randomization, or to ≤ 15 mL, or occurrence of a clinically significant re-bleeding event, defined as a sustained drop of more than two points on the Glasgow Coma Scale (GCS) motor score with CT-demonstrated ICH enlargement. CT scans were subsequently obtained every 24 hours until dosing was complete to evaluate safety and drainage.\n\nMedical Treatment Protocol\nAll subjects were managed using the American Heart Association recommendations for the treatment of non-traumatic (spontaneous) ICH.18–19 This allowed for a standard approach to monitoring patients’ airway, ventilation, intracranial pressure (ICP), sedation, and pharmacological treatment of intracranial mass effect. Patients randomized to receive standard medical care received follow up CT scans and other monitoring assessments on the same schedule as those randomized to receive MIS+rt-PA.\n\nFollow-up\nSubjects were followed with an MRI scan at Day 7. Subjects returned to clinic on Days 30, 180 (stages one and two), and 365 (stage two) and were contacted by phone at Days 90 (stages one and two) and 270 (stage two). A certified examiner assessed the modified Rankin Scale (mRS), Barthel Index (BI), Stroke Impact Scale (SIS), Glasgow Outcome Scale (GOS), extended GOS (eGOS), NIH Stroke Scale (NIHSS, clinic visits only) and a repeat CT (days 30 and 180 only).\n\nImage analysis\nTo optimize accuracy and minimize investigator bias, clot volumes were analyzed by a core laboratory utilizing semi-automated segmentation and Hounsfield thresholds.9 This was performed using OsiriX software (version 4.1) on DICOM images of each subject’s stability and treatment scans. This approach has been validated for accuracy and inter-rater reliability.20 The core lab values were utilized in all analyses. Core lab defined location as either lobar or deep (putamen or thalamus).\n\nPrimary and Secondary Outcomes\nThe aim of the MIS+rt-PA treatment was to achieve near total clot dissolution without procedure-related safety events that would endanger the lives of the patients beyond the risks associated with intensive medical treatment. The primary safety outcomes were 30-day mortality, 7-day procedure-related mortality, 30-day bacterial brain infection, and symptomatic bleeding within 72-hour after the last dose. The primary efficacy outcome was the adjusted 180-day dichotomized (mRS 0–3 vs. 4–6.) expressed as the proportion of all mRS subjects ≤3.\n\nSecondary efficacy outcomes were 180-day ordinal mRS, 365-day ordinal mRS, and difference in clot-size reduction at the end of the treatment for each group. All adverse and serious adverse events were reported during the acute treatment period and all serious adverse events until the end of the follow-up.\n\nStatistical analysis\nAnalyses are presented at three levels: primary planned safety analysis, primary intention to treat efficacy analysis, and exploratory analyses. The latter two are adjusted analyses.16\n\nTarget Sample Size\nThe study was designed and powered to explore safety and dosing for MIS+rt-PA. It was not powered to observe effect of treatment on functional outcome. This study had 90% power to detect a doubling in the rate of any rebleeding from 8% to 16% between dose groups of 15 subjects who received the MIS+rt-PA intervention at each dose level. The study had 80% power to detect a difference in rates of clot dissolution of 3% per day or greater, between groups of 15 subjects on different doses of rt-PA (stage one). It had a 91% to 99% power to observe one or more symptomatic bleeds for 15 subjects if the true bleeding rate was 15%. For stages one and two combined, assuming a total of 80 subjects, it had from 52% to 62% power to detect an absolute difference of 25% in the mortality rate assuming a 50% mortality rate. The target sample size for stage one was 20 subjects per dose group and for stages one and two combined the final target sample size was a total of 96 subjects.\n\nSafety Analysis\nAnalyses tested the hypothesis that there was no difference between the treatments being compared. We defined and pre-specified thresholds for the safe use of MIS+rt-PA for the treatment of ICH relative to standard medical care: for 30-day mortality (70%), symptomatic brain bleeding (35%), and bacterial brain infection (15%). We tested rates of events across groups by Fisher’s exact test and calculated exact binomial 95% confidence intervals (CI) for the rate of events. The method of Kaplan and Meier was used to estimate the survival functions (with 95% CI) for patients in both groups.\n\nIntention-to-Treat Efficacy Analysis\nWe estimated the mean benefit of MISTIE treatment vs. medical control using the ITT principle. Specifically, we estimated the difference between the probability of having 180-day mRS ≤3, referred to as a good outcome, under treatment vs. control. This average treatment effect was estimated using a simple difference in proportions among those with observed 180-day outcomes (unadjusted estimator) and also using an estimator that adjusts (adjusted estimator) for missing outcome data using the double-robust methodology for censored data of Rotnitzky et al.21,22 The adjusted estimator is fully described in the appendix (page 10); it has greater precision than the unadjusted estimator because of adjustments for potential imbalances between study arms in the prognostic baseline covariates: NIHSS, GCS, ICH volume, and intraventricular haemorrhage (IVH) volume.21\n\nExploratory Analyses\nPatient characteristics, safety, and outcome measures were reported by each site. To describe medical events we utilized terms and definitions from the Medical Dictionary for Regulatory Activities (MedDRA) and centrally adjudicated. Longitudinal plots were used to depict the percent ICH clot reduction from stability over time for each participant. LOESS (locally weighted scatter-plot smoothing) was applied to calculate mean clot reduction over time by treatment group.23\n\nTo investigate the role of clot volume reduction by MIS+rt-PA on outcome, we used logistic regression models to estimate the association between the primary outcome measure of dichotomized 180-day modified Rankin Scores ≤3 with treatment group, clot removal, and the baseline variables identified in the study protocol24: ICH clot size at randomisation, age, enrollment NIHSS, presence of IVH, and location of ICH. The multivariable logistic regression models were created by first considering univariable analyses to determine the independent associations between each covariate and the outcome. For parsimony, the variables chosen for the multivariable regression analyses, in addition to treatment, were those with p<0.1 in the univariable analyses; these variables are similar to those from previous ICH studies.6,8,25 Other prespecified baseline variables that were non-significant in the univariate analyses were systematically considered as candidate explanatory variables in the multivariate analysis, for the purpose of hypothesis generation. As in any variable selection method for model building, our approach has limitations and should be regarded as exploratory; see Sauerbrei et al.26 for a discussion of model building approaches. Sensitivity analyses were performed that considered all possible ‘good’ and ‘bad’ outcomes for patients with missing 180-day mRS scores to determine a possible tipping point that would change the statistical association between the outcome and clot removal.27,28 Logistic regression was used for sensitivity analyses of subgroups.\n\nSurgical Removal\nTo manage the influence of time on the subjects, we defined volume of clot removed at the specific times defined as follows: for patients in the MIS+rt-PA arm, the end of treatment (EOT) was defined to be 24 hours after the last dose of rt-PA was administered; the EOT scan for patients in the medical management arm was defined as the scan closest to the median EOT scan time for the surgical patients (4 days post randomization).9 The EOT scan among patients who received delayed craniotomy in the medical management arm was defined, on an ITT basis, as the scan prior to craniotomy. All analyses were performed using the statistical packages STATA (version 12.0) and R (version 3.2). The trial was registered on clinicaltrials.gov (NCT00224770).\n\nRole of the funding source\nThe NIH/NINDS provided input regarding the study design during the grant review process and the NIH/NINDS-appointed DSMB provided the same during active recruitment. The NIH/NINDS-appointed DSMB and Genentech, Inc. approved the decision to submit the paper for publication. DFH had full access to all study data and had final responsibility for the decision to submit for publication.\n\nResults\nThe trial ended after target enrollment was achieved. Study enrollment for stage one took place from February 2, 2006 to August 2, 2009. (See Fig.1). Stage two enrollments took place from December 21, 2009 through April 3, 2012, with the final follow-up visit occurring on April 8, 2013 after approval of the planned protocol amendment. The demographic characteristics of the randomized subjects are shown in Table 1. Fifty-four subjects (stages one and two combined) were randomized to the intervention: eight (15%) achieved the surgical goal at the end of the surgical procedure (i.e., after aspiration and catheter placement, and 46 (85%) received rt-PA via the catheter to further reduce the haematoma size (MIS+rt-PA). Forty-two subjects (stages one and two combined plus 6 subjects from stage one endoscopy arm) were randomized to medical care. Delayed deterioration led to craniotomy in four medical and in two MIS+rt-PA subjects (post MIS procedure). Overall, event rates were below pre-specified safety thresholds and the primary safety profile of symptomatic events was similar for both groups (Table 2). The entire surgical group had non-significantly more asymptomatic and significantly more total bleeding (Table 2). Kaplan-Meier analysis of survival over 365 days demonstrated no adverse effect of MIS+rt-PA on survival (hazard ratio 1.32 (95% CI: 0.618, 2.82) log rank p=0.473); see Figure S1 on page 13 in the Supplementary Appendix). Those randomized to the treatment arm achieved more rapid ICH volume reduction when compared to the standard medical care group (Fig. 2). Thirty-one of thirty-five neurosurgeons easily acquired the technical skills (87% training efficiency). There were no differences in volume of clot removed between a surgeon’s 1st and 4th procedure performed or between “neophyte” and “expert” surgeon (data not shown).\n\nBoth rt-PA doses increased clot removal, when compared to the control group, with no differences in symptomatic bleeding rate 0 (0%) vs. 2 (13%) for 1.0. mg vs 0.3 mg, respectively and 1 (2%) for control (difference between doses 95% CI: −3.87%, 30.54%; p=0.483); leading to the selection of the 1.0 mg dose for stage two (Table S6, appendix page 22). Overall, for both stages one and two symptomatic bleeding was 1 (2%) vs. 5 (9%); difference between treatment groups 6.9% (95%CI: 4.6%, 18.1%; p=0.2263). Reduction of clot volume over time and for the ITT analysis at about Day 4 is shown in Figure 2. Overall, the mean (SD) percent reduction of haematoma size (EOT ICH/Randomization ICH) in the MIS+rt-PA group was 57% (± 25%). The mean (SD) EOT ICH was 20 (± 14) mL in the MIS+rt-PA subjects and 41 (± 15) mL p< 0.0001 in the medical management subjects (mean [95% CI] difference: 21 [15mL, 27 mL]).\n\nResults: ITT Efficacy Analysis\nThe primary efficacy outcome was the proportion of all subjects with mRS ≤3 at 180 days was 21% for medical and 33% for MIS arms. The unadjusted estimate of the absolute benefit (i.e., the difference between the probability of having 180 day mRS ≤ 3 under treatment vs. control) is 0.109 [95%CI: −0.088, 0.294], based on the n=96 ITT randomized participants. The adjusted estimate using the robust method of Rotnitzky et al.21,22 is an absolute benefit of 0.162 [95%CI: 0.003, 0.323].\n\nA secondary outcome was mRS ≤3 at 365 days which was only measured for stage two participants (n=56, who had extended follow-up). The unadjusted estimate of the absolute benefit at 365 days is 0.117 [95%CI: −0.146, 0.370] and the adjusted estimate was and 0.115 [95%CI: −0.171, 0.306].\n\nAdditional secondary analyses focus on ordinal (rather than dichotomous) mRS scores. The proportion in each mRS category at 180 days (stages one and two participants) and at 365 days (stage two participants only) is shown in Table 3 demonstrating the beneficial trend is maintained at the later time frame.\n\nResults: Exploratory Analyses\nResults of the logistic regression analysis on the binary indicator good vs. unfavorable mRS scores are presented in Table S1 on page 17 of the Supplementary Appendix. When we considered univariable (unadjusted) models, we found that pre-randomized ICH volume, age, enrollment NIHSS, the presence of any pre-randomization IVH, and the absolute clot volume remaining at the EOT were statistically significant; assignment to MIS+rt-PA resulted in a nonsignificant benefit (similar to the estimates in the ITT efficacy analysis above). Table S1 shows the results of the multivariable logistic regression of good 180-day outcome on the aforementioned variables. After controlling for age, enrollment NIHSS, pre-randomized ICH volume and presence of IVH, and assignment to MIS+rt-PA, the absolute volume of clot remaining at the EOT is statistically significant. Specifically, the model predicts that with all other variables held constant, each 10 mL of additional clot remaining at the end of treatment is associated with a relative reduction in the odds of a good 180-day outcome by almost 50% (Adjusted Odds Ratio 0.496; [95%CI] 0.259, 0.949, p= 0.034). This is consistent with the hypothesis that clot volume reduction is an important mechanism through which assignment to MIS+rt-PA results in greater probability of mRS ≤3 at 180 days. Unadjusted ITT analyses in different subgroups are shown in Figure S2 on page14 of the Supplementary Appendix. There were no statistically significant results by subgroup, but all point estimates are in the beneficial direction of the MIS+rt-PA treatment compared to medical management and the point estimate for deep clot location corresponds to greater benefit than for lobar clot location, although again not statistically significant.\n\nDiscussion\nMIS+rt-PA appears safe when tested in our phase 2 study, with a possible advantage of better functional outcome at 180 days. However, increased asymptomatic bleeding is a major cautionary finding. MISTIE II is an important test of a very gentle approach to ICH evacuation, minimizing potential tissue injury inherent in craniotomy. It employs image guidance and a novel combination of surgery and drug treatment. The MISTIE II approach was reliably reproduced by surgeons new to the treatment concept but trained in the general principles. The surgical technique is a simple and logical extension of routine image guidance and intracerebral catheter placement. Where both pragmatic (craniotomy) and simple translational (factor VIIa) approaches have failed in trials, our results are promising and contrary to the belief that surgical manipulations to remove blood may damage brain tissue and impair long-term function.5,29,30 Because supportive medical care is the only universally-accepted ICH treatment, these results are promising19,30 and consistent with trends from studies of convenience samples or at single sites.31,32 We have demonstrated that MIS can be performed safely at multiple sites, that rt-PA can be combined with MIS safely, and that the MISTIE treatment, though different from current practice, can be adopted without difficulty at interested sites. Thus, MISTIE could be a promising approach to a worldwide health problem. If the apparent benefits of the MISTIE approach are replicable, the findings could lead to a change in treatment of ICH.\n\nSeveral limitations are considered. This trial size is small and screening yield low (123 enrolled of 4103 screened). It was powered to observe relatively high safety thresholds (15% bleeding), not efficacy; thus, the range of estimated benefit in the ITT analysis is wide and the true benefit could be different. However, all known baseline severity factors (ICH size, IVH size, age, NIHSS, GCS and stability) were nearly balanced between arms. The point estimates in both adjusted ITT analyses are suggestive of a treatment benefit. Safety conclusions are similarly limited by sample size; the substantial difference in asymptomatic bleeding demonstrates that combining MIS and alteplase still has important risks.\n\nWe hypothesize that the effect of the MISTIE treatment on mRS outcome is mediated through clot volume reduction, although such a relationship cannot be assessed without a second trial. We considered potential confounders of the relation between clot-reduction and mRS outcomes, such as length of ICU care and use of ICP monitoring; these were similar in both treatment groups. Surgical bias could unknowingly account for good outcomes; however, the usual source of this problem—selection of less severe subjects for surgery—did not occur, as the randomized surgical subjects were slightly, but non-significantly, more impaired at baseline, and all subjects were consented without knowledge of surgical allocation, further limiting the possibility of surgical selection bias. A bias could also be that the population was not fully representative of the general population of ICH subjects and that the routine care that medical management subjects received may account for the surgical benefit by having selected a sicker subgroup. This is not likely, as the distribution of good and poor outcomes for the medical subjects is similar to that found in observations of other ICH populations. A bias in the amount of rehabilitation care a particular group received is also possible. Finally it remains possible that specialized skills, such as surgical skill or superior stroke center organizational resources produced the benefits rather than the MISTIE treatment, rendering the results not reproducible by a wider set of surgeons or centers. This seems unlikely, as the majority of the surgeons, although trained in image guidance and catheter placement, previously had not combined these skills to treat ICH. Similarly, attention to BP control in MISTIE is already a well-developed and standard approach in established stroke center protocols.8,18,23,25,33\n\nOur outcome data suggest that MIS+rt-PA has the potential to be efficacious where routine craniotomy has failed. Comparisons to existing trial data31 and meta-analysis data32,34,35 are reassuring for the possible generalizability of these findings. Mortality was low and not different for medical or surgical subjects and was similar to STICH I & II mortalities,36,37 suggesting that the surgical procedure itself is low risk. This is in agreement with other MIS observations.32 The low mortality may relate to the infrequent discontinuation of care. Interestingly, the deep ICHs that responded so poorly to invasive craniotomy in STICH I appear to have benefitted from MIS plus rt-PA.\n\nAdministration of rt-PA following MIS also appears safe in this small sample utilizing mortality and symptomatic bleeding as the main safety measures, but only if performed under MISTIE protocol conditions. Some rebleeding must be expected in ICH patients and with exposure to surgery and thrombolytic drug. The significantly increased occurrence of asymptomatic bleeding provides biologic plausibility for further safety evaluations. The combined use of imaging to define clot stability and BP control appears to have limited the frequency of symptomatic bleeding events in both arms of MISTIE and the absence of a symptomatic rebleeding difference between MIS+rt-PA and controls is a reassuring safety profile for a thrombolytic treatment approach; external monitoring and core imaging lab assessments for enlargement reinforce our confidence in this safety profile. However, the presence of higher frequencies for all bleeding categories in the treatment arm demonstrates that the possible benefits of MIS+rt-PA come with a clear potential bleeding risk that must be managed with clinical vigilance. A larger sample is needed to confirm that the current clinical vigilance (ICH stability, dose and BP control) is reproducible in the widest possible population. A phase 3 study would provide a better estimate of safety and particularly bleeding events.\n\nThe MISTIE approach targets two major sources of ICH morbidity: mass effect and inflammation. The functional outcomes in the treatment group are consistent with better tissue preservation9,10 and, when compared to the medical management group equally treated with ICH stabilization and BP control, reassuring for the potential to reproduce the result in other populations. The trial design was not able to differentiate whether better tissue preservation was attributable to mass-effect reduction or to removal of inflammation-provoking blood products; most likely both are important effects of clot reduction. Because removal took place over three to four days, it is likely that some degree of secondary injury from mass effect and inflammation occurs over days, not hours. If the MISTIE approach of minimal mechanical manipulation is to be employed the majority of subjects (85%) will require rt-PA irrigation to achieve large reductions of clot volume. Analysis of subgroups suggests the potential for benefit in a window of at least 48 hours. If the time window is this large, then MISTIE treatment could possibly be scheduled urgently rather than in an emergent manner. The model and subgroup findings represent hypothesis generating information such as time dependence of treatment and require independent confirmation. For example if much damage occurs by chemical means in the initial hours there could be additional benefit to very early removal or biochemical blockade of such events.\n\nTesting the reproducibility of our results will require at least 500 subjects in a randomized trial; possibly more, if the estimate of therapeutic effect is falsely large or if the symptomatic bleeding risk is underestimated. A rigorous test should include stringent reproduction of the standard elements of the surgical and drug-administration tasks used in MISTIE II in a cohort of subjects recruited from the widest possible set of stroke hospitals utilizing image guidance, CT imaging, and BP control to treat ICH. Decreases (s) in treatment related bleeding events might benefit outcome. Testing generalisability will provide a better estimate of the number of treatment candidates. Safety and preliminary outcome data indicate that MIS+rt-PA is a realistic approach to ICH, possibly improving long-term function and the ability to live at home, and perhaps, decreasing cost, even for patients with large ICH volumes.\n\nPanel: Research in Context\nEvidence before this study\nMinimally invasive surgery was reviewed in a recent meta-analysis by Zhou et al. This review of international databases, websites, and conference summaries such as Pubmed and the International Clinical Trials Registry were searched through December 2011 using the following key words: intracerebral, intracranial, cerebral, brain, putaminal, intraparenchymal, basal ganglia hemorrhage, thalamic, hemorrhagic stroke, hemorrhage, hematoma, minimally invasive, minimal surgical procedures, endoscopy, stereotaxy(ic), aspiration, keyhole, or craniopuncture. Inclusion criteria were nontraumatic (spontaneous) ICH diagnosed on a CT and randomized controlled trials with minimally invasive surgery compared to a control group. Exclusion criteria were traumatic brain injuries, infratentorial ICH, and studies with quality assessments less than 2 on the Cochrane criteria scale. An Egger test was conducted to check for publication bias for primary and secondary outcomes (P=0.377 and P=0.805 respectively).\n\nWe have thirty years of evidence that clinical injury from ICH is directly related to the size of the clot. Benefit from the obvious solution of reducing the clot size by mechanical means has been difficult to demonstrate. Now with the completion of STICH 1 & 2, we have a strong indication that pragmatic use of open craniotomy does not produce the presumed benefits. Today, when caring for the millions of spontaneous ICHs that occur yearly, clinicians are faced with substantial class 1 evidence demonstrating no effect of routine craniotomy on the functional performance of subjects experiencing brain hemorrhage. STICH 1 also demonstrated that subjects with deep basal ganglia hematomas were particularly likely to experience a poor outcome, if they underwent craniotomy. These findings were consistent with samples from the general population and suggest, in a congruent manner, that an alternate approach to ICH be considered. Small studies have tested the idea that catheter-based, minimally invasive clot volume reduction can be performed without loss of life and that individual subjects experience improved outcome in increased proportion. Because of the significant morbidity and mortality associated with ICH, hyper acute craniotomy and deep location of ICH in particular, we chose to organize a two-stage test of the possibility that minimally invasive surgery, performed on stabilized subjects provides benefit from clot reduction without exposing patients to as much injury as was possibly occurring from open craniotomy. Further testing of this idea could include studies of the recovery process as well as larger trials.