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"abstract": "BACKGROUND\nThe aim of this study is to report the perioperative outcomes of cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy (HIPEC) in patients ≥75 years from a Spanish multi-institutional experience.\n\n\nMETHODS\nThis multi-institutional retrospectively analyzed a prospectively collected clinical data from 10 Spanish hospitals that are part of the Spanish Group Peritoneal Cancer Surgery (GECOP). We assessed postoperative morbidity rates and performed univariate and multivariate analyses of factors associated with overall (grade I-IV) and major (grade III-IV) postoperative morbidity.\n\n\nRESULTS\nA total of 85 patients aged ≥75 years were included. Forty six postoperative adverse events were detected in 37 patients (43.5%). Twenty five complications in 20 patients (23.5%) were mild (grade I-II) and 16 complications in 12 patients (14.1%) were moderate-severe (grade III-IV). Five patients died in the first 90 days after the procedure (5.9%). After multivariate analysis, independent factors associated with postoperative complications were: PCI> 12 (OR: 4.14, 95% CI 1.22-14.12, p = 0.043) and the need for perioperative blood transfusion (OR: 14.91, 95% CI 3.87-57.46, p < 0.001). Regarding grade III-IV complications, after multivariate analysis, the presence of preoperative albumin levels <3.5 mgr/dl (OR: 9.15, 95% CI 1.38-60.57, p = 0.017), need for diaphragmatic peritonectomy procedures (OR: 11.32, 95% CI 1.40-91.32, p = 0.023) and perioperative blood transfusion (OR: 8.58, 95% CI 1.44-51.16, p = 0.018) were independent factors.\n\n\nCONCLUSIONS\nCytoreductive surgery and performing HIPEC by experienced groups in selected patients aged ≥75 years can be performed with morbidity and mortality similar to that described in the literature.",
"affiliations": "Hospital Clínico Universitario Virgen De La Arrixaca, Murcia, IMIB-Arrixaca, Murcia, Spain. Electronic address: cascalescirugia@gmail.com.;Hospital Clínico Universitario Virgen De La Arrixaca, Murcia, IMIB-Arrixaca, Murcia, Spain.;Hospital Universitario Reina Sofía, Córdoba, Andalucia, Spain.;Hospital Clínico Universitario Virgen De La Arrixaca, Murcia, IMIB-Arrixaca, Murcia, Spain.;Hospital Universitario De Torrecárdenas, Almería, Andalucia, Spain.;Hospital De Sant Joan De Espi Moises Broggi, Sant Joan De Espi, Cataluña, Spain.;Hospital Universitario Son Espases, Palma de Mayorca, Islas Baleares, Spain.;Hospital De Sant Joan De Espi Moises Broggi, Sant Joan De Espi, Cataluña, Spain.;Hospital Universitario De Fuenlabrada, Madrid, Spain.;Hospital General Universitario, Valencia, Valencia, Spain.;Hospital General Universitario Gregorio Marañón, Madrid, Spain.;Hospital Quirón de Torrevieja, Alicante, Comunidad Valenciana, Spain.;Hospital Quirón de Torrevieja, Alicante, Comunidad Valenciana, Spain.;MD Anderson Cancer Center, Madrid, Spain.;Hospital Clínico Universitario Virgen De La Arrixaca, Murcia, IMIB-Arrixaca, Murcia, Spain.",
"authors": "Cascales-Campos|P A|PA|;López-López|V|V|;Muñoz-Casares|F C|FC|;Feliciangeli|E|E|;Torres Melero|J|J|;Barrios|P|P|;Morales|R|R|;Ramos|I|I|;Ortega|G|G|;Camps|B|B|;González-Bayón|L|L|;Bretcha-Boix|P|P|;Farré-Alegre|J|J|;González-Moreno|S|S|;Gil|J|J|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-7404",
"issue": "25(2)",
"journal": "Surgical oncology",
"keywords": "Cytoreductive; Elderly; HIPEC; Morbidity; Mortality",
"medline_ta": "Surg Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D010478:Chemotherapy, Cancer, Regional Perfusion; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006979:Hyperthermia, Induced; D008297:Male; D009017:Morbidity; D009367:Neoplasm Staging; D010534:Peritoneal Neoplasms; D011183:Postoperative Complications; D011379:Prognosis; D011446:Prospective Studies; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "9208188",
"other_id": null,
"pages": "111-6",
"pmc": null,
"pmid": "27312037",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Morbidity and mortality outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients aged 75 years and over: Spanish group of peritoneal cancer surgery (GECOP) multicenter study.",
"title_normalized": "morbidity and mortality outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in patients aged 75 years and over spanish group of peritoneal cancer surgery gecop multicenter study"
} | [
{
"companynumb": "ES-ACTAVIS-2016-12298",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "We report the first case, to our knowledge, of Candida arteritis in a liver transplant recipient. The patient presented with hemorrhagic shock requiring emergency arterial repair. As Candida albicans, Candida tropicalis, and Candida glabrata were growing in the arterial tissue, the patient received antifungal therapy for 5 months, but died because of chronic graft dysfunction. No evidence of fungal infection was found in the tissue on postmortem examination.",
"affiliations": "Liver Transplant Unit, Hospital Universitari de Bellvitge - Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), University of Barcelona, Hospitalet de Llobregat, Barcelona, Spain.",
"authors": "Lladó|L|L|;Solé|C|C|;Bodro|M|M|;Baliellas|C|C|;Sabé|N|N|;Petit|A|A|;Ramos|E|E|;Carratalà|J|J|;Fabregat|J|J|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; D000077612:Anidulafungin; D065819:Voriconazole",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12218",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "16(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "Candida; arteritis; infection; liver transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000077612:Anidulafungin; D000935:Antifungal Agents; D001167:Arteritis; D002177:Candidiasis; D054714:Echinocandins; D017809:Fatal Outcome; D006084:Graft Rejection; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D065819:Voriconazole",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "465-8",
"pmc": null,
"pmid": "24750364",
"pubdate": "2014-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Candida arteritis occurring in a liver transplant recipient.",
"title_normalized": "candida arteritis occurring in a liver transplant recipient"
} | [
{
"companynumb": "ES-PFIZER INC-2014177815",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ANIDULAFUNGIN"
},
"drugadditional": "3",
... |
{
"abstract": "The diagnosis of non-cirrhotic portal hypertension (NCPH), a rare but potentially life-threatening complication in human immunodeficiency virus (HIV)-positive individuals, often occurs only after the emergence of fatal manifestations such as bleeding of esophageal varices. We herein report a female Japanese HIV patient who developed NCPH approximately 4 years after discontinuation of 65 months of didanosine (ddI) administration. The patient presented with severe ascites, bloody bowel discharge, extreme abdominal swelling, and symptoms of portal hypertension but no sign of liver cirrhosis. Examination revealed esophageal varices, oozing-like bleeding from a wide part of the colon, significant atrophy of the right lobe of the liver, and arterio-portal shunting and recanalization from the left medial segment branch of the portal vein to a paraumbilical vein, but no visible obstruction of the main trunk of the portal vein. Treatment for esophageal varices consisted of coagulation therapy with argon plasma after enforcement by endoscopic sclerotherapy and oral administration of β-blockers for elevated portal blood pressure. The patient has not experienced gastrointestinal bleeding in the approximately 5 years since the diagnosis of NCPH. Reviewing this case suggests the importance of suspecting NCPH in HIV patients with liver dysfunction of unknown etiology with a history of ddI and other purine analogs use, as well as the importance of controlling portal hypertension and esophageal varices in the treatment of NCPH.",
"affiliations": "AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan. Electronic address: yaji-k@onh.go.jp.;AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan.;AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan.;AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan.;AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan.;Histopathology, National Hospital Organization Osaka National Hospital, Japan.;Departments of Gastroenterology, National Hospital Organization Osaka National Hospital, Japan.;AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan.;Departments of Gastroenterology, National Hospital Organization Osaka National Hospital, Japan.;Histopathology, National Hospital Organization Osaka National Hospital, Japan.;AIDS Medical Center, National Hospital Organization Osaka National Hospital, 2-1-14 Hoenzaka, Chuo-ku, Osaka 540-0006, Japan.",
"authors": "Yajima|Keishiro|K|;Uehira|Tomoko|T|;Otera|Hiroshi|H|;Koizumi|Yusuke|Y|;Watanabe|Dai|D|;Kodama|Yoshinori|Y|;Kuzushita|Noriyoshi|N|;Nishida|Yasuharu|Y|;Mita|Eiji|E|;Mano|Masayuki|M|;Shirasaka|Takuma|T|",
"chemical_list": "D044966:Anti-Retroviral Agents; D016049:Didanosine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "20(9)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Didanosine; HIV; Non-cirrhotic portal hypertension; Purine analog",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000328:Adult; D044966:Anti-Retroviral Agents; D016049:Didanosine; D005260:Female; D015658:HIV Infections; D006801:Humans; D006975:Hypertension, Portal; D008103:Liver Cirrhosis",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "582-5",
"pmc": null,
"pmid": "25034388",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of non-cirrhotic portal hypertension associated with anti-retroviral therapy in a Japanese patient with human immunodeficiency virus infection.",
"title_normalized": "a case of non cirrhotic portal hypertension associated with anti retroviral therapy in a japanese patient with human immunodeficiency virus infection"
} | [
{
"companynumb": "JP-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2011-EU-00864GD",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIDANOSINE"
},
... |
{
"abstract": "Morquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa.\n\n\n\nA total of 33 patients, aged 5-63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease.\n\n\n\nIn Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.",
"affiliations": "Division of Medical Genetics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.;Division of Medical Genetics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada.;Medical Genetics Division, Centre Hospitalier Universitaire Sherbrooke, Sherbrooke, QC, Canada.;Medical Genetics Division, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC, Canada.;Division of Medical Genetics, Montreal Children's Hospital, McGill University Health Centre, Montreal, QC, Canada. john.mitchell@muhc.mcgill.ca.",
"authors": "Moisan|Lina|L|;Iannuzzi|David|D|;Maranda|Bruno|B|;Campeau|Philippe M|PM|;Mitchell|John J|JJ|0000-0002-6055-6858",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13023-020-01545-y",
"fulltext": "\n==== Front\nOrphanet J Rare Dis\nOrphanet J Rare Dis\nOrphanet Journal of Rare Diseases\n1750-1172 BioMed Central London \n\n1545\n10.1186/s13023-020-01545-y\nResearch\nClinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study\nMoisan Lina 1 Iannuzzi David 1 Maranda Bruno 2 Campeau Philippe M. 3 http://orcid.org/0000-0002-6055-6858Mitchell John J. john.mitchell@muhc.mcgill.ca 14 1 grid.416084.f0000 0001 0350 814XDivision of Medical Genetics, Montreal Children’s Hospital, McGill University Health Centre, Montreal, QC Canada \n2 grid.411172.00000 0001 0081 2808Medical Genetics Division, Centre Hospitalier Universitaire Sherbrooke, Sherbrooke, QC Canada \n3 grid.411418.90000 0001 2173 6322Medical Genetics Division, Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Montreal, QC Canada \n4 grid.416084.f0000 0001 0350 814XDivision of Pediatric Endocrinology, Montreal Children’s Hospital, McGill University Health Centre, A04.6309, 1001 Decarie, Montreal, QC Canada \n29 9 2020 \n29 9 2020 \n2020 \n15 27023 4 2020 14 9 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nMorquio A syndrome is a rare, autosomal recessive, progressively debilitating disorder, with multi-system impairments and high medical burden. Quebec, Canada has a large Morquio A population, which is considered unique due to the presence of founder pathogenic variants. The objectives of this study were to document the genetic and clinical heterogeneity of patients with Morquio A in Quebec, to better characterize the phenotype of those with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the natural history of the patients treated with elosulfase alfa enzyme replacement therapy. Patients with Morquio A were genotyped for pathogenic variants in the lysosomal enzyme N-acetylgalactosamine-6-sulfatase. Clinical data were retrospectively collected from medical charts of patients and included medical history, height, physical examination, respiratory function tests, electrocardiogram, echocardiogram, endurance in the 6-min walk test (6MWT), and activities of daily living (ADL) as assessed by the Mucopolysaccharidosis Health Assessment Questionnaire (MPS-HAQ). Longitudinal data were collected retrospectively and prospectively for patients treated with elosulfase alfa.\n\nResults\nA total of 33 patients, aged 5–63 years, were included in the analysis. Patients with the founder pathogenic variant (n = 17) generally exhibited a non-classical form of Morquio A. As compared with patients with a non-founder pathogenic variant (n = 16), these patients were generally taller, had greater endurance and were better able to perform ADL. However, they still had significant musculoskeletal disease. Most of the 26 patients treated with elosulfase alfa, regardless of pathogenic variant, showed improvements in endurance and ADL. After 5 to 12 months of treatment, the mean improvement from baseline in the 6MWT was 23% and 10 of 14 patients improved in at least one MPS-HAQ domain. Endurance and ADL generally continued to improve or maintained stable in the long term (up to 7 years). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease.\n\nConclusions\nIn Quebec, Canada, Morquio A frequently manifests as a non-classical form of the syndrome due to a founder effect. Patients treated with elosulfase alfa generally show long-term improvement or stability in endurance and function, regardless of pathogenic variant.\n\nKeywords\nCanadaFounder effectsGenetic disordersMucopolysaccharidosis IVAActivities of daily livingWalk testhttp://dx.doi.org/10.13039/100008484BioMarin Pharmaceuticalissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nMorquio A syndrome, also called mucopolysaccharidosis IVA (MPS IVA), is an ultra-rare, genetically transmitted lysosomal storage disorder caused by a deficiency of the N-acetylgalactosamine-6-sulfatase (GALNS) enzyme [1, 2]. Deficiency of the GALNS enzyme manifests as a failure to degrade glycosaminoglycans (GAGs), namely keratan sulfate (KS) and chondroitin-6-sulfate (C6S), resulting in excessive accumulation of these GAGs [2] and subsequent activation of secondary pathways of inflammation. The result of the GAG accumulation is a progressively debilitating and potentially life-threatening disorder, with multi-system impairments and a high medical burden [3]. The main organ affected is bone, with accumulation of KS and C6S resulting in impaired development of cartilage and bone and eventual systemic skeletal spondyloepiphyseal dysplasia [2, 4, 5]. The clinical presentation is heterogeneous [6] and typically includes marked skeletal and joint abnormalities, coarsening of facial features, short-trunk dwarfism with short neck, restrictive and obstructive lung disease, impaired cardiac function, hearing and vision loss, abdominal manifestations (hepatomegaly, hernias), waddling gait leading to increased fall risk, and dental abnormalities [4, 5, 7]. Classical forms of Morquio A syndrome are also associated with fatigue, sleep apnea, shortness of breath, tracheal obstruction, and recurrent upper respiratory tract infections [5]. Over time, the progressive loss of functional capacity and endurance leads to reduced quality of life [3]. Many individuals become wheelchair-dependent and require multiple surgeries [3, 6]. Morquio A patients typically have a shortened life expectancy, with the main cause of death being respiratory failure [6, 8].\n\nAvailable prevalence data for Morquio A syndrome are derived from epidemiologic studies conducted in individual countries. The birth prevalence ranges from 1 per 71,000 in the United Arab Emirates to 1 in 500,000 in Japan, with most countries having < 0.5 cases per 100,000 live births [9]. Morquio A appears to be more prevalent than in most countries in Quebec, Canada, although precise numbers are not available. In 1973, a survey of the main hospitals in Quebec conducted by Gadbois et al. identified 48 patients with the disease distributed within 27 families [10]. The high prevalence of Morquio A in Quebec is explained by the fact that French Canadians represent a unique population with a higher rate of some recessive genetic diseases that reflects the presence of founder pathogenic variants [11].\n\nTreatment of Morquio A syndrome has traditionally been supportive in nature, with the goals of managing symptoms with physical therapy and surgery [7]. Enzyme replacement therapy with elosulfase alfa (VIMIZIM®, BioMarin Pharmaceutical Inc, CA, USA) was approved by the US Food and Drug Administration in February 2014, by the European Medicines Agency in April 2014, and by Health Canada in September 2014 [12]. Approvals were based on the findings of a 24-week, placebo-controlled, Phase 3 trial that randomized 176 patients [13]. Once-weekly intravenous infusions of elosulfase alfa (2 mg/kg) significantly improved endurance based on the 6-min walk test (6MWT), and the most common adverse events were infusion-related reactions and hypersensitivity [13]. These improvements were sustained over 120 weeks among patients participating in an extension study of the trial [14]. Another long-term study showed no trends towards decreasing endurance and maintained tolerability and safety over 5 years in 17 patients, many of whom elected to be treated with home infusions [15].\n\nCanadian patients with Morquio A syndrome face substantial barriers to accessing elosulfase alfa treatment because of the absence of an orphan drug plan in Canada and marked differences in approval processes across provinces [16]. Given the cost of orphan medications and possible pharmacogenetic effects in the Quebec population, data supporting clinical efficacy are critical. This report documents the genetic and clinical heterogeneity of Morquio A syndrome in a series of patients from Quebec, and describes longitudinal data from those treated with elosulfase alfa.\n\nMethods\nStudy design and objectives\nThis was a longitudinal observational study of patients with Morquio A syndrome in Quebec, Canada. All patients with a confirmed Morquio A diagnosis who provided consent to participate in the study are included.\n\nThe main objectives of the study were to document the genetic and clinical heterogeneity of the Morquio A patient population in Quebec in general, to characterize the phenotype of patients with the French Canadian founder pathogenic variant (NM_000512.5: c.1171A>G, p.Met391Val), and to describe the disease course of those treated with elosulfase alfa.\n\nThe study protocol was approved by the institutional review board at McGill University. All patients (or their guardians) provided written informed consent before study entry. The study was conducted in accordance with the Declaration of Helsinki and International Conference of Harmonization Good Clinical Practice guidelines [17].\n\nGenetic testing\nAll patients were genotyped for pathogenic variants in GALNS. Patients were stratified by the presence or absence of the French Canadian founder pathogenic variant c.1171A>G, p.Met391Val. Patients with at least one copy of this pathogenic variant were included in the founder pathogenic variant group, regardless of the presence of other pathogenic variants (because of suggestions that, in compound heterozygotes, the phenotype of the allele with residual activity will be displayed [18]).\n\nData collection\nClinical data were retrospectively collected from November 2009 to December 2014 and prospectively from January 2015 to May 2019 via chart review of medical records. Clinical data were collected approximately every 6 months or at every clinic visit [7]. Clinical assessments for which data are presented include medical history, height (z-score was calculated [19]), physical examination, respiratory function tests (forced expiratory volume in 1 s [FEV1] and forced vital capacity [FVC]), electrocardiogram, echocardiogram, endurance, and activities of daily living (ADL). Endurance was assessed by the 6MWT [7]. ADL were assessed by the MPS Health Assessment Questionnaire (MPS-HAQ; originally developed for patients with MPS I [13]). The MPS-HAQ assesses self-care (eating/drinking, dressing, bathing, grooming, tooth brushing, and toileting), mobility (dexterity, mobility, walking, stair climbing, and gross motor skills), and caregiver-assistance required (Care Services) [20]. Total self-care and mobility domain scores range from 0 (not difficult at all) to 10 (extremely difficult) and 11 (unable to do). The total Care Services domain score ranges from 13 (independent) to 52 (complete assistance required) [20]. Decreasing scores imply improvements.\n\nFor some of the patients, some data could retrospectively be collected from the MOR-001 natural history study (NCT00787995; [1, 21]), the Phase 3 MOR-004 and MOR-005 studies (NCT01275066 and NCT01415427; [13, 14]), and the Phase 2 MOR-008 study (NCT01609062; [22]), and were included in this study.\n\nStatistical analysis\nDescriptive statistics were used to summarize data. Baseline data are presented for all patients. For patients initiating elosulfase alfa therapy, data at baseline and at last follow-up are presented. Baseline was defined as the closest measurement prior to, or on the day of, first treatment for patients treated with elosulfase alfa, and as the first measurement recorded for the other patients. For baseline measurements and change from baseline, the founder pathogenic variant group was compared with the non-founder pathogenic variant group by an unpaired t test of unequal variance (P < 0.05 was considered significant). Missing data was not included in the analysis.