\n\nAdded value of this study\nTo the best of our knowledge MISTIE II is the first rigorous study of brain MIS because it was a multisite study with a standardized surgical task designed to eliminate cortical incision, electrocautery, toxic exposure to thrombin and the attendant additional loss of deep brain tissue. The results provide evidence of safety of the MIS approach and identify the best dose of thrombolytic to be employed for clot volume reduction. It identifies that you cannot combine MIS and alteplase without increased incidence of asymptomatic bleeding. The need for meticulous management of bleeding risk is inherent in this finding. In addition, results produced an estimate of treatment effect that is substantial (>10% absolute benefit) and longstanding (one year). As such, these data provide novel safety, surgical performance and overall proof of concept for the hypothesis that MIS has robust potential as a unique intervention for intracerebral hemorrhage.\n\nImplications of all the available evidence\nAlthough this manuscript focuses on the results of MISTIE II and the possible role of clot volume reduction as a mechanism of treatment, it is consistent, in a clearly defined prospective manner, with the external data from single site and meta-analysis of convenience samples. The data provide a sound basis to estimate a treatment effect and inform clinical goals for the surgical task of clot size reduction, if performed in the standard manner described (i.e., single tissue trajectory, small tissue cannula, minimal mechanical manipulation). The manuscript highlights the possibility that MIS is a technique with promise to mechanically reduce lesion size in all or many subjects and has the potential to directly alter the course of events set in motion by the presence of blood clot within brain tissue and treat a disease for which we have no therapy. Trials utilizing this approach will require well-defined management of bleeding risk and identification of relevance or not to amyloid vasculopathy. The time window for ICH trials remains broad as sub group analysis in MISTIE did not find benefit or detriment in the times observed. The precise role of clinical stability in patient selection is another subject for future trials. The findings have stimulated multiple smaller tests of parts of our MIS thought process with many variations of equipment and surgical technique. Sharing the full results of MISTIE II is likely to stimulate further investigations of a worldwide problem that is serious and growing. An investigator-initiated, publically sponsored NIH trial MISTIE 3 is underway to prospectively test the generalizability of the MISTIE 2 surgical task and medical stabilization protocol.\n\nSupplementary Material\n This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.\n\nContributions. DFH and MZ organized the trial hypotheses, designed the trial, and provided guidance about the data analysis and interpretation/presentation of the data. DFH drafted most of the sections of the manuscript. EFA, CW, WCB, RSG, RD, JLC, JH, PC, PV, NM, IA, ADM, BG, PK, KL, and NMcB were involved in the design of the study and provided contributions to the writing and revising of the manuscript. KL, NMcB, SWM, and AJBH organized and managed the trial including trial start-up, data collection, quality assurance, and trial close-out. DG, TCM, NU, and WAM provided the region of interest calculations for all volumetric measurement results. WZ, CK, and JRC provided independent review and adjudication of all safety events. RET, JM, MR, CBT, GY, and EH were involved in the statistical analysis, data interpretation, and contributed to the development and revisions to the manuscript. SJ provided critical review of the manuscript. The MISTIE II investigators contributed equally to the identification and, when eligible, randomization of trial participants.\n\nDeclaration of Interests. IA, DFH, SWM, NU, KL, NMc, WAM, MR (R01NS046309 and U01NS062851), CBT, and PV report grants from the National Institute of Neurological Disorders and Stroke (NINDS) during the conduct of the study. DFH reports non-financial support from Genentech and Johnson& Johnson (Codman) during the conduct of the study, grants from NINDS outside the submitted work, and expert testimony. SWM reports personal fees from Johns Hopkins University outside the submitted work. JM reports grants from the National Institutes of Health during the conduct of the study and has a patent (C13388—primary intracerebral haemorrhage prediction employing logistic regression and features extracted from CT) pending for Johns Hopkins. ADM reports grants from the National Institutes of Health during the conduct of the study, non-financial support as the Director of the Newcastle Neurosurgery Foundation, and personal fees from Advisor to Stryker and Draeger outside the submitted work. BG reports grants from Johns Hopkins University (MISTIE National Institutes of Health grant) during the conduct of the study and grants from the National Institutes of Health Research (UK) Health Technology Assessment Programme outside the submitted work. All other authors declare no competing interests.\n\nWe thank the patients and families who volunteered for this study, Rachel Dlugash for her assistance with data summarization, and Pat Reilly for her guidance. Minimally Invasive Surgery and rt-PA in ICH Evacuation Phase II (MISTIE II) was supported by grant R01NS046309 awarded to Dr. Daniel Hanley from the National Institutes of Health (NIH)/National Institute of Neurological Disorders and Stroke (NINDS). Alteplase was donated by Genentech, Inc. Catheters and introducers were donated by Codman, Inc.\n\nFigure 1 CONSORT diagram of the MISTIE II trial\nincludes 6 medical subjects from Tier III (not shown); ITT efficacy analysis\n\nFigure 2 ICH removal by treatment group\nThis figure demonstrates the treatment effectiveness measured in terms of amount and timing of ICH removal. Panel A is a plot of percent of clot remaining as measured on daily CT scan after achieving clot size stability and initiating MIS+rt-PA, thin lines are individual subjects. Dense blue and red lines are the fitted average response. The gray-shaded area is the 95% confidence intervals of this average response. The black line identifies the average occurrence of the 24-hour post last treatment time point. Panel B represents the distribution of each subject’s clot removal expressed as absolute volume reduction on the day 4 EOT CT scan. The dashed line indicates the 50th percentile subject and respective ICH volume reduction for the medical subject cohort. The dotted line indicates the 50th percentile subject and respective volume reduction for this subject in the MIS+rt-PA group. All volumes were detrmined by the core lab. Removal is as defined in the methods.\n\nTable 1 Baseline Demographics and Characteristics by Treatment Group.\n\n\tMedical (N=42)\tMIS+rt-PA (N=54)\tP values\t\nDemographic variables\t\t\t\t\n\t\n Age in Years: Mean (SD)\t61.1 (12.3)\t60.7 (11)\t\t\n Age in Years: Median (IQR)\t62 (49.5 - 73)\t60 (54 - 69)\t\t\n\t\n Gender: Male\t28 (66.7%)\t35 (64.8%)\t\t\n\t\n Race\t\t\t\t\n Caucasian\t23 (54.8%)\t30 (55.6%)\t\t\n African American\t11 (26.2%)\t18 (33.3%)\t\t\n Hispanic\t5 (11.9%)\t4 (7.4%)\t\t\n Other\t3 (7.1%)\t2 (3.7%)\t\t\n\t\nBaseline variables\t\t\t\t\n\t\n Diabetes\t11 (26.2%)\t14 (25.9%)\t\t\n History of Hypertension\t34 (81%)\t49 (90.7%)\t\t\n Other Cardiovascular Disease\t14 (33.3%)\t22 (40.7%)\t\t\n Alcohol Abuse\t7 (16.7%)\t17 (31.5%)\t\t\n\t\n Presentation Blood Pressure\t\t\t\t\n Systolic BP (mmHg): Mean (SD)\t186.7 (34.1)\t186.4 (33.0)\t\t\n Diastolic BP (mmHg): Mean (SD)\t101.9 (20.4)\t106.8 (27.7)\t\t\n\t\n Enrollment GCS\t\t\t\t\n 3–8\t13 (31%)\t17 (31.5%)\t\t\n 9–12\t12 (28.6%)\t20 (37%)\t\t\n 13–15\t17 (40.5%)\t17 (31.5%)\t\t\n\t\n Enrollment NIHSS: Mean (SD)\t21.6 (8.9)\t22.8 (8.5)\t\t\n Enrollment NIHSS: Median (IQR)\t21 (17 - 27)\t22 (18 - 29)\t\t\n\t\n Stability CT (last CT prior to enrollment)\t\t\t\t\n ICH Volume (mL): Mean (SD)\t43.1 (15.3)\t48.2 (19.6)\t\t\n ICH Volume (mL): Median (IQR)\t41.4 (33.2 - 50)\t43.4 (31.6 - 59.3)\t\t\n IVH Volume (mL): Mean (SD)\t2.4 (3.9)\t4.6 (7.7)\t\t\n IVH Volume (mL): Median (IQR)\t0.7 (0 - 3.1)\t0.8 (0 - 4.4)\t\t\n\t\n Clot Location\t\t\t\t\n Lobar\t15 (35.7%)\t18 (33.3%)\t\t\n Deep\t27 (64.3%)\t36 (66.7%)\t\t\n\t\nTreatment variables\t\t\t\t\n\t\n % With ICP monitoring\t10 (23.8%)\t9 (16.7%)\t0.444\t\n\t\n % Ventilated\t16 (38.1%)\t25 (46.3%)\t0.533\t\n\t\n Time from Ictus to Randomization (Days)\t1.3 (0.6)\t1.2 (0.5)\t0.174\t\n\t\n Systolic BP (mmHg): Mean (SD)\t145.3 (20.7)\t143.9 (21.1)\t0.741\t\n\t\n Diastolic BP (mmHg): Mean (SD)\t73 (14.9)\t71.2 (13.1)\t0.534\t\n\t\n Time from Randomization to Surgery\n(Hours)\t\t6.6 (7.8)\t\t\n\t\n Surgery (elapsed time from symptom\nonset)\t\t\t\t\n ≤ 36 Hours\t\t31 (57.4%)\t\t\n > 36 Hours\t\t23 (42.6%)\t\t\n\t\n Number of Doses of rt-PA: Median (IQR)\t\t3.5 (2 - 5.8)\t\t\n\t\n Days in ICU (IQR)†\t8 (5–13)\t8 (6–15)\t0.839\t\n\t\n Days to return home (IQR)‡\t89 (54–146)\t51 (36–89)\t0.031\t\n* SD, Standard deviation; IQR, inter-quartile range. Unless otherwise specified, the values are expressed as count and % within group.\n\n† P=0.839 comparing medical to MIS+rt-PA.\n\n‡ P=0.031 comparing medical to MIS+rt-PA\n\nTable 2 Adjudicated Safety Events, with Thresholds for Randomized Medical and MIS+rt-PA with 95%CI.\n\nEvent\tStudy-\nstop\nthreshold\tMedical\n(N=42)\tMIS+rt-PA\n(N=54)\tp-value\t\n\t\tno (%)\t95% CI\tno (%)\t95% CI\t\t\nDied within 0–7 days\t10%\t0 (0%)\t(0%, 8.4%)\t1 (1.9%)\t(0.1%, 9.9%)\t0.562\t\nDied Within 0–30 Days\t70%\t4 (9.5%)\t(2.7%, 22.6%)\t8 (14.8%)\t(6.6%, 27.1%)\t0.542\t\nBacterial Brain Infection\n0–30 Days\t15%\t1 (2.4%)\t(0.1%, 12.6%)\t0 (0%)\t(0%, 6.6%)\t0.438\t\nSymptomatic Bleed 72 h\npost last dose†\t35%\t1 (2.4%)\t(0.1%, 12.6%)\t5 (9.3%)\t(3.1%, 20.3%)\t0.226\t\nAsymptomatic Bleed 72\nh post last dose‡\tn/a\t3 (7.1%)\t(1.5%, 19.5%)\t12 (22.2%)\t(12%, 35.6%)\t0.051\t\nSymptomatic or\nAsymptomatic Bleed 72\nh post last dose§\tn/a\t4 (9.5%)\t(2.7%, 22.6%)\t15 (27.8%)\t(16.4%, 41.6%)\t0.038\t\n Bacterial brain infection criteria included cultured organism identification in the presence of fever, relevant lab values, and associated clinical symptoms.\n\n† Symptomatic bleeding criteria included radiographic evidence of an increase in clot volume (>5ml increase) associated with a decrease in the GCS motor scale score of more than two points sustained for a minimum of eight hours or associated clinical symptoms in the opinion of the site investigator.\n\n‡ Asymptomatic brain bleeding was reported and adjudicated to include those events where clot size increase (>5ml increase) was confirmed by the core lab on volumetric measurement of the CT scan by comparison to the most previous CT scan, but where no alteration of GCS was noted.\n\n§ Symptomatic or asymptomatic bleed is the total of all adjudicated bleeding events.\n\nTable 3 Functional Outcome Showing Modified Rankin Scale Scores at Days 180 and 365 Comparing MISTIE Treatment vs. Medical Controls for All Randomized subjects.\n\n\tTreatment Group\nDay 180\tTreatment Group\nDay 365\t\nmRS Score\tMedical\n(N=42)\tMIS+rt-PA\n(N=54)\tMedical\n(N=31)\tMIS+rt-PA\n(N=25)\t\n0\t0 (0.0%)\t0 (0.0%)\t0 (0.0%)\t1 (4.0%)\t\n1\t0 (0.0%)\t1 (1.9%)\t1 (3.2%)\t3 (12.0%)\t\n2\t4 (9.5%)\t6 (11.1%)\t2 (6.5%)\t2 (8.0%)\t\n3\t5 (11.9%)\t11 (20.4%)\t3 (9.7%)\t2 (8.0%)\t\n4\t12 (28.6%)\t13 (24.1%)\t6 (19.4%)\t3 (12.0%)\t\n5\t6 (14.3%)\t7 (13.0%)\t3 (9.7%)\t2 (8.0%)\t\n6\t11 (26.2%)\t14 (25.9%)\t11 (35.5%)\t10 (40.0%)\t\nMissing\t4 (9.5%)\t2 (3.7%)\t5 (16.1%)\t2 (8.0%)\t\n Includes participants from primary analysis set (which includes randomized patients from stages one and two). For graphical display see Supplement Figure S4.\n\n** Includes only randomized participants enrolled in stage two, i.e., those enrolled after protocol change extending follow-up to 365 days.\n==== Refs\nReferences\n1 Krishnamurthi RV Feigin VL Forouzanfar MH Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990–2010: findings from the Global Burden of Disease Study 2010 The Lancet Global Health 2013 1 e259 e281 25104492 \n2 Hachinski V Donnan GA Gorelick PB Stroke: working toward a prioritized world agenda Stroke; a journal of cerebral circulation 2010 41 1084 1099 \n3 Cadilhac DA Dewey HM Vos T Carter R Thrift AG The health loss from ischemic stroke and intracerebral hemorrhage: evidence from the North East Melbourne Stroke Incidence Study (NEMESIS) Health and Quality of Life Outcomes 2010 8 49 20470370 \n4 Christensen MC Mayer S Ferran JM Quality of life after intracerebral hemorrhage: results of the Factor Seven for Acute Hemorrhagic Stroke (FAST) trial Stroke; a journal of cerebral circulation 2009 40 1677 1682 \n5 Mendelow AD Gregson BA Fernandes HM Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial Lancet 2005 365 387 397 15680453 \n6 Mendelow AD Gregson BA Rowan EN Murray GD Gholkar A Mitchell PM Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial Lancet 2013 382 397 408 23726393 \n7 Mayer SA Brun NC Begtrup K Efficacy and safety of recombinant activated factor VII for acute intracerebral hemorrhage N Engl J Med 2008 358 2127 2137 18480205 \n8 Anderson CS Heeley E Huang Y Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage N Engl J Med 2013 368 2355 2365 23713578 \n9 Mould WA Carhuapoma JR Muschelli J Minimally invasive surgery plus recombinant tissue-type plasminogen activator for intracerebral hemorrhage evacuation decreases perihematomal edema Stroke; a journal of cerebral circulation 2013 44 627 634 \n10 Wagner KR Xi G Hua Y Ultra-early clot aspiration after lysis with tissue plasminogen activator in a porcine model of intracerebral hemorrhage: edema reduction and blood-brain barrier protection J Neurosurg 1999 90 491 498 10067918 \n11 Morgan T Zuccarello M Narayan R Keyl P Lane K Hanley D Preliminary findings of the minimally-invasive surgery plus rtPA for intracerebral hemorrhage evacuation (MISTIE) clinical trial Acta Neurochir Suppl 2008 105 147 151 19066101 \n12 Hanley DF Lane K Broaddus WC Mistie Trial: 365-day Results Demonstrate Improved Outcomes and Cost Benefit International Stroke Conference 2013 Honolulu, Hawaii American Heart Association \n13 Montes JM Wong JH Fayad PB Awad IA Stereotactic computed tomographic-guided aspiration and thrombolysis of intracerebral hematoma: protocol and preliminary experience Stroke 2000 31 834 840 10753984 \n14 Rohde V Rohde M Reinges L Mayfrank L Gilsbach JM Frameless stereotactically guided catheter placement and fibrinolytic therapy for spontaneous intracerebral hematomas: technical aspects and initial clinical results Minim Invasive Neurosurg 2000 43 9 17 10794561 \n15 Zuccarello M Brott T Derex L Early surgical treatment for supratentorial intracerebral hemorrhage: a randomized feasibility study Stroke 1999 30 1833 1839 10471432 \n16 MIS+rtPA for ICH Evacuation (MISTIE) at http://clinicaltrials.gov/show/NCT00224770 .) \n17 Josephson CB White PM Krishan A Al-Shahi Salman R Computed tomography angiography or magnetic resonance angiography for detection of intracranial vascular malformations in patients with intracerebral haemorrhage Cochrane Database Syst Rev 2014 9 CD009372 \n18 Morgenstern LB Hemphill JC 3rd Anderson C Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association Stroke; a journal of cerebral circulation 2010 41 2108 2129 \n19 Broderick J Connolly S Feldmann E Guidelines for the management of spontaneous intracerebral hemorrhage in adults: 2007 update: a guideline from the American Heart Association/American Stroke Association Stroke Council, High Blood Pressure Research Council, and the Quality of Care and Outcomes in Research Interdisciplinary Working Group Circulation 2007 116 e391 e413 17938297 \n20 Morgan TC Dawson J Spengler D The Modified Graeb Score: an enhanced tool for intraventricular hemorrhage measurement and prediction of functional outcome Stroke 2013 44 635 641 23370203 \n21 Rotnitzky A Lei Q Sued M Robins JM Improved double-robust estimation in missing data and causal inference models Biometrika 2012 99 439 456 23843666 \n22 Colantuoni E Rosenblum M Leveraging Prognostic Baseline Variables to Gain Precision in Randomized Trials Stat Med (In Press). Working paper available here: http://goo.gl/bj6WHA \n23 Cleveland WSGE Shyu WM Local Regression Models Statistical models in S 1992 309 376 \n24 Tuhrim S Horowitz DR Sacher M Volume of ventricular blood is an important determinant of outcome in supratentorial intracerebral hemorrhage Critical Care Medicine 1999 27 617 621 10199544 \n25 Davis SM Broderick J Hennerici M Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage Neurology 2006 66 1175 1181 16636233 \n26 Sauerbrei W Royston P Binder H Selection of important variables and determination of functional form for continuous predictors in multivariable model building Stat Med 2007 26 5512 5528 18058845 \n27 Yan X Lee S Li N Missing data handling methods in medical device clinical trials J Biopharm Stat 2009 19 1085 1098 20183466 \n28 Liublinska V Rubin DB Sensitivity analysis for a partially missing binary outcome in a two-arm randomized clinical trial Stat Med 2014 33 4170 4185 24845086 \n29 Steiner T Kaste M Forsting M Recommendations for the management of intracranial haemorrhage - part I: spontaneous intracerebral haemorrhage. The European Stroke Initiative Writing Committee and the Writing Committee for the EUSI Executive Committee Cerebrovasc Dis 2006 22 294 316 16926557 \n30 Steiner T Al-Shahi Salman R Beer R European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage Int J Stroke 2014 9 840 855 25156220 \n31 Zhou H Zhang Y Liu L Minimally invasive stereotactic puncture and thrombolysis therapy improves long-term outcome after acute intracerebral hemorrhage Journal of Neurology 2011 258 661 669 21340523 \n32 Zhou X Chen J Li Q Minimally Invasive Surgery for Spontaneous Supratentorial Intracerebral Hemorrhage: A Meta-Analysis of Randomized Controlled Trials Stroke; a journal of cerebral circulation 2012 43 2923 2930 \n33 Ziai W Stadnik A Zhang L Stabilizing Bleeding Prior To Acute Therapies For Spontaneous Intracerebral Hemorrhage Stroke 2014 45 \n34 Gregson BA Broderick JP Auer LM Individual patient data subgroup meta-analysis of surgery for spontaneous supratentorial intracerebral hemorrhage Stroke 2012 STROKEAHA. 111.640284 \n35 Zhou X Chen J Li Q Minimally invasive surgery for spontaneous supratentorial intracerebral hemorrhage a meta-analysis of randomized controlled trials Stroke 2012 43 2923 2930 22989500 \n36 Mendelow AD Gregson BA Fernandes HM Early surgery versus initial conservative treatment in patients with spontaneous supratentorial intracerebral haematomas in the International Surgical Trial in Intracerebral Haemorrhage (STICH): a randomised trial The Lancet 2005 365 387 397 \n37 Mendelow AD Gregson BA Rowan EN Early surgery versus initial conservative treatment in patients with spontaneous supratentorial lobar intracerebral haematomas (STICH II): a randomised trial The Lancet 2013 382 397 408\n\n", "fulltext_license": "CC BY-NC-ND", "issn_linking": "1474-4422", "issue": "15(12)", "journal": "The Lancet. Neurology", "keywords": null, "medline_ta": "Lancet Neurol", "mesh_terms": "D000368:Aged; D002543:Cerebral Hemorrhage; D003131:Combined Modality Therapy; D005260:Female; D005343:Fibrinolytic Agents; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D019060:Minimally Invasive Surgical Procedures; D017063:Outcome Assessment, Health Care; D019106:Postoperative Hemorrhage; D025321:Surgery, Computer-Assisted; D017131:Thrombectomy; D010959:Tissue Plasminogen Activator", "nlm_unique_id": "101139309", "other_id": null, "pages": "1228-1237", "pmc": null, "pmid": "27751554", "pubdate": "2016-11", "publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial", "references": "20651276;25156220;19265046;23391763;25872751;25104492;16926557;24845086;21340523;16636233;10067918;10794561;10199544;17938297;18058845;10471432;23726393;20498453;22511006;19066101;10753984;23713578;23843666;18480205;22989500;23370203;20183466;15680453;25177839;20470370", "title": "Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial.", "title_normalized": "safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation mistie a randomised controlled open label phase 2 trial" }	[ { "companynumb": "US-ROCHE-1851840", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "ALTEPLASE" }, "drugadditional": null, "druga...
{ "abstract": "We report the clinical case of a 12-years' intoxication by doxycycline. A patient with a depersonalization and derealization syndrome took 1 g doxycycline per day. In addition to hepatocellular necrosis with cholestasis, nephrotoxicity, leukopenia, anaemia and skin hyperpigmentation he suffered from hitherto unreported adverse cardiac events as intermittent supraventricular tachycardia and sporadic Wenckebach heart block. Despite a long period of self-medication these side-effects were reversible.", "affiliations": "Department of Internal Medicine D, Westfälische Wilhelms-University, Münster, Germany. Gerald.Westermann@t-online.de", "authors": "Westermann\|G W\|GW\|;Böhm\|M\|M\|;Bonsmann\|G\|G\|;Rahn\|K H\|KH\|;Kisters\|K\|K\|", "chemical_list": "D004318:Doxycycline", "country": "England", "delete": false, "doi": "10.1046/j.1365-2796.1999.00606.x", "fulltext": null, "fulltext_license": null, "issn_linking": "0954-6820", "issue": "246(6)", "journal": "Journal of internal medicine", "keywords": null, "medline_ta": "J Intern Med", "mesh_terms": "D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D002908:Chronic Disease; D004318:Doxycycline; D006327:Heart Block; D006801:Humans; D017495:Hyperpigmentation; D007970:Leukopenia; D008297:Male; D012651:Self Medication; D013617:Tachycardia, Supraventricular", "nlm_unique_id": "8904841", "other_id": null, "pages": "591-2", "pmc": null, "pmid": "10620103", "pubdate": "1999-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Chronic intoxication by doxycycline use for more than 12 years.", "title_normalized": "chronic intoxication by doxycycline use for more than 12 years" }	[ { "companynumb": "DE-PFIZER INC-2015214257", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "DOXYCYCLINE" }, "drugadditional": null, ...
{ "abstract": "Pentazocine, a non-narcotic analgesic, though has no addictive potential but abused frequently via parenteral route for its psychological dependence. It causes local sclerosis resulting in non-healing ulcer at injection sites. Diabetes mellitus suppress host immunity, making them vulnerable to various bacterial skin and soft tissue infection among which mkethicillin resistant staphylococcus aureus (MRSA) infection are predominant. We report a case, a 50-year-old shopkeeper who used to inject pentazocine primarily as analgesic, later became addicted to it. Blindly injecting the drug in any approachable soft tissue resulted in woody induration of local skin with multiple ulcers in his both arms. He later developed type 2 Diabetes mellitus which made the scenario even worser.", "affiliations": null, "authors": "Phaujdar\|Sibaji\|S\|;Sarkar\|Rathindra Nath\|RN\|;Bhattacharyya\|Kuntal\|K\|", "chemical_list": "D009294:Narcotics; D010423:Pentazocine", "country": "India", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0004-5772", "issue": "62(10)", "journal": "The Journal of the Association of Physicians of India", "keywords": null, "medline_ta": "J Assoc Physicians India", "mesh_terms": "D003924:Diabetes Mellitus, Type 2; D003875:Drug Eruptions; D006801:Humans; D008297:Male; D008875:Middle Aged; D009294:Narcotics; D010423:Pentazocine; D015819:Substance Abuse, Intravenous", "nlm_unique_id": "7505585", "other_id": null, "pages": "52-4", "pmc": null, "pmid": "25906524", "pubdate": "2014-10", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Parenteral pentazocine and diabetes mellitus: a double whammy for cutaneous complication.", "title_normalized": "parenteral pentazocine and diabetes mellitus a double whammy for cutaneous complication" }	[ { "companynumb": "IN-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-99008", "fulfillexpeditecriteria": "1", "occurcountry": "IN", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "GLIMEPIRIDE" }, "dru...
{ "abstract": "BACKGROUND\nA nested qualitative interview study within the CONSTRUCT trial was conducted to explore experiences and perceptions of patients with acute severe ulcerative colitis following treatment with infliximab or ciclosporin, surgery, or other medication.\n\n\nMETHODS\nTwo hundred seventy patients with steroid-resistant ulcerative colitis were randomised to either infliximab or ciclosporin. Interviews were conducted with 20 trial participants. Thirty-five data capture events took place in total, 20 interviews conducted 3 months after treatment and a further 15 interviews with the same cohort as second interviews at 12 months.\n\n\nRESULTS\nDisease duration varied but similar stories emerged about how people adjusted to living with ulcerative colitis. Issues raised by patients included; the debilitating effect of the disease on quality of life, living with the unpredictability of symptoms and treatment, dealing with embarrassment and stigma and the desire to share knowledge of the disease with others to combat the private nature of this debilitating illness and bring greater visibility to patient experience of symptoms and outcomes.\n\n\nCONCLUSIONS\nPatients were more positive about treatment with infliximab than ciclosporin, mainly due to the cumbersome intravenous regimen required for ciclosporin. Prompt diagnosis is required and early reporting of changes in symptoms is encouraged to ensure appropriate treatment.\n\n\nBACKGROUND\nThis trial is registered with the ISRCTN registry; number ISRCTN22663589 . The date of registration was 16/05/2008.", "affiliations": "Centre for Healthcare Resilience and Implementation Science, Australian Institute of Health Innovation, Macquarie University, Sydney, Australia. frances.rapport@mq.edu.au.;Bristol Medical School, University of Bristol, Bristol, UK.;Swansea University Medical School, Swansea, UK.;Swansea University Medical School, Swansea, UK.;Swansea University Medical School, Swansea, UK.;Swansea University Medical School, Swansea, UK.", "authors": "Rapport\|Frances\|F\|http://orcid.org/0000-0002-4428-2826;Clement\|Clare\|C\|;Seagrove\|Anne C\|AC\|;Alrubaiy\|Laith\|L\|;Hutchings\|Hayley A\|HA\|;Williams\|John G\|JG\|", "chemical_list": "D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D000069285:Infliximab", "country": "England", "delete": false, "doi": "10.1186/s12876-019-1085-y", "fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central London 108510.1186/s12876-019-1085-yResearch ArticlePatient views about the impact of ulcerative colitis and its management with drug treatment and surgery: a nested qualitative study within the CONSTRUCT trial http://orcid.org/0000-0002-4428-2826Rapport Frances frances.rapport@mq.edu.au 1Clement Clare c.clement@bristol.ac.uk 2Seagrove Anne C. a.c.seagrove@swansea.ac.uk 3Alrubaiy Laith L.Alrubaiy@swansea.ac.uk 3Hutchings Hayley A. H.A.Hutchings@swansea.ac.uk 3Williams John G. J.G.Williams@swansea.ac.uk 31 0000 0001 2158 5405grid.1004.5Centre for Healthcare Resilience and Implementation Science, Australian Institute of Health Innovation, Macquarie University, Sydney, Australia 2 0000 0004 1936 7603grid.5337.2Bristol Medical School, University of Bristol, Bristol, UK 3 0000 0001 0658 8800grid.4827.9Swansea University Medical School, Swansea, UK 15 10 2019 15 10 2019 2019 19 1667 4 2019 1 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\nA nested qualitative interview study within the CONSTRUCT trial was conducted to explore experiences and perceptions of patients with acute severe ulcerative colitis following treatment with infliximab or ciclosporin, surgery, or other medication.\n\nMethods\nTwo hundred seventy patients with steroid-resistant ulcerative colitis were randomised to either infliximab or ciclosporin. Interviews were conducted with 20 trial participants. Thirty-five data capture events took place in total, 20 interviews conducted 3 months after treatment and a further 15 interviews with the same cohort as second interviews at 12 months.\n\nResults\nDisease duration varied but similar stories emerged about how people adjusted to living with ulcerative colitis. Issues raised by patients included; the debilitating effect of the disease on quality of life, living with the unpredictability of symptoms and treatment, dealing with embarrassment and stigma and the desire to share knowledge of the disease with others to combat the private nature of this debilitating illness and bring greater visibility to patient experience of symptoms and outcomes.\n\nConclusion\nPatients were more positive about treatment with infliximab than ciclosporin, mainly due to the cumbersome intravenous regimen required for ciclosporin. Prompt diagnosis is required and early reporting of changes in symptoms is encouraged to ensure appropriate treatment.\n\nTrial registration\nThis trial is registered with the ISRCTN registry; number ISRCTN22663589. The date of registration was 16/05/2008.\n\nKeywords\nQualitative researchPatientUlcerative colitisCiclosporinInfliximabSurgeryhttp://dx.doi.org/10.13039/501100000664Health Technology Assessment ProgrammeHTA 06/78/03Williams John G. issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nUlcerative colitis (UC) is a chronic debilitating disease that affects ~ 150,000 people in the UK [1, 2]. There are many unanswered questions regarding the causes and course of the disease, its treatment, management, and outcome; despite a background of rapidly developing new therapies. Patients with acute severe colitis will require hospital admission. Treatment includes intravenous steroids but about 40% of patients are resistant to this [3, 4]. In the past, when no other treatment was available, emergency colectomy was the only option. Although mortality following emergency colectomy has fallen over time, 10% of patients die within 3 months of surgery [5]. Infliximab and ciclosporin are immunosuppressive drugs that offer hope for the treatment of steroid resistant UC, with evidence that they are both effective in the short term [6, 7], particularly among patients who respond partially to steroid treatment.\n\nThis article describes a qualitative study undertaken as part of a trial: Comparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis: a Trial (CONSTRUCT), a UK-wide pragmatic randomised controlled trial (RCT) comparing the clinical and cost effectiveness of infliximab and ciclosporin for patients with steroid resistant UC, using quantitative, qualitative, health economic and data-linkage research methods [8–10]. This article adheres to CONSORT guidelines for reporting parallel group randomised trials [11] where the information is pertinent to the qualitative study being presented. The CONSTRUCT trial as a whole has been reported with adherence to CONSORT guidelines elsewhere [8, 9].\n\nCONSTRUCT’s primary outcome measure was patients’ quality of life and the trial showed no significant differences between the two treatments in this measure of clinical effectiveness [8]. The qualitative element of the study contributed to the trial’s specific objectives of comparing quality of life across the two treatment groups from the patient perspective, investigating participants’ views about the two treatments, experiences of the drug regimens and opinions about how easy each drug was to handle, including perceptions of side effects and ongoing quality of life. The main aim of the qualitative study was to investigate patients’ priorities for their health and wellbeing, views of different drug treatment and surgery, and opinion regarding how well they responded to treatment.\n\nWhilst studies have acknowledged specific characteristics of UC such as fatigue [12–15]; unpredictability [16, 17]; stigma [18] and surgical treatment [19, 20], to the best of the authors’ knowledge, no studies, qualitative or otherwise, have reported, in depth and across a wide UK-based patient cohort on adult patient experience of UC in relation to infliximab, ciclosporin, or surgical intervention. However, qualitative studies have considered: patient experience in relation to non-medical adaptation and non-medical intervention [21], disease burden [22], and a full review has been undertaken of generic meanings around living with inflammatory disease [23]. In addition, some qualitative studies have been undertaken relating to adolescent experience and those transitioning to early adulthood [24, 25], such as a study of adolescent hospitalization, and paediatric-provider relationships, as patients transition out of care settings. This gap is somewhat surprising given that qualitative methods are well suited to investigating personal experience in relation to drug taking or surgical intervention [26], and individual perceptions and belief and meaning systems [27, 28] and can help to clarify patients’ understanding of their disease and its treatment.\n\nIn order to determine and understand CONSTRUCT trial participants’ experiences and perceptions of living with UC and to disclose details of their experiences of two treatments with or without surgical intervention, the study team conducted telephone interviews at two stages in the study: at approximately 3 months, and again at 12 months after patients received treatment. This article presents a description of the interviews and outcomes following qualitative analyses of the interview data.\n\nMethods\nDesign\nBetween June 2010 and February 2013, and with approval from a multicentre research ethics committee, CONSTRUCT recruited patients from 52 district general and teaching hospitals in England, Scotland and Wales. With informed consent, 270 patients, aged 18 and over, with acute severe UC, who failed to respond to intravenous steroids, were recruited to the trial and randomly allocated to treatment with infliximab or ciclosporin. The definition of acute severe ulcerative colitis used was patients admitted as emergency admissions with severe colitis [29], a Mayo Score of at least 2 (on endoscopic finding or clinical judgement) who had failed to respond to a course of about 2–5 days of intravenous hydrocortisone therapy, who also had either: histological diagnosis of ulcerative colitis in that episode; histological diagnosis of indeterminate colitis in that episode when clinical judgement suggested a diagnosis of ulcerative colitis rather than Crohn’s disease; symptoms typical of ulcerative colitis awaiting histology; or history of ulcerative colitis confirmed histologically. Patients did not choose which treatment they received or whether they had surgery. After consenting to participate in the trial they were randomly allocated to receive infliximab or ciclosporin. Surgery was one of the predefined outcomes measured in the trial and was offered as part of patient care if recommended by the clinical team. At the time of consent to the trial, participants were asked to consent to be interviewed at approximately 3 months and again at 12 months post allocation.\n\nFor this qualitative study there were no exclusion criteria. We purposively recruited equal numbers of participants from the ciclosporin and infliximab groups who had participated in the original trial and randomly received either infliximab or ciclosporin (baseline characteristics of the participants can be found in Table 1). Detailed inclusion and exclusion criteria for the trial and more extensive detail about all aspects of study design, data collection, analysis and reporting can be found in the full study report [9].\nTable 1 Demographic characteristics of interview participants\n\nPatient characteristic\tGroup a\tGroup b\t\n\nGender\n\t\n Male\t7\t7\t\n Female\t3\t3\t\n\nEthnicity\n\t\n White\t8\t10\t\n Asian or Asian British\t2\t0\t\n Black or Black British\t0\t0\t\n Other\t0\t0\t\n Mixed\t0\t0\t\n\nWeight (mean, kg)\n\t72.7 (range 52 to 102)\t76.9 (range 53 to 125)\t\n\nHeight (mean, m)\n\t1.68 (range 1.55 to 1.79)\t1.71 (range 1.58 to 1.80)\t\n\nSmoking Status\n\t\n Non-smoker/ Ex-smoker\t6\t5\t\n Never smoker\t4\t5\t\n Smoker\t0\t0\t\n\nTruelove & Witt’s score\n\t\n Severe\t9\t5\t\n Not severe\t1\t5\t\n\nMedian Mayo Score\n\t3\t3\t\n\nFamily History\n\t\n Yes\t2\t2\t\n No\t8\t8\t\n\nQuality of life scores\n\t\n EQ 5D\t0.38 (range − 0.08 to 0.73)\t0.56 (range 0.29 to 0.81)\t\n CCQ-32 (mean)\t0.35 (0.13 to 0.56)\t0.37 (range 0.24 to 0.49)\t\n\n\nAs 52 hospitals in the UK took part in CONSTRUCT, the trial participants were geographically widely dispersed, so for participant convenience and confidentiality, semi-structured interviews [30] were conducted by telephone when the patients were at home. Semi-structured interviews are a useful approach if a researcher wishes to ensure research participants have the time and space to expand on their answers narratively. Using this approach, participants were encouraged to explain any nuance or ambiguity in their initial answers and could expand, safe in the knowledge that they would not be interrupted. Using a telephone interview technique ensured wider data capture and greater reach and scope than would have been achievable had face-to-face interviews been attempted. Travel pressures and the accompanying resource implications were removed as was the potential for patients to get embarrassed discussing sensitive topics with a stranger, face-to-face [31].\n\nSemi-structured interviews enabled the trial qualitative researcher to guide the interviewees through the questions whilst giving participants the opportunity to not only develop their responses but also raise issues that were important to them. In accordance with the qualitative study aims, the researcher explored participants’ priorities for their health and wellbeing, the ease with which patients were able to take the drugs and drug experience including their view of a drug’s side effects, and their response to treatment including the possibility of having to undergo surgery following drug treatments. An interview schedule was developed comprising key questions aligned to these aims. The opening questions were designed to encourage participants to think and talk about their health, what was important to them, and what good and poor health meant to them. These questions were followed by more specific questions about their treatment experiences, drug regimens, management of drugs and outcomes.\n\nAfter the interviews commenced, it became apparent that some of the participants that had required surgery to treat their UC had had that surgery, between randomisation and their three-month follow-up and while the interview schedule was originally designed to examine overall views of surgical intervention, should it be necessary, the interview schedule was extended to capture the views of these participants as well.\n\nSample and recruitment\nThe CONSTRUCT Protocol [10] defined a sample of 10% of the total of 480 randomised participants to be interviewed. Purposive quota sampling supported the identification of 12 consenting patients from each arm of the trial in view of the belief that a total of 24 participants, interviewed on two occasions (n = 48 data capture events), would yield a range of views and opinions regarding therapy and surgical intervention, as well as a mix of participants according to age and gender and patients from a range of centres. The sample size was supported by the literature’s response to sample size adequacy in qualitative research studies [32] and the need to ‘represent the voice of the people’, with the aim of achieving data saturation at this point, or continuing sampling until data saturation was achieved (where no new data codes and categories are evident) [33]. As interviews would inherently disclose which trial arm the participant was in, the interviewers and analysts were unable to remain blinded. However, this would enable exploration of experiences of the drugs in depth, to meet the qualitative study aims and thus was deemed acceptable. Any potential bias in interpretation would be addressed by having more than one person analyse the data and come together as a group for consensus [34].\n\nAnalysis\nData were analysed using both thematic and schema analyses and in accordance with the interview schedule [35]. Thematic analysis is an approach to analysis that implies both implicit and explicit ideas evident in the data collected, through the coding and classification of data into meaningful and relevant categories and themes. These categories and themes, as they are developed and refined, link the raw data to ‘summary markers’ that indicate the raw data’s main content and context. As a result, the thematic analytic framework needs to be both comprehensive and succinct, encapsulating the main issues arising in the raw material in an abbreviated fashion that is both accepted and clear [36]. Schema analysis, on the other hand, concentrates on identifying patterns within text which can provide valuable information about how people work, behave or communicate, concentrating on these speech patterns in relation to the original study aims and objectives [37]. Schema analysis presents these patterns as people’s approach to the use of cognitive simplification. It examines through speech patterns how people express their views, opinion and experiences and how they make sense of complex information to which they are exposed. Analysis starts with a thorough reading and rereading of pieces of text, such as interview or focus group transcripts, followed by the identification of key issues evident as themes and categories within the text. At the same time schema analysis looks at the repetitive aspects of patterns of speech and at the way people introduce metaphor to present themselves to others [37].\n\nThe thematic analysis commenced after four interviews had been completed and continued iteratively until data saturation was confirmed to have been reached [33] and where no new codes or themes were revealed. Due to the rich and detailed amount of data arising from the interviews we also deemed that ‘information power’ was sufficient to meet the study aims and objectives [24]. The transcripts were distributed to three qualitative researchers, one of whom was the primary researcher involved in data capture. Each researcher read the transcripts and considered the themes that were emerging. The three researchers then met to discuss their findings and develop an analysis framework and an iterative process followed with all the transcripts, whereby themes and concomitant categories were honed down and clarified amongst all three researchers through consensus agreement.\n\nThe wider CONSTRUCT study team was then involved in a schema analysis exercise [38]. This process was chosen for four reasons: a) to enhance the thematic analysis framework by verifying that all framework elements were cogent and comprehensible, b) to be multidisciplinary, c) to build consensus into the data assessment process to ensure decision-making and interpretation was rigorous and trustworthy, and c) to give those involved with the analysis of other study datasets an insight into the lives of the participant group. Members of the study team, a multi-disciplinary group of gastroenterologists, researchers, statisticians and trialists were asked to read three participant transcripts, one from a participant treated with infliximab, one from a participant treated with ciclosporin and one from a participant who had had ciclosporin followed by surgery. The members involved were then asked to write one-page schematic overviews of the main features of each of the three texts, in keeping with participants’ health and illness stories, and as they related to quality of life and drug regime issues. These overviews were then reviewed and integrated into one overview of each interview which was then discussed and refined in group discussions between team members. Data analysis followed a similar pathway to the team’s previous, qualitative, gastroenterology trials data, including secondary assessment by a team of qualitative data analysts of a subset of all interview transcripts to ensure the thematic template was rigorous and findings efficacious. As teamwork continued, combined analyses or all transcript schemas contributed to a final thematic framework [39].\n\nResults\nNumber of interviews conducted\nWhilst 24 participant interviews were planned, after 20 three-month interviews had been analysed, data saturation was reached, with multiple qualitative analyst coming up with the same themes and no new themes arising, and it was agreed that no further interviews were needed for the first stage of data capture. The 20 interviews at 3 months were split evenly between those randomised to infliximab and those to ciclosporin, and three in each group had also had a colectomy. There were three females and seven males in each treatment group and their ages ranged from 21 to 75 years, as shown in Table 2.\nTable 2 Details of interview participants\n\n\tInfliximab\tCiclosporin\t\nMales\tFemales\tMales\tFemales\t\nNumber interviewed\t7\t3\t7\t3\t\nAge range\t23–64\t21–44\t27–75\t31–59\t\nMean age\t44\t32\t51\t43\t\n\n\nWe conducted 35 interviews with 20 participants. The full cohort were approached for a second interview at 12 months and at this stage only 15 of the interviewees from the original cohort of 20 agreed to a second interview (eight infliximab, seven ciclosporin patients). The reduction in numbers resulted from: one participant having died, two participants not wishing to take part and our inability to contact two participants. From each of the two treatment groups, one participant (one male and one female), had undergone a colectomy, while one male participant who had undergone a colectomy before the first interview had since had two further operations (pouch surgery followed by ileostomy closure).\n\nThe length of time since the participants had been diagnosed with UC varied from just a few weeks to as long as 30 years. However, those who had only recently been diagnosed had generally been experiencing symptoms for several months. The demographic information for those patients who agreed to be interviewed was compared to the cohort of patients who were not interviewed and found to be comparable.\n\nWith many participants working, the interviews often took place when people returned home from work. The interviews lasted 30–45 min on average, and all participants agreed that the interviews could be recorded. Transcribed interviews were reviewed by the primary qualitative researcher before being anonymised by using the participant’s study ID, with all names and geographical details removed.\n\nResults of the interview analysis\nDespite a wide age range amongst participants, and variation in the duration of their disease, similar stories were revealed about living and adjusting to UC, the physical, mental and emotional impact of the condition, the treatments, and people’s concerns and hopes for the future. The details of the participants’ experiences of UC are presented in a narrative form to reflect participants’ descriptions of how they ‘journeyed’ through their illness, and according to their individual storylines, which they generally presented as: realisation of the problem, receipt of treatment, management of the condition and views of what the future held. Presenting the findings in this way indicates the joined-up story of an illness course experienced as chronic, in terms of how UC becomes present and begins to take root in people’s lives, as well as people’s ongoing expectations and the consequences of the illness in the longer-term.\n\nSimilar findings from the interviews at 3 and 12 months are not reported to avoid repetition, but new views and experiences revealed at the 12-month interviews are included. By presenting outcomes in this way, we have aimed to identify both personal experience of health and illness, and opinions of care and treatment options from an individualistic perspective and over a period of 1 year. Data capture and analysis extended over the year and was finalised early 2016.\n\nAll quotes are from trial participants. Quotations are presented in italics followed by an anonymised code for each participant and the line number of the quote from the transcript.\n\nParticipants’ views on their general health\nFor many of the participants, UC was the only significant illness they had experienced, and even for those with longer term UC, their recent inpatient stay was often their first admission to hospital with the disease. Thus, it soon became apparent that many participants had managed their problems themselves at home, and had not given much thought to the implications of ill-health, or needing to enter more formal healthcare facilities. It is against this background that participants reflected on their desire to continue to lead a ‘normal’ life, to retain the ‘freedoms’ to which they were accustomed, and to have the energy to undertake everyday activities including socialising, working and travelling, without constraint. They considered good health as having plenty of energy, not being reliant on medication, being symptom- and pain-free and not having to go to the toilet every few minutes. In contrast, participants related bad health to being ‘imprisoned’, that is to say, housebound, unable to socialise and to be burdened with physical constraints relating to pain, discomfort, lack of energy and a dependency on others.\n\nThese issues were raised on a number of occasions, especially when participants were asked how their UC affected their quality of life. Here the intensity of the suffering caused by UC became strongly apparent, particularly for those who had experienced symptoms for only a few weeks or months: “a bit of a bolt out of the blue” (GHI0028.164). For this latter group in particular, admission to hospital was a shock and a frightening experience, and 3 months after their treatment they were still adjusting to this life-changing event.\n\nAt 12 months, while the course of the disease for the participants had differed, their basic desire to live a normal life, to be able to socialise, work and travel, had not changed.\n\nOnset of illness and diagnosis\nA picture emerged of a convoluted and sometimes frustrating treatment story from early onset to diagnosis, via an often-misdiagnosed disease. The story frequently began with mild symptoms, such as going to the toilet more often and having some bleeding, which led to an eventual General Practitioner (GP) visit with a misdiagnosis of haemorrhoids: “I wasted about a month going to see the doctor and he just gave me stuff for piles” (LMN0009.111). Some participants visited their GP several times, but it was only when their symptoms did not settle and became worse, particularly if weight-loss occurred, that they were referred for an endoscopy. Some participants who knew they had UC ‘soldiered on’ with their symptoms, and a couple of participants described feeling like ‘frauds’ as inpatients amongst some of the seriously ill people in nearby beds.\n\nA range of issues were raised by participants who discussed not only their experience of taking drugs, but also their ability to control symptoms and manage medication and the impact of medication on symptom control. Some participants found medication control adapted well to their changing physical state while others experienced difficulties in attempting to manage UC. For this latter group, a range of different medications had been tested with unpredictable results over time. Of the full cohort, the participants who fared the best in recognising signs and symptoms, management of drugs and appreciation of different treatment options were those who knew they had UC before their admission. These participants were cognisant of the fact that as time progressed, treatment options narrowed to the more powerful drugs or surgery, which was still seen as the final resort.\n\nUnpredictability of the disease\nThe unpredictability of the course of the disease was a problem for many who had no idea when their next flare-up might occur. A flare-up resulted in pain and discomfort, increased and urgent bowel movements and bloody diarrhoea, necessitating frequent, rushed visits to the toilet. Participants described this loss of bodily function as being unable to rely on their bodies, leading to a sense of giving up control over their bodies. Life was planned around access to toilets amid the fear of having an ‘accident’, and participants jokingly commented on their knowledge of all the toilet stops on a regular car journey.\n\nIf a flare-up was not controlled, symptoms such as frequent toilet use – maybe 20 to 30 times during the day and night, had a massive impact on their lives, leading to severe quality of life deterioration within a matter of weeks. Participants described how normal life ceased to be manageable very quickly and how the unpredictability of the disease had a knock-on effect on their ability or desire to pursue everyday activities which had previously been a major part of their lives. When this was the case, all other activities had to be curtailed, in order for daily lives to be manageable: “Colitis can make you a prisoner that you don’t venture far away from a toilet” (DEF0016.60).\n\nAt 12 months, all participants continued to be followed up at hospital and were on medication for UC; six patients reported no further symptoms, whilst three had experienced flare-ups. They understood that if symptoms developed, a prompt change in medication could prevent them becoming as ill as they had been before, and that they would need to contact their inflammatory bowel disease (IBD) nurse or GP for advice as they: “would want to catch it earlier” (BCD0012.214).\n\nImpact of symptoms on the life course\nThe impact of symptoms like diarrhoea and disturbed nights resulted in people’s health deteriorating. This resulted in reduced activities, and impacted socialising and working arrangements, to a state that people found themselves, in effect, housebound. During these phases, participants described suffering from a lack of energy, weight loss and exhaustion, the latter being something that many people emphasised several times during the interview: “basically tiredness was one of the things that was really difficult” NOP0004.91). For many participants, life had to be put on hold; engendering a significant change which they found difficult to cope with: “Flare-up – it was dictating to me what I was able to do, not me dictating it” (RST0021.15).\n\nThose in employment described how they had tried to continue working for as long as possible until they reached a point where it was simply physically impossible for them to carry on. An issue for some younger UC participants was the potential detrimental effect on their careers, as a result of ongoing flare-ups requiring time off work.\n\nThe condition could, therefore, be seen to cause huge changes in lifestyle for those who had to take time off work, who could not venture out to socialise, and for those with young children who were unable to care for them properly.\n\nThere appears to be a trajectory for participants of any age of debilitation, in that they change from someone with an active lifestyle, to someone for whom the disease has an increasingly detrimental effect, which often leads to a state, that participants describe, in both mental and emotional terms, as reducing possibilities in their lives. This effects: going to the toilet, being in great pain and being bored but unable to do anything to alleviate the boredom:\n\n\n\n“I was spending all day in a chair or in bed barely able to eat and my life just consisted of going to the toilet and sitting still trying to occupy my mind and not go crazy.” (GHI0028.19)\n\n\n\n\n\nFor some patients, UC took them entirely by surprise, changing them from someone with good health to someone with a chronic condition. For many, life took a different and unexpected path, where their freedom to travel, pursue hobbies and to work was curtailed or restricted because they could not rely on their body functioning properly. For those wishing to travel, there was the added difficulty of obtaining travel insurance.\n\nDuring the 12-month interviews, the quality of life for participants who managed to bring their symptoms under control, had improved, with some even able to plan events with confidence. Participants spoke of the impact of extreme illness, and being diagnosed with a chronic disease, leading directly to significant life changes, affecting their jobs, precipitating a house move, or perhaps leading to self-employment.\n\nEmbarrassment about sharing knowledge with others\nIn contrast to some other chronic conditions, many UC sufferers considered it to be an embarrassing illness because of its association with ‘bottoms’, ‘bleeding from your bottom’, diarrhoea and going to the toilet. As a result, participants explained that they were selective about who they shared information about their disease with, often only discussing it with close family members and friends, rather than with acquaintances or work colleagues. However, when informed, employers and work colleagues were often found to be understanding and supportive.\n\nUC is a ‘secret’ disease, difficult to discuss with few clear and recognisable manifestations. In addition, manifestations change rapidly and this unpredictability can lead to problems in treatment planning and therapeutic discussion. Participants in this study noted that others were often unaware of what the experience of UC was like for them, particularly members of the wider public implying a lack of a broader awareness of UC as a chronic condition. Participants, including those who had had surgery, remarked that a lack of public interest and awareness was exacerbated by little media interest, few reviews of the disease, and rare media discussions about the profile of UC compared to other chronic conditions. Participants noted that were famous people to come forward more frequently, who had the disease, more media interest might be engendered. The low profile was attributed to the embarrassing aspects of the disease which meant it was perceived differently to other chronic conditions.