\n\nResults\nDemographic and baseline clinical characteristics\nWe evaluated 33 patients with Morquio A syndrome from Quebec who provided consent to participate in the study (Table 1). There were more males (58%) than females (42%) in the overall population. Mean age was 25.9 years (range: 5–63 years; median: 21 years), and the mean height of adults (n = 23) was 1.23 m. As determined based on height data, compared with Morquio A-specific growth charts [23], phenotype was determined as classical in 12 patients, non-classical in 16 patients, and intermediate in five patients (Table 1). Four patients previously participated in the MOR-001 natural history study (patients 2, 19, 26, and 27), four in the MOR-004 and MOR-005 studies (patients 3, 7, 25, and 29), and three in the MOR-008 study (patients 26, 27, and 34). Twenty six patients had received treatment with elosulfase alfa. In these patients, elosulfase alfa was administered according to labeling as 2 mg/kg intravenously once every week.Table 1 Baseline characteristics of individual patients with Morquio A syndrome\n\nID\tGALNS pathogenic variants\tSex\tAge (years)\tHeight z-scoreb\tAdult height (m)a\tElosulfase alfa treatment\tPhenotypec\t\nFounder pathogenic variant group\t\n 1\t1171A>G\t121A>T\tM\t43\t− 4.1\t1.47\tNo\tNC\t\n 3\t1171A>G\t901G>T\tF\t23\t− 5.8\t1.23\tYes\tNC\t\n 7\t1171A>G\t1171A>G\tF\t25\t− 4.8\t1.25\tYes\tNC\t\n 17\t1171A>G\t405_422+1del\tF\t60\t− 6.8\t1.19\tNo\tNC\t\n 18\t1171A>G\t841_867_del\tF\t36\t− 4.3\t1.36\tYes\tNC\t\n 20\t1171A>G\t1171A>G\tF\t14\t− 2.5\t–\tYes\tNC\t\n 21\t1171A>G\t405_422 + 1del\tF\t58\t− 6.5\t1.25\tYes\tNC\t\n 22\t1171A>G\t121A>T\tM\t7\t− 7.8\t–\tYes\tI\t\n 24\t1171A>G\t121A>T\tM\t45\t− 6.1\t1.32\tYes\tI\t\n 26\t1171A>G\t1354T>A\tM\t21\t− 1.6\t1.67\tYes\tNC\t\n 27\t1171A>G\t1354T>A\tF\t17\t− 1.6\t–\tYes\tNC\t\n 29\t1171A>G\t404_422del19\tF\t17\t− 5.4\t–\tYes\tNC\t\n 30\t1171A>G\t1157G>A\tM\t36\t− 6.1\t1.32\tYes\tI\t\n 31\t1171A>G\t1171A>G\tM\t40\t− 4.9\t1.39\tYes\tNC\t\n 32\t1171A>G\t121A>T\tF\t40\t− 5.5\t1.27\tNo\tNC\t\n 33\t1171A>G\t1171A>G\tM\t23\t− 3.1\t1.41\tNo\tNC\t\n 34\t1171A>G\t1171A>G\tF\t16\t− 1.4\t–\tYes\tNC\t\nNon-founder pathogenic variant group\t\n 2\t244+1G>T\t901G>T\tM\t27\t− 7.5\t1.21\tYes\tC\t\n 4\t901G>T\t121A>T\tM\t12\t− 7.6\t–\tYes\tC\t\n 5\t901G>T\t121A>T\tM\t10\t− 4.6\t–\tYes\tI\t\n 6\t901G>T\t704C>A\tF\t9\t− 7.1\t–\tYes\tC\t\n 8\t901G>T\t319G>A\tM\t16\t− 6.7\t–\tYes\tC\t\n 9\t121A>T\t841_867_del\tF\t63\t− 6.9\t1.05\tYes\tI\t\n 11\t901G>T\t405_422+1_del\tM\t27\t− 11.1\t0.92\tYes\tC\t\n 12\t901G>T\t405_422+1_del\tM\t25\t− 10.4\t0.98\tYes\tC\t\n 13\t901G>T\t121A>T\tF\t35\t− 8.0\t1.15\tYes\tNC\t\n 14\t1157G>A\t1157G>A\tM\t15\t− 5.6\t–\tNo\tC\t\n 15\t1157G>A\t1157G>A\tM\t21\t− 11.0\t0.92\tNo\tC\t\n 16\t1157G>A\t1157G>A\tM\t19\t− 11.5\t–\tNo\tC\t\n 19\t244T>C\t244T>C\tF\t20\t− 1.9\t1.36\tYes\tNC\t\n 23\t901G>T\t901G>T\tM\t5\t− 5.2\t–\tYes\tC\t\n 25\t406_424del19\t1480A>G\tM\t15\t− 7.2\t–\tYes\tC\t\n 28\t938C>T\t938TC>T\tM\t16\t− 7.8\t–\tYes\tC\t\nBold indicates a homozygote founder pathogenic variant\n\nPatient 10 withdrew consent and is therefore not included in the analysis\n\n1171A>G: founder pathogenic variant; F: female; GALNS: N-acetylgalactosamine-6-sulfatase gene; ID: patient identification number; M: male; NA: not available\n\naAdult height is only presented for patients ≥ 18 years of age\n\nbZ-score was calculated at https://apps.cpeg-gcep.net/quickZ_WHO\n\ncPhenotypes were determined based on Morquio A-specific growth charts [23]: patients were classified as classical (C) when height was ≤ 50th % ile, as intermediate (I) when height was > 50th and < 75th %ile, and as non-classical (NC) when height was ≥ 75th %ile\n\n\n\nEjection fraction was available for 15 patients, and was within normal limits (55–70%) in these patients. Lung function data were available for 20 patients; FEV1/FVC ratio was within the normal range (> 70%) in most of these patients (Table 2). It should be noted that for many patients, it was difficult to interpret FEV1 and FVC data as % predicted cannot be calculated for individuals with short stature for whom norms are not available. Eleven out of 26 patients with available echocardiogram data had evidence of cardiac abnormalities. These included ten patients with valve disease and one patient with ascending aorta dilatation that worsened over time (see footnote Table 2 for details). These abnormalities were of clinical significance in six patients (patients 2, 8, 11, 19, 25, and 31). Two patients (11 and 12), both with a non-founder pathogenic variant and significant respiratory involvement died during the study due to cardiac arrest. These patients were siblings and died 1 year apart. They both had classical disease and significant respiratory involvement. Patient 11 had a previous cardiac arrest, and death occurred during activity, likely due to arrhythmia. Patient 12 died in same manner. The exact cause of death could not be determined, as there was no autopsy. Four patients (see footnote Table 2 for details) had difficulty sustaining respiratory efforts and pulmonary function could not be measured.Table 2 Cardiac and lung function of individual patients at baseline and after elosulfase alfa treatment\n\nID\tCardiac abnormalities at baselinee\tEjection fraction (%)a\tLung functionb\nFEV1/FVC (%)c\t\nBaseline\tElosulfase alfa treatment\tBaseline\tElosulfase alfa treatment\t\nFollow-up\tDuration\tFollow-up\tDuration\t\nFounder pathogenic variant group\t\n 1\tNo\t70\tNT\t\t73\tNT\t\t\n 3\tNo\tNA\t65\t6.5 years\t91\t91\t2 years\t\n 7\tNo\tNA\t65\t4.5 years\t85\t85\t6 years\t\n 17\tNA\tNA\tNT\t\tNA\tNT\t\t\n 18\tNo\t>50\t60\t3 years\t88\t86\t3 years\t\n 20\tYes\tNA\t67\t4 years\t81\t88\t7 years\t\n 21\tYes\t75\tNA\t\t84\tNA\t\t\n 22\tNA\tNA\tNA\t\t87\t92\t2.5 years\t\n 24\tNo\tNA\t70\t6 months\tNA\t80\t2 years\t\n 26\tNo\tNA\t61\t2 years\t86\t82\t6 years\t\n 27\tNo\tNA\t65\t5 years\t83\t83\t5 years\t\n 29\tNo\t59\t49\t5 years\t91\t91\t6.5 years\t\n 30\tNo\t60\tNA\t\tNA\t\t\t\n 31\tYesd\tNA\t70\t6 months\tNA\t86\t2 years\t\n 32\tNo\t74\tNT\t\tNA\tNT\t\t\n 33\tNo\tNA\tNT\t\t86\tNT\t\t\n 34\tNA\tNA\t60\t1 year\t89\t89\t6 years\t\nNon-founder pathogenic variant group\t\n 2\tYes\tNA\tNA\t\t91\t90\t1.5 years\t\n 4\tNA\tNA\tNA\t\tNA\tNA\t\t\n 5\tNo\tNA\t59\t1 year\tNA\tNA\t\t\n 6\tYes\t67\tNA\t\tNA\tNA\t\t\n 8\tYes\t78\t82\t3 years\t84\t100\t3 years\t\n 9\tYes\t70\t65\t3 years\t79\t77\t3 years\t\n 11\tYes\t70\t65\t1 year\tNA\tNA\t\t\n 12\tNo\t55\t55\t3 years\tNA\t68\t3 years\t\n 13\tNo\tNA\tNA\t\tNA\tNA\t\t\n 14\tNA\t60\tNT\t\t71\tNT\t\t\n 15\tNA\t78\tNT\t\t101\tNT\t\t\n 16\tNA\t69\tNT\t\t71\tNT\t\t\n 19\tYes\tNA\tNA\t\t85\t86\t4 years\t\n 23\tNo\tNA\tNA\t\tNA\tNA\t\t\n 25\tYes\t62\tNA\t\t98\tNA\t\t\n 28\tYes\tNA\t79\t1 year\tNA\t92\t1 year\t\nFor patients who received elosulfase alfa, the baseline measurement (closest measurement prior to, or on the day of, first treatment) was included. For other patients, the first measurement recorded is included in the table\n\nFEV1 forced expiratory volume in 1 s, FVC forced vital capacity, ID patient identification number, NA not available, NT no elosulfase alfa treatment\n\naNormal range 55–70%\n\nbPulmonary abnormalities included the following: Patients 8, 9, 25, and 29 had difficulty sustaining respiratory efforts\n\ncNormal range ≥ 70%\n\ndBaseline echographic examination of subject 31 was performed 4 months after initiating elosulfase alfa\n\neCardiac abnormalities included the following: Patient 2 had a mitral valve insufficiency and aortic valve stenosis; Patient 6 had a thickened aortic valve and mitral valve with trivial mitral regurgitation; Patient 8 had ascending aorta dilatation that worsened overtime; Patient 9 had atrioventricular valve sclerosis; Patient 11 had mitral valve thickening and aortic valve replacement; Patient 19 had pulmonary valve stenosis and pulmonary artery dilation; Patient 20 had mild pulmonary and tricuspid regurgitation; Patient 21 had atrioventricular valve sclerosis; Patient 25 had moderate mitral valve regurgitation and left ventricular outflow obstruction; Patient 28 had a slight reformation of the mitral valve; and Patient 31 had a bicuspid aortic valve and aortic root dilation\n\n\n\nGenetic data were available for all patients; 17 patients expressed at least one copy of the French Canadian founder pathogenic variant (c.1171A>G, p.Met391Val), five of which were homozygotes, and 16 patients had only non-founder pathogenic variants (Table 1).\n\nDisease traits related to founder pathogenic variant\nPatients with the founder pathogenic variant tended to exhibit a non-classical form of Morquio A syndrome, while most patients without the founder pathogenic variant had a classical phenotype (Tables 1, 2 and 3, Fig. 1). Although most patients, regardless of pathogenic variant, were substantially shorter than normalized World Health Organization values, patients with the founder pathogenic variant were significantly (P = 0.001) taller by z-score than most patients in the non-founder group (Fig. 1a). Nevertheless, many of the founder patients still had significant musculoskeletal disease. Patients with the founder pathogenic variant could also walk slightly farther during the 6MWT than non-founder patients, though the difference was not statistically significant (P = 0.281) (Fig. 1b). In addition, patients with the founder pathogenic variant had better ability to perform ADL, as measured with the MPS-HAQ, compared with patients with a non-founder pathogenic variant; the domains of self-care, mobility, and care services were all better (lower scores) for those with the founder pathogenic variant (P = 0.001, P = 0.075, and P = 0.001, respectively) (Fig. 1c). Finally, patients with the founder pathogenic variant showed less cardiac abnormalities and impairments in respiratory function than those with non-founder pathogenic variants.Table 3 Baseline 6MWT and MPS-HAQ results of individual patients\n\nID\tEndurance\tMPS-HAQ\t\n6MWT (m)\tSC\tMOB\tCS\t\nFounder pathogenic variant group\t\n 1\t27\t3.1\t6.6\t22\t\n 3\t321\t0.2\t4.7\t23\t\n 7\t138\t0.7\t6.3\t26\t\n 17\tNM\t2.4\t5.7\t14\t\n 18\t371\tNA\tNA\tNA\t\n 20\t246\t1.9\t3.3\t23\t\n 21\t330\t1.2\t2.2\t23\t\n 22\tNA\tNA\tNA\tNA\t\n 24\t230\t1.2\t5.7\t13\t\n 26\t423\t0.4\t2.1\t15\t\n 27\t338\t0.04\t1.6\t14\t\n 29\t123\t2.1\t4.5\t21\t\n 30\tNM\t5.2\t8.6\t20\t\n 31\t535\t1.5\t2.5\t13\t\n 32\tNA\t0.8\t2.7\t13\t\n 33\tNM\t0.3\t5.6\t33\t\n 34\t347\tNA\tNA\tNA\t\nNon-founder pathogenic variant group\t\n 2\tNM\t8.8\t9.8\t47\t\n 4\t289\t2.7\t1.2\t17\t\n 5\t458\t1.5\t0.9\t19\t\n 6\t261\tNA\tNA\tNA\t\n 8\t225\tNA\tNA\tNA\t\n 9\tNM\t9.5\t10.0\t51\t\n 11\tNM\t9.2\t10.0\t52\t\n 12\tNM\t2.9\t8.3\t42\t\n 13\t439\t0.4\t3.1\t13\t\n 14\t141\t4.4\t8.0\t37\t\n 15\tNM\t7.6\t10.0\t48\t\n 16\t25\t5.2\t9.0\t37\t\n 19\t171\t3.2\t5.6\t36\t\n 23\tNA\t4.1\t1.5\t30\t\n 25\t120\t5.1\t8.7\t28\t\n 28\t36\tNA\tNA\tNA\t\nFor patients who received elosulfase alfa, the baseline measurement (closest measurement prior to, or on the day of, first treatment) was included. For other patients, the first measurement recorded is included in the table\n\n6MWT 6-min walk test, CS care services, ID patient identification number, MOB mobility, MPS-HAQ Mucopolysaccharidosis Health Assessment Questionnaire, NA not available, NM not mobile, SC self-care\n\nFig. 1 Baseline measures. a Mean ± SD height z-score (for children) or SD from the average of people of the same age and sex (for adults), b Mean ± SD distance in the 6-min walk test, and c mean ± SD score for the self-care, mobility, and care services domains of the MPS-HAQ. 1171A>G: founder pathogenic variant; MPS-HAQ: Mucopolysaccharidosis Health Assessment Questionnaire; SD: standard deviation. *P = 0.001\n\n\n\nLongitudinal data of patients treated with elosulfase alfa\nOf the 26 patients who had received treatment with elosulfase alfa; 13 had a founder pathogenic variant and 13 had a non-founder pathogenic variant. The duration of treatment varied from 6 months to 7 years.\n\nFor patients treated with elosulfase alfa and assessed between 5 and 12 months after the start of treatment, changes from baseline in 6MWT and MPS-HAQ results were variable (Fig. 2). However, there was no significant difference between patients with the founder or non-founder pathogenic variant at 5 to 12 months for either 6MWT (P = 0.896) or MPS-HAQ (self-care P = 0.1134; mobility P = 0.3423; care services P = 0.806). Importantly, many patients from both groups showed improvements in the 6MWT within this timeframe (Fig. 2). The mean improvement in the 6MWT for all patients, regardless of pathogenic variant, was 23%. For the MPS-HAQ, we observed ≥ 10% improvement (decrease in score) in at least one domain in 10 of 14 patients with available data, regardless of pathogenic variant; seven patients improved in at least two domains, and three patients improved in all three domains. Some patients had low baseline scores with little room for improvement. In general, patients showing initial improvements were able to sustain these over long-term treatment (Fig. 2).Fig. 2. 6MWT and MPS-HAQ results in patients treated with elosulfase alfa after 5 or 6 to 12 months, 1.5 to 2.5 years, and (for 6MWT) 3.5 to 4.5 years. Individual patient responses in 6MWT and MPS-HAQ were classified as no change from baseline, ≥ 10% improvement (longer distance on the 6MWT or lower score on the MPS-HAQ) from baseline, ≥ 10% worsening (shorter distance on the 6MWT or higher score on the HAQ) from baseline, or no measure available. Note that the closest measurement to, but not exceeding, the largest time of treatment was included. For 6MWT, some patients (5, 13, and 31) had normal 6MWT for height [29], and patient 26 had a decrease in 6MWT at 1.5 to 2.5 years because of back surgery (but returned to normal 6MWT for height in later years). 1171A>G: founder pathogenic variant; 6MWT: 6-min walk test; CS: care services; MPS-HAQ: Mucopolysaccharidosis Health Assessment Questionnaire; M: mobility; SC: self-care\n\n\n\nPatients treated with elosulfase alfa for a longer time showed improvements in the 6MWT regardless of pathogenic variant (Fig. 3a, b). In both groups, improvements in endurance were generally maintained, or continued to improve, over many years of treatment. MPS-HAQ results in the long term were more variable, but several patients showed long-term improvements, regardless of pathogenic variant (Fig. 4). Overall, the spread of MPS-HAQ scores for patients with non-founder pathogenic variants was greater than for those with the founder pathogenic variant (Fig. 4), perhaps because phenotypes within the founder group were more uniform than within the non-founder group, which showed a wider variation of phenotypes.Fig. 3 Individual patient 6-min walk test distances over time following treatment with elosulfase alfa. Note for patient 28, distance improved to 153 m, but this was with a walker and has not been included on the figure. 1171A>G: founder pathogenic variant\n\nFig. 4 Individual patient MPS-HAQ scores over time for the domains of self-care, mobility, and care services, following treatment with elosulfase alfa. Note that lower scores indicate a better outcome. 1171A>G: founder pathogenic variant; HAQ: Health Assessment Questionnaire\n\n\n\nOverall, ejection fraction and FEV1/FVC ratio of patients treated with elosulfase alfa remained stable over time (for up to 7 years), regardless of pathogenic variant (Table 2). Four out of 19 treated patients with echocardiogram data at follow-up showed progression of cardiac disease (patients 2, 11, 19, and 25, all from the non-founder pathogenic variant group).\n\nLongitudinal data of untreated patients are not presented as data for these patients were too limited to make any meaningful comparison with treated patients.\n\nDiscussion\nThis is the first report of Morquio A syndrome in French Canadians from Quebec in over 45 years. In 1973, Gadbois and colleagues described the physical appearance and biochemical characteristics of 48 Quebecois with the disease [10]. Our observations expand on these data and highlight the phenotypic variability in this unique population. Over half of our patient sample expressed the French Canadian founder pathogenic variant in GALNS (i.e., c.1171A>G, p.Met391Val). This pathogenic variant appears to be associated with a more non-classical form of Morquio A syndrome than most non-founder pathogenic variants, as shown by a greater mean adult height, a better endurance and ability to perform ADL, and less cardiac abnormalities and impairments in lung function. The majority of patients received treatment with elosulfase alfa. These patients generally showed improvements over time in 6MWT and MPS-HAQ outcomes, regardless of whether or not they had the French Canadian founder pathogenic variant.\n\nThe improvements in the 6MWT and MPS-HAQ observed in the patients receiving elosulfase alfa were similar to those observed in international clinical trials. In the Phase 3 trial, patients randomized to elosulfase alfa 2 mg/kg for 24 weeks (n = 58) showed a mean improvement in 6MWT distance of 17.9% over baseline (versus 6.4% for placebo; n = 59) [13]. This is similar to the findings in our study (23% improvement over baseline after 5–12 months, regardless of pathogenic variant), and above the mean minimal clinically important difference in the 6MWT estimated for respiratory, cardiovascular, and muscular diseases (7–9%) [4]. In the Phase 3 extension trial, 6MWT remained stable with elosulfase alfa treatment over 120 weeks [14], while two sequential open-label studies in 17 patients showed sustained improvements over up to 5 years of treatment [15]. These clinical trial results are also similar to our findings of 6MWT improvements or maintenance over a period of up to 7 years. In addition, we observed improvements in MPS-HAQ outcomes, similar to those seen in the Phase 3 clinical trial [20, 24]. It should be kept in mind that 6MWT distance increases with age and height in children, which may partly explain long-term increases in the test in younger patients [25, 26]. Nevertheless, long-term increases or stability in the 6MWT were also seen in most adult patients. These long-term results should be interpreted in light of the progressive nature of Morquio A. Published natural history data have shown a gradual decline in 6MWT and MPS-HAQ results over time in the absence of treatment [1, 14, 20]. The finding that most patients in our study showed stable or improved endurance and/or MPS-HAQ scores over time indicates that elosulfase alfa can slow down the gradual regression in these measures.\n\nThe findings of our study contribute to a better understanding of the clinical characteristics and genetic underpinnings in Quebecois, as well as the natural history of the disease in those receiving elosulfase alfa. Although elosulfase alfa, the first and only medical therapy available to modify the disease at a cellular level, has been approved in Canada for patients with Morquio A syndrome, treatment poses a sizeable economic burden to patients. There are currently no conditions for coverage by the Quebec Public Prescription Drug Insurance Plan (elosulfase alfa can only be prescribed through exceptional patient status) and no formal guidelines that provide criteria for its use. Instead, there is considerable debate and policy discussion, particularly with regard to cost and which patients are most likely to benefit. Our data support the international and Canadian management guidelines for Morquio A, which recommend initiation of treatment as early as possible in light of the progressive nature of the disease [27, 28]. Given the clinical heterogeneity, individual treatment goals should be established by a multidisciplinary team taking into account the disease burden at the time of treatment initiation and the anticipated measurable benefits over time.\n\nSeveral limitations of our study should be acknowledged. Though observational studies are useful in identifying relationships between characteristics, such as associations between genetic pathogenic variants and phenotype, causality cannot be established in the absence of a more stringent methodology involving required clinic visits and formal statistical analyses of variance with a complete data set. In addition, this study had no restrictions on surgery, other treatments, or activities before a clinic visit, and all could have influenced the assessments at that visit. 6MWT, respiratory function tests and echocardiograms were often performed locally, which may also have introduced some variability in the results. There were limitations with the scoring systems used and the expectation of improvement with treatment. For patients who have normal or near-normal scores in a test at baseline, stability may be an important outcome. Finally, our data are incomplete for several reasons: not all patients in Quebec with Morquio A syndrome gave consent for participation; many patients needed to travel long distances which may have resulted in missed data points; the 6MWT and MPS-HAQ were not routinely performed in all patients; assessments were not always performed in the recommended time window due to e.g. surgeries; and some patients were too young to complete the respiratory function tests. However, despite missing data, the available data were sufficient to show significant differences in clinical characteristics between the founder pathogenic variant and the non-founder pathogenic variant groups.\n\nConclusions\nMorquio A syndrome is a progressively debilitating lysosomal storage disorder that is heterogeneous in presentation and concentrated in the Quebecois population. We demonstrated a founder effect in French Canadians from Quebec with Morquio A, which manifests as a non-classical form of the disease related to the founder pathogenic variant in about half of the study population. Despite the observed founder effect, Quebecois patients did not appear to respond differently to therapy than patients in other Morquio A populations represented in clinical trials of elosulfase alfa. Improvements or stability in the 6MWT and/or MPS-HAQ in treated patients were seen regardless of GALNS pathogenic variant and were in line with those reported for patients in the clinical trials. Overall, the results of our study confirm published evidence for the beneficial effects of elosulfase alfa across multiple domains over both short and long time periods. In addition, they support the treatment plan proposed by the Canadian management guidelines, which involves initiation of treatment as early as possible, a cohesive follow-up approach, and establishment of individual treatment goals based on disease/functional stabilization and/or prevention of symptom onset [27]. Nevertheless, since enzyme replacement therapy with elosulfase alfa only partially improves the health and function of patients with Morquio A syndrome, continued research to develop additional disease-modifying treatments is needed.\n\nAbbreviations\n6MWT6-Min walk test\n\nADLActivities of daily living\n\nC6SChondroitin-6-sulfate\n\nFEV1Forced expiratory volume in 1 s\n\nFVCForced vital capacity\n\nGAGsGlycosaminoglycans\n\nGALNSN-Acetylgalactosamine-6-sulfatase\n\nIDPatient identification number\n\nKSKeratan sulfate\n\nMPSMucopolysaccharidosis\n\nMPS-HAQMucopolysaccharidosis Health Assessment Questionnaire\n\nNANot available\n\nNTNo elosulfase alfa treatment\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nThe authors would like to thank all study participants. Medical writing assistance was provided by Janelle Keys, PhD, CMPP, of ProScribe—Envision Pharma Group and by Ismar Healthcare, and was funded by BioMarin Pharmaceutical Inc. All medical writing services complied with international guidelines for Good Publication Practice (GPP3).\n\nAuthors’ contributions\nAll authors participated in the collection of the data, interpretation of study results, and in the drafting and critical revision of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nBioMarin Pharmaceutical Inc. provided financial support for the preparation of this manuscript, but was not involved in any aspects of manuscript preparation.\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 study protocol was approved by the institutional review board at McGill University. All patients (or their guardians) provided written informed consent before study entry. The study was conducted in accordance with the Declaration of Helsinki and International Conference of Harmonization Good Clinical Practice guidelines.\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nJJM has been an investigator on clinical trials with BioMarin, Takeda, Ultragenyx, Enzyvant, and Sanofi-Genzyme, and has received consulting fees from BioMarin, Ultragenyx, Enzyvant and Sanofi-Genzyme; PMC is an investigator on the BioMarin MARS study and has received consulting fees from BioMarin; BM is an investigator on the BioMarin MARS study; all other authors have no conflicts of interest to declare.\n==== Refs\nReferences\n1. Harmatz PR Mengel KE Giugliani R Valayannopoulos V Lin SP Parini R Guffon N Burton BK Hendriksz CJ Mitchell JJ Martins AM Jones SA Guelbert N Vellodi A Wijburg FA Yang K Slasor P Decker C Longitudinal analysis of endurance and respiratory function from a natural history study of Morquio A syndrome Mol Genet Metab 2015 114 186 194 10.1016/j.ymgme.2014.10.015 25582974 \n2. Tomatsu S Yasuda E Patel P Ruhnke K Shimada T Mackenzie WG Mason R Thacker MM Theroux M Montaño AM Alméciga-Diaz CJ Barrera LA Chinen Y Sly WS Rowan D Suzuki Y Orii T Morquio A syndrome: diagnosis and current and future therapies Pediatr Endocrinol Rev 2014 12 Suppl 1 141 151 25345096 \n3. Hendriksz CJ Lavery C Coker M Ucar SK Jain M Bell L Lampe C Burden of disease in patients with Morquio A syndrome: results from an international patient-reported outcomes survey Orphanet J Rare Dis 2014 9 32 10.1186/1750-1172-9-32 24602160 \n4. Schrover R Evans K Giugliani R Noble I Bhattacharya K Minimal clinically important difference for the 6-min walk test: literature review and application to Morquio A syndrome Orphanet J Rare Dis 2017 12 78 10.1186/s13023-017-0633-1 28441951 \n5. Khan SA Peracha H Ballhausen D Wiesbauer A Rohrbach M Gautschi M Mason RW Giugliani R Suzuki Y Orii KE Orii T Tomatsu S Epidemiology of mucopolysaccharidoses Mol Genet Metab 2017 121 227 240 10.1016/j.ymgme.2017.05.016 28595941 \n6. Jezela-Stanek A Rozdzynska-Swiatkowska A Kulpanovich A Ciara E Marucha J Tylki-Szymanska A Novel data on growth phenotype and causative genotypes in 29 patients with Morquio (Morquio-Brailsford) syndrome from Central-Eastern Europe J Appl Genet 2019 60 163 174 10.1007/s13353-019-00491-1 30927141 \n7. Hendriksz CJ Berger KI Giugliani R Harmatz P Kampmann C Mackenzie WG Raiman J Villarreal MS Savarirayan R International guidelines for the management and treatment of Morquio A syndrome Am J Med Genet A 2015 167A 11 25 10.1002/ajmg.a.36833 25346323 \n8. Lavery C Hendriksz C Mortality in patients with Morquio syndrome A JIMD Rep 2015 15 59 66 24718838 \n9. Leadley RM Lang S Misso K Bekkering T Ross J Akiyama T Fietz M Giugliani R Hendriksz CJ Hock NL McGill J Olaye A Jain M Kleijnen J A systematic review of the prevalence of morquio A syndrome: challenges for study reporting in rare diseases Orphanet J Rare Dis 2014 9 173 10.1186/s13023-014-0173-x 25404155 \n10. Gadbois P Moreau J Laberge C Morquio's disease in the province of Quebec Union Med Can 1973 102 602 607 4268299 \n11. Casals F Hodgkinson A Hussin J Idaghdour Y Bruat V de Maillard T Grenier JC Gbeha E Hamdan FF Girard S Spinella JF Lariviere M Saillour V Healy J Fernandez I Sinnett D Michaud JL Rouleau GA Haddad E Le Deist F Awadalla P Whole-exome sequencing reveals a rapid change in the frequency of rare functional variants in a founding population of humans PLoS Genet 2013 9 e1003815 10.1371/journal.pgen.1003815 24086152 \n12. Health Canada. Summary basis of decision—Vimizim. https://hpr-rps.hres.ca/reg-content/summary-basis-decision-detailTwo.php?lang=en&linkID=SBD00199. Accessed July 2020.\n13. Hendriksz CJ Burton B Fleming TR Harmatz P Hughes D Jones SA Lin SP Mengel E Scarpa M Valayannopoulos V Giugliani R Slasor P Lounsbury D Dummer W STRIVE Investigators Efficacy and safety of enzyme replacement therapy with BMN 110 (elosulfase alfa) for Morquio A syndrome (mucopolysaccharidosis IVA): a phase 3 randomised placebo-controlled study J Inherit Metab Dis 2014 37 979 990 10.1007/s10545-014-9715-6 24810369 \n14. Hendriksz CJ Parini R AlSayed MD Raiman J Giugliani R Solano Villarreal ML Mitchell JJ Burton BK Guelbert N Stewart F Hughes DA Berger KI Slasor P Matousek R Jurecki E Shaywitz AJ Harmatz PR Long-term endurance and safety of elosulfase alfa enzyme replacement therapy in patients with Morquio A syndrome Mol Genet Metab 2016 119 131 143 10.1016/j.ymgme.2016.05.018 27380995 \n15. Hendriksz C Santra S Jones SA Geberhiwot T Jesaitis L Long B Qi Y Hawley SM Decker C Safety, immunogenicity, and clinical outcomes in patients with Morquio A syndrome participating in 2 sequential open-label studies of elosulfase alfa enzyme replacement therapy (MOR-002/MOR-100), representing 5 years of treatment Mol Genet Metab 2018 123 479 487 10.1016/j.ymgme.2018.02.011 29526614 \n16. McMillan HJ Campbell C We need a \"made in Canada\" orphan drug framework CMAJ 2017 189 E1274 E1275 10.1503/cmaj.170195 29038319 \n17. von Elm E Altman DG Egger M Pocock SJ Gotzsche PC Vandenbroucke JP The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies Bull World Health Organ 2007 85 867 872 10.2471/BLT.07.045120 18038077 \n18. Tomatsu S Montaño AM Nishioka T Gutierrez MA Peña OM Trandafirescu GG Lopez P Yamaguchi S Noguchi A Orii T Mutation and polymorphism spectrum of the GALNS gene in mucopolysaccharidosis IVA (Morquio A) Hum Mutat 2005 26 500 512 10.1002/humu.20257 16287098 \n19. https://apps.cpeg-gcep.net/quickZ_WHO. Accessed July 2020.\n20. Hendriksz CJ Parini R AlSayed M Raiman J Giugliani R Mitchell J Burton BK Guelbert N Stewart FJ Hughes DA Matousek R Hawley SM Decker C Harmatz PR Impact of long-term elosulfase alfa on activities of daily living in patients with morquio a syndrome in an open-label, multi-center, phase 3 extension study Mol Genet Metab 2018 123 127 134 10.1016/j.ymgme.2017.11.015 29248359 \n21. Harmatz P Mengel KE Giugliani R Valayannopoulos V Lin SP Parini R Guffon N Burton BK Hendriksz CJ Mitchell J Martins A Jones S Guelbert N Vellodi A Hollak C Slasor P Decker C The Morquio A Clinical Assessment Program: baseline results illustrating progressive, multisystemic clinical impairments in Morquio A subjects Mol Genet Metab 2013 109 54 61 10.1016/j.ymgme.2013.01.021 23452954 \n22. Burton BK Berger KI Lewis GD Tarnopolsky M Treadwell M Mitchell JJ Muschol N Jones SA Sutton VR Pastores GM Lau H Sparkes R Genter F Shaywitz AJ Harmatz P Safety and physiological effects of two different doses of elosulfase alfa in patients with Morquio A syndrome: a randomized, double-blind, pilot study Am J Med Genet A 2015 167A 2272 2281 10.1002/ajmg.a.37172 26069231 \n23. Montaño AM Tomatsu S Brusius A Smith M Orii T Growth charts for patients affected with Morquio A disease Am J Med Genet A 2008 146A 1286 1295 10.1002/ajmg.a.32281 18412124 \n24. Hughes D Giugliani R Guffon N Jones SA Mengel KE Parini R Matousek R Hawley SM Quartel A Clinical outcomes in a subpopulation of adults with Morquio A syndrome: results from a long-term extension study of elosulfase alfa Orphanet J Rare Dis 2017 12 98 10.1186/s13023-017-0634-0 28535791 \n25. Lammers AE Hislop AA Flynn Y Haworth SG The 6-minute walk test: normal values for children of 4–11 years of age Arch Dis Child 2008 93 464 468 10.1136/adc.2007.123653 17675356 \n26. Li AM Yin J Au JT So HK Tsang T Wong E Fok TF Ng PC Standard reference for the six-minute-walk test in healthy children aged 7 to 16 years Am J Respir Crit Care Med 2007 176 174 180 10.1164/rccm.200607-883OC 17463419 \n27. Clark LA, Campeau P, Danielson D, et al. Canadian expert opinion: recommendations for the use of elosulfase alfa in the management of Morquio A syndrome (MPS IVA) 2016. https://www.researchgate.net/publication/273058862_Canadian_expert_opinion_Recommendations_for_the_use_of_Elosulfase_alfa_in_the_management_of_Morquio_A_syndrome_MPS_IVA. Accessed July 2020.\n28. Akyol MU Alden TD Amartino H Ashworth J Belani K Berger KI Borgo A Braunlin E Eto Y Gold JI Jester A Jones SA Karsli C Mackenzie W Marinho DR McFadyen A McGill J Mitchell JJ Muenzer J Okuyama T Orchard PJ Stevens B Thomas S Walker R Wynn R Giugliani R Harmatz P Hendriksz C Scarpa M Committee MPSCPS, Co-Chairs MPSCP Recommendations for the management of MPS IVA: systematic evidence- and consensus-based guidance Orphanet J Rare Dis 2019 14 137 10.1186/s13023-019-1074-9 31196221 \n29. Casanova C Celli BR Barria P Casas A Cote C de Torres JP Jardim J Lopez MV Marin JM Montes de Oca M Pinto-Plata V Aguirre-Jaime A Six Minute Walk Distance Project (ALAT) The 6-min walk distance in healthy subjects: reference standards from seven countries Eur Respir J 2011 37 150 156 10.1183/09031936.00194909 20525717\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1750-1172",
"issue": "15(1)",
"journal": "Orphanet journal of rare diseases",
"keywords": "Activities of daily living; Canada; Founder effects; Genetic disorders; Mucopolysaccharidosis IVA; Walk test",
"medline_ta": "Orphanet J Rare Dis",
"mesh_terms": "D000203:Activities of Daily Living; D002170:Canada; D006801:Humans; D009085:Mucopolysaccharidosis IV; D011792:Quebec; D012189:Retrospective Studies",
"nlm_unique_id": "101266602",
"other_id": null,
"pages": "270",
"pmc": null,
"pmid": "32993725",
"pubdate": "2020-09-29",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": "29248359;30927141;25346323;29526614;28441951;4268299;27380995;29038319;24602160;24718838;17675356;28535791;16287098;20525717;26069231;25404155;31196221;23452954;25345096;24810369;25582974;18412124;24086152;28595941;18038077;17463419",
"title": "Clinical characteristics of patients from Quebec, Canada, with Morquio A syndrome: a longitudinal observational study.",
"title_normalized": "clinical characteristics of patients from quebec canada with morquio a syndrome a longitudinal observational study"
} | [
{
"companynumb": "CA-BIOMARINAP-CA-2020-133035",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ELOSULFASE ALFA"
},
"drugadditional": "3",... |
{
"abstract": "BACKGROUND\nThe number of young women who wish to become pregnant opting for kidney transplants is increasing, as becoming pregnant under hemodialysis or peritoneal dialysis is associated with many risks. However, there have been reports indicating that these patients are subject to a higher risk of miscarriage compared to women with normal renal function. We examine and report cases of patients that experienced pregnancy after undergoing kidney transplantation at our hospital.\n\n\nMETHODS\nOf the kidney transplantation cases that were performed at our hospital between 1985 and 2016, there were 7 cases of pregnancy. The serum creatinine levels, urine protein findings, etc, of these 7 cases were examined during the pre-pregnancy, pregnancy, childbirth, and postpartum periods.\n\n\nRESULTS\nAll 7 cases were able to give birth. There were two cases of transient postpartum hypertension. There were no cases of obvious pregnancy toxemia or fetal growth retardation. Two of the cases resulted in the failure of the transplanted kidneys.\n\n\nCONCLUSIONS\nAccording to previous studies on pregnancy and childbirth after kidney transplantation, the presence of high blood pressure and proteinuria as well as the renal function at the time of pregnancy is closely associated with postpartum renal function. Urine protein was detected prior to pregnancy in both cases and resulted in the failure of the transplanted kidneys. The influence of immunosuppressants on the mother and fetus is also an important consideration.\n\n\nCONCLUSIONS\nWe believe it is extremely important to ensure a thorough informed consent process prior to pregnancy and systematic use of immunosuppressants for young female transplant recipients.",
"affiliations": "Department of Kidney Transplantation Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan. Electronic address: yukihara7@hotmail.co.jp.;Department of Kidney Transplantation Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.;Department of Kidney Transplantation Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.;Department of Kidney Transplantation Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.;Department of Kidney Transplantation Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.;Department of Kidney Transplantation Surgery, Hachioji Medical Center, Tokyo Medical University, Tokyo, Japan.",
"authors": "Kihara|Y|Y|;Konno|O|O|;Yokoyama|T|T|;Nakamura|Y|Y|;Ueno|T|T|;Iwamoto|H|H|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.03.081",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(8)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2531-2534",
"pmc": null,
"pmid": "30316392",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An Examination of Pregnancy Cases After Kidney Transplantation: Single-Center Experience.",
"title_normalized": "an examination of pregnancy cases after kidney transplantation single center experience"
} | [
{
"companynumb": "PHHY2018JP169741",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe safe and effective methods of fetal anesthesia/analgesia during ultrasound guided direct fetal procedure are yet to be determined. The authors investigated whether maternal diazepam/fentanyl administration meets this purpose.\n\n\nMETHODS\nThe medical/anesthesia records were retrospectively reviewed in cases between 2001 and 2010 at a tertiary perinatal center. Success rate as well as maternal and fetal complications were analysed.\n\n\nRESULTS\nAmong the 150 procedures in 118 fetuses, diazepam 10 mg and fentanyl 200 µg sufficiently prevented fetal movement upon the procedure in 56% of the procedures. Supplemental anesthetic agents such as nitrous oxide and propofol were needed in other cases. No serious maternal complication was noted, while fetal cardiac arrest/severe bradycardia was noted in three fetuses, one of which was successfully resuscitated by intracardiac adrenalin injection.\n\n\nCONCLUSIONS\nMaternal diiazepam/fentanyl administration offered adequate fetal condition without significant maternal complications. Since these procedures are performed to treat severe fetal conditions, preparation for fetal resuscitation is also important.",
"affiliations": "Department of Anesthesiology, Kyorin University School of Medicine, Shinkawa, Mitaka, Japan.",
"authors": "Ohashi|Yuki|Y|;Terui|Katsuo|K|;Tamura|Kazumi|K|;Tanaka|Motoshi|M|;Baba|Kazunori|K|",
"chemical_list": "D000701:Analgesics, Opioid; D006993:Hypnotics and Sedatives; D003975:Diazepam; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.3109/14767058.2012.722733",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1476-4954",
"issue": "26(2)",
"journal": "The journal of maternal-fetal & neonatal medicine : the official journal of the European Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstetricians",
"keywords": null,
"medline_ta": "J Matern Fetal Neonatal Med",
"mesh_terms": "D061605:Administration, Intravenous; D000701:Analgesics, Opioid; D000758:Anesthesia; D003975:Diazepam; D005260:Female; D005283:Fentanyl; D046128:Fetal Therapies; D006801:Humans; D006993:Hypnotics and Sedatives; D011247:Pregnancy; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "101136916",
"other_id": null,
"pages": "158-60",
"pmc": null,
"pmid": "22928538",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Success rate and challenges of fetal anesthesia for ultrasound guided fetal intervention by maternal opioid and benzodiazepine administration.",
"title_normalized": "success rate and challenges of fetal anesthesia for ultrasound guided fetal intervention by maternal opioid and benzodiazepine administration"
} | [
{
"companynumb": "PHHY2013JP039019",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": null,
"drugad... |
{
"abstract": "Computed tomography (CT) is used for staging osteolytic lesions and detecting fractures in patients with multiple myeloma (MM). In the OsteoLysis of Metastases and Plasmacell-infiltration Computed Tomography 2 study (OLyMP-CT) study we investigated whether patients with and without vertebral fractures show differences in bone mineral density (BMD) or microstructure that could be used to identify patients at risk for fracture. We evaluated whole-body CT scans in a group of 104 MM patients without visible osteolytic lesions using an underlying lightweight calibration phantom (Image Analysis Inc., Columbia, KY, USA). QCT software (StructuralInsight) was used for the assessment of BMD and bone structure of the T11 or T12 vertebral body. Age-adjusted standardized odds ratios (sORs) per SD change were derived from logistic regression analyses, and areas under the receiver operating characteristics (ROC) curve (AUCs) analyses were calculated. Forty-six of the 104 patients had prevalent vertebral fractures (24/60 men, 22/44 women). Patients with fractures were not significantly older than patients without fractures (mean ± SD, 64 ± 9.2 versus 62 ± 12.3 years; p = 0.4). Trabecular BMD in patients with fractures versus without fractures was 169 ± 41 versus 192 ± 51 mg/cc (AUC = 0.62 ± 0.06, sOR = 1.6 [1.1 to 2.5], p = 0.02). Microstructural variables achieved optimal discriminatory power at bone thresholds of 150 mg/cc. Best fracture discrimination for single microstructural variables was observed for trabecular separation (Tb.Sp) (AUC = 0.72 ± 0.05, sOR = 2.4 (1.5 to 3.9), p < 0.0001). In multivariate models AUCs improved to 0.77 ± 0.05 for BMD and Tb.Sp, and 0.79 ± 0.05 for Tb.Sp and trabecular thickness (Tb.Th). Compared to BMD values, these improvements of AUC values were statistically significant (p < 0.0001). In MM patients, QCT-based analyses of bone structure derived from routine CT scans permit discrimination of patients with and without vertebral fractures. Rarefaction of the trabecular network due to plasma cell infiltration and osteoporosis can be measured. Deterioration of microstructural measures appear to be of value for vertebral fracture risk assessment and may indicate early stages of osteolytic processes not yet visible.",
"affiliations": "Section for Biomedical Imaging, Department of Radiology and Neuroradiology, University-Clinics Schleswig Holstein, Campus Kiel, Kiel, Germany.;Section for Biomedical Imaging, Department of Radiology and Neuroradiology, University-Clinics Schleswig Holstein, Campus Kiel, Kiel, Germany.;Section for Biomedical Imaging, Department of Radiology and Neuroradiology, University-Clinics Schleswig Holstein, Campus Kiel, Kiel, Germany.;Section for Biomedical Imaging, Department of Radiology and Neuroradiology, University-Clinics Schleswig Holstein, Campus Kiel, Kiel, Germany.;Section for Biomedical Imaging, Department of Radiology and Neuroradiology, University-Clinics Schleswig Holstein, Campus Kiel, Kiel, Germany.;Section for Biomedical Imaging, Department of Radiology and Neuroradiology, University-Clinics Schleswig Holstein, Campus Kiel, Kiel, Germany.;Section for Immun- and Stemcell- Therapy, Department of Inner Medicine, University-Clinics Schleswig Holstein, Campus Kiel, Kiel, Germany.;Section for Biomedical Imaging, Department of Radiology and Neuroradiology, University-Clinics Schleswig Holstein, Campus Kiel, Kiel, Germany.;Section for Biomedical Imaging, Department of Radiology and Neuroradiology, University-Clinics Schleswig Holstein, Campus Kiel, Kiel, Germany.",
"authors": "Borggrefe|Jan|J|;Giravent|Sarah|S|;Thomsen|Felix|F|;Peña|Jaime|J|;Campbell|Graeme|G|;Wulff|Asmus|A|;Günther|Andreas|A|;Heller|Martin|M|;Glüer|Claus C|CC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/jbmr.2443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-0431",
"issue": "30(7)",
"journal": "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research",
"keywords": "BMD; FRACTURE RISK; MULTIPLE MYELOMA; OSTEOPOROSIS; QCT; TRABECULAR SEPARATION; VERTEBRAL FRACTURE",
"medline_ta": "J Bone Miner Res",
"mesh_terms": "D019540:Area Under Curve; D015519:Bone Density; D001842:Bone and Bones; D016022:Case-Control Studies; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D016017:Odds Ratio; D016103:Spinal Fractures; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8610640",
"other_id": null,
"pages": "1329-37",
"pmc": null,
"pmid": "25545497",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Association of QCT Bone Mineral Density and Bone Structure With Vertebral Fractures in Patients With Multiple Myeloma.",
"title_normalized": "association of qct bone mineral density and bone structure with vertebral fractures in patients with multiple myeloma"
} | [
{
"companynumb": "DE-CELGENE-DEU-2015074299",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nStem-cell transplantation can cure primary immunodeficiencies. However, in patients with pre-existing organ toxicity, patients younger than 1 year, and those with DNA or telomere repair disorders, chemotherapy-based conditioning is poorly tolerated and results in major morbidity and mortality. We tested a novel antibody-based minimal-intensity conditioning (MIC) regimen to assess whether this approach allowed curative donor stem-cell engraftment without non-haemopoietic toxicity.\n\n\nMETHODS\n16 high-risk patients underwent stem-cell transplantation for primary immunodeficiencies with an MIC regimen consisting of two rat anti-CD45 monoclonal antibodies YTH 24.5 and YTH 54.12 for myelosuppression, and alemtuzumab (anti-CD52) and fludarabine, and low dose cyclophosphamide for immunosuppression. Donors were matched siblings (n=5), and matched (9) and mismatched (2) unrelated donors.\n\n\nRESULTS\nAntibody-based conditioning was well tolerated, with only two cases of grade 3 and no grade 4 toxicity. Rates of clinically significant acute (n=6, 36%) and chronic graft-versus-host disease (GVHD) (n=5, 31%) were acceptable. 15 of 16 patients (94%) engrafted, of whom 11 (69%) achieved full or high-level mixed chimerism in both lymphoid and myeloid lineages, and three achieved engraftment in the T-lymphoid lineage only. One patient needed retransplantation. At a median of 40 months post-transplant, 13 of 16 patients (81%) in this high-risk cohort were alive and cured from their underlying disease.\n\n\nCONCLUSIONS\nMonoclonal antibody-based conditioning seems well tolerated and can achieve curative engraftment even in patients with severe organ toxicity or DNA repair defects, or both. This novel approach represents a shift from the paradigm that intensive chemotherapy or radiotherapy, or both, is needed for donor stem-cell engraftment. This antibody-based conditioning regimen may reduce toxicity and late effects and enable SCT in virtually any primary immunodeficiency patient with a matched donor.\n\n\nBACKGROUND\nNone.",
"affiliations": "Great Ormond Street Children's Hospital, London, UK.",
"authors": "Straathof|Karin C|KC|;Rao|Kanchan|K|;Eyrich|Matthias|M|;Hale|Geoff|G|;Bird|Prudence|P|;Berrie|Eleanor|E|;Brown|Lucinda|L|;Adams|Stuart|S|;Schlegel|Paul G|PG|;Goulden|Nicholas|N|;Gaspar|H Bobby|HB|;Gennery|Andrew R|AR|;Landais|Paul|P|;Davies|E G|EG|;Brenner|Malcolm K|MK|;Veys|Paul A|PA|;Amrolia|Persis Jal|PJ|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000074323:Alemtuzumab; D003520:Cyclophosphamide; D017493:Leukocyte Common Antigens; D014740:Vidarabine; C024352:fludarabine",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(09)60945-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "374(9693)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000074323:Alemtuzumab; D000818:Animals; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000912:Antibodies, Neoplasm; D002675:Child, Preschool; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D007223:Infant; D053208:Kaplan-Meier Estimate; D017493:Leukocyte Common Antigens; D008297:Male; D051381:Rats; D018183:Transplantation Chimera; D019172:Transplantation Conditioning; D016896:Treatment Outcome; D014740:Vidarabine",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "912-20",
"pmc": null,
"pmid": "19729196",
"pubdate": "2009-09-12",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1/2 study.",
"title_normalized": "haemopoietic stem cell transplantation with antibody based minimal intensity conditioning a phase 1 2 study"
} | [
{
"companynumb": "GB-PFIZER INC-2021173953",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "A child with rheumatic carditis developed acute renal failure due to renal papillary necrosis while receiving a short course of aspirin treatment. It is suggested that in this child the aspirin therapy predisposed the renal medulla to hypoxic damage induced by the carditis and congestive heart failure. It is therefore recommended that children receiving aspirin or other nonsteroidal anti-inflammatory drugs, even for a short time, be closely observed and the drug discontinued of hypoxia is evident. Moreover, during illnesses tending to cause hypoxia such as carditis, aspirin or other nonsteroidal anti-inflammatory drugs are best avoided since they are additional risk factors for renal damage.",
"affiliations": "Division of Pediatrics A, Soroka Medical Center, Beer Sheva, Israel.",
"authors": "Gradus|D B|DB|;Zuker|N|N|;Barki|Y|Y|",
"chemical_list": "D001241:Aspirin",
"country": "Israel",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-2180",
"issue": "25(4)",
"journal": "Israel journal of medical sciences",
"keywords": null,
"medline_ta": "Isr J Med Sci",
"mesh_terms": "D001241:Aspirin; D002648:Child; D006801:Humans; D007681:Kidney Papillary Necrosis; D008297:Male; D009205:Myocarditis; D012214:Rheumatic Heart Disease; D012307:Risk Factors",
"nlm_unique_id": "0013105",
"other_id": null,
"pages": "196-8",
"pmc": null,
"pmid": "2708025",
"pubdate": "1989-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal papillary necrosis in a child with rheumatic carditis treated with aspirin.",
"title_normalized": "renal papillary necrosis in a child with rheumatic carditis treated with aspirin"
} | [
{
"companynumb": "IL-BAYER-RCH-347780",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": "1",
"druga... |
{
"abstract": "BACKGROUND\nThere is limited knowledge of the genetic alterations in acral melanoma metastases at different anatomic sites. Here, we characterized the genetic abnormalities of metastases in a 51-year-old man with stage IIIC heel melanoma who developed concomitant brain and cutaneous metastases in spite of multiple treatment modalities.\n\n\nMETHODS\nMelanoma cells were isolated following palliative resection of the patient's cortical tumor and biopsy of cutaneous thigh metastasis. Mutational analysis using polymerase chain reaction amplification and BLAST, as well as exome sequencing (160 Mb coverage) was performed on the tumors, cell lines generated thereof and normal lymph nodes.\n\n\nRESULTS\nAll specimens had neuroblastoma RAS viral oncogene homolog Q61K mutations. There was a 40-fold higher somatic mutation frequency in the brain metastasis compared to the cutaneous metastasis. The former showed truncations of DNA mismatch repair genes (MLH1 and MSH2), and non-canonical BRAF (v-raf murine sarcoma viral oncogene homolog B1), PIK3CA and NF-1 mutations not observed in the extracranial lesion. Genomic profiling of each cell line was concordant with the respective original tumor tissue.\n\n\nCONCLUSIONS\nWe present the mutational differences between brain and cutaneous acral melanoma metastases in a patient with concomitant lesions. Further genetic and functional studies are needed to understand the biology of metastatic disease appearing at different sites.",
"affiliations": "Division of Surgical Oncology, Department of Surgery, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.;Program of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.;Program of Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.;Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.;Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.;Broad Institute of the Massachusetts Institute of Technology (MIT) and Harvard University, Cambridge, MA, USA.;Division of Surgical Oncology, Department of Surgery, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.;Division of Surgical Oncology, Department of Surgery, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA. chyoon@partners.org.;Division of Surgical Oncology, Department of Surgery, Dana-Farber/Brigham and Women's Cancer Center, Harvard Medical School, Boston, MA, USA.",
"authors": "Sharma|Gaurav|G|;Lian|Christine G|CG|;Lin|William M|WM|;Amin-Mansour|Ali|A|;Jané-Valbuena|Judit|J|;Garraway|Levi|L|;Bao|Wendi|W|;Yoon|Charles H|CH|;Ibrahim|Nageatte|N|",
"chemical_list": "C501486:MLH1 protein, human; D025542:Neurofibromin 1; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D016283:Proto-Oncogene Proteins p21(ras)",
"country": "United States",
"delete": false,
"doi": "10.1111/cup.12746",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-6987",
"issue": "43(10)",
"journal": "Journal of cutaneous pathology",
"keywords": "NRAS; acral melanoma; brain metastases; cutaneous metastases; mismatch repair genes",
"medline_ta": "J Cutan Pathol",
"mesh_terms": "D001706:Biopsy; D001932:Brain Neoplasms; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009362:Neoplasm Metastasis; D025542:Neurofibromin 1; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D012878:Skin Neoplasms",
"nlm_unique_id": "0425124",
"other_id": null,
"pages": "884-91",
"pmc": null,
"pmid": "27251777",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
"references": "12173339;15009714;15161053;15488754;16291983;16619000;16911282;17931798;18245465;18546366;19182786;20179022;21205303;21221095;21472718;21803805;22183965;22578220;22817889;23362874;23396013;23770567;23945592;23993026;24803579;24913711;25265492;26027431;26091043;26112808;26410082;8823767;9128946",
"title": "Distinct genetic profiles of extracranial and intracranial acral melanoma metastases.",
"title_normalized": "distinct genetic profiles of extracranial and intracranial acral melanoma metastases"
} | [
{
"companynumb": "PHHY2016US091571",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PANOBINOSTAT"
},
"drugadditional": null,
"dr... |
{
"abstract": "To investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).\n\n\n\nIn a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.\n\n\n\nLD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.\n\n\n\nA rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.",