\n\nAt 12 months, similar issues arose, but a participant reflected: “that you need to be able to speak to people and share what’s happened to you” (TUV0001.584), while two surgery participants, in particular, were keen to share their experiences with other sufferers and help them understand the impact of surgery and coping with a stoma.\n\nImpact of UC on family and friends\nThe life-changing nature of UC clearly impacts on families and friends, particularly during periods of flare up. Those with young children found themselves unable to look after and play with their children, while others found it affected their partner’s social life and could affect family travel plans:\n\n\n“ … would like to go around the world with my wife and we can afford it now but I simply, at the moment haven’t really got the energy for it” (ABC0010.86).\n\n\n\n\nHowever, the predominant observation made by participants was that the support provided by family and friends was invaluable, in both practical and emotional terms. Ensuring others could support them was a positive outcome, and helped patients to cope mentally, as the condition became more difficult to manage.\n\nAt 12 months, the impact of UC on family and friends was spoken about by those who had had surgery. A participant who visited his workplace to discuss returning to work was aware that word had got out that he had a stoma and found some individuals did not look him in the eye easily but were: “constantly staring to see if they could see this thing” (DEF0016.680). He found this rude, and his wife was so annoyed that she had to walk away. However, one participant felt that friends and family got bored with the disease so talking to the interviewer was helpful: “talking to an absolute stranger, vague stranger, there’s something quite soothing about it … just go through it from start to finish” (MNO0034.729).\n\nAcquiring knowledge about ulcerative colitis\nParticipants appeared to be well-informed about their condition, using the internet to find out more and turning to support group literature, such as documentation provided by ‘Crohn’s and Colitis UK’ (a national support organisation). In addition, many patients were in contact with an IBD nurse at their local hospital, from whom they received information and help when their symptoms exacerbated. However, participants commented on the lack of availability of an IBD nurse at all hospitals and were of the opinion that their support would be invaluable, and their role should be introduced more thoroughly.\n\nDespite information available, participants had a number of unanswered questions surrounding the cause of their UC. They spoke about the possible genetic links to their disease and mentioned the need for more research in the area, in order to ensure that other family members could be supported if they did get UC or could be prevented from suffering with the disease. Participants were also unsure about what triggered a flare–up and wanted more information on this particular aspect of their disease, including information about the links between UC, stress and diet. Ultimately, participants wanted to see a cure for the condition; and whilst recognising that it might be too late for them, they wished to support others from having to suffer with the disease.\n\nParticipants appeared to be less questioning about UC at 12 months, as only a few comments arose about the cause and cure. However, the suggestion that they had easy access to care appeared to be more important to them at this point in their disease.\n\nShared treatment decisions\nParticipants were well-informed about their UC, knew the signs and symptoms that indicated a flare-up and the various treatments available to them, and with this knowledge, they saw themselves as taking part in shared decision-making about their treatment with clinicians. This was particularly evident with regards to surgery as an option, when participants clearly understood that they had failed to respond to the medical treatments:\n\n\n\n“ … spoke long and hard to the surgeon and medical doctors and we all agreed that my quality of life would be improved if the bowel was gone” (DEF0016.362)\n\n\n\n\n\nParticipants clearly understood that if they failed to respond to the various treatments, there could be a time when their body would make a treatment decision for, them rather than the decision being made by them or their clinician: “if you are so bad and it gets to the point where it could put your life at risk then obviously you have to have it done” (JKL0033.521).\n\nComparison of infliximab and ciclosporin from the participant perspective\nAll the participants except one had only ever experienced one of the drugs, (ciclosporin or infliximab) and were extremely ill when the treatment was first administered. As a consequence, whichever drug led to a participant’s health improving, was viewed positively, particularly if it meant that surgery could be avoided.\n\nCiclosporin\nParticipants found being hooked up to a drip continuously for several days at a time was problematic, in that it was restrictive: “… loss of freedom, I found that quite irritating, personally found that frustrating” (BCD0012.218). It also meant being woken up at night for infusion bag-changes which caused anxiety, especially when a bag-change was delayed. Some found the infusion easier than the oral form of ciclosporin, as blood tests were required to monitor ciclosporin levels, tablets were large and had a distinctive smell, and participants had to remember to take tablets and have them with them when they went away. However, tablets meant ‘no needles’ and could be taken at home.\n\nThere were a number of side effects directly linked to ciclosporin, including mood swings, rashes on arms, tingling in fingers and toes, increased facial and body hair, tiredness, hand tremors and cramps in the hands and feet. Women in particular worried about facial hair during the period in which they took ciclosporin.\n\nTwo participants did not respond to intravenous ciclosporin and required emergency surgery. A third participant initially responded but relapsed and was given infliximab (the only participant to have experience of receiving both treatments). In the short term, those who did respond commented that they had avoided surgery, it got their condition under control and that they felt much better. At 3 months, participants found it difficult to comment on the impact of ciclosporin on their current health as most were no longer taking it and were on other medications.\n\nInfliximab\nParticipants found the short intravenous infusion easy: “I was just lying in a hospital bed so I could doze off, read a book” (KLM0010.153). They had the same opinion about further treatments that could be provided to them as an outpatient - appreciating the shorter time the treatment took and not having to take tablets: “there is not any managing of it because it’s a two-hour infusion and then you’re not due back in for another six to eight weeks so in that way it’s fantastic” (OPQ0005.395).\n\nThe side effects of infliximab were more immediate, such as a ‘weird’ sensation in the legs, feeling vague and ‘dopey’ and becoming very hot during the infusion, and one participant described getting hot at night for two to 3 weeks following infusion.\n\nThree participants did not respond to infliximab and required surgery. A participant who was switched to infliximab noticed a positive difference in her condition within a day. In the short term, those who responded well had positive comments to make, as the treatment meant they avoided surgery. They noticed a rapid difference in their state of health and viewed infliximab as a ‘miracle drug’ (GHT0034.331). Again, it was difficult for participants to comment on whether they felt the infliximab was still having an effect at 3 months as they were taking other medications. A couple of participants felt the effects were still lasting and two participants felt the effects wore off as they neared the time of their next infusion.\n\nBy the time of the second interview, none of the participants were receiving ciclosporin or infliximab. One participant from each group had experienced a flare-up whilst four infliximab and two ciclosporin participants had no further symptoms since completing the trial treatment.\n\nAt 12 months the majority of the participants spoke more about other treatments they had received since the trial treatment, but two recalled that ciclosporin had been a successful treatment. Three commented on the convenience of infliximab and that they would be happy to have it again, whilst one stated that treatment with infliximab: “every so often would have been easy-peasy” (QRS028.342) when compared with having surgery and living with a stoma. One participant explained that because of funding restrictions, her local primary care trust would not allow her to continue treatment with infliximab and she felt her: “quality of life would be much better now if I was able to continue it” (MNO0034.780).\n\nSurgery\nSurgery was considered a final option by most participants who took part in the interview study, who described surgery in terms of the fear and anxiety it raised in them. They used a range of terms to describe their worries, terminology that was particularly indicative of a sense of loss of a body part, such as ‘losing’ a colon. Participants were particularly nervous about the outcome of surgery and the possibility of having to wear a colostomy bag weighed heavily on their minds, as the following quotation indicates from one patient who was extremely concerned before their operation at the thought of having to get used to a colostomy bag, post-operations but whose fears were allayed when they ended up not needing one: “… I walked out of there without a bag … it’s just the fear of the unknown [having to manage with a colostomy bag], the effect it can have on your life I suppose, life changes” (TUV0001.242).\n\nNevertheless, for those who went through with surgery the end result was commonly unexpectedly positive, and most participants, in weighing up the consequences of surgical intervention, retained an open mind to the possibility of this being an ultimate outcome of their disease progression were drug or therapeutic intervention to fail. Those who were told that they would need to have surgery often described becoming resigned to the inevitability of the operation, accepting the next steps in their treatment: “I felt really fed up so I was actually quite happy, to be honest to have the operation by the time it came round … it wasn’t really a difficult decision to make in the end” (GHI0028.207).\n\nSurgery participants would have wanted to continue with medical treatment, but after surgery had taken place they expressed relief that it had been done, as it meant an end to their UC: “… the moment I woke up after the operation I thought, ‘cor this is fantastic’ … the fog had cleared” (STU0008.188). However, one participant had fought against surgery when diagnosed 55 years before, and was relieved that he had not had the surgery as a young man, whilst another described feeling suicidal after surgery. Most participants viewed surgery as having been a good decision but stressed that it did create issues in relation to the practicalities of managing the stoma and the bag, restricting them to certain types of clothing and causing concern about how others would react to seeing the bag, thus curtailing activities such as swimming: “I’ve got to keep my T-shirt on which is something I wouldn’t look forward to because I like to jump in the sea … I don’t want people staring at me all the time” (STU0008.155). Participants conveyed the point that being older made it a little easier to cope with the outcomes of surgery: “… I think when you’re a bit older it is a lot easier to deal with, mentally really” (QRS0028.307).\n\nSome participants were selective about whom they told about surgery, because they felt people would not understand. They tended to tell family and close friends, and where necessary, work colleagues, and they generally found that people were supportive. However, some participants were clearly very conscious of the physical changes to their body and the impact on personal relationships, whilst partners were often said to be understanding and supportive.\n\nSeveral participants spoke about the possibility of having surgery to restore bowel continuity and closure of their colectomy and age was shown to influence attitudes, with younger participants keen to get on with the process of getting life back to normal and older participants appearing more likely to accept life with the stoma: “If I was, don’t know, 20 years younger, I’d probably go for reversal because I wouldn’t want to live with the bag” (QRS0028.289).\n\nAt the 12-month interview point participants who had had a colectomy remarked on strong ongoing personal relationships and little detrimental effect as a result of surgery. One participant, who had had surgery during his first admission, had gone on to have two further operations to achieve reversal following which he noted improved quality of life and felt no regrets. Two men had found that intimate relationships had suffered but these were an exception to the rule. Indeed, at 12 months many surgical patients considered surgery as a cure.\n\nConcerns, hopes and aspirations for the future\nParticipants who were yet to have surgery were worried about where their disease course might take them and what future treatment might hold for them. Recently diagnosed patients took time in their adjustment to the disease especially if they did not yet have corresponding signs and symptoms that led them to feel unwell or mentally vulnerable. The disease often precipitated a gradual physical and mental decline and consequently participants found it hard to perceive of a time when their bowel habits would deteriorate still further, and where the need for medication would be more pressing Nevertheless even for those people whose symptoms had resolved, taking medication was a constant reminder that: ‘it might come back’ (BCD0012.520&600). Younger patients worried about the effects of the disease on long-term plans, including starting a family or sustaining relationships.\n\nThe 12-month follow-up interviews were a reminder to patients of how life had changed. Seven of the eight participants who had not needed surgery were coming to accept the challenges and limitations imposed by their illness and seemed more confident in recognising their treatment needs. They were reassured by ready access to advice and guidance from all specialist staff, including IBD nurses, but surgery remained a clear area of uncertainty. Participants had a range of questions still unanswered about: stoma reversal, impact of surgery on personal relationships, stoma management and others’ involvement in future care including close others needing to handle their stoma.\n\nDiscussion\nGiven that CONSTRUCT’s primary outcome measure was patients’ quality of life and the trial showed no significant differences between the two treatments in this measure of clinical effectiveness [8, 9], the results of this qualitative study assume greater importance, and the validity of the findings require detailed scrutiny. The participants’ views about UC and treatment with infliximab, ciclosporin and surgery are important, unique and detailed, and were derived from a broad age range, and a UK-wide cohort of patients in the largest UC trial of its kind. The interviewees were chosen at random, but stratified by age, treatment and surgery, and the demographic and baseline characteristics of the 20 participants interviewed, 15 of whom were interviewed on two occasions, were no different from the rest of the participant population in the study. Applying the criteria of credibility, transferability, dependability and confirmability set out by Guba in assessing the rigour and trustworthiness of data [40], we believe we used a rigorous and valuable qualitative approach. This included checking that the data being collected and the analysis of that data was shaped by what the participant population was saying, ascertained by both building the qualitative dataset iteratively, so that comments made by one participant could be expanded and enriched by the comments of others, and by ensuring data analysis included extensive team work and cross comparisons. We have used this approach across a range of disease-types [39, 41], and it is dependent on clarification by multiple analysts, working together, that knowledge and understanding is agreed, and consensus has been reached.\n\nThe data from interviews reported in this article, with patients at both three and 12 months after being admitted to hospital with UC, highlights the immense physical and mental strain of the disease on people’s lives. This closely aligns with the findings of Rubin et al., who in their 2008 study describe the difficulties patients face in living with the debilitating disease and the struggles patients face managing long-term medication-taking [42]. Some aspects of this appear to set the suffering of people with UC apart from other chronic diseases, as a result of unpredictable symptoms and the urgency of needing a toilet. In addition, unique to UC, is the consensus view that this is an embarrassing disease, and thus difficult to share with others, along with the stigma associated with having a bowel problem. Taft et al. have defined UC as a long-term secret disease, leading to increased psychological distress and reduced quality of life, going so far as to describe it as the disease of body stigma as a result of the uniquely related bodily functions involved [43]. In this study, this clearly affected participants’ thoughts about their quality of life, relationships with others, plans for social and work life, and future aspirations for disease management.\n\nUnique to this study are detailed views about the use and handling of two UC drugs, ciclosporin and infliximab, unlike other publications on patient experience of UC more generically focused on patient experience across disease symptoms and treatments [23]. All the participants bar one had only ever experienced one of the drugs, (ciclosporin or infliximab) and were extremely ill when the treatment was first administered. As a consequence, whichever drug the participant received was viewed positively, particularly if it meant that surgery could be avoided. However, ciclosporin was reported in a more negative light than infliximab across the cohort, particularly in terms of the length of time necessary for the intravenous infusion, as opposed to those receiving an infusion with infliximab, which was quick and straightforward. Participants being treated with ciclosporin also commented on the size of the oral medication, the problems surrounding having to take tablets on a daily basis, the inconvenience of having to have regular blood tests, and the long list of side effects linked to taking ciclosporin. The participants in this study who were allocated infliximab liked the fact that they only had to return every few weeks to clinic for ongoing treatment, and that they did not have to remember to take tablets every day. Participants noticed side effects with both treatments, but those with infliximab tended to be more immediate, and lasted for a shorter period of time. It is interesting to note the comments of the only participant who was able to compare the two treatments who mentioned that it was only after taking infliximab that they really began to feel better. The lack of comparative data between the two drugs may reflect the fact that in the UK, infliximab is restricted for use by some funding agencies (primary healthcare Trusts). This is confirmed to be the case by Crohn’s and Colitis UK, who in their online information sheet explain that ‘Infliximab is a very expensive drug, so hospitals have to apply for funding before they can use it on a patient and must review how effective it is from time to time’. [44] Frustration at this was expressed in the results section of this paper by one participant (MNO0034.780) who felt that as a result of such restrictions, she had not been encouraged to continue her infliximab treatment.\n\nThe interviewees included a widely-based constituency in terms of disease diagnosis and consequent treatment pathways. There were those who had been diagnosed with UC many years ago, some of whom had suffered from the disease before diagnosis for an extended period of time, whilst others who had been diagnosed during their recent admission to hospital, had only had a short-lived experience of extreme symptoms. However, the severity of symptoms was something all participants had in common, which for many indicated how quickly health can deteriorate with UC, even leading to the need for a hospital admission.\n\nThe extent to which UC had impacted on quality of life for participants was clear because of the emphasis put on how highly they valued what they called their ‘normal’ life; their ability to work and socialise. Their normal life was taken away by the physical symptoms and these combined with being woken at night to use the toilet, caused severe fatigue, which has also been noted in other studies [12–15]. These symptoms had a significant impact on people’s normal life, and as their quality of life deteriorated and they became socially isolated, this affected their ability to work and made them feel even more isolated and inadequate.\n\nWhilst studies acknowledge that UC is an unpredictable disease [16, 17], before the detailed reports of our participants, there was little evidence of exactly what this meant for patients, nor how the use of specific drugs and longer-term impact of drug-taking influenced views of UC. However, the interview data in this trial demonstrated that the issue of unpredictability: exactly when a flare-up might occur, whether treatment would be effective and for how long, as well as concern about soiling oneself, was significant and ever-present for people who had to work around the effects of symptoms when planning journeys. For others, projecting about the longer-term experiences of treatment management, and the physical difficulties of having to abide by long-term treatments and all they entailed led to despair. For some, changes of strategy to enable patients to live with the disease were needed and to counteract some of the most pressing worries, for example: changes in lifestyle, curtailment of holidays, stopping hobbies and attending sports events. Interestingly, unpredictability also extended to the way participants spoke about their treatment and whether it would work. For some, the need for eventual surgery was also uncertain and led to additional anxieties exacerbated by thoughts about outcomes of surgery and when it might be urgently required.\n\nAlthough the stigma associated with UC has been described before [1] this qualitative study demonstrates participants’ feelings about the extent of the embarrassment people experience, and highlighted how this is not something people find they can readily speak about. Taft et al., in their study of stigma related to inflammatory bowel disease reported that stigma was a widespread phenomenon noting that from a patient cohort of 211 patients, 84% reported related stigma impacting quality of life, self-esteem, adherence to drug regimes, and self-efficacy [43]. Apart from concerns about accidents, participants in our study indicated their extensive worries about sharing information with family and friends or work acquaintances. Participants felt that a wider public understanding of the disease, which could be achieved via media channels, would alleviate some of the embarrassment factor, and help patients discuss the disease in more detail with others. A media awareness campaign could serve as an important way of raising awareness about UC (and Crohn’s disease), informing the general public of both the disease and about different surgical interventions and outcomes. The literature indicates that misunderstandings around UC and public knowledge of digestive health and related diseases can be traced back decades. In a 1987 publication by Kreps et al. [45], for example, a widescale survey of the American public’s knowledge of gastroenterological disorders and their impact identified an uninformed and misinformed general public, with little health promotional support, leading to minimal healthcare prevention strategies and poor self-management of care.\n\nIt was difficult for participants in this study to attribute their condition at three and 12 months to the trial treatment, as very few were still taking the trial drug (ciclosporin is not used in the longer term and there are funding issues with infliximab). However, if the drugs had been successful it was clear that they got the participants to the point where other medication could then maintain their remission.\n\nIn total, eight of the interviewees had had a colectomy and their data added to the evidence [19, 20] about patients’ experiences of surgery as a necessary and often essential treatment for UC. This qualitative study demonstrates that before surgery patients feared the unknown, and surgery was seen as a last resort, and then only when everything else had failed to save their colon was surgery a possibility. However, most patients were pleased with the results of surgery, and some expressed regret that it had not been carried out earlier. The unpredictability of UC has been emphasised in this study and for many having surgery suddenly removes the unpredictability of symptoms and medical treatment. However, after 12 months, difficulties of living with a stoma came to the fore for some people, leading to a deterioration in quality of life if the operation could not be reversed.\n\nStrengths and limitations\nThe results of this qualitative interview study demonstrate the importance of incorporating qualitative data within a clinical trial as this rich data clearly complements the study’s overall aims and objectives. In a clinical trial showing no significant difference in clinical effectiveness between the two drugs infliximab and ciclosporin, understanding patients’ views about their disease and its treatment becomes more important as patient views help inform disease management. The data collected in this study provides an in-depth view from a patient perspective, of the reality of living and adjusting to the disease, the degree to which the disease impacts on people’s lives, and the effects of treatment.\n\nThe study has its limitations, however; whilst qualitative research does not seek population representativeness, or provide generalisable findings, the number of interviews could be considered a study limitation and we cannot make claims for the whole of the UC patient population in the UK, in particular with regard to patient views about surgery as a treatment for UC. More research needs to be conducted to explore the views of UC patients, post-surgery, postulating to a global populous and in order to provide more information to aid the decision-making process of those facing surgery. As the views of participants following surgery was generally positive, there should be further research into the surgical treatment of UC as a real alternative to medical treatment.\n\nConclusion\nTo conclude, this article is the first to report a qualitative study comparing infliximab and ciclosporin in relation to patient experience and the treatment of UC, from a patient perspective, and showing how patients treated with infliximab generally had a more positive outlook on treatment than those treated with ciclosporin.\n\nThe qualitative study covered a wide range of domains regarding the patient journey, confirming the degree, type and severity of the physical symptoms that patients with UC experience, particularly when suffering a flare-up, and illustrating some of the ways that people learned to live with the disease. However, importantly, these data show the wider effects of these symptoms on patients’ lives and indicate how easily people can become socially isolated and stigmatized as their health deteriorates and symptoms become more extreme. Consequently, we conclude that greater efforts should be made to ensure prompt diagnosis, to encourage known UC patients to report changes in their symptoms, and for appropriate treatment to be given as quickly as possible, sensitive to the needs of patients and the possibility that not only symptoms, but also personal experiences can rapidly change.\n\nA significant issue that emerged was that UC and its treatment remain a significant burden on patients’ lives because of its unpredictability and lack of knowledge surrounding the disease and we recommend that better support and greater information should be considered a priority, to enable patients to manage the impact of their symptoms and ongoing treatment regimes, more effectively. Greater information should also be available for the general public and a new, and concerted effort made to improve healthcare promotion strategies to increase disease-knowledge.\n\nSurgery has been shown as a positive option for many patients. In light of this, further research is needed investigating the implications of surgical treatment of UC, as a real alternative to medical treatment, in line with patients’ views, post-surgery, to support the decision-making process of those facing surgery.\n\nFinally, an awareness raising campaign about UC (and Crohn’s disease), including details about surgery, would encourage people to seek help earlier and help to destigmatise UC, thereby reducing the embarrassment felt by sufferers and those living with the outcomes of surgery.\n\nAbbreviations\nCONSTRUCTComparison Of iNfliximab and ciclosporin in STeroid Resistant Ulcerative Colitis\n\nGPGeneral practitioner\n\nIBDInflammatory bowel disease\n\nRCTRandomised controlled trial\n\nUCUlcerative colitis\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank the trial participants for taking part in the interviews. We also thank Sarah Wright for her help with thematic analysis of the data. We wish to acknowledge the general support and attention from the funding body (NIHR HTA) and patients involved in this study.\n\nAuthors’ contributions\nFR, the lead author, designed the qualitative element of CONSTRUCT. ACS conducted all the interviews and alongside FR, undertook the thematic analysis; LA, CC, HAH, FR, ACS and JGW took part in the schematic analysis. JGW was the Chief Investigator for CONSTRUCT. All authors have provided input into drafts of this article. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication. All authors have read and approved the manuscript in its final state.\n\nAuthors’ information\nThe views and opinions expressed herein are those of the authors and do not necessarily reflect those of the NIHR HTA, National Health Service or the Department of Health.\n\nFunding\nThis publication presents independent research funded by the National Institute for Health Research Health Technology Assessment (NIHR HTA) programme; project number 06/78/03. The NIHR HTA funded CONSTRUCT; they and their staff supported the project work and approved the right for the CONSTRUCT team to publish but did not influence any aspect of publication details. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work.\n\nAvailability of data and materials\nThe data that support the findings of this study are available from the corresponding author, Frances Rapport, upon reasonable request. The data are not publicly available in order to protect patient privacy.\n\nEthics approval and consent to participate\nThe Research Ethics Committee for Wales gave ethical approval for the study (08/MRE09/42). This committee had jurisdiction to review multi-site studies and Clinical Trials of Investigational Medical Products (CTIMPs) in patients. In addition, each participating trust or health board gave National Health Service Research and Development approval. The trial has European Union Drug Regulating Authorities Clinical Trials number (2008–001968-36) and clinical trial authorisation from the Medicines and Healthcare products Regulatory Agency. Written consent to participate was obtained from study participants.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. 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Kreps GL Ruben BD Baker MW Rosenthal SR Survey of public knowledge about digestive health and diseases: implications for health education Public Health Rep 1987 102 3 270 3108942\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-230X", "issue": "19(1)", "journal": "BMC gastroenterology", "keywords": "Ciclosporin; Infliximab; Patient; Qualitative research; Surgery; Ulcerative colitis", "medline_ta": "BMC Gastroenterol", "mesh_terms": "D000223:Adaptation, Psychological; D003093:Colitis, Ulcerative; D016572:Cyclosporine; D003967:Diarrhea; D000078385:Embarrassment; D005221:Fatigue; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D008297:Male; D036301:Qualitative Research; D011788:Quality of Life; D057545:Social Stigma", "nlm_unique_id": "100968547", "other_id": null, "pages": "166", "pmc": null, "pmid": "31615445", "pubdate": "2019-10-15", "publication_types": "D016428:Journal Article; D016448:Multicenter Study; D065007:Pragmatic Clinical Trial; D016449:Randomized Controlled Trial", "references": "27595142;30125834;3108942;24407484;25276253;22894661;19180581;20155319;20334633;25847427;23311461;22973418;24785401;11121902;22706127;29649672;15352901;17977817;23124372;25376979;15306569;19959823;20155849;22058580;16373009;26425861;28746358;13260656;28827271;17229218;25653237;22778720;19067414;3930339;27329657", "title": "Patient views about the impact of ulcerative colitis and its management with drug treatment and surgery: a nested qualitative study within the CONSTRUCT trial.", "title_normalized": "patient views about the impact of ulcerative colitis and its management with drug treatment and surgery a nested qualitative study within the construct trial" }	[ { "companynumb": "GB-JNJFOC-20160620066", "fulfillexpeditecriteria": "1", "occurcountry": "GB", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "INFLIXIMAB" }, "drugadditional": null, ...