"affiliations": "Pediatrics, Stanford University, Stanford, California, USA.;Institute for Immunity, Transplantation and Infection, Center for Biomedical Informatics Research, Medicine, Stanford University, Stanford, California, USA.;Pathology, Seattle Children's Hospital, Seattle, Washington, USA.;Radiology, Baylor College of Medicine, Houston, Texas, USA.;Genetics, Stanford University, Stanford, California, USA.;Genetics, Stanford University, Stanford, California, USA.;Pediatrics, Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.;Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.;Children's Hospital Colorado, Aurora, Colorado, USA.;Pediatrics, Stanford University, Stanford, California, USA.;Radiology, Stanford University, Stanford, California, USA.;Public Health Services, Biostatistics, University of Miami School of Medicine, Miami, Florida, USA.;Helen DeVos Children's Hospital, Grand Rapids, Michigan, USA.;Pediatrics, Washington University in Saint Louis, Saint Louis, Missouri, USA.;Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.;Medicine, Metro Health Hospital, Wyoming, Michigan, USA.;Boston Children's Hospital, Boston, Massachusetts, USA.;Pediatrics, Children's Hospital of Los Angeles, Los Angeles, California, USA.;Children's of Alabama, Birmingham, Alabama, USA.;Pediatrics, Columbia University Medical Center, New York, New York, USA.;Rheumatology, Ospedale Pediatrico Bambino Gesu, Roma, Italy.;Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.;Boston Children's Hospital, Boston, Massachusetts, USA.;Arthritis Associates of South Florida, Delray Beach, Florida, USA.;Pediatrics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.;Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.;Joseph M Sanzari Children's Hospital, Hackensack, New Jersey, USA.;Boston Children's Hospital, Boston, Massachusetts, USA.;Boston Children's Hospital, Boston, Massachusetts, USA.;Pediatrics, Prince of Wales Hospital, New Territories, Hong Kong.;Children's Mercy Hospitals and Clinics, Kansas City, Missouri, USA.;Pediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.;Children's Hospital of Georgia, Augusta, Georgia, USA.;Pediatrics, Al Mafraq Hospital, Abu Dhabi, Abu Dhabi, United Arab Emirates.;Randall Children's Hospital at Legacy Emanuel, Portland, Oregon, USA.;Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.;Pediatrics, University of Utah Health Sciences Center, Salt Lake City, Utah, USA.;Joseph M Sanzari Children's Hospital, Hackensack, New Jersey, USA.;Children's Hospital Colorado, Aurora, Colorado, USA.;Children's Hospital at Montefiore, Bronx, New York, USA.;Children's Hospital Colorado, Aurora, Colorado, USA.;Johns Hopkins All Children's Hospital, Saint Petersburg, Florida, USA.;Pediatrics, Kaiser Permanente Roseville Medical Center, Roseville, California, USA.;Pediatrics, Hospital for Special Surgery, New York, New York, USA.;Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Cook Children's Medical Center, Fort Worth, Texas, USA.;Akron Children's Hospital, Akron, Ohio, USA.;Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.;Rady Children's Hospital, San Diego, California, USA.;Pediatrics, University of Nebraska Medical Center College of Medicine, Omaha, Nebraska, USA.;Pediatrics, University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota, USA.;Pediatrics, Hospital for Special Surgery, New York, New York, USA.;Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.;Hospital for Sick Children, Toronto, Ontario, Canada.;Emma Children's Hospital AMC, Amsterdam, The Netherlands.;University of Washington School of Medicine, Seattle, Washington, USA.;Pediatrics, University of Wisconsin Madison School of Medicine and Public Health, Madison, Wisconsin, USA.;Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.;Children's of Alabama, Birmingham, Alabama, USA.;Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.;Harvard Medical School, Boston, Massachusetts, USA.;Pediatrics, University of Minnesota Medical School Twin Cities, Minneapolis, Minnesota, USA.;Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.;Institute for Immunity, Transplantation and Infection, Center for Biomedical Informatics Research, Medicine, Stanford University, Stanford, California, USA.;Medicine, Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, California, USA.;Public Health Services, Biostatistics, University of Miami School of Medicine, Miami, Florida, USA.;Biomedical Data Science, Stanford University, Stanford, California, USA.;Biomedical Data Science, Stanford University, Stanford, California, USA.;Genetics, Stanford University, Stanford, California, USA.;Institute for Immunity, Transplantation and Infection, Microbiology and Immunology, Stanford University, Stanford, California, USA.;Institute for Immunity, Transplantation and Infection, Center for Biomedical Informatics Research, Medicine, Stanford University, Stanford, California, USA.;Pediatrics, Stanford University, Stanford, California, USA mellins@stanford.edu.",
"authors": "Saper|Vivian E|VE|;Chen|Guangbo|G|;Deutsch|Gail H|GH|;Guillerman|R Paul|RP|;Birgmeier|Johannes|J|;Jagadeesh|Karthik|K|;Canna|Scott|S|;Schulert|Grant|G|;Deterding|Robin|R|;Xu|Jianpeng|J|;Leung|Ann N|AN|;Bouzoubaa|Layla|L|;Abulaban|Khalid|K|;Baszis|Kevin|K|;Behrens|Edward M|EM|;Birmingham|James|J|;Casey|Alicia|A|;Cidon|Michal|M|;Cron|Randy Q|RQ|;De|Aliva|A|;De Benedetti|Fabrizio|F|;Ferguson|Ian|I|;Fishman|Martha P|MP|;Goodman|Steven I|SI|;Graham|T Brent|TB|;Grom|Alexei A|AA|;Haines|Kathleen|K|;Hazen|Melissa|M|;Henderson|Lauren A|LA|;Ho|Assunta|A|;Ibarra|Maria|M|;Inman|Christi J|CJ|;Jerath|Rita|R|;Khawaja|Khulood|K|;Kingsbury|Daniel J|DJ|;Klein-Gitelman|Marisa|M|;Lai|Khanh|K|;Lapidus|Sivia|S|;Lin|Clara|C|;Lin|Jenny|J|;Liptzin|Deborah R|DR|;Milojevic|Diana|D|;Mombourquette|Joy|J|;Onel|Karen|K|;Ozen|Seza|S|;Perez|Maria|M|;Phillippi|Kathryn|K|;Prahalad|Sampath|S|;Radhakrishna|Suhas|S|;Reinhardt|Adam|A|;Riskalla|Mona|M|;Rosenwasser|Natalie|N|;Roth|Johannes|J|;Schneider|Rayfel|R|;Schonenberg-Meinema|Dieneke|D|;Shenoi|Susan|S|;Smith|Judith A|JA|;Sönmez|Hafize Emine|HE|;Stoll|Matthew L|ML|;Towe|Christopher|C|;Vargas|Sara O|SO|;Vehe|Richard K|RK|;Young|Lisa R|LR|;Yang|Jacqueline|J|;Desai|Tushar|T|;Balise|Raymond|R|;Lu|Ying|Y|;Tian|Lu|L|;Bejerano|Gill|G|;Davis|Mark M|MM|;Khatri|Purvesh|P|;Mellins|Elizabeth D|ED|0000-0003-2577-139X;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/annrheumdis-2019-216040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4967",
"issue": "78(12)",
"journal": "Annals of the rheumatic diseases",
"keywords": "DMARDs (biologic); adult onset still's disease; inflammation; juvenile idiopathic arthritis; treatment",
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D001171:Arthritis, Juvenile; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007223:Infant; D008168:Lung; D008171:Lung Diseases; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D014057:Tomography, X-Ray Computed; D014481:United States",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "1722-1731",
"pmc": null,
"pmid": "31562126",
"pubdate": "2019-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "29093484;25047945;31419311;29494731;30587248;26160873;14613283;19220077;21280009;18085671;25103284;29092853;7028379;29373737;27307527;15062595;19586803;30848528;18085728;9455875;20617213;26282180;30326612;1387414;22820514;26034148;30652265;27332999;23322471;27799155;21205713;25077692;27699580;18955570;23139240;25421226;22290637;20609861;28416023;31379071;18024538;23625987;23855313;17885266;19148933;25913036;11596165;17287477;8570301;21540304;24982109;9694696;21415192;21352207;20042763;23252526;12119235;25009050;22550210;1747143;18955567;183578;30104171;23252525;27931082;23166334;22367785;15520901;23723976;23886500;25437959;22802353;25954001;8947094;29484482;23462434;24929266;27472698;16916345;1409138",
"title": "Emergent high fatality lung disease in systemic juvenile arthritis.",
"title_normalized": "emergent high fatality lung disease in systemic juvenile arthritis"
} | [
{
"companynumb": "PHEH2018US014769",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Pediatric patients with end-stage renal failure due to severe drug-resistant nephrotic syndrome are at risk of rapid recurrence after renal transplantation. Treatment options include plasmapheresis, high-dose of cyclosporine A/methylprednisolone and more recently-rituximab (anti-B CD20 monoclonal depleting antibody). We report five patients with immediate (1-2 days) post-transplant recurrence of nephrotic syndrome, treated with this kind of combined therapy including 2-4 weekly doses of 375 mg/m(2) of rituximab. Only two (of five) patients have showed full long-term remission, while the partial remission was seen in two cases, and no clinical effect at all was achieved in one patient. The correlation between B CD19 cells depletion and clinical effect was present in two cases only. Severe adverse events were present in two patients, including one fatal rituximab-related acute lung injury.\n\n\nCONCLUSIONS\nThe anti-CD20 monoclonal antibody may be not effective in all pediatric cases of rapid post-transplant recurrence of nephrotic syndrome, and benefit/risk ratio must be carefully balanced on individual basis before taking the decision to use this protocol.\n\n\nBACKGROUND\n• nephrotic syndrome may recur immediately after renal transplantation • plasmapheresis combined with pharmacotherapy is used as rescue management • rituximab was reported as effective drug both in primary and post-transplant nephrotic syndrome What is New: • rituximab may not be effective is several cases of post-transplant nephrotic syndrome due to variety of underlying mechanisms of the disease, which may be or not be responsive to this drug • there may be no correlation between drug-induced depletion of specific B cells and clinical effect; this might suggest B-cell independent manner of rituximab action.",
"affiliations": "Department of Nephrology, Kidney Transplantation & Hypertension, The Children's Memorial Health Institute, Warsaw, Poland. r.grenda@czd.pl.;Department of Nephrology, Kidney Transplantation & Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Nephrology, Kidney Transplantation & Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.;Histocompatibility Lab, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Nephrology, Kidney Transplantation & Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.",
"authors": "Grenda|Ryszard|R|;Jarmużek|Wioletta|W|;Rubik|Jacek|J|;Piątosa|Barbara|B|;Prokurat|Sylwester|S|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00431-016-2747-1",
"fulltext": "\n==== Front\nEur J PediatrEur. J. PediatrEuropean Journal of Pediatrics0340-61991432-1076Springer Berlin Heidelberg Berlin/Heidelberg 274710.1007/s00431-016-2747-1Original ArticleRituximab is not a “magic drug” in post-transplant recurrence of nephrotic syndrome Grenda Ryszard r.grenda@czd.pl 1Jarmużek Wioletta w.jarmuzek@czd.pl 1Rubik Jacek j.rubik@czd.pl 1Piątosa Barbara b.piatosa@czd.pl 2Prokurat Sylwester s.prokurat@czd.pl 11 Department of Nephrology, Kidney Transplantation & Hypertension, The Children’s Memorial Health Institute, Warsaw, Poland 2 Histocompatibility Lab, The Children’s Memorial Health Institute, Warsaw, Poland Communicated by Mario Bianchetti\n\n30 6 2016 30 6 2016 2016 175 9 1133 1137 4 4 2016 12 6 2016 15 6 2016 © The Author(s) 2016\nOpen Access This 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.Pediatric patients with end-stage renal failure due to severe drug-resistant nephrotic syndrome are at risk of rapid recurrence after renal transplantation. Treatment options include plasmapheresis, high-dose of cyclosporine A/methylprednisolone and more recently—rituximab (anti-B CD20 monoclonal depleting antibody). We report five patients with immediate (1–2 days) post-transplant recurrence of nephrotic syndrome, treated with this kind of combined therapy including 2–4 weekly doses of 375 mg/m2 of rituximab. Only two (of five) patients have showed full long-term remission, while the partial remission was seen in two cases, and no clinical effect at all was achieved in one patient. The correlation between B CD19 cells depletion and clinical effect was present in two cases only. Severe adverse events were present in two patients, including one fatal rituximab-related acute lung injury.\n\nConclusion: The anti-CD20 monoclonal antibody may be not effective in all pediatric cases of rapid post-transplant recurrence of nephrotic syndrome, and benefit/risk ratio must be carefully balanced on individual basis before taking the decision to use this protocol.\nWhat is Known:\n\n• nephrotic syndrome may recur immediately after renal transplantation\n\n• plasmapheresis combined with pharmacotherapy is used as rescue management\n\n• rituximab was reported as effective drug both in primary and post-transplant nephrotic syndrome\n\t\n\nWhat is New:\n\n• rituximab may not be effective is several cases of post-transplant nephrotic syndrome due to variety of underlying mechanisms of the disease, which may be or not be responsive to this drug\n\n• there may be no correlation between drug-induced depletion of specific B cells and clinical effect; this might suggest B-cell independent manner of rituximab action\n\t\n\n\nKeywords\nNephrotic syndromeRenal transplantationRapid recurrenceRituximabissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2016\n==== Body\nIntroduction\nThe recurrence of primary renal disease after renal transplantation is a risk factor of inferior outcome [23]. Drug-resistant nephrotic syndrome leading to end-stage renal failure is one the most aggresive glomerular diseases recurring after renal transplanation [1]. Immediate recurrence suggests the role of preformed and circulating protein permeability factor(s), which bind to specific targets in transplanted kidney. Identification of responsible factor(s) is an ongoing subject of clinical investigations for years, and several hypotheses have been raised, including protein permeability factor suggested by Savin’s group [21], soluble urokinase type plasminogen activator receptor (suPAR) [24], cardiothropin-like cytokine 1(CLC-1) [13], and anti-CD40 antibody [4]. The hypothesis of circulating factor(s)-related mechanism of post-transplant recurrence of nephrotic syndrome is translated into therapeutic protocols, including plasmapheresis (to remove the factor(s)) [17, 18], corticosteroids (to stabilize the cytoskeleton of podocytes and reduce podocytes apoptosis) [19], cyclosporine A (to stabilize the cytoskeleton of podocytes) [5], and rituximab (monoclonal antibody depleting B CD20 cells) to deplete the cytokines-producers [7, 15]. There are conflicting data on efficacy of rituximab used for treatment of post-transplant recurrence of nephrotic syndrome in adult and pediatric patients. The purpose of our study was to present the summary of our experience with the efficacy and safety of rituximab in five children after first renal transplantation, who presented rapid recurrence of nephrotic syndrome.\n\nPatients and methods\nA retrospective chart review was performed and included five children at the age from 5 to 12 years (at the day of renal transplantation), who presented immediate (day 1 or 2) recurrence of nephrotic syndrome (NS) post-transplant. The criterion of chart selection was the use of rituximab for the treatment of NS recurrence after transplantation. The drug-resistant nephrotic syndrome was the underlying cause of end-stage renal disease. Focal segmental glomerulosclerosis (FSGS) was present in native renal biopsy in two patients, mesangial-proliferative glomerulonephritis (MesPGN) in two, and minimal change nephrotic syndrome (MCNS) in one case. One patient had confirmed heterozygous podocine (NPHS2) genetic mutation (p.R229Q). There was 3 to 8 years interval between introducing dialysis and primary renal transplantation. There were four deceased donor-related and one living-related transplantation performed, the last one in a patient with genetic podocine mutation (patient’s father was a donor). All patients received triple immunosuppression (CsA + MMF + Pred). All five demonstrated immediate recurrence of nephrotic syndrome (four on the day 1 and one on the second day post-transplant), with gross proteinuria and oliguria. Plasmapheresis was introduced in all five patients, and in four cases, rituximab was directly added to the protocol at the dose of 375 mg/m2 on weekly basis. In one case, the introduction of rituximab was delayed due to primary promising effect of plasmapheresis; however, once the patient became plasmapheresis-dependent, the drug was added during fourth month post-transplant [8]. Four patients received four weekly doses, and in one case the drug administration was limited to two doses due to severe relapsing infections The count of B CD19 cells was monitored on weekly and then monthly basis by flow cytometry. The clinical characteristics and treatment course in summarized in Table 1. The complete remission was achieved in two patients (no. 1 and no. 3), with complete depletion of B CD19 for up to 4 and 2 months (after last dose of rituximab), respectively, and with no adverse drug-related adverse events. The remission was sustained within 7 and 5 years of follow-up, respectively, with no specific treatment beyond standard triple immunosuppression (CsA + MMF + Pred). Only partial remission (significant, however floating proteinuria; from 0.4 to 3.5 g and from 0.5 to 2.0 g/24 hours; respectively) was seen in two cases (no. 4 and no. 5), presenting complete B CD19 depletion up to 7 and 4 months after treatment, respectively. Serious adverse events were present in these two cases, including relapsing severe infections (blood culture was positive for Klebsiella pneumoniae) (case no. 4), which limited the number of scheduled rituximab doses to 2 and severe acute lung injury (RALI) (case no. 5). Patient no. 4 lost the graft 2.5 years after transplantation due to chronic nephropathy. Patient no. 5 died due to non-infectious rapid lung fibrosis. There was no therapeutic effect at all in the case no. 2, who was also finally given oral galactose; however, the graft was never functioning and was removed 7 months post-transplant.Table 1 Clinical chacteristics and treatment course of five children with post-transplant recurrence of nephrotic syndrome\n\nPatient no.\tAge at diagnosis of NS (years), gender renal biopsy\tAge at trans-plantation (years) origin of the graft\tTiming of NS recurrence post-transplant (days)\tTreatment day of rituximab introduction after transplantation\tDuration of B CD19 depletion (months)/correlation of number of B CD19 cells to clinical effect\tClinical effects renal graft biopsy\tSAE\t\n1\t2, male\nFSGS\t5.5 deceased donor\t1\tPF + CsA + MMF + MP + rituximab\n4 × 375 mg/m2 day 133\t4\nYes\tComplete remission (7 years of follow-up)\nMCNS\tNo\t\n2\t2, female\nMCNS\t5 deceased donor\t1\tPF + CsA + MMF + MP + rituximab\n4 × 375 mg/m2 + galactose day 25\t3\nNo\tFailure; graft removed 7 months later\nFSGS\tNo\t\n3\t2, female\nMesPGN\n(NPHS2 gene mutation-single heterozygous mutation; p.R229Q)\t10 living-related donor\t1\tPF + CsA + MMF + MP + rituximab\n4 × 375 mg/m2 day 15\t2\nYes\tComplete remission (5 years of follow-up)\nFSGS\tNo\t\n4\t6, female\nFSGS\t12 deceased donor\t1\tPF + CsA + MMF + MP + rituximab\n2 × 375 mg/m2 day 21\t7\nno\tPartial remission; graft removed 2.5 years later\nFSGS\tRelapsing severe infections\t\n5\t6, male\nMesPGN\t10 deceased donor\t2\tPF + CsA + MMF + MP + rituximab\n4 × 375 mg/m2 day 15\t4\nno\tPartial remission\nMPGN\tRALI (fatal)\t\n\nMesPGN mesangial-proliferative glomerulonephritis, FSGS focal segmental glomerulosclerosis, MCNS minimal change nephrotic syndrome, NPHS2 podocine, CsA cyclosporine A, MMF mycophenolate mofetil, MP methylprednisolone, PF plasmapheresis, SAE serious adverse events, RALI rituximab-related acute lung injury\n\n\n\nDiscussion\nRituximab has been used for treatment of post-transplant nephrotic syndrome for a decade, and initial reports were in favor to the drug efficacy [7, 12, 16]. Our preliminary experience (case no. 1) was also very positive [8] and encouraged us to use this protocol. The reports published later on have revealed the conflicting data on clinical efficacy. Published 13 studies (mainly case reports or case series reports) included overall 44 pediatric patients treated with rituximab for post-transplant recurrence of nephrotic and among those 27 patients (55 %) presented complete remission, 14 (28.5 %) partial remission of nephrotic syndrome, and no effect was present in the remaining 8 (16.5 %) cases [14].\n\nRituximab was always used in combination with plasmapheresis and other drugs\nIt must be noted that most of the reported patients, treated for recurrence of nephrotic syndrome after renal transplantation with rituximab, underwent the combined therapy with plasma exchange and post-transplant triple immunosuppression including calcineurine inhibitors, steroids, and antiproliferative drugs, so the final clinical effect (if positive) might be the summary result of several therapeutic mechanisms. Moreover, the timing of introduction and the number of rituximab doses used in this setting was variable, as the drug was given also preemptively (as prophylaxis) at the day of transplantation [6] or as rescue therapy of overt recurrence of nephrotic syndrome [7, 12, 16, 22]. The number of doses ranged from single to six weekly doses of 375 mg/m2. The correlation between B CD20/CD19 cells depletion and clinical effect was also variable [14]. Among patients described in our report, four (out of five) have received rituximab as first-line therapy, and in remaining one, the drug was prescribed as second-line treatment due to persistent dependency from plasmapheresis. In four of our cases, four fixed weekly doses of 375 mg/m2 were given, and in remaining one, the number of scheduled doses was limited to two, due to relapsing infections. It is not clear whether the time interval (shorter versus longer) between post-transplant NS recurrence and introduction of rituximab is important for the overall efficacy of this intervention. Some authors expressed such suggestion in the discussion of their reports; however, there is no evidence so far. Almost universally, rituximab therapy was combined with plasmapheresis, and other suggestions stated that rituximab should be introduced early after the evidence of plasmapheresis failure [10, 12, 22].\n\nWhy the efficacy of rituximab is variable\nIt is not clear, whether the lack of significant clinical effect in three (of five) of our cases is related to specificity of this particular setting of the patients, in whom the recurrence was immediate (day 1 or 2), which may suggest the high concentration/activity of hypothetic circulating factors. Unfortunately, at the time of this treatment the evaluation of suPAR concentration in serum or urine was not available. The clinical course of these cases also show that long waiting time on dialysis (from 3 to 8 years) has no protective effect in terms of risk of rapid recurrence of nephrotic syndrome, as was carefully suggested based on some clinical observations [2]. Using similar approach, we faced two successful and three disappointing cases. B cells depletion was achieved in all cases, irrespective from the clinical outcome, so apparently rituximab was effective in terms of pharmacodynamics activity, independent from the absence of clinical effect in those patients, who did not respond. This might correspond with the data on B cell-independent mechanism of rituximab, which may act via regulation (preservation) of sphingomyelin phosphodiesterase acid-like 3b (SMLPD-3b), a protein which is involved in the podocyte cytoskeleton activity [6]. The anecdotal use of galactose in case no. 2, based on hypothesis of local inhibition of protein permeability factor in podocytes by galactose, was not effective either [20, 21]. Probably achieving (or not) the complete remission in particular cases is the effect of random targeting (or not) the patient, in whom the mechanism of nephrotic syndrome is directly related to abnormal activity of B cells. It is also possible that partial efficacy is related to B-independent manner of rituximab action [6]. Interestingly, the complete depletion of B cells was also present in our case no. 2, who showed complete resistance to rituximab, suggesting that there are specific cases, in whom neither B cell-dependent nor B cell-independent (local) mechanisms of the drug are relevant to reduce heavy post-transplant proteinuria. This is possible that this patient had T cell-dependent mechanism of the disease; however, plasmapheresis, which theoretically should be helpful in removing T cell driven cytokines (such as IL-13 stimulating local expression of CD80 molecule in podocytes) [3], was not effective either. Current experience on potential of use of abatacept (specific inhibitor of CD80) in post-transplant recurrence of NS, resistant to plasmapheresis, and rituximab [25] was not known at the time when our case was treated.\n\nUnfortunately, we are still at an early stage of distinguishing the different patterns of the mechanisms of post-transplant nephrotic syndrome; however, recent data on the use of diagnostic tool to identify patients at high risk of FSGS recurrence are encouraging [4].\n\nOne of our patients had heterozygous mutation of podocine and received living-related transplant. There were some reports on recurrence of nephrotic syndrome after renal transplantation in children with podocine genetic mutations, with high variety in terms of post-transplant time to proteinuria (range 4 to 10 years). The final outcome of reported six cases was good [11]. As the recurrence was immediate (first day) in our case, we presume that she presented combined, genetic defect and immunological injury, and the latter one was the major cause of rapid recurrence.\n\nSafety concern\nAnother issue is safety of this protocol. We have faced two cases of severe adverse events, including severe recurrent bacterial infections in case no. 4 suggesting overimmunosuppression. The most significant adverse event was RALI (rituximab-associated acute lung injury) in case no. 5, which was reported in details as case report [9]. The risk/benefit ratio is then individual and must be taken into consideration.\n\nIn summary, we present disappointing results of rituximab plasmapheresis-based rescue protocol of treating immediate recurrence of post-transplant nephrotic syndrome. It is unclear, whether aggressive pattern of immediate recurrence was the reason of the treatment failure in three cases. Center experience was the reason of the evolution of our attitude in terms of using this protocol, from enthusiastic to reluctant.\n\nAbbreviations\nB CD19, B CD20Lymphocytes B expressing specific receptors bound by monoclonal antibody (rituximab)\n\nCsACyclosporine A\n\nMMFMycophenolate mofetil\n\nMPMethylprednisolone\n\nPFPlasmapheresis\n\nNSNephrotic syndrome\n\nFSGSFocal segmental glomerulosclerosis\n\nMCNSMinimal change nephrotic syndrome\n\nMesPGNMesangial-proliferative glomerulonephritis\n\nIL-13Interleukin 13\n\nCD80T-cell co-stimulatory molecule\n\nRevisions received: 18 May 2016; 13 June 2016\n\nAuthor’s contribution\nRG was a senior consultant in all medical cases, created the idea, and has written the manuscript.\n\nWJ was a member of medical team involved in therapeutic process and reviewed the manuscipt.\n\nJR was a member of medical team involved in therapeutic process and reviewed the manuscipt.\n\nBP performed immunological monitoring in all cases and reviewed the manuscript.\n\nSP was a member of medical team, involved in therapeutic process, and reviewed the manuscipt.\n\nCompliance with ethical standards\nAll procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nFunding\nThe study did not receive fundings.\n\nConflict of interest\nThe authors declare that they have no conflict of interest.\n\nInformed consent\nInformed consent was obtained from all individual participants included in this study.\n==== Refs\nReferences\n1. Bacchetta J Cochat P Primary disease recurrence—effects on paediatric renal transplantation outcomes Nat Rev Nephrol 2015 11 6 371 384 10.1038/nrneph.2015.54 25917555 \n2. Cochat P Fargue S Mestrallet G Jungraithmayr T Koch-Nogueira P Ranchin B Zimmerhackl LB Disease recurrence in paediatric renal transplantation Pediatr Nephrol 2009 24 11 2097 2108 10.1007/s00467-009-1137-6 19247694 \n3. Davin J-C The glomerular permeability factors in idiopathic nephrotic syndrome Pediatr Nephrol 2016 31 207 215 10.1007/s00467-015-3082-x 25925039 \n4. Delville M Sigdel T Wei C Li J Hsieh S Fornoni A Burke G Bruneval G Naesens M Jackson A A circulating antibody panel for pretransplant prediction of FSGS recurrence after kidney transplantation Sci Transl Med 2014 6 256 256ra136 10.1126/scitranslmed.3008538 25273097 \n5. Faul C Donnelly M Merscher-Gomez S Chang Y Franz S Delgaauw J Chang J Choi H Campbell K Kim K Reiser J Mundel P The actin cytoskeleton of kidney podocytes is a direct target of antiproteinuric effect of cyclosporine A Nat Med 2008 14 931 938 10.1038/nm.1857 18724379 \n6. Fornoni A Sageshima J Wei C Merscher-Gomez S Aguillon-Prada R Jauregui AN Li J Mattiazzi A Ciancio G Chen L Zilleruelo G Rituximab targets podocytes in recurrent focal segmental glomerulosclerosis Sci Transl Med 2011 3 85 85ra46 10.1126/scitranslmed.3002231 21632984 \n7. Gossmann J Scheuermann EH Porubsky S Lachel H Geiger H Hauser I Abrogation of nephrotic proteinuria by rituximab treatment in renal transplant patient with relapsed focal segmental glomerulosclerosis Transpl Int 2007 20 558 560 10.1111/j.1432-2277.2007.00477.x 17433091 \n8. Grenda R Jarmużek W Piątosa B Rubik J Long-term effect of rituximab in maintaining remission of recurrent and plasmapheresis-dependent nephrotic syndrome post-renal transplantation—case report Pediatr Transplant 2011 15 6 E121 E125 20331516 \n9. Grenda R Jarmużek W Rubik J Migdał M Pronicki M Fatal rituximab-associated lung injury syndrome in a patient treated with rituximab for recurrence of post-transplant nephrotic syndrome Pediatr Transplant 2015 19 5 E115 120 10.1111/petr.12481 25929598 \n10. Hickson L Gera M Amer H Iqbal CW Moore TB Milliner DS Cosio F Larson T Stegall M Ishitani M Kidney transplantation for primary focal segmental glomerulosclerosis: outcomes and response to therapy for recurrence Transplantation 2009 87 8 1232 1239 10.1097/TP.0b013e31819f12be 19384172 \n11. Holmberg C Jalanko H Congenital nephrotic syndrome and recurrence of proteinuria after renal transplantation Pediatr Nephrol 2014 29 2309 2317 10.1007/s00467-014-2781-z 24682440 \n12. Hristea D Hadaya K Marangon N Buhler L Villard J Morel P Martin P Successful treatment of recurrent focal segmental glomerulosclerosis after kidney transplantation by plasmapheresis and rituximab Transpl Int 2007 20 102 105 10.1111/j.1432-2277.2006.00395.x 17181660 \n13. Mc Carthy E Sharma M Savin V Circulating permeability factors in idiopathic nephrotic syndrome and focal segmental glomerulosclerosis Clin Am J Soc Nephrol 2010 5 2115 2121 10.2215/CJN.03800609 \n14. Messina M Gallo E Mella A Pagani F Biancone L Update on the treatment of focal segmental glomerulosclerosis in renal transplantation World J Transplant 2016 6 1 54 68 10.5500/wjt.v6.i1.54 27011905 \n15. Pescovitz MD (2006) Rituxumab, an anti-CD20 monoclonal antibody: history and mechanism of action. Am J Transplant 859–866\n16. Pescovitz M Book B Sidner R Resolution of recurrent focal segmental glomerulosclerosis proteinuria after rituximab treatment N Eng J Med 2006 354 1961 1963 10.1056/NEJMc055495 \n17. Ponticelli C Recurrence of focal segmental glomerular sclerosis after renal transplantation Nephrol Dial Transplant 2010 25 25 31 10.1093/ndt/gfp538 19875378 \n18. Pradhan M Petro J Palmer J Meters H Baluarte K Early use of plasmapheresis for recurrent post-transplant FSGS Pediatr Nephrol 2003 18 934 938 10.1007/s00467-003-1208-z 12836097 \n19. Ransom R Lam N Hallett M Atkinson S Smoyer W Glucocorticoids protect and enhance recovery of cultured murine podocytes via actin filament stabilisation Kidney Int 2005 68 2473 2483 10.1111/j.1523-1755.2005.00723.x 16316324 \n20. Savin VJ McCarthy E Sharma R Sharma D Sharma M Galactose binds to focal segmental glomerulosclerosis permeability factor and inhibits its activity Transl Res 2008 151 288 292 10.1016/j.trsl.2008.04.001 18514139 \n21. Savin V Sharma R Sharma M McCarthy E Swan S Ellis E Lovell H Warady B Gunwar S Chonko A Circulating factor associated with increased glomerular permeability to albumin in recurrent focal segmental glomerulosclerosis N Eng J Med 1996 334 878 883 10.1056/NEJM199604043341402 \n22. Sethna C Benchimol C Hotchkiss H Frank R Infante L Vento S Trachtman H Treatment of recurrent focal segmental glomerulosclerosis in pediatric kidney transplant recipients: effect of rituximab J Transplant 2011 2011 389542 10.1155/2011/389542 21577271 \n23. Van Stralen KJ Verrina E Belingheri M Dudley J Dusek J Grenda R Macher M Puretic Z Rubik J Rudaitis S Rudin C Schaefer F Jager KJ ESPN/ERA-EDTA Registry. Impact of graft loss among kidney diseases with a high risk of post-transplant recurrence in the paediatric population Nephrol Dial Transplant 2013 28 4 1031 1038 10.1093/ndt/gfs549 23300261 \n24. Wei C El Hindi S Li J Fornoni A Goes N Sageshima J Maiguel D Karumanchi SA Yap HK Saleem M Circulating urokinase receptor as a cause of focal segmental glomerulosclerosis Nat Med 2011 17 8 952 960 10.1038/nm.2411 21804539 \n25. Yu C-C Fornoni A Weins A Hakroush S Maiguel D Abatacept in B7-1-positive proteinuric kidney disease N Eng J Med 2013 369 2453 2454 10.1056/NEJMoa1304572\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0340-6199",
"issue": "175(9)",
"journal": "European journal of pediatrics",
"keywords": "Nephrotic syndrome; Rapid recurrence; Renal transplantation; Rituximab",
"medline_ta": "Eur J Pediatr",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008168:Lung; D055370:Lung Injury; D008297:Male; D009404:Nephrotic Syndrome; D011183:Postoperative Complications; D012008:Recurrence; D012074:Remission Induction; D012189:Retrospective Studies; D000069283:Rituximab",
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"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
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"title": "Rituximab is not a \"magic drug\" in post-transplant recurrence of nephrotic syndrome.",
"title_normalized": "rituximab is not a magic drug in post transplant recurrence of nephrotic syndrome"
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"abstract": "There is little evidence regarding the best treatment in case of dilated cervix and exposed membranes in twins. Current options for its management include vaginal progesterone, cervical cerclage and cervical pessary, but none of them had shown effectiveness compared to expectant management. We presented a case of twin pregnancy at 22 6/7 weeks' gestation admitted to the hospital because of cervical insufficiency with bulging of membranes. An Arabin pessary was positioned after a failed attempt of cervical cerclage and no antibiotic was given in absence of signs of infection. Cesarean delivery was performed at 24 weeks' gestation because of spontaneous preterm labor and spontaneous rupture of membranes with the first baby in a transverse lie position. At the uterus section, the first baby was stillborn, with Arabin pessary strictly adherent to his ecchymotic head, while the second baby was born alive. After diagnostic histopathological and microbiological investigations, we hypothesized that the first twin died for funisitis/sepsis and mechanical insult due to the strict adhesion of the pessary to the fetal head. We concluded that in case of bulging membranes and dilated cervix, antibiotic treatment should be evaluated, also in absence of signs/symptoms of infection or suspicion of rupture of the membranes, and pessary insertion should be avoided, namely at second trimester, because of the risk of its dislocation inside the uterus when contractions start and potential hurt to extremely preterm fetus.",
"affiliations": "Unit of Obstetrics and Gynecology, Mother-Infant and Adult Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy - francesca.monari@unimore.it.;Unit of Obstetrics and Gynecology, Mother-Infant and Adult Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Neonatal, Mother-Infant and Adult Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Obstetrics and Gynecology, Mother-Infant and Adult Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Obstetrics and Gynecology, Mother-Infant and Adult Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy.",
"authors": "Monari|Francesca|F|;Salerno|Cristina|C|;Torcetta|Francesco|F|;Po'|Gaia|G|;Facchinetti|Fabio|F|",
"chemical_list": null,
"country": "Italy",
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"doi": "10.23736/S2724-606X.20.04721-8",
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"issn_linking": "2724-606X",
"issue": "73(3)",
"journal": "Minerva obstetrics and gynecology",
"keywords": null,
"medline_ta": "Minerva Obstet Gynecol",
"mesh_terms": "D002584:Cervix Uteri; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D010570:Pessaries; D011247:Pregnancy; D059285:Pregnancy, Twin; D047928:Premature Birth; D018805:Sepsis; D050497:Stillbirth",
"nlm_unique_id": "101777346",
"other_id": null,
"pages": "384-387",
"pmc": null,
"pmid": "34008394",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intrapartum stillbirth for sepsis complicating Arabin cervical pessary placement in a twin pregnancy.",
"title_normalized": "intrapartum stillbirth for sepsis complicating arabin cervical pessary placement in a twin pregnancy"
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"abstract": "Visceral angioedema is a rare complication of therapy with angiotensin-converting enzyme (ACE) inhibitors. Clinical presentation includes nausea, vomiting, abdominal pain and diarrhea. Early detection of this entity can prevent recurrent episodes and unnecessary invasive procedures, including surgery. This article describes a 46-year-old-woman who presented to the emergency department with abdominal pain, associated with nausea and vomiting. She had been taking ramipril for 15 days. A computed tomography was performed which revealed thickening of a jejunal segment, with submucosal edema. ACE inhibitor-associated angioedema was suspected and the medication was discontinued, with resolution of symptoms in 48 h. After 7 months of follow-up, the patient is asymptomatic. Despite of its rarity, ACE inhibitor-induced small-bowel angioedema should be included in the differential diagnosis when patients receiving ACE inhibitor therapy present with abdominal complaints.",
"affiliations": "Gastroenterology Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal.;Radiology Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal.;Gastroenterology Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal.;Gastroenterology Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal.;Gastroenterology Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal.",
"authors": "Oliveira|Ana Maria|AM|;Santiago|Inês|I|;Carvalho|Rita|R|;Martins|Alexandra|A|;Reis|Jorge|J|",
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"delete": false,
"doi": "10.1016/j.jpge.2015.09.008",
"fulltext": "\n==== Front\nGE Port J GastroenterolGE Port J GastroenterolGE Portuguese Journal of Gastroenterology2341-45452387-1954Karger Publishers S2341-4545(15)00135-010.1016/j.jpge.2015.09.008Clinical CaseIsolated Visceral Angioedema Induced by Angiotensin-Converting Enzyme Inhibitor Angioedema Visceral Isolado Induzido por Inibidor da Enzima de Conversão da Angiotensina Oliveira Ana Maria anaoliveira.fml@gmail.coma⁎Santiago Inês bCarvalho Rita aMartins Alexandra aReis Jorge aa Gastroenterology Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugalb Radiology Department, Hospital Prof. Doutor Fernando Fonseca, Amadora, Portugal⁎ Corresponding author. anaoliveira.fml@gmail.com24 11 2015 May-Jun 2016 24 11 2015 23 3 162 165 21 7 2015 27 9 2015 © 2015 Sociedade Portuguesa de Gastrenterologia. Published by Elsevier Espa˜na, S.L.U.2015Sociedade Portuguesa de GastrenterologiaThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Visceral angioedema is a rare complication of therapy with angiotensin-converting enzyme (ACE) inhibitors. Clinical presentation includes nausea, vomiting, abdominal pain and diarrhea. Early detection of this entity can prevent recurrent episodes and unnecessary invasive procedures, including surgery.\n\nThis article describes a 46-year-old-woman who presented to the emergency department with abdominal pain, associated with nausea and vomiting. She had been taking ramipril for 15 days.\n\nA computed tomography was performed which revealed thickening of a jejunal segment, with submucosal edema.\n\nACE inhibitor-associated angioedema was suspected and the medication was discontinued, with resolution of symptoms in 48 h.\n\nAfter 7 months of follow-up, the patient is asymptomatic.\n\nDespite of its rarity, ACE inhibitor-induced small-bowel angioedema should be included in the differential diagnosis when patients receiving ACE inhibitor therapy present with abdominal complaints.\n\nResumo\nO angioedema visceral é uma complicação rara da terapêutica com inibidores da enzima de conversão da angiotensina (IECA).\n\nO quadro clínico inclui náuseas, vómitos, dor abdominal e diarreia.\n\nO reconhecimento precoce desta entidade pode evitar episódios recorrentes e procedimentos invasivos desnecessários, incluindo cirurgia.\n\nDescrevemos o caso clínico de uma mulher de 46 anos, que recorreu ao serviço de urgência por dor abdominal, acompanhada de náuseas e vómitos. Estava medicada desde há quinze dias com ramipril.\n\nA tomografia computorizada identificou espessamento parietal de um segmento jejunal, com edema submucoso.\n\nFoi colocada a hipótese diagnóstica de angioedema visceral induzido por IECA.\n\nSuspendeu-se a terapêutica com ramipril, com remissão completa da sintomatologia em 48 horas.\n\nApós 7 meses de follow-up, encontra-se assintomática.\n\nApesar da sua raridade, o angioedema visceral induzido por IECA deve ser incluído no diagnóstico diferencial de dor abdominal nos doentes medicados com IECA.\n\nKeywords\nAngioedemaAngiotensin-Converting Enzyme InhibitorsVisceraPalavras-chave\nAngioedemaInibidores da Enzima de Conversão da AngiotensinaVísceras\n==== Body\n1 Case report\nA 46-year-old-woman presented to the emergency department with a one-day crampy abdominal pain, associated with nausea and vomiting. The patient's past medical history was relevant for hypertension, for which she was taking ramipril for 15 days.\n\nShe denied additional medication besides ramipril. She also denied smoking. She had no known allergies to drugs or environmental agents, and her travel history was negative.\n\nThere was no family history for any diseases.\n\nOn physical examination, she was afebrile, with a heart rate of 67 beats per minute and a blood pressure of 123/76 mmHg. She had no stridor or facial swelling. Breath sounds were normal. Abdominal exam disclosed tenderness in the periumbilical area.\n\nLaboratory investigations revealed a white blood cell count of 11.100 microliter (μL) (9.400 neutrophils/μL; 100 eosinophils/μL; 1.400 lymphocytes/μL) and C-reactive protein of 2.5 miligrams/deciliter (mg/dL) (normal value < 0.3 mg/dL); serum electrolytes, liver enzymes, serum amylase and renal function tests were in the normal range. Serologies for celiac disease and Crohn's disease were negative.\n\nChest X-ray did not reveal any changes and upright abdominal X-ray revealed air-fluid levels.\n\nAn abdominal computed tomography (CT) was performed which revealed thickening of a jejunal segment, with submucosal edema giving a “target-sign” appearance. There was also moderate ascites (Fig. 1).Figure 1 Abdominal computed tomography with oral and intravenous contrast revealing thickening of a jejunal segment, with submucosal edema (arrows) giving a so-called “target-sign” appearance (images a and b). Image (c) shows moderate ascites (arrow).\n\n\n\nPush enteroscopy was performed 3 days after onset of symptoms and did not reveal any changes (the estimated depth of insertion was proximal jejunum). Biopsies were performed which revealed normal results.\n\nShe was diagnosed with visceral angioedema secondary to angiotensin-converting enzyme (ACE) inhibitor therapy. Ramipril was discontinued, and symptoms resolved completely in 48 h. Upright abdominal X-ray was repeated and did not reveal air-fluid levels.\n\nShe was discharged home after 6 days on calcium channel blocker.\n\nAfter 7 months of follow-up, the patient is asymptomatic.\n\n2 Discussion\nAngiotensin-converting enzyme (ACE) inhibitors have achieved widespread usage in the treatment of cardiovascular and renal disease; they have proved effectiveness in the treatment of hypertension, they decrease mortality in congestive heart failure and left ventricular dysfunction after myocardial infarction and they delay the progression of diabetic nephropathy.1\n\nThe most common adverse reactions are cough and skin rash.2 Peripheral angioedema has been reported in 0.1–0.2% of patients, and visceral angioedema has been reported to occur even less commonly.3, 4, 5, 6\n\nThese drugs inhibit competitively the activity of ACE to prevent formation of angiotensin II from angiotensin I. Inhibition of this enzyme also leads to accumulation of kinins including bradykinin.1\n\nVisceral angioedema pathogenesis is not clear. The most plausible mechanism is an increase in the levels of bradykinin and its metabolite.7 Bradykinin increases vascular permeability1 and promotes vasodilation4, 8, 9 by stimulating the production of arachidonic acid metabolites, nitric oxide, and endothelium-derived hyperpolarizing factor in vascular endothelium, thereby leading to angioedema.10\n\nIn fact, during an acute attack of angioedema secondary to ACE inhibition, the bradykinin concentration can increase to more than 10 times the normal level9 and fall to normal levels during remission after withdrawal of the drug.11\n\nACE-inhibitor-induced angioedema of the intestine is more common in women12 in the fifth decade of life.11, 13\n\nClinical presentation includes nausea, vomiting, abdominal pain and diarrhea.14, 15, 16, 17 Symptoms typically present within 24–48 h after initiation of ACE inhibitor,18 but there are case reports between 2 weeks and 18 months after initiation of therapy13 and there is one case report 9 years after initiation of therapy.6\n\nAlthough the CT features are not pathognomonic, they provide valuable clues to the diagnosis; a previous case series suggested CT findings of ascites, small bowel wall thickening, dilation without obstruction, and straightening should prompt inclusion of the diagnosis in the differential while taking an ACE-inhibitors.19\n\nInflammatory bowel disease, infection, vasculitis, ischemic bowel and mechanical obstruction all need to be considered in the differential.20, 21\n\nSupportive care and cessation of ACE-inhibitor usage are the cornerstones of treatment.17 Symptoms usually resolve within 48 h13, 20, 22, 23 as illustrated by the presented case. Nevertheless, in a previous study,11 a median of 10 months (range from 1 day to 10 years) elapsed between the onset of angioedema and withdrawal of the ACE inhibitor. In the presented case, due to the prompt diagnosis, ramipril therapy was withdrawn in the same day as angioedema presentation.\n\nRecurrent angioedema has been reported to occur in 1.5–10% of patients after changing from ACE-inhibitor to angiotensin II receptor blockers. However, it is believed that this may actually represent residual effects of ACE-inhibitor angioedema.24\n\nIt is important to recognize this entity as many of the patients discussed in the literature underwent unnecessary invasive procedures such as exploratory laparotomy, intestinal biopsy and resection.16, 18, 20, 21\n\nIn conclusion, ACE inhibitors-induced small-bowel angioedema should be included in the differential diagnosis in any patient with unexplained abdominal pain while on ACE inhibitors.16, 18\n\nEthical disclosures\nProtection of human and animal subjects\nThe authors declare that the procedures followed were in accordance with the regulations of the relevant clinical research ethics committee and with those of the Code of Ethics of the World Medical Association (Declaration of Helsinki).\n\nConfidentiality of data\nThe authors declare that they have followed the protocols of their work center on the publication of patient data.\n\nRight to privacy and informed consent\nThe authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.\n\nConflicts of interest\nThe authors have no conflicts of interest to declare.\n==== Refs\nReferences\n1 Brown N. Vaughan D. Angiotensin-converting enzyme inhibitors Circulation 97 1998 1411 1420 9577953 \n2 Parish R.C. Miller L.J. Adverse effects of angiotensin converting enzyme (ACE) inhibitors. An update Drug Saf 7 1992 14 31 1536695 \n3 Marmery H. Mirvis S.E. Angiotensin-converting enzyme inhibitor-induced visceral angioedema Clin Radiol 61 2006 979 982 17018312 \n4 Vleeming W. van Amsterdam J.G. Stricker B.H. de Wildt D.J. ACE inhibitor induced angioedema. Incidence, prevention and management Drug Saf 18 1998 171 188 9530537 \n5 Vallurupalli K. Coakley K.J. MDCT features of angiotensin-converting enzyme inhibitor-induced visceral angioedema Am J Roentgenol 196 2011 W405 W411 21427304 \n6 Orr K.K. Myers J.R. Intermittent visceral edema induced by long-term enalapril administration Ann Pharmacother 38 2004 825 827 15039478 \n7 Molinaro G. Cugno M. Perez M. Lepage Y. Gervais N. Agostoni A. Angiotensin-converting enzyme inhibitor-associated angioedema is characterized by a slower degradation of des-arginine-bradykinin J Pharmacol Exp Ther 303 2002 232 237 12235256 \n8 Anderson M.W. deShazo R.D. Studies of the mechanism of angiotensin-converting enzyme (ACE) inhibitor-associated angioedema: the effect of an ACE inhibitor on cutaneous responses to bradykinin, codeine, and histamine J Allergy Clin Immunol 85 1990 856 858 2185292 \n9 Pellacani A. Brunner H.R. Nussberger J. Plasma kinins increase after angiotensin-converting enzyme inhibition in human subjects Clin Sci 87 1994 567 574 7874846 \n10 Vanhoutte P.M. Endothelium and control of vascular function: state of the art lecture Hypertension 13 1989 658 667 2661425 \n11 Agostoni A. Cicardi M. Cugno M. Zingale L.C. Gioffré D. Nussberger J. Angioedema due to angiotensin-converting enzyme inhibitors Immunopharmacology 44 1999 21 25 10604520 \n12 Campo P. Fernandez T.D. Canto G. Mayorga C. Angioedema induced by angiotensin-converting enzyme inhibitors Curr Opin Allergy Clin Immunol 13 2013 337 344 23743513 \n13 Korniyenko A. Alviar C.L. Cordova J.P. Messerli F.H. Visceral angioedema due to angiotensin-converting enzyme inhibitor therapy Clevel Clin J Med 78 2011 297 304 \n14 Korniyenko A. Alviar C.L. Cordova J.P. Messerli F.H. Role of angiotensin-converting enzyme inhibitors in visceral angioedema Int J Cardiol 148 2011 377 379 21367475 \n15 Oudit G. Girgrah N. Allard J. ACE inhibitor-induced angioedema of the intestine: case report, incidence, pathophysiology, diagnosis and management Can J Gastroenterol 15 2001 827 832 11773949 \n16 Chase M.P. Fiarman G.S. Scholz F.J. MacDermott R.P. Angioedema of the small bowel due to an angiotensin-converting enzyme inhibitor J Clin Gastroenterol 31 2000 254 257 11034011 \n17 Haines E.C. Wall G.C. Possible angiotensin-converting enzyme inhibitor (ACEI)- induced small bowel angioedema J Pharm Pract 24 2011 564 567 21676850 \n18 Campbell T. Peckler B. Hackstadt R.D. Payor A. ACE inhibitor-induced angioedema of the bowel Case Rep Med 2010 2010 690695 21209819 \n19 Scheirey C.D. Scholz F.J. Shortsleeve M.J. Katz D.S. Angiotensin-converting enzyme inhibitor-induced small-bowel angioedema: clinical and imaging findings in 20 patients Am J Roentgenol 197 2011 393 398 21785085 \n20 Augenstein V.A. Heniford B.T. Sing R.F. Intestinal angioedema induced by angiotensin-converting enzyme inhibitors: an underrecognized cause of abdominal pain J Am Osteopat Assoc 113 2013 221 223 \n21 Byrne T.J. Douglas D.D. Landis M.E. Heppell J.P. Isolated visceral angioedema: an underdiagnosed complication of ACE inhibitors Mayo Clin Proc 75 2000 1201 1204 11075752 \n22 Mohammad M. Parmar C. Jafri H. Scott M. Lisinopril induced visceral angioedema in a newly diagnosed hypertensive patient Ibnosina J Med Biomed Sci 3 2011 135 138 \n23 Khan M.U. Baig M.A. Javed R.A. Ali S. Qamar U.R. Vasavada B.C. Benazepril induced isolated visceral angioedema: a rare and under diagnosed adverse effect of angiotensin converting enzyme inhibitors Int J Cardiol 118 2007 e68 e69 17395288 \n24 Thalanayar P.M. Ghobrial I. Lubin F. Karnik R. Bhasin R. Drug-induced visceral angioedema J Community Hosp Intern Med Perspect 4 2014 4 [eCollection 2014]\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2387-1954",