{ "abstract": "BACKGROUND\nValacyclovir has been used for prophylaxis against cytomegalovirus (CMV) infection after hematopoietic stem cell transplantation (HSCT). We investigated the efficacy and safety of high-dose Valacyclovir as pre-emptive therapy in patients with CMV antigenemia after HSCT.\n\n\nMETHODS\nIn a retrospective single center study of 61 patients, we compared the rates of viral clearance, recurrent antigenemia and adverse events in patients with pp65 CMV antigenemia who received high dose Valacyclovir (n = 15), Valganciclovir (n = 16), and Foscarnet (n = 30).\n\n\nRESULTS\nOverall, 60/61 (98 %) of cases achieved CMV antigenemia clearance by day 28, and no patient developed CMV disease. After adjusting for age, sex, diagnosis, CMV serological status, donor type, CMV antigen level, graft-versus-host disease (GVHD) therapy, and conditioning regimen, there were no significant differences in the rates of viral clearance at day 14 in patients who received Valganciclovir (0.18, 95 % confidence interval (CI) 0.01 to 2.15, p = 0.17) and Foscarnet (OR 0.22, 95 % CI 0.03 to 2.40, p = 0.22), compared with Valacyclovir (assigned OR = 1.00). Recurrent antigenemia by day 180 after clearance of the initial CMV episode occurred in 34/61 (56 %) of patients. Using the multivariate model adjusting for the same covariates, there were also no significant differences in secondary episodes of CMV between treatment groups. With regards to adverse effect monitoring, Foscarnet led to significantly increased creatinine levels (P = 0.009), while Valganciclovir led to significant decrease in neutrophil counts (P = 0.012).\n\n\nCONCLUSIONS\nHigh dose Valacyclovir is a potential alternative to Valganciclovir and Foscarnet in the stable post-HSCT patient who has cytopenia and is not keen for inpatient treatment of CMV antigenemia.", "affiliations": "Department of Hematology, Singapore General Hospital, Singapore, Singapore.;Department of Hematology, Singapore General Hospital, Singapore, Singapore.;Department of Hematology, Singapore General Hospital, Singapore, Singapore.;Department of Hematology, Singapore General Hospital, Singapore, Singapore.;Department of Hematology, Singapore General Hospital, Singapore, Singapore.;Department of Hematology, Singapore General Hospital, Singapore, Singapore.;Department of Hematology, Singapore General Hospital, Singapore, Singapore.", "authors": "Ong\|Shin-Yeu\|SY\|;Truong\|Ha-Thi-Thu\|HT\|;Diong\|Colin Phipps\|CP\|;Linn\|Yeh-Ching\|YC\|;Ho\|Aloysius Yew-Leng\|AY\|;Goh\|Yeow-Tee\|YT\|;Hwang\|William Ying-Khee\|WY\|", "chemical_list": null, "country": "England", "delete": false, "doi": "10.1186/s12878-015-0028-2", "fulltext": "\n==== Front\nBMC HematolBMC HematolBMC Hematology2052-1839BioMed Central London 2810.1186/s12878-015-0028-2Research ArticleUse of Valacyclovir for the treatment of cytomegalovirus antigenemia after hematopoietic stem cell transplantation Ong Shin-Yeu shinyeu.ong@mohh.com.sg Truong Ha-Thi-Thu ha.truong@sgh.com.sg Diong Colin Phipps colin.phipps.diong@sgh.com.sg Linn Yeh-Ching yehching.linn@sgh.com.sg Ho Aloysius Yew-Leng aloysius.ho.y.l@sgh.com.sg Goh Yeow-Tee goh.yeow.tee@sgh.com.sg Hwang William Ying-Khee william.hwang.y.k@sgh.com.sg Department of Hematology, Singapore General Hospital, Singapore, Singapore 19 6 2015 19 6 2015 2015 15 85 12 2014 15 5 2015 © Ong et al. 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\nValacyclovir has been used for prophylaxis against cytomegalovirus (CMV) infection after hematopoietic stem cell transplantation (HSCT). We investigated the efficacy and safety of high-dose Valacyclovir as pre-emptive therapy in patients with CMV antigenemia after HSCT.\n\nMethods\nIn a retrospective single center study of 61 patients, we compared the rates of viral clearance, recurrent antigenemia and adverse events in patients with pp65 CMV antigenemia who received high dose Valacyclovir (n = 15), Valganciclovir (n = 16), and Foscarnet (n = 30).\n\nResults\nOverall, 60/61 (98 %) of cases achieved CMV antigenemia clearance by day 28, and no patient developed CMV disease. After adjusting for age, sex, diagnosis, CMV serological status, donor type, CMV antigen level, graft-versus-host disease (GVHD) therapy, and conditioning regimen, there were no significant differences in the rates of viral clearance at day 14 in patients who received Valganciclovir (0.18, 95 % confidence interval (CI) 0.01 to 2.15, p = 0.17) and Foscarnet (OR 0.22, 95 % CI 0.03 to 2.40, p = 0.22), compared with Valacyclovir (assigned OR = 1.00). Recurrent antigenemia by day 180 after clearance of the initial CMV episode occurred in 34/61 (56 %) of patients. Using the multivariate model adjusting for the same covariates, there were also no significant differences in secondary episodes of CMV between treatment groups. With regards to adverse effect monitoring, Foscarnet led to significantly increased creatinine levels (P = 0.009), while Valganciclovir led to significant decrease in neutrophil counts (P = 0.012).\n\nConclusion\nHigh dose Valacyclovir is a potential alternative to Valganciclovir and Foscarnet in the stable post-HSCT patient who has cytopenia and is not keen for inpatient treatment of CMV antigenemia.\n\nissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nCytomegalovirus (CMV) infection poses a serious clinical challenge to hematopoietic stem cell transplant (HSCT) patients as it can result in numerous complications associated with significant morbidity and mortality. These include retinitis, encephalitis, pneumonia, hepatitis and gastrointestinal ulceration. Two approaches for the prevention of CMV infection are currently practiced. The first is universal prophylaxis with routine administration of an antiviral agent to all patients after transplant. Benefits of prophylaxis is that monitoring may not be required if an effective antiviral is used, but some patients are exposed to drug-related toxicities unnecessarily. The second approach is pre-emptive therapy, that is initiated when CMV infection is detected, but before the development of CMV-associated symptoms. Pre-emptive therapy depends on early detection of CMV in blood, which is aided by the ready availability of pp65 antigenemia and DNA PCR-based assays. Both approaches are equally effective in preventing CMV disease.\n\nGanciclovir, and its modified oral formulation, Valganciclovir (GCV), are first line agents for pre-emptive therapy against CMV [1–3]. When cytopenias are present, Foscarnet is used as an alternative. Although as effective as ganciclovir, Foscarnet is associated with renal toxicity and requires inpatient therapy, hence it is reserved as second line therapy [4, 5]. Valacyclovir satisfies several criteria for an ideal pre-emptive therapeutic agent due to its low toxicity profile, and excellent bioavailability after oral administration [6]. High dose Valacyclovir has already been shown to be safe and effective in CMV prophylaxis after solid organ and stem cell transplantation [7–13], but has not been adequately studied as an antiviral for pre-emptive therapy against CMV antigenemia. Valacyclovir is potentially an important alternative agent in patients with cytopenia who are not eligible for Ganciclovir, and who are unwilling to be hospitalized for intravenous Foscarnet.\n\nWe hypothesized that Valacyclovir could be useful as a single agent against CMV antigenemia after HSCT, without significant hematologic or renal toxicity. To evaluate this treatment approach, a retrospective cohort study comparing the use of Valacyclovir, Valganciclovir, and Foscarnet was performed in our institution. The primary outcome was viremia clearance. Secondary outcomes included recurrent antigenemia and adverse events.\n\nMethods\nPatients\nAll consecutive adult patients who underwent allogeneic bone marrow, peripheral blood stem cell, or cord blood transplantation at Singapore General Hospital between January 2008 and September 2011 were included if they had an initial episode of CMV antigenemia before a single antiviral (Valacyclovir, Valganciclovir, or Foscarnet) was started for pre-emptive therapy. Departmental practice guidelines, integrated with patients’ preferences, determined the choice of antiviral regimen. Ganciclovir is the first line pre-emptive therapy for CMV in our inpatients, while Foscarnet is used in patients with neutropenia or previous ganciclovir treatment failure. Outpatients with normal gastrointestinal absorption received Valganciclovir, while patients with neutropenia received Valacyclovir. Patients who developed CMV disease before or at the time of the initial detection of CMV antigenemia were excluded. All patients also received acyclovir for prophylaxis against varicella zoster virus and trimethoprim-sulfamethoxazole for Pneumocystis jirovecii prophylaxis until immunosuppression was discontinued. Prophylaxis for fungal infections was either posaconazole or itraconazole. Calcineurin-inhibitor-based therapies were the most commonly used GVHD prophylaxis regimens, with the inclusion of anti-thymocyte globulins (ATG) in unrelated donor transplants. All participants gave their informed consent for participation in the research database and the database collection was approved by the institutional review board of the Singapore General Hospital.\n\nDetection of CMV reactivation\nAll patients were screened for CMV infection using a CMV pp65 antigenemia assay at least twice in the first week after transplant, and at least once a week subsequently. The CMV antigenemia assay was performed as described previously [14], and ≥ 1 CMV antigen positive cell per million leukocytes was used as the threshold for pre-emptive therapy.\n\nPre-emptive therapy\nPatients were treated with either Foscarnet at 90 mg/kg twice daily (BID), or 45 mg/kg BID if creatinine clearance is less than 60 ml/min; Valganciclovir a 900 mg BID or 450 mg BID if creatinine clearance is less than 60 ml/min, or Valacyclovir 2 g four times daily (QID) or 1 g QID in the presence of renal impairment. The median duration of treatment was 14 days. Clearance of CMV antigenemia was defined as 0 positive cells per million leukocytes via the CMV pp65 antigenemia assay. The incidence of recurrent CMV antigenemia after treatment with each agent was recorded for 180 days after the clearance of an initial episode of CMV antigenemia. Patients who relapsed after successful clearance of CMV antigenemia were treated at the discretion of the physician.\n\nMonitoring of adverse events\nPatients were monitored for the development of CMV disease as defined previously [15], as well as significant side effects of Valacyclovir, Valganciclovir, or Foscarnet. Haemograms and biochemical panels were performed at least once a week to look for neutropenia, thrombocytopenia and renal impairment. Mortality rates and causes of mortality for up to 6 months post-transplant were recorded.\n\nStatistical analysis\nValues are expressed as median (range), and the significance of differences was determined using the chi-square test or analysis of variance, as appropriate. Some analyses compared changes in pre- and post-treatment cell counts and serum creatinine between two groups; these were analyzed using the paired t-test. Multivariable logistic regression models were used to determine the odds of viral clearance at day 14, and of recurrent antigenemia in patients treated with Valganciclovir and Foscarnet, compared with Valacyclovir. Potential confounders considered include age, gender, CMV serological status, donor type, CMV antigen level at diagnosis, conditioning regimen, and graft-versus-host disease therapy.\n\nResults\nPatient characteristics\nThe demographic characteristics of the three groups of patients are shown in Table 1. Comparisons of the three groups for parameters that could influence CMV reactivation showed significant difference with respect to age, but not CMV serological status, sex, donor type, indication for transplant and conditioning regimen. Patients requiring systemic corticosteroids or other agents (e.g. ertanercept, mycophenolate mofetil, tacrolimus) for treatment of GVHD were statistically similar between groups.Table 1 Patient characteristics\n\n\tAll (n = 61)\tValacyclovir (n = 15)\tValganciclovir (n = 16)\tFoscarnet (n = 30)\t\nP\na\n\t\nMedian age, years (range)\t41 (16–66)\t47 (18–61)\t50 (30–57)\t37 (16–66)\t0.017\t\nMale, N (%)\t31 (50.8)\t9 (60.0)\t5 (31.3)\t27 (56.7)\t0.186\t\nDiagnosis, N (%)\t\t\t\t\t0.509\t\n\tAcute myeloid leukemia\t30 (49.2)\t7 (46.7)\t9 (56.3)\t14 (46.7)\t\t\n\tAcute lymphoid leukemia\t13 (21.3)\t3 (20.0)\t1 (6.3)\t9 (30.0)\t\t\n\tNon-Hodgkin’s lymphoma\t2 (3.3)\t1 (6.7)\t1 (6.3)\t0 (0.0)\t\t\n\tMyelodysplastic syndrome\t6 (9.8)\t1 (6.7)\t1 (6.3)\t4 (13.3)\t\t\n\tOthers\t10 (16.4)\t3 (20.0)\t4 (25.0)\t3 (10.0)\t\t\nConditioning regimen, N (%)\t\t\t\t\t0.374\t\n\tMyeloabalative\t32 (53.3)\t9 (60.0)\t11 (68.8)\t12 (41.4)\t\t\n\tNon-Myeloabalative\t14 (23.3)\t2 (13.3)\t3 (18.8)\t9 (31.0)\t\t\n\tReduced Intensity\t14 (23.3)\t4 (26.7)\t2 (12.5)\t8 (27.6)\t\t\nDonor type, N (%)\t\t\t\t\t0.078\t\n\tRelated\t31 (50.8)\t11 (73.3)\t10 (62.5)\t10 (33.3)\t\t\n\tUnrelated\t21 (34.4)\t2 (13.3)\t5 (31.3)\t14 (46.7)\t\t\n\tCord Blood\t9 (14.8)\t2 (13.3)\t1 (6.25)\t6 (20.0)\t\t\nCMV serologic status, N (%)\t\t\t\t\t0.586\t\n\tDonor-/recipient+\t9 (14.8)\t1 (6.7)\t3 (18.8)\t5 (16.7)\t\t\n\tDonor+/recipient+\t52 (85.3)\t14 (93.3)\t13 (81.3)\t25 (83.3)\t\t\nGVHD (during study)\t\t\t\t\t0.155\t\n\tNone\t27 (44.3)\t5 (33.3)\t4 (25.0)\t18 (60.0)\t\t\n\tGrade I-II\t30 (49.2)\t9 (60.0)\t10 (62.5)\t11 (36.7)\t\t\n\tGrade II-IV\t4 (6.6)\t1 (6.7)\t2 (12.5)\t1 (33.3)\t\t\nGVHD treatment\t\t\t\t\t0.119\t\n\tNone\t25 (41.0)\t5 (33.3)\t3 (18.8)\t17 (56.7)\t\t\n\tSteroids\t30 (49.1)\t9 (60.0)\t11 (68.9)\t10 (33.3)\t\t\n\tOthers\t6 (9.8)\t1 (6.7)\t2 (12.5)\t3 (10.0)\t\t\nPre-treatment laboratory results, median (range)\t\n\tCreatinine (μM)\t78 (40–240)\t86 (46–182)\t72 (44–240)\t78 (40–205)\t0.601\t\n\tANC (x103/mm3)\t2.6 (0.2-22.8)\t2.4 (0.2-6.6)\t3.6 (1.1-15.6)\t1.7 (0.8-22.8)\t0.093\t\n\tPlatelet (x103/mm3)\t64 (7–260)\t98 (15–197)\t68 (7–244)\t32.5 (8–260)\t0.053\t\n\nCMV, cytomegalovirus; GVHD, graft versus host disease; ANC, absolute neutrophil count\n\n\naP value for difference by treatment group, based on chi-square test or analysis of variance\n\nTable 2 Response to pre-emptive CMV therapy\n\n\tAll (n = 61)\tValacyclovir (n = 15)\tValganciclovir (n = 16)\tFoscarnet (n = 30)\t\nP\n\t\nMedian time to antigenemia (days from transplant, range)\t27 (12–387)\t39 (16–387)\t31.5 (15–119)\t24.5 (12–104)\t0.084\t\nMedian viral load (No. of CMV positive cells per million leukocytes, range)\t3 (1–750)\t3 (1–40)\t3 (2–181)\t3.5 (1–750)\t0.772\t\nClearance, N (%)\t60 (98.1)\t15 (100)\t16 (100)\t29 (96.7)\t0.591\t\nRecurrent antigenemia, N (%)\t34 (55.8)\t7 (46.7)\t11 (68.8)\t16 (53.3)\t0.434\t\nMedian days to recurrence\t43.5 (11–173)\t59 (27–173)\t42 (14–94)\t38 (11–163)\t0.081\t\n\nCMV, cytomegalovirus\n\n\n\nCMV antigenemia and pre-emptive treatment\nThe median number of CMV antigen-positive cells at the initiation of pre-emptive therapy did not differ between groups (P = 0.77), and the median viral load for all included patients was 3 (range 1 to 750). Overall, 60/61 (98 %) of cases achieved CMV antigenemia clearance by day 28, with no significant differences between treatment groups (p = 0.591). By day 14, clearance rates among groups who received Valacyclovir, Valganciclovir, and Foscarnet were 14/15 (93 %), 13/16 (81 %), and 22/30 (73 %) respectively. After adjusting for age, sex, diagnosis, CMV serological status, donor type, CMV antigen level, GVHD therapy, and conditioning regimen, there were no significant differences in the rates of viral clearance at day 14 in patients who received Valganciclovir (odds ratio (OR) 0.18, 95 % confidence interval (CI) 0.01 to 2.15, p = 0.17) and Foscarnet (OR 0.22, 95 % CI 0.03 to 2.40, p = 0.22), compared with Valacyclovir (assigned OR = 1.00).\n\nAlthough high rates of CMV clearance were achieved, recurrent antigenemia by day 180 after clearance of the initial CMV episode occurred in 55.8 % of patients. After adjusting for the same covariates, there were no significant differences in secondary episodes of CMV among patients who received Valganciclovir (OR 3.36, 95 % CI 0.62 to 18.3, p = 0.17) and Foscarnet (OR 1.02, 95 % CI 0.20 to 5.25, p = 0.98, compared with Valacyclovir (OR = 1.00). No patients developed CMV disease during the course of the study. Response to pre-emptive CMV treatment using the three different anti-virals are detailed in Table 2.\n\nAdverse events and survival\nThe elevation in serum creatinine levels was significantly higher after treatment with Foscarnet, compared to Valacyclovir or Valganciclovir (P = 0.009). Treatment with Valganciclovir led to a significant decrease in neutrophil counts, compared to Foscarnet or Valacyclovir (P = 0.012). Changes in pre- and post-treatment platelet levels did not differ significantly between groups (Table 3). One patient died of neutropenic enterocolitis on post-transplant day 102 in the Valacyclovir group, one patient died of disease progression on post-transplant day 138 in the Valganciclovir group, and three patients died of disease progression and sepsis on post-transplant days 81, 129, and 131 in the Foscarnet group.Table 3 Hematological and renal toxicity of treatment\n\n\t\tAll (n = 61)\tValacyclovir (n = 15)\tValganciclovir (n = 16)\tFoscarnet (n = 30)\t\nP\n\t\nChange in parameter (post-treatment – pre-treatment), median (range)\t\n\tCreatinine (μM)\t14 (−31 to 126)\t2 (−31 to 57)\t−2.5 (−70 to 73)\t31.6 (−65 to 126)\t0.009\t\n\tANC (x103/mm3)\t−0.05 (−20.6 to 5.0)\t0.19 (−4.2 to 3)\t−1.5 (−7.5 to −1.1)\t1.1 (−20.6 to 5.0)\t0.012\t\n\tPlatelet (x103/mm3)\t6 (−123 to 196)\t6 (−72 to 82)\t−7.5 (−123 to 196)\t13 (−92 to 150)\t0.335\t\n\nANC, Absolute neutrophil count\n\n\n\nDiscussion\nIn this retrospective study, pre-emptive therapy with Valacyclovir, Valganciclovir and Foscarnet achieved high viral clearance rates in post-HSCT patients with CMV antigenemia (98 %). After adjusting for potential confounders including age, sex, CMV serotype, CMV antigen level at diagnosis, donor type, conditioning regimen and GVHD treatment, the rates of viral clearance and recurrent antigenemia were not significantly different in patients receiving high dose Valacyclovir, compared with Ganciclovir or Foscarnet. Viral clearance with Valacyclovir was achieved with significantly less reduction in neutrophil count or rise in creatinine levels. However, it is important to bear in mind that patients who received Valacyclovir in our study were discharged outpatients who were at least one month post-transplant, had no other active infection, and were not debilitated. Thus our findings may only extend to the stable post-HSCT patient.\n\nAnother limitation of our study is the use of a low threshold value of 1 CMV-positive cell per million leukocytes to start pre-emptive therapy. It has been suggested that low positive results may represent transient reactivation [16], or even a rare false positive result [17], hence clearance may in part be spontaneous. However, Boeckh et al. showed that the discontinuation of gancyclovir below the threshold of 3 positive cells per 50,000 leukocytes led to a risk of CMV disease [18]. When a single positive cell is used as trigger, the rate of CMV disease was reduced [19]. Other investigators have also used a single positive cell as trigger, recognizing that even low viral loads might be significant in the HSCT patient [16, 20, 21]. Given the rapid doubling time of CMV in immunosuppressed paients [22], withholding anti-CMV therapy may pose significant risks. Future studies applying a higher threshold to begin pre-emptive therapyin a larger group of patients are needed to confirm the therapeutic effect of Valacyclovir in high-level CMV antigenemia.\n\nTo our knowledge, no previous report has investigated the use of Valacyclovir for pre-emptive therapy of CMV antigenemia, although several randomized and retrospective studies have demonstrated the efficacy of Valacyclovir as prophylactic therapy. For example, results from large randomized multicenter studies have shown that Valacyclovir is more effective in preventing CMV antigenemia than oral acyclovir [11], and has similar efficacy as Ganciclovir in preventing CMV infection and disease [12]. Similarly, retrospective reports have established the potential benefit of Valacyclovir as a prophylactic agent against CMV reactivation, compared with no or other forms of CMV prophylaxis, with significantly reduced rates and delay of CMV reactivation [10, 13]. The small sample size in our study precludes definitive conclusions about the efficacy of Valacyclovir as pre-emptive therapy in HSCT patients, but results are encouraging. Importantly, Valacyclovir represents a cost effective alternative to Valganciclovir [23].\n\nLimitations of this study include its retrospective study design, non-randomized treatment allocation, and small sample size. In recent years, more institutions have switched from pp65 antigenemia assays to quantitative PCR methods to guide pre-emptive therapy. PCR based methods are rapid, more sensitive, provide more precise quantitation of CMV, and can be used in patients with severe neutropenia. Its disadvantage includes inter-assay and inter-laboratory variability in viral load reporting, which has complicated attempts to standardize thresholds for initiating and stopping pre-emtive therapy. Recently, the WHO international reference standard was developed, which enables uniform viral load reporting and interpretation. It remains to be studied if the viral load threshold for preemptive therapy using Valacyclovir is comparable to that using Valganciclovir or Foscarnet.\n\nConclusions\nIn conclusion, pre-emptive Valacyclovir, Foscarnet and Valacyclovir led to similar clearance of CMV antigenemia and rates of recurrence. High dose Valacyclovir is potentially a safe and cost-effective option for pre-emptive treatment of CMV antigenemia in the stable post-HSCT patient who has cytopenia or prefers outpatient treatment. These findings must be interpreted in light of limitations inherent to retrospective observational studies. Further prospective randomized studies are needed to validate the efficacy suggested by the results of this retrospective study.\n\nCompeting interests\n\nThe authors declare that they have no competing interests\n\nAuthors’ contributions\n\nAll authors contributed to the intellectual development of this paper. WHYK had the idea for the study. OSY and HTTT collected data, OSY analyzed the data and wrote the first draft paper. CPD, YCL, AHYL, YTG and WHYK provided patients, and critical corrections to the manuscript. All authors read and approved the final manuscript.\n==== Refs\nReferences\n1. Akyurekli C Chan JY Elmoazzen H Tay J Allan DS Impact of ethnicity on human umbilical cord blood banking: a systematic review Transfusion 2014 54 2122 2127 10.1111/trf.12630 24697816 \n2. Kanda Y Mineishi S Saito T Seo S Saito A Suenaga K Ohnishi M Niiya H Nakai K Takeuchi T Pre-emptive therapy against cytomegalovirus (CMV) disease guided by CMV antigenemia assay after allogeneic hematopoietic stem cell transplantation: a single-center experience in Japan Bone Marrow Transplant 2001 27 437 444 10.1038/sj.bmt.1702805 11313674 \n3. 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Reischig T Opatrny K Jr Bouda M Treska V Jindra P Svecova M A randomized prospective controlled trial of oral ganciclovir versus oral valacyclovir for prophylaxis of cytomegalovirus disease after renal transplantation Transpl Int 2002 15 615 622 10.1111/j.1432-2277.2002.tb00120.x 12478408 \n8. Reischig T Nemcova J Vanecek T Jindra P Hes O Bouda M Treska V Intragraft cytomegalovirus infection: a randomized trial of valacyclovir prophylaxis versus pre-emptive therapy in renal transplant recipients Antivir Ther 2010 15 23 30 10.3851/IMP1485 20167988 \n9. Pavlopoulou ID Syriopoulou VP Chelioti H Daikos GL Stamatiades D Kostakis A Boletis JN A comparative randomised study of valacyclovir vs oral ganciclovir for cytomegalovirus prophylaxis in renal transplant recipients Clin Microbiol Infect 2005 11 736 743 10.1111/j.1469-0691.2005.01215.x 16104989 \n10. Vusirikala M Wolff SN Stein RS Brandt SJ Morgan DS Greer JP Schuening FG Dummer JS Goodman SA Valacyclovir for the prevention of cytomegalovirus infection after allogeneic stem cell transplantation: a single institution retrospective cohort analysis Bone Marrow Transplant 2001 28 265 270 10.1038/sj.bmt.1703129 11535994 \n11. Ljungman P de La Camara R Milpied N Volin L Russell CA Crisp A Webster A Randomized study of valacyclovir as prophylaxis against cytomegalovirus reactivation in recipients of allogeneic bone marrow transplants Blood 2002 99 3050 3056 10.1182/blood.V99.8.3050 11929799 \n12. Winston DJ Yeager AM Chandrasekar PH Snydman DR Petersen FB Territo MC Randomized comparison of oral valacyclovir and intravenous ganciclovir for prevention of cytomegalovirus disease after allogeneic bone marrow transplantation Clin Infect Dis 2003 36 749 758 10.1086/367836 12627359 \n13. Mori T Aisa Y Shimizu T Nakazato T Yamazaki R Ikeda Y Okamoto S Prevention of cytomegalovirus infection by valaciclovir after allogeneic bone marrow transplantation from an unrelated donor Int J Hematol 2006 83 266 270 10.1532/IJH97.E0523 16720561 \n14. Tan BH Chlebicka NL Low JG Chong TY Chan KP Goh YT Use of the cytomegalovirus pp 65 antigenemia assay for preemptive therapy in allogeneic hematopoietic stem cell transplantation: a real-world review Transpl Infect Dis 2008 10 325 332 10.1111/j.1399-3062.2008.00325.x 18627578 \n15. Ljungman P Griffiths P Paya C Definitions of cytomegalovirus infection and disease in transplant recipients Clin Infect Dis 2002 34 1094 1097 10.1086/339329 11914998 \n16. Yanada M Yamamoto K Emi N Naoe T Suzuki R Taji H Iida H Shimokawa T Kohno A Mizuta S Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation Bone Marrow Transplant 2003 32 801 807 10.1038/sj.bmt.1704232 14520425 \n17. Lesprit P Scieux C Lemann M Carbonelle E Modai J Molina JM Use of the cytomegalovirus (CMV) antigenemia assay for the rapid diagnosis of primary CMV infection in hospitalized adults Clin Infect Dis 1998 26 646 650 10.1086/514572 9524838 \n18. Boeckh M Gooley TA Myerson D Cunningham T Schoch G Bowden RA Cytomegalovirus pp 65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study Blood 1996 88 4063 4071 8916975 \n19. Boeckh M Bowden RA Gooley T Myerson D Corey L Successful modification of a pp 65 antigenemia-based early treatment strategy for prevention of cytomegalovirus disease in allogeneic marrow transplant recipients Blood 1999 93 1781 1782 10084817 \n20. Boivin G Belanger R Delage R Beliveau C Demers C Goyette N Roy J Quantitative analysis of cytomegalovirus (CMV) viremia using the pp 65 antigenemia assay and the COBAS AMPLICOR CMV MONITOR PCR test after blood and marrow allogeneic transplantation J Clin Microbiol 2000 38 4356 4360 11101564 \n21. Leruez-Ville M Ouachee M Delarue R Sauget AS Blanche S Buzyn A Rouzioux C Monitoring cytomegalovirus infection in adult and pediatric bone marrow transplant recipients by a real-time PCR assay performed with blood plasma J Clin Microbiol 2003 41 2040 2046 10.1128/JCM.41.5.2040-2046.2003 12734246 \n22. Emery VC Investigation of CMV disease in immunocompromised patients J Clin Pathol 2001 54 84 88 10.1136/jcp.54.2.84 11215290 \n23. Reischig T Kacer M The efficacy and cost-effectiveness of valacyclovir in cytomegalovirus prevention in solid organ transplantation Expert Rev Pharmacoecon Outcomes Res 2014 14 771 779 10.1586/14737167.2014.965157 25252996\n\n", "fulltext_license": "CC BY", "issn_linking": "2052-1839", "issue": "15()", "journal": "BMC hematology", "keywords": null, "medline_ta": "BMC Hematol", "mesh_terms": null, "nlm_unique_id": "101609487", "other_id": null, "pages": "8", "pmc": null, "pmid": "26090121", "pubdate": "2015", "publication_types": "D016428:Journal Article", "references": "12478408;24697816;9113493;20167988;18627578;11830461;11914998;10084817;7670405;14520425;11101564;11535994;11215290;11313674;9524838;11929799;12734246;16104989;16720561;25252996;12627359;8916975;8669888", "title": "Use of Valacyclovir for the treatment of cytomegalovirus antigenemia after hematopoietic stem cell transplantation.", "title_normalized": "use of valacyclovir for the treatment of cytomegalovirus antigenemia after hematopoietic stem cell transplantation" }	[ { "companynumb": "SG-MYLANLABS-2017M1039243", "fulfillexpeditecriteria": "1", "occurcountry": "SG", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "VALACYCLOVIR HYDROCHLORIDE" }, "drugadditiona...
{ "abstract": "BACKGROUND\nThere is a surge of cardiovascular disease (CVD) in Africa. CVD is the leading cause of mortality among patients with severe mental illness (SMI) in developed countries, with little evidence from the African context.\n\n\nOBJECTIVE\nTo determine the prevalence and risk factors for MetS among South African patients with SMI.\n\n\nMETHODS\nIn a cross sectional study, individuals with SMI treated with antipsychotics and a control group without a mental illness, matched for age, gender and ethnicity were evaluated for MetS using the 2009 Joint Interim statement (JIS) criteria.\n\n\nRESULTS\nOf the 276 study group subjects, 65.9% were male, 84.1% black African, 9.1% white, 5.4% of Indian descent and 1.5% coloured (mixed race) with a mean age of 34.7 years (±12.5). Schizophrenia was the most common diagnosis (73.2%) and 40% were taking first generation antipsychotics. The prevalence of MetS was 23.2% (M: 15.4%, F: 38.3%) in the study group and 19.9% (M: 11.9%, F: 36.3%) in the control group (p = 0.4). MetS prevalence was significantly higher in study subjects over 55 years compared to controls (p = 0.03). Increased waist circumference (p< 0.001) and low high density lipoprotein (HDL) cholesterol (p = 0.003) were significantly more prevalent in study subjects compared to controls. In study subjects, risk factors associated with MetS included age (OR: 1.09, 95% CI 1.06-1.12, p < 0.001), female gender (OR: 2.19, 95% CI 1.06-4.55, p = 0.035) and Indian descent (OR: 5.84, 95% CI 1.66-20.52, p = 0.006) but not class of antipsychotic (p = 0.26).\n\n\nCONCLUSIONS\nThe overall MetS prevalence was not increased in patients with SMI compared to controls; however, the higher prevalence of the individual components (HDL cholesterol and waist circumference) suggests an increased risk for CVD, especially in patients over 55 years.", "affiliations": "Department of Psychiatry, Nelson R Mandela School of Medicine, University of KwaZulu - Natal, Durban, South Africa.;Department of Psychiatry, Nelson R Mandela School of Medicine, University of KwaZulu - Natal, Durban, South Africa.;Department of Diabetes and Endocrinology, Nelson R Mandela School of Medicine, University of KwaZulu - Natal, Durban, South Africa.", "authors": "Saloojee\|Shamima\|S\|;Burns\|Jonathan K\|JK\|;Motala\|Ayesha A\|AA\|", "chemical_list": "D014150:Antipsychotic Agents", "country": "United States", "delete": false, "doi": "10.1371/journal.pone.0149209", "fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2688223010.1371/journal.pone.0149209PONE-D-15-39474Research ArticleMedicine and Health SciencesPharmacologyDrugsAntipsychoticsPeople and PlacesPopulation GroupingsEthnicitiesAfricansBiology and Life SciencesBiochemistryLipidsCholesterolBiology and Life SciencesPhysiologyPhysiological ParametersBody WeightBody Mass IndexMedicine and Health SciencesPhysiologyPhysiological ParametersBody WeightBody Mass IndexMedicine and Health SciencesMental Health and PsychiatrySchizophreniaBiology and Life SciencesPhysiologyPhysiological ParametersBody WeightObesityMedicine and Health SciencesPhysiologyPhysiological ParametersBody WeightObesityMedicine and Health SciencesEpidemiologyEthnic EpidemiologyBiology and Life SciencesBiochemistryProteinsLipoproteinsMetabolic Syndrome in South African Patients with Severe Mental Illness: Prevalence and Associated Risk Factors Metabolic Syndrome and Severe Mental IllnessSaloojee Shamima 1Burns Jonathan K 1Motala Ayesha A 21 \nDepartment of Psychiatry, Nelson R Mandela School of Medicine, University of KwaZulu - Natal, Durban, South Africa2 \nDepartment of Diabetes and Endocrinology, Nelson R Mandela School of Medicine, University of KwaZulu - Natal, Durban, South Africavan Amelsvoort Therese EditorMaastricht University, NETHERLANDSCompeting Interests: the authors have declared that no competing interests exist\n\nConceived and designed the experiments: SS JKB AAM. Performed the experiments: SS. Analyzed the data: SS JKB AAM. Wrote the paper: SS JKB AAM.\n\n E-mail: saloojees1@ukzn.ac.za16 2 2016 2016 11 2 e01492097 9 2015 28 1 2016 © 2016 Saloojee et al2016Saloojee et alThis is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background\nThere is a surge of cardiovascular disease (CVD) in Africa. CVD is the leading cause of mortality among patients with severe mental illness (SMI) in developed countries, with little evidence from the African context.\n\nObjective\nTo determine the prevalence and risk factors for MetS among South African patients with SMI.\n\nMethod\nIn a cross sectional study, individuals with SMI treated with antipsychotics and a control group without a mental illness, matched for age, gender and ethnicity were evaluated for MetS using the 2009 Joint Interim statement (JIS) criteria.\n\nResults\nOf the 276 study group subjects, 65.9% were male, 84.1% black African, 9.1% white, 5.4% of Indian descent and 1.5% coloured (mixed race) with a mean age of 34.7 years (±12.5). Schizophrenia was the most common diagnosis (73.2%) and 40% were taking first generation antipsychotics. The prevalence of MetS was 23.2% (M: 15.4%, F: 38.3%) in the study group and 19.9% (M: 11.9%, F: 36.3%) in the control group (p = 0.4). MetS prevalence was significantly higher in study subjects over 55 years compared to controls (p = 0.03). Increased waist circumference (p< 0.001) and low high density lipoprotein (HDL) cholesterol (p = 0.003) were significantly more prevalent in study subjects compared to controls. In study subjects, risk factors associated with MetS included age (OR: 1.09, 95% CI 1.06–1.12, p < 0.001), female gender (OR: 2.19, 95% CI 1.06–4.55, p = 0.035) and Indian descent (OR: 5.84, 95% CI 1.66–20.52, p = 0.006) but not class of antipsychotic (p = 0.26).\n\nConclusion\nThe overall MetS prevalence was not increased in patients with SMI compared to controls; however, the higher prevalence of the individual components (HDL cholesterol and waist circumference) suggests an increased risk for CVD, especially in patients over 55 years.\n\nThis publication was made possible by grant number: R24TW008863 from the Office of the U.S. Global AIDS Coordinator and the U. S. Department of Health and Human Services, National Institutes of Health (NIH OAR and NIH ORWH). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the government.” Data AvailabilityAll relevant data are within the paper.Data Availability\nAll relevant data are within the paper.\n==== Body\nIntroduction\nMetabolic syndrome (MetS) gained prominence in the psychiatric literature in the past decade because the leading cause of premature mortality in patients with severe mental illness (SMI) from developed countries is reported to be cardiovascular disease (CVD) [1–3]. There is little doubt that MetS is a risk factor for diabetes mellitus and CVD [4], although the clinical utility and criteria by which MetS is defined is debatable [5,6]. Regarding the elevated risk of CVD in SMI, there have been several reports on the prevalence and associated risk factors for MetS in SMI globally [7–12]. Reported prevalence rates range from 9.3% in Indonesia [8] to 21% in Mexico [9], 27.5% in Japan [10], 57% in England [11] and 68% in Australia [12]. In a recent meta—analysis on data from 27 countries for the period 2003–2011, Mitchell et al. reported an overall prevalence of 32.5% in patients with schizophrenia and related disorders [13].\n\nThere is limited information regarding the prevalence of MetS in patients with SMI from Africa. The meta—analysis by Mitchell et al.[13] did not include any studies from Africa; also, only 0.001% of the patients enrolled in schizophrenia trials throughout the world are recruited from Africa [14]. Data for South Africa are limited to three studies [15–17]. A study of 84 long term in patients that included patients with cognitive and personality disorders reported a MetS prevalence of 32% [15] while the other two reported on the prevalence of MetS in patients taking a single antipsychotic [16,17]. From population studies in South Africa, the reported prevalence of MetS is 22.1% in rural [18] and 31.7% in urban black South African communities [19].\n\nIn many high income countries, more than 80% of antipsychotic prescriptions are for second generation antipsychotics (SGAs) and the metabolic side effects and magnitude of risk attributable to SGA medication is well established [20–22]. However, evidence comparing the metabolic side effects of individual older and cheaper, first generation antipsychotics (FGAs) which are still widely prescribed in Africa [23] is mostly derived from studies conducted prior to 1994, and is of low quality [24] prompting a call for more recent studies [24,25].\n\nRegarding risk factors for MetS in SMI, reports on the gender distribution of MetS in SMI is variable, because although many studies report a higher prevalence in females [7,9,26,27] some report a higher prevalence in males [10,12,28]. More than two thirds of the studies in the meta—analysis by Mitchell et al. [13] did not report on ethnicity, and there is limited and mixed evidence for the increased prevalence of MetS among ethnic minorities with SMI from the United States (US) [29].\n\nThe sparse information regarding the prevalence and risk factors for MetS in South African patients with SMI is of concern, because Mensah et al. have shown that from 1990 to 2013 there was an 81% increase in CVD deaths in Sub Saharan Africa (SSA), with more women dying of CVDs (512 269) than men (445 445) [30].\n\nThis study was therefore undertaken to determine the prevalence of MetS and associated risk factors in South African patients with SMI treated with antipsychotic medication.\n\nMethods\nWe conducted a cross—sectional study in the psychiatric unit at King Edward VIII Hospital (KEH) in Durban, South Africa from February 2012 to December 2014. KEH is a 922 bedded general hospital with 20 psychiatric beds and serves a population of approximately 360 000 individuals. The psychiatric unit has two full time psychiatrists and provides a regional level service for other district hospitals without psychiatrists; but also serves as a district hospital because it is close to a large informal settlement without community mental health clinics. The study subjects were 18–65 year old patients with SMI of black, white, Asian Indian or coloured (mixed) ethnicity. In—or out—patients with schizophrenia, bipolar 1 mood disorder or schizoaffective disorder diagnosed using the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000) [31] criteria on antipsychotic medication for at least three months were included. Subjects who were taking a single antipsychotic only were assigned to the monotherapy group. Those subjects who were on two or more antipsychotics at the same time for at least six weeks and those who were taking antipsychotics combined with sodium valproate or an antidepressant were assigned to the polytherapy group. Control subjects were recruited by placing posters explaining the purpose and procedures for the study at the entrance, exit and other high traffic areas in the hospital. Hospital staff, health science students and members of the public who were physically healthy and who had no lifetime diagnosis or treatment for a mental illness were invited to participate in the study. Control and study subjects who were HIV positive or pregnant were excluded. Control subjects were matched for age gender and ethnicity with study subjects.\n\nAll consenting study and control subjects were interviewed and information regarding demographic and clinical characteristics was recorded on a specifically designed questionnaire. Study subject records were examined for diagnosis of mental illness and currently administered antipsychotic. At KEH, chlorpromazine and haloperidol are first line antipsychotic agents with risperidone and clozapine as alternatives. Olanzapine, quetiapine, aripiprazole and amisulpride are available only by special motivation.\n\nEthics Statement\nThis study was approved by the Biomedical Research Ethics Committee of the University of KwaZulu—Natal. Written informed consent was obtained from all study and control subjects in English or Isizulu.\n\nAnthropometric measurements were conducted as per the World Health Organization (WHO) (2000, 1995) protocols [32]. Weight in kilograms (kg) and height in centimetres (cm) were measured for calculation of the body mass index (BMI). BMI (kg/m2) was categorized as normal (< 25), overweight (25–29.9) and obese (> 30). Waist circumference was measured using a soft tape measure at the mid -point between the upper border of the iliac crest and the inferior margin of the last rib. Blood pressure was measured with the subject in the sitting position after a ten minute rest; two readings were taken with a minimum interval of ten minutes and the mean of the two readings was used to record the blood pressure. Venous blood sampling was performed after an overnight fast for plasma glucose and serum lipids (total cholesterol, total triglycerides, high density lipoprotein [HDL] cholesterol, low density lipoprotein [LDL] cholesterol). Plasma glucose, HDL and triglycerides were measured by the enzymatic method utilizing Beckman Coulter GLU, HDLD and TG reagent respectively on a Beckman Coulter DxC 600 instrument. LDL cholesterol was calculated by the Freidewald formula.\n\nMetS was defined using the 2009 Joint Interim Statement (JIS) definition [4] and is diagnosed by the presence of any 3 of the following 5 risk factors: (i) increased waist circumference; waist circumference cut off points used: whites, blacks and coloureds: men ≥ 94 cm, women ≥ 80 cm; Indians: men ≥ 90 cm, women ≥ 80 cm (ii) elevated blood pressure: systolic >130 mmHg (or on treatment) and/or diastolic >85 mmHg (or on treatment) (iii) elevated fasting plasma glucose ≥ 5.6 mmol/l (or on treatment) (iv) elevated fasting triglycerides ≥1.7 mmol/l (or on treatment) and (v) reduced HDL cholesterol ≤1.0 mmol/l men (or on treatment), ≤ 1.3 mmol/l women (or on treatment).\n\nStatistical analysis\nAll statistical analyses were performed using SAS version 9.3 (SAS Institute Inc,. Cary).\n\nThe demographic and clinical characteristics of participants were summarized using means ± standard deviation (SD) or medians and interquartile ranges (IQR) for continuous variables and as proportions (%) for categorical variables. To compare differences in continuous demographic and clinical variables between the study and control groups and by class of antipsychotic medication, Student’s t-test, F-test, Wilcoxon-Mann-Whitney test and Kruskal-Wallis test were used depending on the data distribution. Fisher’s exact test was used to compare categorical variables. The difference in the prevalence of MetS and it’s individual components between the study and control groups and by class of antipsychotic medication was determined using Fisher’s exact test. To determine risk factors associated with MetS, multivariate logistic regression models were used were used. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated to determine the independent risk factors associated with MetS. A p value <0.05 was deemed to be statistically significant.\n\nResults\nStudy group and control group\nTable 1 shows the clinical and laboratory characteristics of the study and control subjects. There were 276 subjects with a SMI in the study group (M:F 182: 94) and majority were of black African ancestry (84.1%). There were no significant differences in the demographic characteristics between the two groups. In the study group, the majority (73.2%) had a diagnosis of schizophrenia with a mean duration of illness of 4.6 (±5.21) years. The most commonly prescribed antipsychotic alone or in combination with other antipsychotics was risperidone (33.9%), and the least commonly prescribed was olanzapine (3.67%). The mean BMI and waist circumference were high in both the study (27.6 ± 7.4 kg/m2; 92.8 ± 15cm, respectively) and control (27.1 ± 7.4 kg/m2; 87.8 ± 15.5cm, respectively) groups. Over half of the study group (55%) and control group (50%) were either overweight or obese.\n\n10.1371/journal.pone.0149209.t001Table 1 Clinical and laboratory characteristics of patients with severe mental illness (study group) and control group.\n\tStudy group (n = 276)\tControl group (n = 276)\tp\t\nGender\t\t\t0.86 a\t\n Male\t65.9(182)\t67.0(185)\t\t\n Female\t34.1 (94)\t33.0(91)\t\t\nAge(years)\t34.7 ± 12.5\t34.7 ± 12\t0.94 b\t\nAge group(years)(% [n])\t\t\t\t\n 18–24\t25.72(71)\t25.36(70)\t\t\n 25–34\t34.06(94)\t34.78(96)\t\t\n 35–44\t17.03(47)\t16.67(46)\t\t\n 45–54\t13.04(36)\t13.41(37)\t\t\n ≥ 55\t10.15(28)\t9.78(27)\t\t\nEthnicity\t\t\t1.00 a\t\n African\t84.1(232)\t84.1(232)\t\t\n White\t9.1(25)\t9.1(25)\t\t\n Indian\t5.4(15)\t5.8(16)\t\t\n Coloured(mixed race)\t1.5(4)\t1.1(3)\t\t\nDiagnosis\t\t\t\t\n Schizophrenia\t73.2(202)\t\t\t\n Schizoaffective disorder\t15.9(44)\t\t\t\n Bipolar mood disorder\t10.9(30)\t\t\t\nFirst generation antipsychotic medication\t\t\t\t\n Zuclopenthixol Decanoate\t14.12(50)\t\t\t\n Chlorpromazine\t10.17(36)\t\t\t\n Flupenthixol Decanoate\t7.91(28)\t\t\t\n Haloperidol\t7.91(28)\t\t\t\nSecond generation antipsychotic medication\t\t\t\t\n Risperidone\t33.90(120)\t\t\t\n Clozapine\t8.19(29)\t\t\t\n Amisulpride\t5.93(21)\t\t\t\n Aripiprazole\t4.24(15)\t\t\t\n Quetiapine\t3.96(14)\t\t\t\n Olanzapine\t3.67(13)\t\t\t\nCigarette smokers\t41.3(114)\t34.8(96)\t0.14 a\t\nBody Mass Index (BMI) (kg/m2)\t27.6 ±7.4\t27.1 ± 7.4\t0.46 b\t\nBMI category:\t\t\t0.46 a\t\n Normal: < 25\t45.3(125/276)\t50.2(138/275)\t\t\n Overweight: 25–29.9\t26.5(73/276)\t22.6(62/275)\t\t\n Obese: > 30\t28.3(78/276)\t27.3(75/275)\t\t\nWaist circumference (cm)\t92.8 ± 15.0\t87.8 ± 15.5\t<0.001 b\t\nBlood pressure(mmHg):\t\t\t\t\n Systolic\t121.9 ± 16.2\t121.8 ± 17.9\t0.95 b\t\n Diastolic\t76.2 ± 10.2\t76.9 ± 12.6\t0.45 b\t\nFasting plasma glucose (mmol/l)\t5.1 ± 1.2\t5.1 ± 1.3\t0.99 b\t\nSerum lipids (mmol/l):\t\t\t\t\n Total cholesterol\t4.1 ± 1.1\t4.1 ± 1.0\t0.96 b\t\n Total triglycerides\t1.1 ± 0.7\t1.0 ± 0.7\t0.40 b\t\n High density lipoprotein cholesterol\t1.1 ± 0.3\t1.2 ± 0.3\t0.01 b\t\n Low density lipoprotein cholesterol\t2.5 ± 0.9\t2.5 ± 0.8\t0.80 b\t\nData are mean ± SD and % (n), unless otherwise indicated p for significant differences between study and control group analysed using\n\na Fisher’s exact test and,\n\nb Student’s t—test.\n\nPrevalence of MetS and individual components\nThe overall prevalence of MetS was 23.2% in the study group and 19.9% in the control group with no significant difference between the two groups (p = 0.4). In both groups the prevalence was higher in women. The prevalence of MetS in the oldest age group was significantly higher in the study group (71.4%) compared to the control group (40.7%) (p = 0.03). In the study group, subjects of Indian descent (60%) and those with schizoaffective disorder (36.4%) had a higher prevalence of MetS compared to African subjects (19.4%) and those with schizophrenia (20.8%) respectively (Table 2). Compared to men, women with schizophrenia (36.4% vs 15%, p = 0.001) and schizoaffective disorder (61.1% vs 19.2%, p = 0.005), but not bipolar disorder (23.8% vs 11.1%, p = 0.4) had a significantly higher prevalence of MetS.\n\n10.1371/journal.pone.0149209.t002Table 2 Prevalence of metabolic syndrome by demographic characteristics and diagnosis in the study and control groups.\n\tStudy group (n = 276)\tControl group (n = 276)\tp a\t\nTotal\t23.2(64)\t19.9(55)\t0.41\t\nGender\t\t\t\t\n Male\t15.4(28/182)\t11.9(22/185)\t0.36\t\n Female\t38.3(36/94)\t36.3(33/91)\t0.88\t\nAge Group (years)\t\t\t\t\n 18–24\t11.3(8/71)\t5.7(4/70)\t0.37\t\n 25–34\t7.5(7/94)\t9.4(9/96)\t0.80\t\n 35–44\t27.7(13/47)\t26.1(12/46)\t1.00\t\n 45–54\t44.4(16/36)\t51.4(19/37)\t0.64\t\n ≥55\t71.4(20/28)\t40.7(11/27)\t0.03\t\nEthnicity\t\t\t\t\n African\t19.4(45/232)\t17.7(41/232)\t0.72\t\n White\t36.0(9/25)\t32.0(8/25)\t1.00\t\n Indian\t60.0(9/15)\t37.5(6/16)\t0.29\t\n Coloured (mixed race)\t25.0(1/4)\t0(0/3)\t\t\nDiagnosis\t\t\t\t\n Schizophrenia\t20.8(42/202)\t\t\t\n Schizoaffective disorder\t36.4(16/44)\t\t\t\n Bipolar mood disorder\t20.0(6/30)\t\t\t\nData are % (n).\n\na Fisher’s exact test.\n\nFor the individual components of MetS (Table 3), the most frequent abnormality in both the study and control groups was increased waist circumference (55.1% and 40.6%, study and control groups, respectively); the least frequent component was elevated serum triglycerides (14.5% and 12.3%, respectively). The prevalence of low serum HDL cholesterol was significantly higher in the study group (52.5%) than the control group (39.9%) (p = 0.003).\n\n10.1371/journal.pone.0149209.t003Table 3 Prevalence of the individual components of metabolic syndrome in the study and control groups.\n\tStudy group (n = 276)\tControl group (n = 276)\tOR (95%CI)\tp\t\nMetabolic Syndrome (MetS)\t23.2(64)\t19.9(55)\t1.21(0.81–1.82)\t0.35 a\t\nIndividual components:\t\t\t\t\t\n Increased waist circumference (cm)\t55.1(152)\t40.6(112)\t1.79(1.28–2.52)\t<0.001 a\t\n Elevated blood pressure (mmHg):\t\t\t\t\t\n Systolic\t17(47)\t24.3(67)\t0.64(0.42–0.97)\t0.05 a\t\n Diastolic\t23.2(64)\t26.8(74)\t0.82(0.56–1.21)\t0.38 a\t\n Elevated fasting plasma glucose (mmol/)\t17.4(48)\t13.8(38)\t1.32(0.83–2.09)\t0.24 a\t\n Elevated serum triglycerides (mmol/l)\t14.5(40)\t12.3(34)\t1.21(0.74–1.97)\t0.45 a\t\n Low HDL –cholesterol (mmol/l)\t52.5(145)\t39.9(110)\t1.67(1.19–2.34)\t0.003a\t\nNumber of MetS criteria met:\t\t\t\t0.06 b\t\n 0\t19.6(54)\t30.8(85)\t\t\t\n 1\t27.5(76)\t26.8(74)\t\t\t\n 2\t29.7(82)\t22.5(62)\t\t\t\n 3\t15.9(44)\t13.8(38)\t\t\t\n 4\t4.4(12)\t4.0(11)\t\t\t\n 5\t2.9(8)\t2.2(6)\t\t\t\nData are % (n). HDL: high density lipoprotein.\n\na z test.\n\nb Fisher’s exact test.\n\nPrevalence of MetS and antipsychotic medication\nAll study subjects were on antipsychotic medication (n = 276), with127 subjects (46%) on monotherapy and 149 (54%) on polytherapy. Of the 149 subjects on polytherapy, 98 (35.5%) were taking an antipsychotic combined with sodium valproate, and 51 (15.5%) were taking two or more antipsychotics at the same time.Of the 98 subjects on sodium valproate 6 (2.2%) subjects were also taking an antidepressant (5 subjects were on a Selective Serotonin Reuptake Inhibitor and 1 was on a Serotonin Noradrenalin Reuptake Inhibitor) and only one subject was taking lithium.\n\nThere was no significant difference (p = 0.9) in the prevalence of MetS in subjects on antipsychotic polytherapy (35/149, 23.5%) compared to those on monotherapy (29/127, 22.8%). In addition, no difference (p = 0.8) was observed in the prevalence of MetS in subjects on antipsychotic monotherapy (22.8%) compared to subjects taking antipsychotics combined with sodium valproate and antidepressant medication (24.5%) or those subjects taking two or more antipsychotics (21.6%, p = 0.9). Too few subjects were taking antipsychotics combined with antidepressants and sodium valproate only for a separate analysis.\n\nRegarding the comparison of metabolic abnormalities in subjects taking FGAs vs SGAs; of the 127 subjects on monotherapy, 32 (11.6%) subjects were taking FGAs and 95 (34.4%) SGAs. No significant difference was observed in the clinical and demographic characteristics between subjects taking FGAs or SGAs as monotherapy (Table 4). There was no difference in the prevalence of MetS or its individual components between subjects on FGA vs SGA monotherapy (p = 0.26) (Table 5) or polytherapy (p = 0.2) (data for polytherapy not shown).\n\n10.1371/journal.pone.0149209.t004Table 4 Demographic and clinical characteristics of subjects with severe mental illness by class of antipsychotic medication in subjects on monotherapy.\n\tSubjects taking FGAs (n = 32)\tSubjects taking SGAs (n = 95)\tp\t\nGender\t\t\t0.7 a\t\n Male\t65.6(21)\t69.5(66)\t\t\n Female\t34.4(11)\t30.5(29)\t\t\nAge (years)\t33.7 ±13.8\t33.3 ± 12.3\t0.9 b\t\nDiagnosis\t\t\t0.5 a\t\n Schizophrenia\t96.9(31)\t88.4(84)\t\t\n Schizoaffective disorder\t3.1 (1)\t9.5 (9)\t\t\n Bipolar mood disorder\t0(0)\t2.1 (2)\t\t\nBody Mass Index (BMI) (kg/m2)\t26.6 ± 7.57\t27.5 ± 6.31\t0.5 b\t\nBMI category:\t\t\t0.5 a\t\n Normal: < 25\t59.3(19)\t47.4(45)\t\t\n Overweight: 25–29.9\t18.8(6)\t23.2(22)\t\t\n Obese: >30\t21.9(7)\t29.5(28)\t\t\nWaist circumference (cm)\t90.5 ± 15.4\t92.3 ± 16\t0.6 b\t\nBlood pressure (mmHg):\t\t\t\t\n Systolic\t119.2 ± 11.3\t122.5 ±17.9\t0.3 b\t\n Diastolic\t72.6 ± 8.5\t76.6 ± 10.2\t0.04 b\t\nFasting plasma glucose (mmol/l)\t5.2 ± 1.3\t5.3 ± 1.4\t0.7 b\t\nSerum Lipids (mmol/l):\t\t\t\t\n Total cholesterol\t4.2 ± 1.1\t4.2 ±1.1\t0.7 b\t\n Total triglycerides\t0.9 ± 0.4\t1.1 ± 0.7\t0.08 b\t\n High Density Lipoprotein cholesterol\t1.2 ± 0.3\t1.1 ± 0.3\t0.2 b\t\n Low Density Lipoprotein cholesterol\t2.6 ± 1.0\t2.6 ±0.9\t0.7 b\t\nData are mean ± SD and % (n), unless otherwise indicated. FGA: first generation antipsychotic, SGA: second generation antipsychotic.\n\na Fisher’s exact test,\n\nb Student’s t—test.\n\n10.1371/journal.pone.0149209.t005Table 5 The prevalence of metabolic syndrome and individual components according to class of medication in subjects on antipsychotic monotherapy.\n\tFGA (n = 32)\tSGA (n = 95)\tp a\t\nMetabolic Syndrome\t15.6(5)\t25.3(24)\t0.26\t\nElevated waist circumference (cm)\t62.5(20)\t51.6(49)\t0.28\t\nElevated blood pressure (mmHg):\t\t\t\t\n Systolic\t6.25(2)\t20(19)\t0.07\t\n Diastolic\t6.25(2)\t21.1(20)\t0.06\t\nElevated fasting plasma glucose (mmol/l)\t18.8(6)\t25.3(24)\t0.45\t\nElevated serum triglycerides (mmol/l)\t3.1(1)\t6.3(6)\t0.5\t\nLow HDL –cholesterol (mmol/l)\t43.8(14)\t52.6(50)\t0.38\t\nData are % (n). HDL: high density lipoprotein. FGA: first generation antipsychotic, SGA: second generation antipsychotic.\n\na z test.\n\nRisk factors associated with MetS\nIn multivariate analysis, significant risk factors associated with MetS included age (OR: 1.09, 95% CI 1.06–1.12, p <0.0001), female gender (OR: 2.19, 95% CI 1.06–4.55, p = 0.035) and Indian descent (OR: 5.84, 95% CI 1.66–20.52, p = 0.006) (Table 6).\n\n10.1371/journal.pone.0149209.t006Table 6 Multivariate analysis of risk factors associated with metabolic syndrome in the study and control groups.\n\tStudy group\tControl group\t\n\tOdds Ratio (95% CI)\tp a\tOdds Ratio (95% CI)\tp a\t\nFemale gender\t2.19(1.06–4.55)\t0.04\t1.31(0.57–3.00)\t0.53\t\nAge\t1.09(1.06–1.12)\t<0.001\t1.07(1.03–1.10)\t<0.001\t\nEthnicity:\t\t\t\t\t\n Indian\t5.84(1.66–20.52)\t0.006\t3.80(1.12–12.89)\t0.03\t\n White and mixed race\t0.51(0.03–8.77)\t0.64\t1.68(0.55–5.13)\t0.36\t\nBody Mass Index (kg/m2)\t1.13(1.07–1.19)\t<0.001\t1.16(1.09–1.23)\t<0.001\t\n*adjusted values.\n\na\nchi-squared test\n\nDiscussion\nIn this study of South African patients with SMI taking antipsychotic medication there was a high but similar prevalence of MetS in the study (23.2%) and control group (19.9%); the prevalence of the individual components viz. increased waist circumference (p< 0.001) and low HDL cholesterol (p = 0.003) was higher in the study group. Significant risk factors for MetS in the study group included age, gender and Indian ethnicity. No significant difference (p = 0.9) was observed in the prevalence of MetS in subjects on monotherapy compared to those on polytherapy and in subjects taking FGAs or SGAs as monotherapy (p = 0.26).\n\nThe prevalence in this study is in keeping with rates reported from Thailand (22.8%) [33], Mexico (21%) [9] and Spain (26.5%) [34], but lower than studies from England (57%) [11], the US (49.2%) [26], Australia (68%) [12], and the overall international prevalence of 32.5% reported by Mitchell et al.[13]. A review by Papanastasiou on the prevalence of MetS in schizophrenia [22], the position statement by De Hert [1] and meta –analysis by Mitchell et al. [13] found that many studies reported a two—fold higher prevalence of MetS in patients with SMI compared to the general population. However, no difference in the prevalence between SMI and control subjects was reported from Venezuela [35] and Mexico [9]. There are several possible explanations for the lower prevalence of MetS in the study group participants including the high proportion of young participants (25.6% of the study subjects were < 25 years), male participants (66% male), the short mean duration of illness (4.6 years), the inclusion of participants with a first episode of SMI and the low proportions of participants taking FGA and SGA medication (chlorpromazine 10.2%, clozapine 8.2% and olanzapine 3.7%) that are associated with the highest risk for MetS [36].