"issue": "23(3)",
"journal": "GE Portuguese journal of gastroenterology",
"keywords": "Angioedema; Angiotensin-Converting Enzyme Inhibitors; Viscera",
"medline_ta": "GE Port J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101685861",
"other_id": null,
"pages": "162-165",
"pmc": null,
"pmid": "28868452",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "2185292;23743513;21427304;21536824;10604520;11034011;11075752;2661425;11773949;21367475;17395288;21209819;25317271;9577953;12235256;21676850;9530537;23485983;15039478;17018312;1536695;7874846;21785085",
"title": "Isolated Visceral Angioedema Induced by Angiotensin-Converting Enzyme Inhibitor.",
"title_normalized": "isolated visceral angioedema induced by angiotensin converting enzyme inhibitor"
} | [
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"companynumb": "PT-ACCORD-193491",
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"patient": {
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"activesubstance": {
"activesubstancename": "RAMIPRIL"
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"abstract": "Fungal endogenous endophthalmitis is an uncommon and potentially blinding infection. Aspergillus is a causative organism in immunocompromized although is virulent enough to afflict immunocompetents. Their propensity to affect macula usually results in a dismal prognosis; thus, improving visual outcome has always been challenging to clinicians. A. nidulans has only rarely been implicated in exogenous endophthalmitis.\nTo report the first case of A. nidulans endogenous endophthalmitis.\nAn asthmatic 42-year-old female presented with sudden unilateral vision loss due to a submacular abscess that progressively worsened in a matter of days. Vitreous PCR analysis after an urgent vitrectomy was positive for A. nidulans with no active systemic foci found. Oral and intravitreal Voriconazole was prescribed but multiple reactivations led to three vitrectomies in total alongside with subretinal Voriconazole, abscess aspiration, and endolaser. There was complete resolution of the infection and, although visual acuity was poor due to macular scar, enucleation was avoided.\nAlthough uncommon, we must consider Aspergillus as the causative organism in apparently immunocompetent patients with history of recent systemic corticosteroids treatment, especially if they suffer a broncopulmonary disorder. Aspergillus is an aggressive organism so a high index of suspicion along with early diagnosis and prompt treatment is the key for better outcomes. We highlight A. nidulans as the causative agent as there are no other reported cases.",
"affiliations": "Hospital General Universitario de Valencia, Valencia, Spain.;Hospital General Universitario de Valencia, Valencia, Spain.;Hospital General Universitario de Valencia, Valencia, Spain.;Hospital General Universitario de Valencia, Valencia, Spain.;Hospital General Universitario de Valencia, Valencia, Spain.;Hospital General Universitario de Valencia, Valencia, Spain.;Hospital General Universitario de Valencia, Valencia, Spain.",
"authors": "Mata-Moret|Lucia|L|https://orcid.org/0000-0001-7374-7138;Monferrer-Adsuara|Clara|C|https://orcid.org/0000-0003-0399-0903;Hernández-Bel|Laura|L|https://orcid.org/0000-0002-4996-3380;Hernández-Garfella|Marisa|M|;Torrecillas-Muelas|Miriam|M|;Ocete-Mochón|Maria Dolores|MD|;Cervera-Taulet|Enrique|E|",
"chemical_list": "D000935:Antifungal Agents; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1177/1120672120932088",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1120-6721",
"issue": "31(6)",
"journal": "European journal of ophthalmology",
"keywords": "Aspergillus nidulans; endogenous endophthalmitis; immunocompetent; subretinal abscess",
"medline_ta": "Eur J Ophthalmol",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D001233:Aspergillus nidulans; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D005260:Female; D006801:Humans; D014821:Vitrectomy; D065819:Voriconazole",
"nlm_unique_id": "9110772",
"other_id": null,
"pages": "NP13-NP17",
"pmc": null,
"pmid": "32486857",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The first case of fungal endogenous endophthalmitis caused by Aspergillus nidulans: Diagnostic and therapeutic challenge.",
"title_normalized": "the first case of fungal endogenous endophthalmitis caused by aspergillus nidulans diagnostic and therapeutic challenge"
} | [
{
"companynumb": "ES-PFIZER INC-202101741839",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": "4",
... |
{
"abstract": "Radiation recall refers to inflammatory reactions triggered by chemotherapeutic agents and develops cutaneously in the previously irradiated areas. Such agents include anthracyclines, taxanes and capecitabine. Radiation recall related to gemcitabine has been reported in lung and breast cancer. Similar phenomenon associated with gemcitabine, the only FDA-approved drug for pancreatic cancer, is rarely reported. We report a patient with inoperable pancreatic cancer who developed gastrointestinal bleeding secondary to radiation-recall related to gemcitabine and review literature. A 57-year-old white male with unresectable pancreatic cancer received capecitabine in combination with radiation therapy followed by capecitabine alone given over approximately a 3-month time period. Computed tomography re-evaluation demonstrated a new liver lesion. The patient was then treated with gemcitabine and irinotecan. On day 15 of cycle 1, he reported progressive worsening of weakness and fatigue, and melena. Physical examination revealed hypotension (84/47 mmHg) and heme-positive stool on rectal examination. He denied aspirin or non-steroidal anti-inflammatory drug use. Chemotherapy was held. Hematocrit was 20% (previously 33%). He was transfused with 3 units of packed red blood cells. An esophago-gastro-duodenal examination was performed which showed antritis and duodenitis consistent with radiation therapy. A single site of oozing was injected with epinephrine. The diffuse gastritis was aggressively treated with proton pump inhibitors. The patient's hematocrit eventually stabilized and was 30% at discharge. Gemcitabine was not resumed. Radiation recall from gemcitabine is rare, but can potentially arise in any site that has been previously irradiated. Gemcitabine should be added to the list of drugs known to cause radiation recall. Treating physicians must be aware of this potential toxicity from gemcitabine either given concomitantly or followed by radiation. We suggest discontinuing gemcitabine if radiation recall is observed. Further studies are warranted into the pathogenesis of this unique phenomenon.",
"affiliations": "Yale University School of Medicine, New Haven, Connecticut 06520, USA. wasif.saif@yale.edu",
"authors": "Saif|M Wasif|MW|;Sellers|Sandra|S|;Russo|Suzanne|S|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.1097/01.cad.0000181590.85476.e3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "17(1)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D003131:Combined Modality Therapy; D003841:Deoxycytidine; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D011832:Radiation Injuries",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "107-11",
"pmc": null,
"pmid": "16317298",
"pubdate": "2006-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gemcitabine-related radiation recall in a patient with pancreatic cancer.",
"title_normalized": "gemcitabine related radiation recall in a patient with pancreatic cancer"
} | [
{
"companynumb": "US-CIPLA LTD.-2014US01443",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that disrupts the genes for bile formation. Liver transplantation (LT) is the only effective treatment for PFIC patients with end-stage liver disease. We describe our experience in terms of clinical characteristics, complications, and outcome of LT for PFIC. CASE REPORT The data of 5 pediatric PFIC patients recipients (3 PFIC1, 1 PFIC2, and 1 PFIC3) who received LT at our Liver Transplant Center from June 2013 to February 2017 were retrospectively analyzed. Four patients received liver transplantation from donation after cardiac death (DCD) donors. One patient received a living donor liver transplantation (LDLT). All the LT recipients received an immunosuppressive regimen of tacrolimus (FK 506) + methylprednisolone + mycophenolate mofetil (MMF). Diarrhea did not improve in 2 PFIC1 patients after LT, and they both developed steatohepatitis several months after LT. The other PFIC1 patient received ABO blood group incompatible LT and developed biliary complications and a severe Epstein-Barr virus infection; this patient underwent endoscopic retrograde cholangiopancreatography. She recovered after treatment with ganciclovir and reduction of tacrolimus dosage. The PFIC2 patient had abnormal liver function 19 months after LT, and recovered after administration of increased dosage of immunosuppressant agents. Liver function in the PFIC3 patient was normal during 2-year follow-up. CONCLUSIONS Liver transplantation is an effective treatment in PFIC patients. However, PFIC1 patients may develop aggravated diarrhea and steatohepatitis after LT. PFIC2 and PFIC3 patients have good outcomes after LT.",
"affiliations": "Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland).;Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland).;Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland).;Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland).;Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland).;Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China (mainland).",
"authors": "Liu|Ying|Y|;Sun|Li-Ying|LY|;Zhu|Zhi-Jun|ZJ|;Wei|Lin|L|;Qu|Wei|W|;Zeng|Zhi-Gui|ZG|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus; D008775:Methylprednisolone",
"country": "United States",
"delete": false,
"doi": "10.12659/AOT.909941",
"fulltext": "\n==== Front\nAnn TransplantAnn. TransplantAnnals of TransplantationAnnals of Transplantation1425-95242329-0358International Scientific Literature, Inc. 3025001510.12659/AOT.909941909941Case ReportLiver Transplantation for Progressive Familial Intrahepatic Cholestasis Liu Ying 1BCDEFSun Li-Ying 23AZhu Zhi-Jun 13GWei Lin 1BQu Wei 1BZeng Zhi-Gui 1B\n1 Liver Transplantation Center, National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China\n2 Intensive Care Unit, Beijing Friendship Hospital, Capital Medical University, Beijing, P.R. China\n3 Beijing Key Laboratory of Tolerance Induction and Organ Protection in Transplantation, Beijing, P.R. ChinaCorresponding Author: Li-Ying Sun, e-mail: sunxlx@outlook.comA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\n2018 25 9 2018 23 666 673 12 3 2018 29 6 2018 © Ann Transplant, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Background\nProgressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that disrupts the genes for bile formation. Liver transplantation (LT) is the only effective treatment for PFIC patients with end-stage liver disease. We describe our experience in terms of clinical characteristics, complications, and outcome of LT for PFIC.\n\nCase Report\nThe data of 5 pediatric PFIC patients recipients (3 PFIC1, 1 PFIC2, and 1 PFIC3) who received LT at our Liver Transplant Center from June 2013 to February 2017 were retrospectively analyzed. Four patients received liver transplantation from donation after cardiac death (DCD) donors. One patient received a living donor liver transplantation (LDLT). All the LT recipients received an immunosuppressive regimen of tacrolimus (FK 506) + methylprednisolone + mycophenolate mofetil (MMF). Diarrhea did not improve in 2 PFIC1 patients after LT, and they both developed steatohepatitis several months after LT. The other PFIC1 patient received ABO blood group incompatible LT and developed biliary complications and a severe Epstein-Barr virus infection; this patient underwent endoscopic retrograde cholangiopancreatography. She recovered after treatment with ganciclovir and reduction of tacrolimus dosage. The PFIC2 patient had abnormal liver function 19 months after LT, and recovered after administration of increased dosage of immunosuppressant agents. Liver function in the PFIC3 patient was normal during 2-year follow-up.\n\nConclusions\nLiver transplantation is an effective treatment in PFIC patients. However, PFIC1 patients may develop aggravated diarrhea and steatohepatitis after LT. PFIC2 and PFIC3 patients have good outcomes after LT.\n\nMeSH Keywords\nCholestasis, IntrahepaticDiarrheaLiver Transplantation\n==== Body\nBackground\nProgressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that disrupts the genes encoding protein transporters responsible for bile formation [1]. PFIC is classified into 3 types (PFIC 1-3): PFIC1 is caused by a mutation of the ATP8B1 gene encoding the FIC1 protein [2], PFIC2 is caused by a mutation of ABCB11 gene encoding the bile salt excretion protein (BSEP), and PFIC3 is due to a mutation of ABCB4 gene encoding the MDR3 protein [3].\n\nThe clinical manifestations in PFIC patients include progressive jaundice, pruritus, and growth retardation. Subsequently, patients develop liver cirrhosis and hepatic failure. Liver transplantation (LT) is the only effective treatment for PFIC at present [4].\n\nWe report 5 cases of PFIC who received LT at our center from June 2013 to February 2017, and their clinical characteristics and outcomes were analyzed.\n\nCase Report\nSince June 2013, 470 patients, including 290 pediatric patients, underwent LT at the Liver Transplant Section in Beijing Friendship Hospital. This is a retrospective study of 5 cases of these 290 pediatric liver transplant recipients for PFIC.\n\nThe 5 PFIC patients (3 with PFIC1, 1 with PFIC2, and 1 with PFIC3) consisted of 3 boys and 2 girls, and their age at liver transplantation ranged from 2 to 7 years old. Four patients received liver transplantation from donation after cardiac death (DCD) donors. One patient received Ditate. ABO blood groups were identical in 4 cases and incompatible in 1 case of PFIC1. All LT recipients received an immunosuppressive regimen of tacrolimus (FK 506) + methylprednisolone + mycophenolate mofetil (MMF). The regimen for ABO incompatibility included administration of rituximab before LT and gamma globulin after LT.\n\nWe analyzed the hospital records of these patients with regard to clinical characteristics, treatment, complications, outcome of LT, and impact of LT on growth. The study conformed to the ethics guidelines of the 1975 Declaration of Helsinki and was approved by Ethics Committee in Beijing Friendship Hospital.\n\nClinical characteristics of PFIC patients\nSince June 2013, we have treated 5 pediatric patients diagnosed with PFIC. Three cases were PFIC1, 1 wasPFIC2, and 1 was PFIC3. Three were boys and the other 2 patients were girls. Their age at liver transplantation ranged from 2 to 7 years old. Clinical symptoms in the PFIC1 and PFIC2 patients were jaundice, pruritus, and growth retardation. The PFIC1 patients also had diarrhea. The PFIC3 patient had ascites and portal hypertension without severe jaundice or pruritus. Their Pediatric End-Stage Liver Disease Model (PELD) score ranged from 5 to 16. Their height S.D. scores ranged from −4.17 to 4.5, and weight S.D. scores ranged from −4.37 to 2.55 (Table 1).\n\nLiver transplantation in PFIC patients\nFour patients received liver transplantation from DCD donors. One patient received LDLT. Blood loss during surgery was 150–300 mL. The cold ischemia time ranged from 110 min to 550 min, and the retrieval warm ischemia time was approximately 3–5 min. The ABO blood groups were identical in 4 cases and incompatible in 1 case of PFIC1. Our regimen for ABO incompatibility included administration of rituximab (375 mg/m2) before LT and gamma globulin (400 mg/kg daily) for 7–10 days after LT. Methylprednisolone was given at 10 mg/kg during surgery. All recipients received an immunosuppressive regimen of tacrolimus (FK 506) + methylprednisolone + mycophenolate mofetil (MMF) after LT.\n\nThe trough level of tacrolimus was maintained at 8–10 ng/mL for 6 months after LT, and then 5–8 ng/mL for the next 6 months. Methylprednisolone was stopped after 3 months and MMF was discontinued after 1 year. Length of hospital stay was 19–54 days (Table 2).\n\nComplications in PFIC patients after LT and treatment\nCase 1 was a PFIC1 patient who recovered well after surgery and was followed up after discharge. However, she had aggravated diarrhea after LT. Following treatment with loperamide and cholestyramine, diarrhea improved. Her liver function was abnormal with increased transaminase (ALT 90 IU/L, AST 74 IU/L) at 7 months after LT. Liver biopsy was performed and showed steatohepatitis with 90% hepatocyte steatosis (Figure 1). The patient was treated with Essentiale (a commercial preparation of essential phospholipids). At 19 months after LT, ALT was 41 IU/L and AST was 55 IU/L. Liver biopsy was repeated and showed 70% hepatocyte steatosis (Figure 2). The latest review results showed that liver function was normal, but liver biopsy showed nonalcoholic steatohepatitis with 66% hepatocyte steatosis and hepatic fibrosis (F3) (Figures 3, 4).\n\nCase 2 was a PFIC1 patient with ABO blood group incompatibility. Her blood group was A and the donor’s blood group was AB. Anti-B IgM was 1: 32 and anti-B IgG was 1: 64. The patient received rituximab (375 mg/m2) before LT and gamma globulin (400 mg/kg daily) for 7 days after LT. On the 12th day after LT, ultrasound showed that left and right branches of the hepatic artery were undetectable and there was a low-echo area in the left liver lobe (Figure 5). Contrast-enhanced ultrasonography was performed, showing that the intrahepatic branches of the hepatic artery were normal, but she still received anticoagulant therapy. She developed biliary complications at 10 months and suffered repeated biliary infections and progressive jaundice (TB 196 mmol/L, DB 108 mmol/L). Ultrasound showed biloma formation in the liver and multiple intrahepatic biliary dilatations. She received percutaneous transhepatic cholangio-drainage (PTCD) followed by endoscopic retrograde cholangiopancreatography (ERCP) (Figures 6, 7). After these treatments, TB gradually decreased to 38 mmol/L and DB decreased to 19 mmol/L. At 2 years after LT, the recipient had a severe Epstein-Barr virus (EBV) infection with high fever and enlarged lymph nodes. EBV-DNA copies were 5×106/mL. Post-transplant lymphoproliferative disease was suspected, and lymph node biopsy of the left axilla was performed. The results showed lymphadenitis accompanied by EBV infection (Figure 8). Ganciclovir was administered and tacrolimus dosage was reduced. Following this treatment, she recovered and was discharged from the hospital.\n\nCase 3 was a PFIC2 patient. The patient recovered well after LT and was discharged from the hospital. He was followed up regularly. At 19 months after LT, his liver function appeared abnormal (ALT 513 IU/L, AST 654 IU/L, TB 18 mmol/L, ALP 254 IU/L, GGT 248 IU/L). B ultrasound of the liver was normal. Immunosuppressants, including methylprednisolone and MMF, were administered again. Tacrolimus trough level was 6.5 ng/mL. Thus, tacrolimus was increased from 1 mg to 1.5 mg every 12 h and tacrolimus trough level was maintained at 7–8 ng/mL. Liver function subsequently recovered (Figure 9).\n\nCase 4 was a PFIC3 patient. He recovered rapidly after LT and was discharged on day 19. Liver function was normal at 1-year follow-up, without complications.\n\nCase 5 was a PFIC1 patient. The patient recovered well after LDLT and liver function was almost normal. He had recurrent diarrhea at 2 months after LDLT. According to the experience of case 1, a protocol liver biopsy was performed at 4 months after LT. The result showed steatohepatitis with 50% hepatocyte steatosis. The patient was treated with Essentiale (Table 3). At 10 months after LT, he had another liver biopsy. The result showed steatohepatitis with 20–30% hepatocyte steatosis, which was better than before (Figure 10).\n\nOutcome and the impact of LT on growth\nAll patients were alive during the follow-up period. At the end of the first year, their height S.D. scores ranged from −2.56 to 4.61, and weight S.D. scores ranged from −2.14 to 2.78 (Table 4). Both height and weight S.D. scores improved from baseline.\n\nDiscussion\nLiver transplantation is the only effective treatment at present for PFIC patients with end-stage liver disease. The indications for LT include severe pruritus, significant growth retardation, liver cirrhosis, and liver failure. PFIC patients usually have growth retardation and metabolic bone disease, mainly related to impaired vitamin D and calcium absorption due to reduced bile secretion. Aydogdu [5] reported a significant improvement at 6 months and 12 months after transplantation in terms of weight and height S.D. compared to baseline at the time of transplantation.\n\nIn the present study, the growth development of all the cases was improved compared to before. Cases 1, 2, and 5 were PFIC1 and suffered growth retardation before LT. After LT, growth retardation improved, but the catch-up growth of 2 of the 3 patients was affected by recurrent diarrhea and biliary complications.\n\nUnlike PFIC2, the timing of LT in PFIC1 is controversial. This is because LT may aggravate diarrhea and affect catch-up growth. The main cause is thought to be expression of the FIC1 gene in various organs, including the liver, pancreas, small intestine, and kidney, and a higher expression level is found in the small intestine than in the liver. Bile acid secretion may be increased in the small intestine after LT and watery diarrhea can lead to metabolic acidosis. Bile acid resin and loperamide may improve the symptoms [6]. In our study, case 1 and 5 showed aggravated diarrhea after LT. Mycophenolate mofetil was stopped and the patients recovered after loperamide and dioctahedral smectite administration. Case 2 was also a PFIC1 patient, but she did not develop aggravated diarrhea after LT.\n\nHori et al. [7,8] reported on 14 patients who underwent living donor liver transplantation (LDLT) for PFIC (11 cases of PFIC1 and 3 cases of PFIC2). Three of the 11 PFIC1 recipients died, while all 3 PFIC2 recipients survived. Eight of the 11 PFIC1 recipients developed steatosis after LDLT. Nine of these 11 PFIC1 recipients developed fibrosis after LDLT. In contrast to the PFIC1 recipients, PFIC2 recipients did not develop steatosis or fibrosis after LDLT. In our study, 2 cases of PFIC1 developed steatohepatitis within 1 year after LT. Long-term follow-up of these recipients is required to monitor for fibrosis.\n\nPFIC2 patients with some subtypes are prone to recurrences of liver diseases [9]. Some patients have a BSEP protein antibody to the donor liver [10]. In some cases, these antibodies have resulted in recurrent graft failure [11]. When allo-antibodies are detected, increased immunosuppression and the initiation of plasmapheresis/molecular adsorbent recirculating system therapies are shown to improve cholestatic episodes after transplantation in some of these PFIC2 patients[11]. The use of rituximab has also been reported to improve symptoms[12]. In our present study, the PFIC2 recipient showed fluctuations in liver function 19 months after LT. He recovered following an increase in immunosuppressants. The PFIC3 recipient recovered well without complications.\n\nConclusions\nLT is currently the only effective treatment for end-stage liver diseases due to PFIC, although LT may worsen the extra-hepatic manifestations in PFIC1 recipients. More attention should be paid to the management of immunosuppressants in PFIC2 recipients because of its relapsing nature. Further studies are necessary find ways to prolong long-term survival and reduce long-term complications in PFIC patients.\n\nSource of support: This study was supported by the Capital Special Program for Health Research and Development (No. 2016-1-2021)\n\nConflict of interests\n\nNone.\n\nFigure 1 Liver biopsy in Case 1 at 7th month after LT. Liver biopsy showed steatohepatitis with 90% hepatocyte steatosis.