\n\nThe high prevalence of increased waist circumference in subjects with SMI in this study is compatible with findings of other studies [1,13,21,22]. In a recent report, more than 80% of patients taking antipsychotic medication had central obesity [11]. This places patients with SMI at increased risk for diabetes mellitus, given that central obesity correlates better with insulin resistance than total body obesity (BMI) [37]. The prevalence of diabetes mellitus is reported to be approximately 12% in patients with SMI and two to three fold higher than that in the general population [38]. However, we did not find a high prevalence of dysglycemia in patients with SMI confirming an earlier study from this district which reported a low prevalence (3.85%) of type 2 diabetes mellitus in a group of chronic hospitalized patients with SMI [39]. Although genetic and lifestyle factors may also account for abnormal glucose homeostasis and frank diabetes with antipsychotic treatment, it is likely that the low prevalence of diabetes mellitus in this study is due to the underutilization of antipsychotics with a higher liability for diabetes mellitus such as clozapine, olanzapine and quetiapine [40]. Prospective studies in African patients with SMI are required to further clarify the risk of dysglycemia.\n\nIn this study, 18,5% of patients were prescribed two or more antipsychotics, and 35,5% were on antipsychotics combined with sodium valproate. There is little empirical support for either practice but both are common internationally [41] with rates of 2–70% [42] and 16–35% [43] respectively. Although it has been shown that combining psychotropic medications results in the potentiating of the metabolic side effects of each of the individual medications [44], the results of this study support and extend the evidence for no independent association between MetS and the prescription of two or more antipsychotics [45] or antipsychotics combined with sodium valproate [46].\n\nFurthermore, an additional analysis showed that there was no difference in the prevalence of MetS between subjects taking FGAs and SGAs as monotherapy (p = 0.26) or polytherapy (0.2). As reported in the literature, possible explanations include the probability that there is no class effect for the metabolic adverse effects of antipsychotics in view of the substantial heterogeneity within each class [21,25,47]; and the current classification of antipsychotics is arbitrary [21]. Taking into account that subjects in this naturalistic study were not randomized to either class of medication and that the comparison by class of antipsychotic medication is a within group analysis, it is also likely that the sample size is insufficient to detect a difference between FGAs and SGAs. However, describing the metabolic side effects of FGAs is still relevant because although many SGA medications are now off patent, two of the three oral antipsychotics on the 19th WHO Model List of Essential Medicines (April 2015) are FGAs [48].\n\nIn a multivariate analysis, significant risk factors associated with MetS were age, female gender and Indian descent. The association of age with MetS that we observed in subjects and controls concurs with that reported in the literature [13,22,28]. However, the higher prevalence of MetS in subjects with SMI under 25 years (11.3%) compared to controls (5.7%) is of concern and consistent with recent reports of the development of MetS in young patients with SMI [49].\n\nThe significant association of female gender with MetS in this study confirms the findings of the landmark CATIE study, one of the largest antipsychotic effectiveness studies to date [26], by contrast, the meta-analysis by Mitchell et al. [13] reported no significant gender difference, while a Korean study found that the risk of MetS was four fold higher in males with schizophrenia[28]. The increased risk for MetS in women compared to men that we observed in the study group may reflect a regional predisposition to obesity and MetS in women because a higher prevalence of obesity and MetS in South African women has been confirmed in epidemiological studies [18,19]. Culturally acceptable attitudes to larger body size may be influencing this phenomenon [50]. Our findings may also be explained by an increased susceptibility to the side effects of antipsychotic medication in women with SMI [51],because in contrast to all the other risk factors for MetS in this study, the increased risk for MetS in women compared to men in the control group, was not statistically significant (p = 0.53). However, even though South African women have a higher prevalence of individual risk factors for CVD such as obesity, diabetes mellitus and HDL cholesterol, a recent study has shown a higher 10 year Framingham risk for CVD in men [52].\n\nRacial differences in the risk for MetS has been documented in patients with SMI previously [29]. However, the elevated risk for MetS that we observed in South Africans of Indian descent with SMI compared to Africans with SMI has to the best of our knowledge not been documented previously. A likely explanation for the high prevalence of MetS in native and migrant Indians include a genetic predisposition to diabetes mellitus and a tendency for higher visceral fat deposition at lower BMI’s than other ethnic groups [53]. We did not confirm the findings of Ader et al [54] who found that African Americans were more susceptible to the metabolic side effects of antipsychotic medication but our findings were in keeping with those of Keenan et al [55] who found a lower risk for MetS in African American subjects with SMI after adjusting for age and gender. This substantiates the need for further studies on the association of ethnicity and MetS among those with SMI in and outside the US.\n\nThe limitations of this study include the cross sectional, observational study design that resulted in disproportionate medication groups, lack of information on lifestyle factors and the recruitment of participants from a single site which limits the generalizability of the results.\n\nConclusion\nThe results of this study show that 1 in 5 African patients with SMI taking either FGA or SGA medication met the criteria for MetS, and 1 in 2 was overweight or obese. 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Schizophr Res . 2011 ;126 : 93 –102 . 10.1016/j.schres.2010.10.014 \n21071179 \n36 Leucht S , Cipriani A , Spineli L , Mavridis D , Örey D , Richter F , et al\nComparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: A multiple-treatments meta-analysis . Lancet . 2013 ;382 : 951 –962 . 10.1016/S0140-6736(13)60733-3 \n23810019 \n37 Ritchie SA , Connell JMC . The link between abdominal obesity, metabolic syndrome and cardiovascular disease . Nutr Metab Cardiovasc Dis . 2007 ;17 : 319 –326 . 10.1016/j.numecd.2006.07.005 \n17110092 \n38 Holt RIG , Mitchell AJ . Diabetes mellitus and severe mental illness: mechanisms and clinical implications . Nat Rev Endocrinol . 2015 ;11 : 79 –89 . 10.1038/nrendo.2014.203 \n25445848 \n39 Lasich AJ , Paruk N , Ramparsad J . A survey of the prevalence of diabetes type 2 amongst schizophrenics in a chronic care treatment facility . Afr J Psychiatry . 2007 ;10 : 143 –146 . 10.4314/ajpsy.v10i3.30246 \n40 Coccurello R , Moles A . Potential mechanisms of atypical antipsychotic-induced metabolic derangement: Clues for understanding obesity and novel drug design . Pharmacol Ther . 2010 ;127 : 210 –251 . 10.1016/j.pharmthera.2010.04.008 \n20493213 \n41 Gallego JA , Bonetti J , Zhang J , Kane JM . Prevalence and correlates of antipsychotic polypharmacy: A systematic review and meta-regression of global and regional trends from the 1970s to 2009 . Schizophr Res. Elsevier B.V. ; 2012 ;138 : 18 –28 . 10.1016/j.schres.2012.03.018 \n42 Fisher MD , Reilly K , Isenberg K , Villa KF . Antipsychotic patterns of use in patients with schizophrenia: polypharmacy versus monotherapy . BMC Psychiatry . 2014 ;14 : 341 \n10.1186/s12888-014-0341-5 \n25433495 \n43 Horowitz E , Bergman LC , Ashkenazy C , Moscona-Hurvitz I , Grinvald-Fogel H , Magnezi R . Off-label use of sodium valproate for schizophrenia . PLOS ONE . 2014 ;9 : 1 –7 . 10.1371/journal.pone.0092573 \n44 Chang HH , Yang YK , Gean PW , Huang HC , Chen PS , Lu RB . The role of valproate in metabolic disturbances in bipolar disorder patients . J Affect Disord. Elsevier B.V. ; 2010 ;124 : 319 –323 . 10.1016/j.jad.2009.12.011 \n45 Correll CU , Frederickson AM , Kane JM , Manu P . Does antipsychotic polypharmacy increase the risk for metabolic syndrome? \nSchizophr Res . 2007 ;89 : 91 –100 . 10.1016/j.schres.2006.08.017 \n17070017 \n46 Zuo S , Fries BE , Szafara K , Regal R . Valproic Acid as a Potentiator of Metabolic Syndrome In Institutionalized Residents on Concomitant Antipsychotics: Fat Chance, or Slim to None? \n2015 ;40 : 126 –132 . 25673963 \n47 Falissard B , Mauri M , Shaw K , Wetterling T , Doble A , Giudicelli A , et al\nThe METEOR study . Int Clin Psychopharmacol . 2011 ;26 : 291 –302 . 10.1097/YIC.0b013e32834a5bf6 \n21876442 \n48 World Health Organization . WHO Model List of Essential Medicines—19th List (April 2015) . 2015 ; 1 –53 .\n49 Foley DL , Mackinnon A , Watts GF , Shaw JE , Magliano DJ , Castle DJ , et al\nCardiometabolic risk indicators that distinguish adults with psychosis from the general population, by age and gender . PLOS ONE . 2013 ;8 : e82606 \n10.1371/journal.pone.0082606 \n24367528 \n50 Draper CE , Davidowitz KJ , Goedecke JH . Perceptions relating to body size, weight loss and weight-loss interventions in black South African women: a qualitative study . Public Heal Nutr available CJ02015 . 2015 ; 1 –9 . 10.1017/S1368980015001688 \n51 Seeman MV . Secondary effects of antipsychotics: Women at greater risk than men . Schizophr Bull . 2009 ;35 : 937 –948 . 10.1093/schbul/sbn023 \n18400811 \n52 Peer N , Lombard C , Steyn K , Gaziano T , Levitt N . Comparability of total cardiovascular disease risk estimates using laboratory and non-laboratory based assessments in urban-dwelling South Africans: the CRIBSA study . S Afr Med J . 2014 ;104 : 691 –696 .25363056 \n53 Palaniappan L , Wong E , Shin J , Fortmann S , Lauderdale DS . Asian Americans Have Greater Prevalence of Metabolic Syndrome Despite Lower Body Mass Index . Int J Obes . 2011 ;35 : 393 –400 .\n54 Ader M , Garvey WT , Phillips LS , Nemeroff CB , Gharabawi G , Mahmoud R , et al\nEthnic heterogeneity in glucoregulatory function during treatment with atypical antipsychotics in patients with schizophrenia . J Psychiatr Res . 2008 ;42 : 1076 –1085 . 10.1016/j.jpsychires.2008.01.004 \n18295798 \n55 Keenan TE , Yu A , Cooper LA , Appel LJ , Guallar E , Gennusa JV , et al\nRacial patterns of cardiovascular disease risk factors in serious mental illness and the overall U.S. population . Schizophr Res . 2013 ;150 : 211 –216 . 10.1016/j.schres.2013.07.022 \n23916188\n\n", "fulltext_license": "CC BY", "issn_linking": "1932-6203", "issue": "11(2)", "journal": "PloS one", "keywords": null, "medline_ta": "PLoS One", "mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D016022:Case-Control Studies; D003710:Demography; D005260:Female; D006801:Humans; D008297:Male; D001523:Mental Disorders; D024821:Metabolic Syndrome; D015999:Multivariate Analysis; D015995:Prevalence; D012307:Risk Factors; D013019:South Africa", "nlm_unique_id": "101285081", "other_id": null, "pages": "e0149209", "pmc": null, "pmid": "26882230", "pubdate": "2016", "publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural", "references": "18501420;25577186;18400811;22534420;19588034;20060174;17558623;17070017;22768830;25673963;25962950;25208906;20493213;24269193;25910596;21876442;25445848;22207632;23506322;17110092;20692814;21071179;26006784;19682863;24367528;16421460;19805654;17448257;22249081;24664210;8594834;20680014;20850274;22009159;25592299;25961431;23916188;23810019;19058842;18606526;24943390;16137860;25363056;21513765;18295798;16025251;24173635;23983991;25433495;21330644;16338246", "title": "Metabolic Syndrome in South African Patients with Severe Mental Illness: Prevalence and Associated Risk Factors.", "title_normalized": "metabolic syndrome in south african patients with severe mental illness prevalence and associated risk factors" }	[ { "companynumb": "ZA-JNJFOC-20160403310", "fulfillexpeditecriteria": "1", "occurcountry": "ZA", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "QUETIAPINE" }, "drugadditional": null, ...
{ "abstract": "BACKGROUND\nClostridium difficile infection (CDI) and Klebsiella pneumoniae carbapenemase producing-Klebsiella pneumoniae (KPC-Kp) bloodstream infection (BSI) are emerging health-care associated (HCA) diseases of public health concern, in terms of morbidity, mortality, and insufficient response to antibiotic therapy. Both agents can be acquired in the hospital but clinical disease can develop in a community setting, after discharge. We report here a putative link between the above-mentioned healthcare associated infections that appeared as a dramatic community onset disease with a fulminant fatal outcome.\n\n\nMETHODS\nWe describe the case of a 63 year old man affected by severe CDI. Even though the patient underwent 72 hours of standard CDI antibiotic treatment, the clinical course was complicated by toxic megacolon and KPC-Kp BSI. The patient died 24 hours after total colectomy.\n\n\nCONCLUSIONS\nThe impact of HCA-BSIs in complicating CDI is still unknown. Intestinal inflammatory injury and disruption of intestinal flora by standard antibiotic treatment could be responsible for promoting difficult-to-treat infections in CDI. By preserving intestinal flora, Fidaxomicin could have a crucial role in preventing BSIs complicating severe CDI.", "affiliations": "Department of Public Health and Infectious Diseases Policlinico Umberto I, \"Sapienza\" University of Rome, Viale del Policlinico 155, 00161 Rome, Italy. mario.venditti@uniroma1.it.", "authors": "Giuliano\|Simone\|S\|;Guastalegname\|Maurizio\|M\|;Jenco\|Miryam\|M\|;Morelli\|Andrea\|A\|;Falcone\|Marco\|M\|;Venditti\|Mario\|M\|", "chemical_list": "D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D001618:beta-Lactamases; C063912:carbapenemase; D000077732:Fidaxomicin", "country": "England", "delete": false, "doi": "10.1186/1471-2334-14-475", "fulltext": "\n==== Front\nBMC Infect DisBMC Infect. DisBMC Infectious Diseases1471-2334BioMed Central London 25178451378210.1186/1471-2334-14-475Case ReportSevere community onset healthcare-associated Clostridium difficile infection complicated by carbapenemase producing Klebsiella pneumoniae bloodstream infection Giuliano Simone smngiu@gmail.com Guastalegname Maurizio guama@email.it Jenco Miryam miryam.jenco@gmail.com Morelli Andrea andrea.morelli@uniroma1.it Falcone Marco marcofalc@libero.it Venditti Mario mario.venditti@uniroma1.it Department of Public Health and Infectious Diseases Policlinico Umberto I, “Sapienza” University of Rome, Viale del Policlinico 155, 00161 Rome, Italy Department of Anesthesiology and Intensive Care, “Villa San Pietro-Fatebenefratelli” Hospital, Rome, Italy Department of Anesthesiology and Intensive Care, “Sapienza” University of Rome, Rome, Italy 1 9 2014 1 9 2014 2014 14 47514 4 2014 18 8 2014 © Giuliano et al.; licensee BioMed Central Ltd. 2014This article is published under license to BioMed Central Ltd. This 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\nClostridium difficile infection (CDI) and Klebsiella pneumoniae carbapenemase producing-Klebsiella pneumoniae (KPC-Kp) bloodstream infection (BSI) are emerging health-care associated (HCA) diseases of public health concern, in terms of morbidity, mortality, and insufficient response to antibiotic therapy. Both agents can be acquired in the hospital but clinical disease can develop in a community setting, after discharge. We report here a putative link between the above-mentioned healthcare associated infections that appeared as a dramatic community onset disease with a fulminant fatal outcome.\n\nCase presentation\nWe describe the case of a 63 year old man affected by severe CDI. Even though the patient underwent 72 hours of standard CDI antibiotic treatment, the clinical course was complicated by toxic megacolon and KPC-Kp BSI. The patient died 24 hours after total colectomy.\n\nConclusion\nThe impact of HCA-BSIs in complicating CDI is still unknown. Intestinal inflammatory injury and disruption of intestinal flora by standard antibiotic treatment could be responsible for promoting difficult-to-treat infections in CDI. By preserving intestinal flora, Fidaxomicin could have a crucial role in preventing BSIs complicating severe CDI.\n\nKeywords\nClostridium difficileKlebsiella pneumoniaeKPCBloodstream infectionsIntestinal floraFidaxomicinissue-copyright-statement© The Author(s) 2014\n==== Body\nBackground\nThe impact of health-care associated (HCA) bloodstream infection (BSI) in complicating Clostridium difficile infection (CDI) is still unknown. We describe for the first time a case of community onset healthcare-associated severe CDI complicated by Klebsiella pneumoniae Carbapenemase producing Klebsiella pneumoniae (KPC-Kp) BSI. CDI and KPC-Kp BSI are recently emerging as two of the more concerning HCA diseases in terms of morbidity, mortality, and inefficient response to antibiotic therapy. A relation between the above-mentioned infections have never been reported until now.\n\nCase presentation\nWe report the case of a 63 year old man, who was admitted on the 6th of February 2014 to the Intensive Care Unit (ICU) of a 1300-bed teaching Institution in Rome because of septic shock syndrome. His past medical history was remarkable for high blood pressure, multi-infarct dementia, Parkinson’s disease and depressive disorder. The patient had been hospitalized on the 15th of January 2014 in a peripheral center for a febrile syndrome due to a urinary tract infection caused by Escherichia coli. During his hospital stay, he underwent a ten-day course of antimicrobial therapy with intravenous ciprofloxacin and was discharged on the 28th of January on treatment with oral Cefditoren pivoxil. On the 3rd of February, the patient was readmitted to the same hospital because of confusion, fever and diarrhea. Clostridium difficile infection (CDI) test was performed (Alere™ C. DIFF QUICK CHECK COMPLETE for simultaneous detection of both glutamate dehydrogenase antigen and toxin A and B). Oral vancomycin 500 mg q6h, intravenous metronidazole 500 mg q6h and intravenous Piperacillin/tazobactam 4.5 g q8h were immediately started. After 72 hours of persistent deterioration despite standard antibiotic therapy administration, the patient was transferred to the ICU of our hospital. At the admission the patient was unconscious (Glasgow Coma Scale of 3), presenting with ileus and septic shock syndrome. Oro-tracheal intubation and fluid resuscitation were performed followed by intravenous norepinephrine. Tigecycline was empirically added to the combination antimicrobial therapy. Three blood cultures were drawn and blood test showed 24000 white blood cells/μl, creatinine 3.6 mg/dl, albumin 2.2 g/dl, lactate 4 mmol/l. Computed tomography scans demonstrated findings compatible with toxic megacolon. A total colectomy was performed but the patient died 24 h after the surgical intervention. All blood cultures drawn at the time of admission to the ICU were positive for a carbapenem-resistant strain of Klebsiella pneumoniae (Vitek 2 system, AST-N089 card bioMérieux, Marcy l’Etoile, France, MICs: Amikacin ≥ 64 mg/l, Amoxicillin/Clavulanic acid ≥ 32 mg/l, Cefepime ≥ 64 mg/l, Cefotaxime ≥ 64 mg/l, Ceftazidime ≥ 64 mg/l, Ciprofloxacin ≥ 4 mg/l, Colistin ≥ 16 mg/l, Ertapenem ≥ 8 mg/l, Fosfomycin ≥ 256 mg/l, Gentamicin 4 mg/l, Imipenem ≥ 16 mg/l, Meropenem ≥ 16 mg/l, Piperacillin/Tazobactam ≥ 128 mg/l, Tigecycline 4 mg/l, Trimethoprim/Sulfamethoxazole ≥ 320 mg/l). Production of KPC enzyme was documented by using a phenotypic test based on the inhibitory activity of boronic acid compounds as reported by Pournaras et al. [1], and carbapenemase producing-Klebsiella pneumoniae (KPC-Kp) was identified. In addition, one blood culture was positive for vancomycin-susceptible Enterococcus faecium. Histologic examination of the colon confirmed diagnosis of pseudomembraneous colitis.\n\nDiscussion and conclusion\nWe believe that this case report is of great interest because our patient contemporarily developed two community-onset healthcare associated infections with a rapidly fatal outcome. Carbapenem-resistant Enterobacteriaceae (CRE) are an emerging issue of great public health concern. In our country, the problem is almost completely represented by carbapenem-resistant K. pneumoniae. Even though data related to incidence are missing, percentage of invasive K. pneumoniae isolates with resistance to carbapenems reportedly ranges between 25% and 50% in Italy [2]. Recently, cases of healthcare-associated carbapenem resistant K. pneumoniae BSIs have been reported in Northern Italy [3]. The phenomenon is also well known in Rome [4] and parallels to an epidemiological shift of CDI occurring in our region and consisting of increased disease incidence and mortality rates [5, 6], that are probably due to the spread of the epidemic strain ribotype 027 CD [6–8]. In the present case, because the initial diagnosis was made in a peripheral center, ribotyping test was not performed. We describe, for the first time, a fatal case of severe CDI complicated by KPC-Kp BSI. This led us to question about the role of severe CDI on predisposing to HCA-BSIs, and vice-versa, on the role of HCA-BSIs in determining the prognosis of severe CD colitis. To our knowledge this issue has never been thoroughly evaluated in the literature until now.\n\nWe already disserted on the putative correlation between CDI and Candida spp. BSI [9]. Analogous mechanisms could be advocated to explain the link between CDI and KPC-Kp BSI. Recently, Perez et al. demonstrated in a mouse model the impact of the administration of antibiotics effective against intestinal flora on promoting the persistence of KPC-Kp colonization of the gastrointestinal tract [10]. Edlund et al., evaluating the ecological disturbances of oral vancomycin following cephalosporin administration in 20 healthy volunteers, showed intestinal Klebsiella spp. overgrowth within 3 days of vancomycin treatment [11]. In the present case, KPC-Kp colonization was acquired in a non-ICU setting, an emerging phenomenon already described in our country [12]. Oral vancomycin administration, highly active against the intestinal flora [13], could have been responsible for persistence and overgrowth of KPC-Kp in the gastrointestinal tract. Gut inflammatory injury caused by severe CDI could be considered the “second hit” allowing bacterial translocation and BSI. The role of severe intestinal inflammation predisposing to bacterial mucosal penetration and blood invasion has been already showed in murine and human models [14, 15]. Moreover, K. pneumoniae has been demonstrated to be one of the most efficient microorganisms in translocating to extraintestinal sites, presenting a very low bacteremia clearance in the liver and spleen [16].\n\nColonic inflammation induced by severe CDI and standard CD antibiotic treatment could promote difficult-to-treat infections/colonizations (i.e. KPC-Kp BSI, Candida spp. BSI [6], or vancomycin resistant-enterococci intestinal colonization [17]. Fidaxomicin, a newly licensed macrocyclic antibiotic recently approved to treat CDI, is characterized by a narrow spectrum of activity almost limited to CD and consequent preservation of intestinal flora compared to vancomycin [13]. Preservation of intestinal flora could represent a useful therapeutic option not only in reducing CDI recurrence rate [9], but also in preventing BSIs secondary to severe CDI.\n\nIn conclusion, clinical impact of BSIs on complicating CDI has not been systematically evaluated until now. Fidaxomicin could represent a useful therapeutic option in preventing difficult-to-treat BSIs secondary to severe CDI. Studies are necessary to validate this hypothesis.\n\nConsent\nWritten informed consent was obtained from the next of a kin of 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\nSimone Giuliano, Maurizio Guastalegname contributed equally to this work.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contribution\n\nAll authors read and approved the final manuscript. SG and MG have made substantial contribution to concept and design of the manuscript. MJ has made contribution to acquisition of data. AM, MF and MV revised the manuscript for important intellectual content and final approval.\n\nAckowledgements\nThe authors are grateful to Dr M.A. Aruc for his contribution in revising the article critically for important intellectual content.\n==== Refs\nReferences\n1. Pournaras S Poulou A Tsakris A Inhibitor-based methods for the detection of KPC carbapenemase-producing Enterobacteriaceae in clinical practice by using boronic acid compounds J Antimicrob Chemother 2010 65 7 1319 1321 10.1093/jac/dkq124 20395214 \n2. European Centre for Disease Prevention and Control Antimicrobial resistance surveillance in Europe 2012. Annual Report of the European Antimicrobial Resistance Surveillance Network (EARS-Net) 2013 Stockholm ECDC \n3. 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Louie TJ Cannon K Byrne B Emery J Ward L Eyben M Krulicki W Fidaxomicin preserves the intestinal microbiome during and after treatment of Clostridium difficile infection (CDI) and reduces both toxin reexpression and recurrence of CDI Clin Infect Dis 2012 55 Suppl 2 S132 S142 10.1093/cid/cis338 22752862 \n14. Johansson ME Gustafsson JK Holmén-Larsson J Jabbar KS Xia L Xu H Ghishan FK Carvalho FA Gewirtz AT Sjövall H Hansson GC Bacteria penetrate the normally impenetrable inner colon mucus layer in both murine colitis models and patients with ulcerative colitis Gut 2014 63 2 281 291 10.1136/gutjnl-2012-303207 23426893 \n15. Mainous MR Tso P Berg RD Deitch EA Studies of the route, magnitude, and time course of bacterial translocation in a model of systemic inflammation Arch Surg 1991 126 1 33 37 10.1001/archsurg.1991.01410250037005 1824677 \n16. Eaves-Pyles T Alexander JW Comparison of translocation of different types of microorganisms from the intestinal tract of burned mice Shock 2001 16 2 148 152 10.1097/00024382-200116020-00011 11508868 \n17. Nerandzic MM Mullane K Miller MA Babakhani F Donskey CJ Reduced acquisition and overgrowth of vancomycin-resistant enterococci and Candida species in patients treated with fidaxomicin versus vancomycin for Clostridium difficile infection Clin Infect Dis 2012 55 S2 S121 S126 10.1093/cid/cis440 22752860\n\n", "fulltext_license": "CC BY", "issn_linking": "1471-2334", "issue": "14()", "journal": "BMC infectious diseases", "keywords": null, "medline_ta": "BMC Infect Dis", "mesh_terms": "D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D001426:Bacterial Proteins; D016360:Clostridioides difficile; D003015:Clostridium Infections; D060085:Coinfection; D003428:Cross Infection; D017809:Fatal Outcome; D000077732:Fidaxomicin; D006761:Hospitals; D006801:Humans; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008297:Male; D008875:Middle Aged; D001618:beta-Lactamases", "nlm_unique_id": "100968551", "other_id": null, "pages": "475", "pmc": null, "pmid": "25178451", "pubdate": "2014-09-01", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": "22752860;21422202;22752862;1824677;23259814;25012877;23522431;24523055;23426893;9314469;23723197;20395214;23137235;11508868;24771335;22800501", "title": "Severe community onset healthcare-associated Clostridium difficile infection complicated by carbapenemase producing Klebsiella pneumoniae bloodstream infection.", "title_normalized": "severe community onset healthcare associated clostridium difficile infection complicated by carbapenemase producing klebsiella pneumoniae bloodstream infection" }	[ { "companynumb": "IT-BAYER-2014-166875", "fulfillexpeditecriteria": "1", "occurcountry": "IT", "patient": { "drug": [ { "actiondrug": null, "activesubstance": { "activesubstancename": "CEFDITOREN PIVOXIL" }, "drugadditional": null, ...