\n\nFigure 2 Liver biopsy in Case 1 at 19th month after LT. Liver biopsy showed 70% hepatocyte steatosis.\n\nFigure 3 Liver biopsy in Case 1 at 31th month after LT. Liver biopsy showed hepatocyte steatosis and hepatic fibrosis (F3).\n\nFigure 4 Post-LT liver function in Case 1. The patient underwent liver biopsy three times due to steatohepatitis. Following treatment with Essentiale, her liver did not significantly improve.\n\nFigure 5 Ultrasound revealed a 6.5×3.9 cm low-echo area (see arrow) in the left liver lobe on day 12 after LT in Case 2.\n\nFigure 6 In case 2, biliary cholangiography showed biloma formation in the liver and multiple intrahepatic biliary dilatations, and biliary drainage was carried out.\n\nFigure 7 In case 2, ERCP showed multiple intrahepatic biliary dilatations, and a stent was implanted.\n\nFigure 8 Biopsy of lymph nodes in the left axilia showed lymhadenitis accompanied by EBV infection with EBER(+) in case 2.\n\nFigure 9 Liver function was abnormal at 19th month after LT in case 3 and recovered after adjustment of immunosuppressant.\n\nFigure 10 Liver biopsy in case 5 at 10th month after L. Liver biopsy showed steatohepatitis with 20–30% hepatocyte steatosis and ballooning degeneration (see arrow).\n\nTable 1 Demographics and characteristics of patients.\n\nCase No.\tPrimary disease\tAge at transplantation (y)\tSex\tClinical symptoms\tPELD score\tHeight S.D. score\tWeight S.D. score\t\n1\tPFIC1\t4\tFemale\tJaundice, pruritus, diarrhea\t16\t−3.72\t−4.03\t\n2\tPFIC1\t3\tFemale\tJaundice, pruritus, diarrhea\t12\t−4.17\t−4.37\t\n3\tPFIC2\t5\tMale\tJaundice, pruritus\t5\t−1.11\t−0.59\t\n4\tPFIC3\t7\tMale\tAscites\t6\t4.5\t2.55\t\n5\tPFIC1\t2\tMale\tJaundice, diarrhea\t8\t−1.9\t−1.52\t\nTable 2 Clinical findings in PFIC patients with liver transplantation.\n\nCase No.\tDonor type\tABO blood group\tOperation time\tBlood loss (mL)\tCold Ischemia time (min)\tRetrieval warm Ischemia time (min)\tImmunosuppressants during LT/post-LT\tTrough level of tacrolimus (ng/mL) within 6 m/after one year\tHospital stay (d)\t\n1\tDCD\tCompatible\t2014/9/2\t150\t420\t5\tMethylprednisolone (10 mg/kg)/FK 506 + methylprednisolone + MMF\t8–10/5–8\t25\t\n2\tDCD\tIncompatible\t2014/7/25\t150\t480\t5\tMethylprednisolone (10 mg/kg)/FK 506 + methylprednisolone + MMF\t8–10/5–8\t54\t\n3\tDCD\tCompatible\t2014/9/23\t200\t370\t5\tMethylprednisolone (10 mg/kg)/FK 506 + methylprednisolone + MMF\t8–10/5–8\t28\t\n4\tDCD\tCompatible\t2016/1/14\t300\t550\t5\tMethylprednisolone (10 mg/kg)/FK 506 + methylprednisolone + MMF\t8–10/5–8\t19\t\n5\tLDLT\tCompatible\t2017/2/23\t230\t110\t3\tMethylprednisolone (10 mg/kg)/FK 506 + methylprednisolone + MMF\t7–10/4–7\t21\t\nTable 3 Complications in PFIC patients after LT and treatment.\n\nCase No.\tComplications\tOccurrence time\tTreatment\t\n1\tDiarrhea\t1st month\tLoperamide, cholestyramine\t\nSteatohepatitis\t7th month\tEssentiale\t\n\n\t\n2\tBiliary complications\t10th month\tPTCD and ERCP\t\nEBV infection\t2 years\tGanciclovir and tacrolimus reduction\t\n\n\t\n3\tLiver function abnormal\t19th month\tIncrease in immunosuppressants\t\n\n\t\n4\tNone\tNone\tNone\t\n\n\t\n5\tDiarrhea\t2nd month\tDioctahedral smectite\t\nSteatohepatitis\t4th month\tEssentiale\t\nTable 4 Outcome and growth after LT.\n\nCase No.\tHeight S.D. score before LT\tHeight S.D. score at the 1st year\tWeight S.D. score before LT\tWeight S.D. score at the 1st year\tOutcome\t\n1\t−3.72\t−2.56\t−4.03\t−2.09\tAlive\t\n2\t−4.17\t−1.89\t−4.37\t−2.14\tAlive\t\n3\t−1.11\t2.43\t−0.59\t2.31\tAlive\t\n4\t4.5\t4.61\t2.55\t2.78\tAlive\t\n5\t−1.9\t−1.7\t−1.52\t−1.2\tAlive\n==== Refs\nReferences\n1 Nakanishi Y Saxena R Pathophysiology and diseases of the proximal pathways of the biliary system Arch Pathol Lab Med 2015 139 858 66 26125426 \n2 van Mil SW Klomp LW Bull LN Houwen RH FIC1 disease: A spectrum of intrahepatic cholestatic disorders Semin Liver Dis 2001 21 535 44 11745041 \n3 de Vree JM Jacquemin E Sturm E Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis Proc Natl Acad Sci USA 1998 95 282 87 9419367 \n4 Mehl A Bohorquez H Serrano M-S Liver transplantation and the management of progressive familial intrahepatic cholestasis in children World J Transplant 2016 6 2 278 90 27358773 \n5 Aydogdu S Cakir M Arikan C Liver transplantation for progressive familial intrahepatic cholestasis: Clinical and histopathological findings, outcome and impact on growth Pediatr Transplant 2007 11 6 634 40 17663686 \n6 Lykavieris P van Mil S Cresteil D Progressive familial intrahepatic cholestasis type 1 and extrahepatic features: No catch-up of stature growth, exacerbation of diarrhea, and appearance of liver steatosis after liver transplantation J Hepatol 2003 39 3 447 52 12927934 \n7 Hori T Egawa H Miyagawa-Hayashino A Living-donor liver transplantation for progressive familial intrahepatic cholestasis World J Surg 2011 35 2 393 402 21125272 \n8 Hori T Egawa H Takada Y Progressive familial intrahepatic cholestasis: A single-center experience of living-donor liver transplantation during two decades in Japan Clin Transplant 2011 25 5 776 85 21158920 \n9 Maggiore G Gonzales E Sciveres M Relapsing features of bile salt export pump deficiency after liver transplantation in two patients with progressive familial intrahepatic cholestasis type 2 J Hepatol 2010 53 981 86 20800306 \n10 Stindt J Kluge S Dröge C Bile salt export pump-reactive antibodies form a polyclonal, multiinhibitory response in antibody-induced bile salt export pump deficiency Hepatology 2016 63 524 37 26516723 \n11 Ketel V Burdelski M Vojnisek Z De novo bile salt transporter antibodies as a possible cause of recurrent graft failure after liver transplantation: A novel mechanism of cholestasis Hepatology 2009 50 510 17 19642168 \n12 Lin HC Alvarez L Laroche G Rituximab as therapy for the recurrence of bile salt export pump deficiency after liver transplantation Liver Transpl 2013 19 1403 10 24115678\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1425-9524",
"issue": "23()",
"journal": "Annals of transplantation",
"keywords": null,
"medline_ta": "Ann Transplant",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D002780:Cholestasis, Intrahepatic; D003967:Diarrhea; D018450:Disease Progression; D005234:Fatty Liver; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008775:Methylprednisolone; D009173:Mycophenolic Acid; D011183:Postoperative Complications; D012189:Retrospective Studies; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "9802544",
"other_id": null,
"pages": "666-673",
"pmc": null,
"pmid": "30250015",
"pubdate": "2018-09-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19642168;12927934;11745041;24115678;21125272;9419367;26125426;17663686;20800306;27358773;26516723;21158920",
"title": "Liver Transplantation for Progressive Familial Intrahepatic Cholestasis.",
"title_normalized": "liver transplantation for progressive familial intrahepatic cholestasis"
} | [
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{
"abstract": "We report a case of serum sickness-like reaction (SSLR) in a 14-year-old male taking minocycline for acne. The patient presented with urticarial rash, arthralgia/arthritis, and tender lymphadenopathy. Symptoms resolved with discontinuation of minocycline and treatment with prednisone, cetirizine, and ibuprofen. SSLR is a rare complication of minocycline treatment that may go unrecognized and underreported.",
"affiliations": "University of South Dakota Sanford School of Medicine, Sioux Falls, South Dakota.;Avera Medical Group Dermatology, Sioux Falls, South Dakota.",
"authors": "Lucido|Christopher T|CT|;Johnson|Jana|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D008911:Minocycline",
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"issue": "74(7)",
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"medline_ta": "S D Med",
"mesh_terms": "D000152:Acne Vulgaris; D000293:Adolescent; D000900:Anti-Bacterial Agents; D018771:Arthralgia; D006801:Humans; D008297:Male; D008911:Minocycline; D012713:Serum Sickness",
"nlm_unique_id": "101265265",
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"pmc": null,
"pmid": "34449992",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Serum Sickness-Like Reaction in an Adolescent Taking Minocycline for Acne.",
"title_normalized": "serum sickness like reaction in an adolescent taking minocycline for acne"
} | [
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"companynumb": "US-VYNE PHARMACEUTICALS INC-2021-VYNE-US003325",
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"activesubstancename": "MINOCYCLINE HYDROCHLORIDE"
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"abstract": "Herpes simplex virus (HSV) hepatitis is a rare and serious complication in immunocompromised patients. We report the case of an HSV hepatitis occurring 4 years after lung transplantation in a cystic fibrosis patient. The presentation was nonspecific, mimicking acute cholecystitis; orogenital signs were absent. The diagnosis was made based on viral cultures performed during cholecystectomy and confirmed by blood quantitative polymerase chain reaction. Although the diagnosis and treatment were delayed, the patient fully recovered with acyclovir, reduced immunosuppression, and intravenous immunoglobulins. The diagnostic difficulties, prognostic factors, and treatments of this infection are discussed.",
"affiliations": "Department of Respiratory Medicine, Strasbourg University Hospital, Strasbourg, France.;Department of Cardiological, Thoracic and Vascular Sciences, University of Padova, Padova, Italy.;Department of Radiology, Strasbourg University Hospital, Strasbourg, France.;Department of Virology, Strasbourg University Hospital, Strasbourg, France.;Institut Hospitalo-Universitaire (IHU), Institute for Minimally Hybrid Invasive Image-Guided Surgery, Strasbourg University Hospital, Strasbourg, France.;Department of Respiratory Medicine, Strasbourg University Hospital, Strasbourg, France.;Department of Respiratory Medicine, Strasbourg University Hospital, Strasbourg, France.",
"authors": "Hirschi|S|S|;Biondini|D|D|;Ohana|M|M|;Solis|M|M|;D'Urso|A|A|;Rosner|V|V|;Kessler|R|R|",
"chemical_list": "D000998:Antiviral Agents; D016756:Immunoglobulins, Intravenous; D000212:Acyclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12459",
"fulltext": null,
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"issue": "17(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "hepatitis; herpes simplex virus; lung transplantation; quantitative polymerase chain reaction",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000212:Acyclovir; D000328:Adult; D000998:Antiviral Agents; D005260:Female; D006525:Hepatitis, Viral, Human; D018258:Herpesvirus 2, Human; D006801:Humans; D016867:Immunocompromised Host; D016756:Immunoglobulins, Intravenous; D016040:Lung Transplantation",
"nlm_unique_id": "100883688",
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"pages": "904-8",
"pmc": null,
"pmid": "26370068",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Herpes simplex virus 2 hepatitis in a lung transplant recipient: a diagnostic challenge.",
"title_normalized": "herpes simplex virus 2 hepatitis in a lung transplant recipient a diagnostic challenge"
} | [
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"companynumb": "FR-ACCORD-038828",
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"activesubstancename": "MYCOPHENOLIC ACID"
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... |
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"abstract": "Thyroid dysfunction in adolescents treated with minocycline for acne has been previously described as transient effect and/or associated with autoimmune thyroiditis. We report nonimmune-mediated thyroid dysfunction associated with minocycline/doxycycline in 3 adolescents whose clinical courses suggest an adverse effect that may be more common, serious, and persistent than realized previously.",
"affiliations": "Division of Pediatric Endocrinology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI. Electronic address: apollock@pediatrics.wisc.edu.;Case Western Reserve University School of Medicine, Cleveland, OH.;Division of Pediatric Endocrinology, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI.",
"authors": "Pollock|Allison J|AJ|;Seibert|Tasa|T|;Allen|David B|DB|",
"chemical_list": "D000900:Anti-Bacterial Agents; D013972:Thyrotropin; D008911:Minocycline; D013974:Thyroxine",
"country": "United States",
"delete": false,
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"issn_linking": "0022-3476",
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"journal": "The Journal of pediatrics",
"keywords": "acne vulgaris; doxycycline; hyperthyroidism; hypothyroidism; minocycline; tetracycline; thyroid dysfunction; thyroiditis",
"medline_ta": "J Pediatr",
"mesh_terms": "D000152:Acne Vulgaris; D000293:Adolescent; D000900:Anti-Bacterial Agents; D004172:Diplopia; D005221:Fatigue; D005260:Female; D006261:Headache; D006801:Humans; D006980:Hyperthyroidism; D008297:Male; D008911:Minocycline; D059606:Polydipsia; D013972:Thyrotropin; D013974:Thyroxine; D015431:Weight Loss",
"nlm_unique_id": "0375410",
"other_id": null,
"pages": "232-4",
"pmc": null,
"pmid": "27059913",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21113440;9074802;14569701;19153345;16514674;22171784;8837329;19890835;17542873;6219651;17230575;10471875;14529072;3788563;14987144;16291409;990789;19664162;10406406;20720371",
"title": "Severe and Persistent Thyroid Dysfunction Associated with Tetracycline-Antibiotic Treatment in Youth.",
"title_normalized": "severe and persistent thyroid dysfunction associated with tetracycline antibiotic treatment in youth"
} | [
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"companynumb": "US-FRESENIUS KABI-FK201604174",
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"activesubstance": {
"activesubstancename": "MINOCYCLINE\\MINOCYCLINE HYDROCHLORIDE"
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... |
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"abstract": "Although opioid-induced muscle rigidity occurs more commonly with large doses and rapid administration of the drugs, there is a number of cases reported, where muscle rigidity was experienced with lower doses of opioids. We present and discuss a case of muscle rigidity induced by an unusually low dose of fentanyl as primary agent during induction of anesthesia. A 79 year old male patient, scheduled for hernia repair, and with a preoperative physical examination of slight hand tremor, received a bolus of 100 mcg (1.2 mcg/kg) fentanyl as primary agent for induction. About 40 sec later he stopped responding, lost consciousness and developed neck and masseter muscle spasm with jaw closure and thoracoabdominal rigidity. Blood pressure was increased significantly. Ventilation was impossible. Rapid oxygen desaturation led us to proceed with IV propofol 150 mg and suxamethonium 100 mg. Opioid-induced muscle rigidity may cause life-threatening respiratory compromise and should be readily recognized and treated by anesthesiologists.",
"affiliations": null,
"authors": "Dimitriou|Vassilios|V|;Zogogiannis|Ioannis|I|;Liotiri|Despoina|D|;Wambi|Freddie|F|;Tawfeeq|Nasser|N|;Koumi|Adnan|A|;Geldhof|Georges|G|",
"chemical_list": "D000701:Analgesics, Opioid; D005283:Fentanyl",
"country": "Lebanon",
"delete": false,
"doi": null,
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"issn_linking": "0544-0440",
"issue": "22(6)",
"journal": "Middle East journal of anaesthesiology",
"keywords": null,
"medline_ta": "Middle East J Anaesthesiol",
"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D020329:Essential Tremor; D005283:Fentanyl; D006801:Humans; D008297:Male; D008397:Masks; D009127:Muscle Rigidity; D012119:Respiration",
"nlm_unique_id": "8604187",
"other_id": null,
"pages": "619-22",
"pmc": null,
"pmid": "25669008",
"pubdate": "2014-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Impossible mask ventilation after an unusually low dose fentanyl-induced muscle rigidity in a patient with essential tremor: a case report and review of the literature.",
"title_normalized": "impossible mask ventilation after an unusually low dose fentanyl induced muscle rigidity in a patient with essential tremor a case report and review of the literature"
} | [
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"companynumb": "SA-DEPOMED, INC.-SA-2016DEP011812",
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"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
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"abstract": "Intravesical administration of bacillus Calmette-Guerin has been shown to be highly effective treatment of superficial bladder cancer. Complications from bacillus Calmette-Guerin therapy are usually minor but serious and even fatal reactions can occur. Five recent cases illustrate the gravity of bacillus Calmette-Guerin sepsis. One man with severe debility and the organic brain syndrome died acutely with a fever of 40 C. Two men had frank sepsis that progressed to multiorgan failure and death. Sepsis progressed despite the use of isoniazid, rifampin and streptomycin. Two men who had equally progressive sepsis with intravesical bacillus Calmette-Guerin survived with the use of cycloserine for the first 72 hours of treatment. Triple antituberculous antibiotics, including cycloserine, may be lifesaving. Sepsis resulted from intravenous absorption through inflamed or disrupted urothelium. Bacillus Calmette-Guerin treatment should not be administered in the presence of severe cystitis or after grossly traumatic catheterization.",
"affiliations": "Department of Urology, West Virginia University Health Sciences Center, Morgantown.",
"authors": "Rawls|W H|WH|;Lamm|D L|DL|;Lowe|B A|BA|;Crawford|E D|ED|;Sarosdy|M F|MF|;Montie|J E|JE|;Grossman|H B|HB|;Scardino|P T|PT|",
"chemical_list": "D000904:Antibiotics, Antitubercular; D001500:BCG Vaccine",
"country": "United States",
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"doi": "10.1016/s0022-5347(17)39731-8",
"fulltext": null,
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"issn_linking": "0022-5347",
"issue": "144(6)",
"journal": "The Journal of urology",
"keywords": null,
"medline_ta": "J Urol",
"mesh_terms": "D000283:Administration, Intravesical; D000368:Aged; D000904:Antibiotics, Antitubercular; D001500:BCG Vaccine; D002295:Carcinoma, Transitional Cell; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure; D014376:Tuberculosis; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "0376374",
"other_id": null,
"pages": "1328-30",
"pmc": null,
"pmid": "2231917",
"pubdate": "1990-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal sepsis following intravesical bacillus Calmette-Guerin administration for bladder cancer.",
"title_normalized": "fatal sepsis following intravesical bacillus calmette guerin administration for bladder cancer"
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"companynumb": "US-SA-2019SA158456",
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"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
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"abstract": "A 64 year-old woman with steroid-dependent immune thrombocytopenia developed anemia. Esophagogastroduodenoscopy revealed the presence of a tumor, which was diagnosed to be diffuse large B-cell lymphoma, in the second portion of the duodenum. 18F-fluorodeoxy glucose positron emission tomography showed an increased uptake mass in the pelvic cavity as well as in the duodenum. Though the duodenal tumor disappeared after 4 cycles of chemotherapy, the pelvic mass did not shrink in size. As a result, laparoscopic resection of the pelvic tumor was performed and the tumor was histologically diagnosed to be a gastrointestinal stromal tumor. Subsequently, the patient was treated with 2 more cycles of the chemotherapy. Eventually, thrombocytopenia completely resolved.",
"affiliations": "Department of Hematology, Tenshi Hospital, Japan.",
"authors": "Takahashi|Tohru|T|;Maruyama|Yumiko|Y|;Saitoh|Mayuko|M|;Itoh|Hideto|H|;Yoshimoto|Mitsuru|M|;Tsujisaki|Masayuki|M|;Nakayama|Masato|M|",
"chemical_list": null,
"country": "Japan",
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"doi": "10.2169/internalmedicine.55.6712",
"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.55.6712Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 27746431Case ReportSynchronous Occurrence of Diffuse Large B-cell Lymphoma of the Duodenum and Gastrointestinal Stromal Tumor of the Ileum in a Patient with Immune Thrombocytopenic Purpura Takahashi Tohru 1Maruyama Yumiko 1Saitoh Mayuko 2Itoh Hideto 2Yoshimoto Mitsuru 2Tsujisaki Masayuki 2Nakayama Masato 31 Department of Hematology, Tenshi Hospital, Japan2 Department of Gastroenterology, Tenshi Hospital, Japan3 Department of Surgery, Tenshi Hospital, JapanCorrespondence to Dr. Tohru Takahashi, tohrut@cocoa.ocn.ne.jp\n\n15 10 2016 55 20 2951 2956 19 10 2015 1 3 2016 The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 64 year-old woman with steroid-dependent immune thrombocytopenia developed anemia. Esophagogastroduodenoscopy revealed the presence of a tumor, which was diagnosed to be diffuse large B-cell lymphoma, in the second portion of the duodenum. 18F-fluorodeoxy glucose positron emission tomography showed an increased uptake mass in the pelvic cavity as well as in the duodenum. Though the duodenal tumor disappeared after 4 cycles of chemotherapy, the pelvic mass did not shrink in size. As a result, laparoscopic resection of the pelvic tumor was performed and the tumor was histologically diagnosed to be a gastrointestinal stromal tumor. Subsequently, the patient was treated with 2 more cycles of the chemotherapy. Eventually, thrombocytopenia completely resolved. \n\nlymphomaGISTITP\n==== Body\nIntroduction\nGastrointestinal stromal tumors (GISTs) are an uncommon mesenchymal neoplasm of the gastrointestinal (GI) tract. They occur most commonly in the stomach (60-70%), followed by the small intestine (20-30%). The synchronous occurrence of other malignancies in the patients with GIST during their clinical courses is relatively common (1,2). However, the synchronous coexistence of GIST and GI lymphoma has only rarely been reported (3-8). We herein report a unique case of ileal GIST which was incidentally discovered during the course of chemotherapy for duodenal diffuse large B-cell lymphoma (DLBCL). The patient had also been diagnosed to have immune thrombocytopenic purpura (ITP) before the diagnosis of DLBCL was made.\n\nCase Report\nA 62-year-old woman was referred to us due to the onset of purpura and thrombocytopenia in April 2012. The white cell count was 4, 320 /μL, the hemoglobin concentration was 11.3 g/dL, and the platelet count was 27,000 /μL. Serum biochemistry tests were normal. Physical examination showed no abnormal findings except for quite a few purpura in the upper and lower extremities. A bone marrow examination revealed normocellular marrow without myelodysplasia, and a chromosomal analysis was normal. She was diagnosed to have ITP. Esophagogastroduodenoscopy (EGD) was performed and chronic gastritis was diagnosed. No tumors in the duodenum were observed at that time. A urea breath test was positive and a combination therapy with antibiotics (amoxicillin 750 mg twice daily and clarithromycin 200 mg twice daily for 7 days) and a proton pump inhibitor (esomeprazole 20 mg twice daily for 7 days) for the eradication of the Helicobacter pylori (HP) was carried out. At the same time, she was started on prednisolone (1 mg/kg per day) because of worsening of the purpura and the platelet count decreased to 21,000 /μL. Her platelet count thereafter quickly increased (Fig. 1). The urea breath test again carried out and the eradication of the HP was found to be successful. However, thrombocytopenia recurred when the steroid dosage was tapered. Because she refused to undergo splenectomy, eltrombopag was used with a small dose of prednisolone to maintain her platelet count. In the meantime, the patient developed mild iron deficiency anemia in October 2014 (at 64 years of age). Occult blood of feces was negative. EGD revealed a circumferential ulcerative tumor mimicking type 2 advanced cancer (Fig. 2A). A pathological examination of the biopsied specimen showed a diffuse infiltration of large lymphoid cells which were positive for CD20 but negative for CD3 (Fig. 3). A flow cytometric analysis showed the tumor cells to be positive for CD 19, 20 and lamda chain, but negative for CD3, 5, 10, 23 and kappa chain. As a result, a diagnosis of DLBCL was made. An 18F-fluorodeoxy glucose (FDG) positron emission tomography (PET) study with a simultaneous whole body computed tomography (CT) scan showed a markedly increased uptake of FDG in the duodenum (Fig. 4A). An FDG-positive round mass in the right pelvic cavity was also found (Fig. 4B). Although the possibility of another malignancy could not be ruled out, the mass was considered to be an enlarged mesenteric lymph node that had been infiltrated by lymphoma cells at that time. She was treated with standard R-CHOP (consisted of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) therapy. After the 4th cycle of the therapy, the duodenal tumor was not detected by EGD (Fig. 2B). An interim FDG-PET study showed that the mass in the pelvic cavity had not shrunk at all, while the duodenal lesion had completely disappeared (Fig. 4C and D). Laparoscopic resection of the tumor with its adjacent ileum was thereafter successfully carried out. The tumor was a well-demarcated capsulated mass measuring 5 cm in diameter and it protruded from the intestine to the peritoneal cavity (Fig. 5). A pathological examination disclosed a proliferation of spindle shaped cells with only slight mitotic activity (Fig. 6). An immunohisotochemical study showed the cells to be positive for CD117(c-KIT) and CD34, and the MIB-1 index was less than 1%. Thus, a diagnosis of GIST with an intermediate risk was made. The patient was treated with 2 more courses of R-CHOP therapy. The FDG-PET study on June 2015 showed no abnormal uptake. Her platelet count had been normal without the administration of steroids or eltrombopag after the chemotherapy. However, lumbago and a pain in the right leg developed in October 2015. A CT scan of the abdomen showed a large mass (9.6×6.6×6.7 cm) in the right lower abdominal cavity. A percutaneous biopsy of the tumor revealed a recurrence of DLBCL. She was treated with ESHAP (consisted of etoposide, cisplatinum, high dose Ara-C, and methyl prednisolone) therapy without success and she died of the tumor progression in November 2015.