{ "abstract": "Advances in hepatitis C virus (HCV) treatment offer high sustained virologic response rates with minimal side-effects. However, benefits of eradicating HCV in hepatocellular carcinoma (HCC) patients whose life expectancies are hard to be determined after palliative therapy still needs to be assessed. This study sought to evaluate prognostic factors for survival in HCV-related HCC patients that responded to the palliative HCC treatment to speculate whether treating HCV would be beneficial in these patients.\n\n\n\nIn this retrospective cohort study, the medical records of 97 patients that showed complete or partial response to the initial HCC treatment were included.\n\n\n\nReceiving HCV treatment [hazard ratio (HR), 0.244; 95% confidence interval (CI), 0.075-0.788; P=0.018] increased the survival, whereas partial response to the initial HCC treatment (HR, 1.795; 95% CI, 1.071-3.008; P=0.026) and increased Child-Turcotte-Pugh score (HR, 2.017; 95% CI, 1.196-3.403; P=0.009) reduced the survival. From 97 patients, 16 patients were eventually treated for HCV. The mean time from the last HCC therapy to HCV treatment was 16.9±13.9 months. The median time of follow-up after HCV treatment was 10.0 months (range, 3 to 47 mo). Among the HCV-treated patients 3 patients had HCC recurred. The time to progression in HCV-treated patients were significantly longer than those untreated for HCV (P=0.032).\n\n\n\nAlthough treating HCV in HCC patient that undergo noncurative HCC treatment is still debatable, this study results carefully suggest that HCV-related HCC patients that responded to the initial HCC palliative treatment might benefit from HCV treatment.", "affiliations": "Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.", "authors": "Yu\|Jung-Hwan\|JH\|;Kim\|Ja Kyung\|JK\|;Lee\|Kwan Sik\|KS\|;Lee\|Jung Il\|JI\|", "chemical_list": "D000998:Antiviral Agents", "country": "United States", "delete": false, "doi": "10.1097/MCG.0000000000000923", "fulltext": null, "fulltext_license": null, "issn_linking": "0192-0790", "issue": "52(6)", "journal": "Journal of clinical gastroenterology", "keywords": null, "medline_ta": "J Clin Gastroenterol", "mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D000066491:Clinical Decision-Making; D018450:Disease Progression; D005260:Female; D006304:Health Status; D019698:Hepatitis C, Chronic; D006801:Humans; D008017:Life Expectancy; D008113:Liver Neoplasms; D008297:Male; D008499:Medical Records; D008875:Middle Aged; D010166:Palliative Care; D018579:Patient Selection; D012189:Retrospective Studies; D013997:Time Factors; D016896:Treatment Outcome", "nlm_unique_id": "7910017", "other_id": null, "pages": "557-562", "pmc": null, "pmid": "28863014", "pubdate": "2018-07", "publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Antiviral Therapy in Patients With Chronic Hepatitis C-related Hepatocellular Carcinoma Responding to Palliative Treatment.", "title_normalized": "antiviral therapy in patients with chronic hepatitis c related hepatocellular carcinoma responding to palliative treatment" }	[ { "companynumb": "KR-GILEAD-2018-0350259", "fulfillexpeditecriteria": "1", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "SOFOSBUVIR" }, "drugadditional": null, ...
{ "abstract": "A 23-year old female was diagnosed with relapsing-remitting multiple sclerosis with two symptomatic attacks. Immunomodulatory treatment with Clift® (Glatiramer Acetate biosimilar) was initiated. Shortly after administration, an asymptomatic increase in liver enzymes was noticed, and therapy was paused. However, we observed an enormous increase in liver enzymes within a few days. Histological work up of a liver biopsy showed microfocal liver necrosis accompanied with increased numbers of CD38-positive lymphocytes as shown by immunohistology, indicating a drug-induced liver injury. Subsequently, under oral prednisolone treatment, liver enzymes normalized. This case highlights the importance of tight monitoring of liver function in the initial phase of a new immunotherapy to unravel asymptomatic hepatotoxicity in time and prevent further damage.", "affiliations": "Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.;Department of Internal Medicine I, University of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.;Department of Pathology, University of Ulm, Albert-Einstein-Allee 23, 89081 Ulm, Germany.;Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.;Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.;Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.;Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany.;Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany; Specialty Hospital of Neurology Dietenbronn, Schwendi, Germany.;Department of Neurology, University of Ulm, Oberer Eselsberg 45, 89081 Ulm, Germany. Electronic address: makbule.senel@uni-ulm.de.", "authors": "Michels\|Sebastian\|S\|;Zizer\|Eugen\|E\|;Barth\|Thomas Fe\|TF\|;Wassner\|Anette\|A\|;Fangerau\|Tanja\|T\|;Taranu\|Daniela\|D\|;Bachhuber\|Franziska\|F\|;Tumani\|Hayrettin\|H\|;Senel\|Makbule\|M\|", "chemical_list": "D059451:Biosimilar Pharmaceuticals; D007155:Immunologic Factors; D000068717:Glatiramer Acetate", "country": "Netherlands", "delete": false, "doi": "10.1016/j.msard.2020.101948", "fulltext": null, "fulltext_license": null, "issn_linking": "2211-0348", "issue": "40()", "journal": "Multiple sclerosis and related disorders", "keywords": "Biosimilars; Clift®; Disease-modifying therapy; Drug-induced liver injury; Glatiramer acetate; Multiple sclerosis", "medline_ta": "Mult Scler Relat Disord", "mesh_terms": "D000328:Adult; D059451:Biosimilar Pharmaceuticals; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D000068717:Glatiramer Acetate; D006801:Humans; D007155:Immunologic Factors; D020529:Multiple Sclerosis, Relapsing-Remitting; D055815:Young Adult", "nlm_unique_id": "101580247", "other_id": null, "pages": "101948", "pmc": null, "pmid": "31972518", "pubdate": "2020-05", "publication_types": "D002363:Case Reports", "references": null, "title": "Drug-induced liver injury associated with the biosimilar glatiramer acetate (Clift®).", "title_normalized": "drug induced liver injury associated with the biosimilar glatiramer acetate clift" }	[ { "companynumb": "DE-FRESENIUS KABI-FK202001341", "fulfillexpeditecriteria": "1", "occurcountry": "DE", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "METHYLPREDNISOLONE" }, "drugadditional": ...
{ "abstract": "We evaluated the efficacy of dexamethasone (DEX) in anti-SSA/Ro-exposed fetuses newly diagnosed with congenital heart block. Previous use of DEX has been anecdotal with varying reports of therapeutic benefit. This was a multicenter, open-label, nonrandomized study involving 30 pregnancies treated with DEX (22 with third-degree block, 6 with second-degree block, 2 with first-degree block) and 10 untreated (9 with third-degree block, 1 with first-degree block). Initial median ventricular rates, age at diagnosis, and degree of cardiac dysfunction were similar between groups. Six deaths occurred in the DEX group. There was no reversal of third-degree block with therapy or spontaneously. In fetuses treated with DEX, 1/6 with second-degree block progressed to third-degree block and 3 remained in second-degree block (postnatally 1 paced, 2 progressed to third degree); 2 reverted to normal sinus rhythm (NSR; postnatally 1 progressed to second degree). DEX reversed the 2 fetuses with first-degree block to NSR by 7 days with no regression at discontinuation. Absent DEX, the 1 with first-degree block detected at 38 weeks had NSR at birth (overall stability or improvement in 4 of 8 in the DEX group vs 1 of 1 in the non-DEX group). Median gestational birth age was 37 weeks in the DEX group versus 38 weeks in the non-DEX group (p = 0.019). Prematurity and small size for gestational age were restricted to the DEX group. Pacemaker use and growth parameters at birth and 1 year were similar between groups. In conclusion, these data confirm the irreversibility of third-degree block and progression of second- to third-degree block despite DEX. A potential benefit of DEX in reversing first- or second-degree block was supported in rare cases but should be weighed against potential steroid side effects such as growth restriction.", "affiliations": "New York Medical College, Valhalla, USA.", "authors": "Friedman\|Deborah M\|DM\|;Kim\|Mimi Y\|MY\|;Copel\|Joshua A\|JA\|;Llanos\|Carolina\|C\|;Davis\|Claudine\|C\|;Buyon\|Jill P\|JP\|", "chemical_list": "D001324:Autoantigens; D005938:Glucocorticoids; C506261:LA protein, human (349-364); D010446:Peptide Fragments; D012261:Ribonucleoproteins; C035401:SS-A antigen; D003907:Dexamethasone", "country": "United States", "delete": false, "doi": "10.1016/j.amjcard.2008.12.027", "fulltext": null, "fulltext_license": null, "issn_linking": "0002-9149", "issue": "103(8)", "journal": "The American journal of cardiology", "keywords": null, "medline_ta": "Am J Cardiol", "mesh_terms": "D000293:Adolescent; D000328:Adult; D001324:Autoantigens; D001327:Autoimmune Diseases; D003907:Dexamethasone; D005260:Female; D005315:Fetal Diseases; D005938:Glucocorticoids; D006327:Heart Block; D006801:Humans; D010446:Peptide Fragments; D011247:Pregnancy; D011446:Prospective Studies; D012261:Ribonucleoproteins; D055815:Young Adult", "nlm_unique_id": "0207277", "other_id": null, "pages": "1102-6", "pmc": null, "pmid": "19361597", "pubdate": "2009-04-15", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural", "references": "15353508;17881751;11046070;18195175;12790838;10555029;16200587;12221431;7138600;17097504;18381509;10913494;16504990;15343606;12006334;14646414;11999879;14730614;835623", "title": "Prospective evaluation of fetuses with autoimmune-associated congenital heart block followed in the PR Interval and Dexamethasone Evaluation (PRIDE) Study.", "title_normalized": "prospective evaluation of fetuses with autoimmune associated congenital heart block followed in the pr interval and dexamethasone evaluation pride study" }	[ { "companynumb": "US-MYLANLABS-2016M1008271", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "DEXAMETHASONE" }, "drugadditional": null, ...
{ "abstract": "An 88-year-old woman underwent attempted percutaneous coronary intervention (PCI) through a right radial approach. Catheterization was complicated by radial artery perforation. Conservative therapeutic options including external compression, advancement of a diagnostic catheter distal to the perforation, and balloon tamponade failed to control the bleeding requiring deployment of a Polytetrafluoroethylene (PTFE)-covered stent to seal the perforation. We describe the stepwise approach advocated for managing a radial perforation and summarize relevant literature available for the same.", "affiliations": "Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: achatterjee@uabmc.edu.;Internal Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.;Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA.", "authors": "Chatterjee\|Arka\|A\|;White\|Jeremy S\|JS\|;Leesar\|Massoud A\|MA\|", "chemical_list": "D011138:Polytetrafluoroethylene", "country": "United States", "delete": false, "doi": "10.1016/j.carrev.2016.08.002", "fulltext": null, "fulltext_license": null, "issn_linking": "1878-0938", "issue": "18(2)", "journal": "Cardiovascular revascularization medicine : including molecular interventions", "keywords": "Covered stent graft; Radial artery catheterization; Radial perforation", "medline_ta": "Cardiovasc Revasc Med", "mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015906:Angioplasty, Balloon, Coronary; D003324:Coronary Artery Disease; D003331:Coronary Vessels; D005260:Female; D006801:Humans; D008297:Male; D062645:Percutaneous Coronary Intervention; D011138:Polytetrafluoroethylene; D017534:Radial Artery; D015607:Stents; D016896:Treatment Outcome", "nlm_unique_id": "101238551", "other_id": null, "pages": "133-135", "pmc": null, "pmid": "27591152", "pubdate": "2017-03", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Management of radial artery perforation during transradial catheterization using a polytetrafluoroethylene-covered coronary stent.", "title_normalized": "management of radial artery perforation during transradial catheterization using a polytetrafluoroethylene covered coronary stent" }	[ { "companynumb": "US-JNJFOC-20170420516", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "5", "activesubstance": { "activesubstancename": "CLOPIDOGREL BISULFATE" }, "drugadditional": "3", ...
{ "abstract": "Stiff person syndrome is a rare neurologic disorder with an estimated incidence of 1:1000000. The underlying pathophysiology is truncal and proximal limb muscle stiffness resulting from continuous co-contracture of agonist and antagonist muscle groups concomitant with superimposed episodic muscle spasms. Loss of gamma-aminobutyric acid-mediated inhibition creates chronic excitation manifested by tonic agonist-antagonist muscle contraction. To date, only three case reports referred indirectly to the anesthetic management of parturients with Stiff person syndrome. The authors describe their management of a parturient with Stiff person syndrome who underwent urgent cesarean delivery under epidural anesthesia.", "affiliations": "Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA. Electronic address: bboettcher@mcw.edu.;Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, USA.;Anesthesia Service, Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, WI, USA.", "authors": "Boettcher\|B T\|BT\|;Muravyea\|M\|M\|;Kuo\|C\|C\|;Drexler\|C\|C\|;Pagel\|P S\|PS\|", "chemical_list": null, "country": "Netherlands", "delete": false, "doi": null, "fulltext": null, "fulltext_license": null, "issn_linking": "0959-289X", "issue": "27()", "journal": "International journal of obstetric anesthesia", "keywords": "Cesarean delivery; Epidural anesthesia; Gamma-aminobutyric acid; Glutamic acid decarboxylase; Stiff person syndrome", "medline_ta": "Int J Obstet Anesth", "mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D000773:Anesthesia, Obstetrical; D002585:Cesarean Section; D004630:Emergencies; D005260:Female; D006801:Humans; D011247:Pregnancy; D016750:Stiff-Person Syndrome", "nlm_unique_id": "9200430", "other_id": null, "pages": "85-8", "pmc": null, "pmid": "27378710", "pubdate": "2016-08", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Anesthetic management of a parturient with Stiff person syndrome for urgent cesarean delivery.", "title_normalized": "anesthetic management of a parturient with stiff person syndrome for urgent cesarean delivery" }	[ { "companynumb": "US-MYLANLABS-2016M1050241", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "CALCIUM CHLORIDE\\POTASSIUM CHLORIDE\\SODIUM CHLORIDE\\SODIUM LAC...
{ "abstract": "Immunotherapy drugs are associated with a multitude of immune-related adverse events. We describe a case of cardiac tamponade in a patient with stage IV lung adenocarcinoma, with almost 100% expression of PDL-1, treated with pembrolizumab. The patient is a 62-year-old male who developed worsening shortness of breath after five cycles of pembrolizumab. He was diagnosed with large pericardial effusion on computed tomography chest. Echocardiogram confirmed tamponade physiology. He was treated with discontinuation of pembrolizumab and urgent pericardial window followed by high dose prednisone with tapering. The patient responded very well to the treatment. We have comprehensively reviewed cases of pericardial effusion secondary to either immune mediated mechanisms or pseudoprogression.", "affiliations": "Department of Internal Medicine, Albany Medical College, Albany, 12208 NY, USA.;Department of Internal Medicine, Albany Medical College, Albany, 12208 NY, USA.;Department of Hematology & Oncology, Stratton VA Medical Center, Albany, 12208 NY, USA.;Department of Cardiology, Stratton VA Medical Center, Albany, 12208 NY, USA.;Department of Hematology & Oncology, Stratton VA Medical Center, Albany, 12208 NY, USA.", "authors": "Khan\|Abdul Moiz\|AM\|0000-0002-0724-0766;Munir\|Ayesha\|A\|;Thalody\|Vimala\|V\|;Munshi\|Mohamed Khalid\|MK\|;Mehdi\|Syed\|S\|", "chemical_list": "D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; C582435:pembrolizumab; D011241:Prednisone", "country": "England", "delete": false, "doi": "10.2217/imt-2019-0067", "fulltext": null, "fulltext_license": null, "issn_linking": "1750-743X", "issue": "11(18)", "journal": "Immunotherapy", "keywords": "PD1 inhibitors; immune checkpoint inhibitors; immune mediated adverse effects; immune toxicities; metastatic lung cancer; pembrolizumab; pericardial effusion; pseudoprogression", "medline_ta": "Immunotherapy", "mesh_terms": "D000077192:Adenocarcinoma of Lung; D000893:Anti-Inflammatory Agents; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D002305:Cardiac Tamponade; D066126:Cardiotoxicity; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010490:Pericardial Effusion; D011241:Prednisone; D016896:Treatment Outcome", "nlm_unique_id": "101485158", "other_id": null, "pages": "1533-1540", "pmc": null, "pmid": "31815569", "pubdate": "2019-12", "publication_types": "D002363:Case Reports; D016428:Journal Article", "references": null, "title": "Cardiac tamponade in a patient with stage IV lung adenocarcinoma treated with pembrolizumab.", "title_normalized": "cardiac tamponade in a patient with stage iv lung adenocarcinoma treated with pembrolizumab" }	[ { "companynumb": "US-009507513-1912USA011464", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "PEMBROLIZUMAB" }, "drugadditional": "1", ...
{ "abstract": "We describe our retrospective clinical experience with ruxolitinib for steroid-refractory acute graft-versus-host disease (GVHD) in pediatric allogeneic hematopoietic stem cell transplant (HSCT) patients. Ruxolitinib was administered orally at 5 mg twice daily for children ≥ 25 kg or 2.5 mg twice daily if <25 kg. We excluded patients who received new immune suppressive agents within 2 weeks before initiation of ruxolitinib from response analysis. Patients were called a treatment failure if ruxolitinib was stopped before completion of 4 weeks of therapy because of adverse effects and not because of progression of acute GVHD. Thirteen patients received ruxolitinib, and 11 patients were assessable for response. One patient achieved a complete response, 4 had a partial response, and 2 had no response at 4 weeks after the first ruxolitinib dose. Four patients were treatment failures. Overall response rate was 45%. Adverse effects (n = 13) included grades 3 to 4 elevated alanine transaminase (n = 7), grades 3 to 4 neutropenia (n = 5), and grade 4 thrombocytopenia (n = 3). Infectious complications in patients included for response analysis (n = 11) were Epstein-Barr viremia (n = 2), adenovirus (n = 2), BK (n = 3), bacterial infections (n = 6), and fungal infections (n = 1). Seven of 13 patients were alive at a median follow-up of 401 days (range, 219 to 969) after HSCT. We observed a high rate of reversible adverse effects in children with steroid-refractory acute GVHD and a fair overall response of ruxolitinib as a salvage therapeutic agent. Further pharmacokinetic studies are needed to determine the best-tolerated dose of ruxolitinib that will achieve efficacy without significant adverse effects.", "affiliations": "Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio. Electronic address: Pooja.khandelwal@cchmc.org.;Division of Pharmacy, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.;Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio.", "authors": "Khandelwal\|Pooja\|P\|;Teusink-Cross\|Ashley\|A\|;Davies\|Stella M\|SM\|;Nelson\|Adam S\|AS\|;Dandoy\|Christopher E\|CE\|;El-Bietar\|Javier\|J\|;Marsh\|Rebecca A\|RA\|;Kumar\|Ashish R\|AR\|;Grimley\|Michael S\|MS\|;Jodele\|Sonata\|S\|;Myers\|Kasiani C\|KC\|", "chemical_list": "D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib", "country": "United States", "delete": false, "doi": "10.1016/j.bbmt.2017.03.029", "fulltext": null, "fulltext_license": null, "issn_linking": "1083-8791", "issue": "23(7)", "journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation", "keywords": "Jak inhibitor; Ruxolitinib; SR graft-versus-host disease; SR-GVHD in children", "medline_ta": "Biol Blood Marrow Transplant", "mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; D016879:Salvage Therapy; D019172:Transplantation Conditioning", "nlm_unique_id": "9600628", "other_id": null, "pages": "1122-1127", "pmc": null, "pmid": "28344057", "pubdate": "2017-07", "publication_types": "D016428:Journal Article", "references": null, "title": "Ruxolitinib as Salvage Therapy in Steroid-Refractory Acute Graft-versus-Host Disease in Pediatric Hematopoietic Stem Cell Transplant Patients.", "title_normalized": "ruxolitinib as salvage therapy in steroid refractory acute graft versus host disease in pediatric hematopoietic stem cell transplant patients" }	[ { "companynumb": "PHHY2017US069090", "fulfillexpeditecriteria": "1", "occurcountry": "US", "patient": { "drug": [ { "actiondrug": "6", "activesubstance": { "activesubstancename": "METHOTREXATE" }, "drugadditional": null, "dr...
{ "abstract": "Drug-induced liver injury (DILI) is currently an increasingly relevant health issue. However, available biomarkers do not reliably detect or quantify DILI risk. Therefore, the purpose of this study was to comparatively evaluate plasma and urinary biomarkers obtained from humans treated with acetaminophen (APAP) using a metabolomics approach and a proton nuclear magnetic resonance (NMR) platform. APAP (3 g/day, two 500 mg tablets every 8 h) was administered to 20 healthy Korean males (age, 20-29 years) for 7 days. Urine was collected daily before and during dosing and 6 days after the final dose. NMR spectra of these urine samples were analyzed using principal component analysis (PCA) and partial least-squares-discrimination analysis. Although the activities of aspartate aminotransferase and lactate dehydrogenase were significantly increased 7 days post-APAP treatment, serum biochemical parameters of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, total bilirubin, γ-glutamyl transpeptidase, and lactate dehydrogenase were within normal range of hepatic function. However, urine and plasma (1)H NMR spectroscopy revealed different clustering between predosing and after APAP treatment for global metabolomic profiling through PCA. Urinary endogenous metabolites of trimethylamine-N-oxide, citrate, 3-chlorotyrosine, phenylalanine, glycine, hippurate, and glutarate as well as plasma endogenous metabolites such as lactate, glucose, 3-hydroxyisovalerate, isoleucine, acetylglycine, acetone, acetate, glutamine, ethanol, and isobutyrate responded significantly to APAP dosing in humans. Urinary and plasma endogenous metabolites were more sensitive than serum biochemical parameters. These results might be applied to predict or screen potential hepatotoxicity caused by other drugs using urinary and plasma (1)H NMR analyses.", "affiliations": "Department of Smart Food and Drug, Inje University , Obang-dong, Gimhae, Gyungnam 621-749, Republic of Korea.", "authors": "Kim\|Ji Won\|JW\|;Ryu\|Sung Ha\|SH\|;Kim\|Siwon\|S\|;Lee\|Hae Won\|HW\|;Lim\|Mi-sun\|MS\|;Seong\|Sook Jin\|SJ\|;Kim\|Suhkmann\|S\|;Yoon\|Young-Ran\|YR\|;Kim\|Kyu-Bong\|KB\|", "chemical_list": "D015415:Biomarkers; D000082:Acetaminophen; D006859:Hydrogen", "country": "United States", "delete": false, "doi": "10.1021/ac402390q", "fulltext": null, "fulltext_license": null, "issn_linking": "0003-2700", "issue": "85(23)", "journal": "Analytical chemistry", "keywords": null, "medline_ta": "Anal Chem", "mesh_terms": "D000082:Acetaminophen; D000328:Adult; D015415:Biomarkers; D056486:Chemical and Drug Induced Liver Injury; D006801:Humans; D006859:Hydrogen; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D010363:Pattern Recognition, Automated; D056910:Republic of Korea; D055815:Young Adult", "nlm_unique_id": "0370536", "other_id": null, "pages": "11326-34", "pmc": null, "pmid": "24127682", "pubdate": "2013-12-03", "publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't", "references": null, "title": "Pattern recognition analysis for hepatotoxicity induced by acetaminophen using plasma and urinary 1H NMR-based metabolomics in humans.", "title_normalized": "pattern recognition analysis for hepatotoxicity induced by acetaminophen using plasma and urinary 1h nmr based metabolomics in humans" }	[ { "companynumb": "KR-JNJFOC-20131205755", "fulfillexpeditecriteria": "2", "occurcountry": "KR", "patient": { "drug": [ { "actiondrug": "1", "activesubstance": { "activesubstancename": "ACETAMINOPHEN" }, "drugadditional": null, ...

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