\n\nFigure 1. Clinical course.\n\n\nFigure 2. Upper gastrointestinal endoscopic examination showed a circumferential ulcerating tumor mimicking a type II-like tumor in the second portion of the duodenum (A). The tumor disappeared after 4 cycles of R-CHOP therapy (B).\n\nFigure 3. A duodenal biopsy showed the diffuse infiltration of large lymphoid cells (Hematoxylin and Eosin staining) (A). The cells were positive for CD20 (B).\n\nFigure 4. FDG-PET/CT study showed a significant uptake in the duodenum (A) and the pelvic mass (B) before chemotherapy. After chemotherapy, the duodenum mass disappeared (C) while the pelvic mass remained (D).\n\nFigure 5. A fixed resected specimen of the pelvic tumor. A well-demarcated mass measuring 5 cm in diameter is observed.\n\nFigure 6. A resected pelvic tumor contained spindle shaped cells (Hematoxylin and Eosin staining) (A). The cells were positive for CD117 (B).\n\nDiscussion\nThe present patient was found to have duodenal DLBCL in her course of ITP. Autoimmune disorders are occasionally associated with lymphoid malignancies. ITP may occur in lymphoproliferative diseases, such as chronic lymphocytic leukemia (9), but it is rare in patients with malignant lymphoma. The prevalence of ITP in non-Hodgkin lymphomas has been reported to be less than 1% (10). Among these, DLBCL is extremely rare. To our knowledge, there have only been 7 reported cases of definitely diagnosed DLBCL associated with ITP in the English literature (Table 1) (11-17). Three cases were primary adrenal lymphomas and two cases were stage IV diseases involving extra nodal lesions (1 mesentery and 1 ascending colon, pancreas, and adrenal gland etc.). Three cases were refractory to steroid therapy (12,14,15). A complete resolution of thrombocytopenia was achieved in two cases after performing successful lymphoma therapies (15,17) and in three cases after splenectomy (12,13,16). The pathogenesis of ITP associated with lymphoma is still not fully understood. In one case, the production of antiplatelet antibody from lymphoma cells was confirmed (14). However, the direct causative relationships between ITP and DLBCLs could not be identified in the other reported cases. The present patient responded well to steroid therapy before undergoing chemotherapy, and thrombocytopenia completely resolved without either steroids or eltrombopag after the chemotherapy. Even after the recurrence of the lymphoma, the platelet counts remained normal. Therefore, it is not likely that the lymphoma cells produced autoantibodies to the platelet in the present case. Rituximab is reported to be effective for chronic ITP refractory to steroids or splenectomy (18). The patients treated with R-CHOP (15, 16, and the present case) showed a resolution of thrombocytopenia without steroids after the therapy. R-CHOP therapy may therefore provide sufficient immunosupression for ITP.\n\nTable 1. Reported Cases of DLBCL Associated with Immune Thrombocytopenic Purpura.\n\nAge/Sex\tOrigin of DLBCL\tTreatment for DLBCL\tResponse\tThrombocytopenia\tReference\t\n69/M\tMesentery\tSurgery + chemotherapy\tCR\tPersisted\t(11)\t\n61/F\tAdrenal glands\tSurgery + chemotherapy\tCR\tResolved by splenectomy\t(12)\t\n63/M\tAdrenal glands\tSurgery + chemotherapy\tCR\tResolved by splenectomy\t(13)\t\n61/F\tAdrenal glands\tChemotherapy\tPR\tImproved by chemotherapy\t(14)\t\n59/F\tColon\tChemotherapy\tCR\tResolved by chemotherapy\t(15)\t\n51/M\tNodal\tChemotherapy\tCR\tResolved by splenectomy\t(16)\t\n80/M\tNasopharynx + LN\tChemotherapy + RT\tCR\tResolved by radiotherapy\t(17)\t\n64/F\tDuodenum\tChemotherapy\tCR\tResolved by splenectomy\tPresent case\t\nDLBCL: diffuse large B-cell lymphoma, CR: complete remission, PR: partial remission, LN: lymph nodes, RT: radiotherapy\n\nThe patient was started on prednisolone immediately after admission because of severe purpura before Helicobacter pylori eradication therapy was started. It was reported that Helicobacter pylori eradication could induce platelet recovery in almost half of ITP patients (19). However, it took 2 to 3 months until the response was obtained. Thrombocytopenia recurred in the present patient when the steroids were tapered. Therefore, the eradication of Helicobacter was not considered to be effective in this case.\n\nGIST is an uncommon neoplasm affecting the gastrointestinal tract. Though approximately 5% of GISTs have a hereditary etiology (20), most GISTs develop in a sporadic fashion and are usually located in the stomach and small intestine. The present patient had sporadic ileal GIST which was incidentally found in the course of duodenal DLBCL. The FDG-positive round mass in the right pelvic cavity was considered to be an enlarged mesenteric lymph node infiltrated by lymphoma cells at first because the tumor did not appear to develop from the intestine. We should have performed a biopsy before the R-CHOP therapy was started. Almost one-third of all reported GISTs are discovered incidentally during the investigative or therapeutic procedures for unrelated diseases. In addition, GI adenocarcinomas are the most prevalent GIST-associated cancers (47%) (1). Wronski et al. reported that 4 of 28 GIST patients (14%) simultaneously had other primary GI malignancies at their institution and they suggested the possible involvement of the same carcinogenic agents (3). There have only been 6 reported cases of concomitant GIST and GI lymphoma to date (Table 2). Three of these cases had gastric GISTs and gastric mucosa associated lymphoid tissue (MALT) lymphomas. To our knowledge, the cases of simultaneous occurrence of DLBCL and GIST in the small intestine have never been reported.\n\nTable 2. Reported Cases of Simultaneous GIST and GI-lymphoma.\n\nAge/Sex\tLocation of GIST\tLocation of lymphoma\tHistology\tReference\t\n77/F\tStomach\tStomach\tDLBCL\t(3)\t\n78/M\tStomach\tStomach\tMALT lymphoma\t(4)\t\n73/M\tStomach\tStomach\tCLL type NHL\t(5)\t\n54/F\tStomach\tStomach\tMALT lymphoma\t(6)\t\n68/M\tStomach\tStomach\tLow grade BCL\t(7)\t\n65/F\tAppendix\tIleocecal lesion\tMCL\t(8)\t\n64/F\tIleum\tDuodenum\tDLBCL\tPresent case\t\nGIST: gastrointestinal stromal tumor, MALT: mucosa associated lymphoid tissue, CLL: chronic lymphocytic leukemia, NHL: non-Hodgkin lymphoma, DLBCL: diffuse large B-cell lymphoma, MCL: mantle cell lymphoma\n\nA recent population-based analysis has also confirmed many significant associations between GISTs and other cancers including non-Hodgkin lymphoma (2). Lymphoma patient may thus have higher tendency to have GIST, and vice versa. However, it is not clear whether these two tumors develop due to the same underlying etiology or not.\n\nWe herein reported a case of concurrent primary duodenal DLBCL and small intestinal GIST associated with ITP. Though the simultaneous occurrence of these diseases may be only coincidental, its clinical course was unique and interesting. We hope that this report will be of some use for the management of double cancer patients associated with autoimmune diseases such as ITP.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Agaimy A , Wünsch PH , Sobin LH , Lasota J , Miettinen M \nOccurrence of other malignancies in patients with gastrointestinal stromal tumors . Semin Diagn Pathol \n23 : 120 -129 , 2006 .17193825 \n2. Murphy JD , Ma GL , Baumgartner JM , et al \nIncreased risk of additional cancers among patients with gastrointestinal stromal tumors: A population-based study . Cancer \n121 : 2960 -2967 , 2015 .25930983 \n3. Wronski M , Ziarkiewicz-Wroblewska B , Gornicka B , et al \nSynchronous occurrence of gastrointestinal stromal tumors and other primary gastrointestinal neoplasms . World J Gastroenterol \n12 : 5360 -5362 , 2006 .16981268 \n4. Kaffes A , Hughes L , Hollinshead J , Katelaris P \nSynchronous primary adenocarcinoma, mucosa-associated lymphoid tissue lymphoma and a stromal tumor in a Helicobacter pylori-infected stomach . J Gastroenterol Hepatol \n17 : 1033 -1036 , 2002 .12167128 \n5. Herbers AH , Keuning JJ \nStaging for CLL-type non-Hodgkin's lymphoma reveals a gastrointestinal stromal tumour . Neth J Med \n63 : 74 -75 , 2005 .15766012 \n6. Salar A , Ramón JM , Barranco C , et al \nDouble diagnosis in cancer patients and cutaneous reaction related to gemcitabine: CASE 1. Synchronous mucosa-associated lymphoid tissue lymphoma and gastrointestinal stromal tumors of the stomach . J Clin Oncol \n23 : 7221 -7223 , 2005 .16192606 \n7. Pamukçuoglu M , Budakoğlu B , Han O , et al \nAn extraordinary case in whom gastrointestinal stromal tumor and low-grade malignant lymphoma are seen together in the stomach . Med Oncol \n24 : 351 -353 , 2007 .17873313 \n8. Rahimi K , Gologan A , Haliotis T , Lamoureux E , Chetty R \nGastrointestinal stromal tumor with autonomic nerve differentiation and coexistent mantle cell lymphoma involving the appendix . Int J Clin Exp Pathol \n2 : 608 -613 , 2008 .19636397 \n9. Kaden BR , Rosse WF , Hauch TW \nImmune thrombocytopenia in lymphoproliferative diseases . Blood \n53 : 545 -551 , 1979 .426906 \n10. Hauswirth AW , Skrabs C , Schützinger C , et al \nAutoimmune thrombocytopenia in non-Hodgkin's lymphomas . Haematologica \n93 : 447 -450 , 2008 .18287133 \n11. Moriwaki Y , Naka M , Yamamoto T , et al \nMalignant lymphoma in the mesentery with immune thrombocytopenia . Intern Med \n31 : 1185 -1189 , 1992 .1286224 \n12. Baudard M , Pagnoux C , Audouin J , et al \nIdiopathic thrombocytopenic purpura as the presenting feature of a primary bilateral adrenal non Hodgkin's lymphoma . Leuk Lymphoma \n26 : 609 -613 , 1997 .9389368 \n13. Yamamoto E , Ozaki N , Nakagawa M , Kimoto M \nPrimary bilateral adrenal lymphoma associated with idiopathic thrombocytopenic purpura . Leuk Lymphoma \n35 : 403 -408 , 1999 .10706466 \n14. Nobuoka A , Sakamaki S , Kogawa K , et al \nA case of malignant lymphoma producing autoantibody against platelet glycoprotein Ib . Int J Hematol \n70 : 200 -206 , 1999 .10561915 \n15. Uchiyama M , Sato K , Ikeda T \nDiffuse large B-cell lymphoma complicated with autoimmune thrombocytopenia . Intern Med \n50 : 1215 -1218 , 2011 .21628938 \n16. Park SY , Kim S , Kim ES , et al \nA case of non-Hodgkin's lymphoma in patient with Coombs' negative hemolytic anemia and idiopathic thrombocytopenic purpura . Cancer Res Treat \n44 : 69 -72 , 2012 .22500164 \n17. Berrang T , Holloway C , Hart J , Yee A , Berry B , Kotb R \nSuccessful treatment of non-Hodgkin lymphoma associated immune thrombocytopenia with involved field radiotherapy . Hematol Oncol \n31 : 218 -220 , 2013 .23606442 \n18. Stasi R , Pagano A , Stipa E , Amadori S \nRituximab chimeric anti-CD20 monoclonal antibody treatment for adults with chronic idiopathic thrombocytopenic purpura . Blood \n98 : 952 -957 , 2001 .11493438 \n19. Emilia G , Longo G , Luppi M , et al \nHelicobacter pylori eradication can induce platelet recovery in idiopathic thrombocytopenic purpura . Blood \n97 : 812 -814 , 2001 .11157503 \n20. Nilsson B , Bümming P , Meis-Kindblom JM , et al \nGastrointestinal stromal tumors: the incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era--a population-based study in western Sweden . Cancer \n103 : 821 -829 , 2005 .15648083\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "55(20)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D004379:Duodenal Neoplasms; D004386:Duodenum; D016145:Endoscopy, Digestive System; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D007082:Ileum; D016403:Lymphoma, Large B-Cell, Diffuse; D008875:Middle Aged; D016553:Purpura, Thrombocytopenic, Idiopathic; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2951-2956",
"pmc": null,
"pmid": "27746431",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22500164;21628938;1286224;15766012;18287133;25930983;10561915;11493438;17193825;16981268;16192606;426906;15648083;19636397;11157503;12167128;17873313;9389368;23606442;10706466",
"title": "Synchronous Occurrence of Diffuse Large B-cell Lymphoma of the Duodenum and Gastrointestinal Stromal Tumor of the Ileum in a Patient with Immune Thrombocytopenic Purpura.",
"title_normalized": "synchronous occurrence of diffuse large b cell lymphoma of the duodenum and gastrointestinal stromal tumor of the ileum in a patient with immune thrombocytopenic purpura"
} | [
{
"companynumb": "JP-ACCORD-045748",
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"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
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{
"abstract": "Venous sclerotherapy is an emerging cosmetic treatment option for dorsal hand varicose veins. Although venous sclerotherapy is considered a safe and effective procedure for treatment of venous malformations and varicosities in both the upper and lower extremities, inadvertent injection of the sclerosing agent into the arterial system has led to reported instances of acute ischemic events and distal limb necrosis. This is a rare but well-documented complication of lower-extremity venous sclerotherapy. Only 2 cases have been reported in upper-extremity venous sclerotherapy, both of which occurred during treatment of complex vascular malformations. We report an instance of acute, distal digit ischemia after elective venous sclerotherapy for a dorsal hand varicosity. As this procedure grows in popularity, it is essential for hand surgeons to be aware of this rare but potentially devastating complication.",
"affiliations": "Department of Orthopaedic Surgery, Icahn School of Medicine Mount Sinai, New York, NY. Electronic address: steven.andelman@mountsinai.org.;Department of Orthopaedic Surgery, Icahn School of Medicine Mount Sinai, New York, NY.;Department of Orthopaedic Surgery, Icahn School of Medicine Mount Sinai, New York, NY.;Department of Orthopaedic Surgery, Icahn School of Medicine Mount Sinai, New York, NY.",
"authors": "Andelman|Steven M|SM|;Walsh|Amanda L|AL|;Rubin|Todd A|TA|;Hausman|Michael R|MR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jhsa.2017.03.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-5023",
"issue": "42(8)",
"journal": "The Journal of hand surgery",
"keywords": "Varicose vein; hand; ischemia; venous sclerotherapy",
"medline_ta": "J Hand Surg Am",
"mesh_terms": "D005260:Female; D006225:Hand; D006801:Humans; D007511:Ischemia; D008875:Middle Aged; D015911:Sclerotherapy; D014648:Varicose Veins",
"nlm_unique_id": "7609631",
"other_id": null,
"pages": "666.e1-666.e5",
"pmc": null,
"pmid": "28410939",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Hand Ischemia Following Elective Venous Sclerotherapy for Dorsal Hand Varicose Veins.",
"title_normalized": "acute hand ischemia following elective venous sclerotherapy for dorsal hand varicose veins"
} | [
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"companynumb": "US-MYLANLABS-2017M1061897",
"fulfillexpeditecriteria": "1",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SODIUM TETRADECYL SULFATE"
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{
"abstract": "OBJECTIVE\nAntiplatelet resistance is known to be associated with symptomatic ischemic complication after endovascular coil embolization. The purpose of our study was to evaluate the relationship between antiplatelet resistance and clinically silent thromboembolic complications using DWI in patients who underwent coil embolization for unruptured intracranial aneurysm.\n\n\nMETHODS\nBetween October 2011 and May 2013, 58 patients with 62 unruptured aneurysms who were measured for antiplatelet response using VerifyNow assay and underwent elective coil embolization for an unruptured aneurysm with posttreatment DWI were enrolled. Diffusion-positive lesions were classified into 3 groups according to the number of lesions (n=0 [grade 0], n<6 [grade I], and n≥6 [grade II]). The relationship between antiplatelet resistance and diffusion-positive lesions was analyzed.\n\n\nRESULTS\nSixty-two endovascular coiling procedures were performed on 58 patients. Clopidogrel resistance was revealed in 23 patients (39.7%) and diffusion-positive lesions were demonstrated in 28 patients (48.3%); these consisted of 19 (32.8%) grade I and 9 (15.5%) grade II lesions. Clopidogrel resistance was not relevant to the development of any diffusion-positive lesion (grade I and II, P=.789) but was associated with the development of multiple diffusion-positive lesions (grade II, P=.002). In the logistic regression prediction model, clopidogrel resistance showed significant correlation with the development of grade II lesions (P=.001).\n\n\nCONCLUSIONS\nMultiple diffusion-positive lesions (≥6 in number) occurred more frequently in patients with clopidogrel resistance after endovascular coiling for unruptured aneurysms.",
"affiliations": "From the Departments of Radiology (B.K., K.K., P.J., S.K., H.K., H.B., J.C.).;From the Departments of Radiology (B.K., K.K., P.J., S.K., H.K., H.B., J.C.) somatom.kim@samsung.com.;From the Departments of Radiology (B.K., K.K., P.J., S.K., H.K., H.B., J.C.).;From the Departments of Radiology (B.K., K.K., P.J., S.K., H.K., H.B., J.C.).;From the Departments of Radiology (B.K., K.K., P.J., S.K., H.K., H.B., J.C.).;From the Departments of Radiology (B.K., K.K., P.J., S.K., H.K., H.B., J.C.).;From the Departments of Radiology (B.K., K.K., P.J., S.K., H.K., H.B., J.C.).;Neurosurgery (S.H., K.J.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Neurosurgery (S.H., K.J.), Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.",
"authors": "Kim|B|B|;Kim|K|K|;Jeon|P|P|;Kim|S|S|;Kim|H|H|;Byun|H|H|;Cha|J|J|;Hong|S|S|;Jo|K|K|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine",
"country": "United States",
"delete": false,
"doi": "10.3174/ajnr.A3955",
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"fulltext_license": null,
"issn_linking": "0195-6108",
"issue": "35(9)",
"journal": "AJNR. American journal of neuroradiology",
"keywords": null,
"medline_ta": "AJNR Am J Neuroradiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001807:Blood Vessel Prosthesis; D000077144:Clopidogrel; D038524:Diffusion Magnetic Resonance Imaging; D004351:Drug Resistance; D004621:Embolization, Therapeutic; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D002532:Intracranial Aneurysm; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D013923:Thromboembolism; D013988:Ticlopidine",
"nlm_unique_id": "8003708",
"other_id": null,
"pages": "1786-92",
"pmc": null,
"pmid": "24831597",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article",
"references": "16235046;15082284;23194833;23314576;24320006;17109936;15569744;11158880;10690717;21990807;23204052;7678184;18483190;24353331;21212667;23624636;12796140;22207508;20223886;15731373;12468790;18518710;16545753;12372750;18617659;16908567;23828107;21467700",
"title": "Thromboembolic complications in patients with clopidogrel resistance after coil embolization for unruptured intracranial aneurysms.",
"title_normalized": "thromboembolic complications in patients with clopidogrel resistance after coil embolization for unruptured intracranial aneurysms"
} | [
{
"companynumb": "KR-SA-2014SA134590",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nBecause of the absence of a dedicated reversal agent, the outcome of pericardial effusion (PE) following procedures performed with uninterrupted apixaban or rivaroxaban is unknown. We report the characteristics of PEs presenting with tamponade in patients undergoing AF ablation with uninterrupted factor Xa inhibition (FXaI) to understand their management and prognosis.\n\n\nRESULTS\nWe performed a multicenter cross-sectional survey in 10 centers across the United States. Patient data were obtained by chart review. In all patients the procedure was performed with uninterrupted FXaI. A total of 16 PEs requiring intervention were reported from 5 centers. Two patients were on apixaban 5 mg BD, the remaining on rivaroxaban 20 mg OD. Eleven PEs occurred in the periprocedural setting, and 5 PEs occurred from 1 to 28 days after the procedure. Pericardiocentesis and drainage were performed in all cases. Protamine and 4-factor prothrombin complex concentrate (4F-PCC) were given in all periprocedural cases. Two patients required surgery: in one case coagulation of the pericardial blood prevented effective drainage, and in the other bleeding was secondary to a steam pop-induced atrial tear. None of the postprocedural cases required FXaI reversal and the dose of rivaroxaban was temporarily reduced. No fatal outcomes or thromboembolic events were reported.\n\n\nCONCLUSIONS\nPericardiocentesis and drainage with FXaI reversal proved effective in the management of acute PEs with tamponade occurring periprocedurally in patients undergoing AF ablation with uninterrupted FXaI. Early postprocedural effusions can be treated with pericardiocentesis without the need of a reversal agent.",
"affiliations": "Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.;Division of Cardiovascular Diseases, University of Kansas Medical Center, Kansas City, Kansas, USA.;Division of Electrophysiology, Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, Massachusetts, USA.;Electrophysiology Section, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.;Electrophysiology Section, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.;Electrophysiology Section, Cardiovascular Division, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.;Electrophysiology and Arrhythmia Services, California Pacific Medical Center, San Francisco, California, USA.;Electrophysiology and Arrhythmia Services, California Pacific Medical Center, San Francisco, California, USA.;Interventional Electrophysiology, Scripps Clinic, La Jolla, California, USA.;Interventional Electrophysiology, Scripps Clinic, La Jolla, California, USA.;Texas Cardiac Arrhythmia Institute, St. David's Medical Center, Austin, Texas, USA.",
"authors": "Gianni|Carola|C|;DI Biase|Luigi|L|;Mohanty|Sanghamitra|S|;Trivedi|Chintan|C|;Bai|Rong|R|;Al-Ahmad|Amin|A|;Burkhardt|J David|JD|;Gallinghouse|G Joseph|GJ|;Horton|Rodney P|RP|;Sanchez|Javier E|JE|;Hranitzky|Patrick M|PM|;Lakkireddy|Dhanunjaya|D|;Mansour|Moussa C|MC|;Santangeli|Pasquale|P|;Zado|Erica S|ES|;Marchlinski|Francis E|FE|;Beheiry|Salwa|S|;Hao|Steven C|SC|;Couts|Linda|L|;Gibson|Douglas|D|;Natale|Andrea|A|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1111/jce.12918",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1045-3873",
"issue": "27(4)",
"journal": "Journal of cardiovascular electrophysiology",
"keywords": "4-factor prothrombin complex concentrate; apixaban; atrial fibrillation ablation; factor Xa inhibitors; pericardial tamponade; rivaroxaban; uninterrupted anticoagulation",
"medline_ta": "J Cardiovasc Electrophysiol",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D001281:Atrial Fibrillation; D021721:Balloon Occlusion; D017115:Catheter Ablation; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010490:Pericardial Effusion; D011183:Postoperative Complications; D011292:Premedication; D011379:Prognosis; D013923:Thromboembolism; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "9010756",
"other_id": null,
"pages": "399-403",
"pmc": null,
"pmid": "26756289",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Management of Periprocedural and Early Pericardial Effusions With Tamponade Following Ablation of Atrial Fibrillation With Uninterrupted Factor Xa Inhibitors: A Case Series.",
"title_normalized": "management of periprocedural and early pericardial effusions with tamponade following ablation of atrial fibrillation with uninterrupted factor xa inhibitors a case series"
} | [
{
"companynumb": "US-JNJFOC-20160201859",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": null,
... |
{
"abstract": "Most young patients with mild-to-moderate aortic stenosis show no symptoms, and sudden death appears only occasionally. We hypothesised that malignant ventricular arrhythmias could be responsible for the high incidence of sudden death in such patients. If multiple factors such as asymptomatic aortic stenosis in association with arrhythmia-provoking agents are involved, could it be sufficient to account for sudden unexpected death? In this study, eight cases of sudden death in young adults, with ages ranging from 22 to 36 years, who had never reported any symptoms that could be related to aortic stenosis, were investigated. Full autopsies were performed, and congenital aortic stenosis in all eight cases was confirmed. DNA testing for channelopathies was negative. Comprehensive toxicological analyses found an electrolyte imbalance, or non-toxic concentrations of amitriptyline, terfenadine, caffeine, and ethanol. Collectively, these results suggest that congenital asymptomatic aortic stenosis without cardiac hypertrophy in young adults is not sufficient to cause sudden death merely on its own; rather, an additional provoking factor is necessary. According to our findings, the provoking factor may be a state of physical or emotional stress, a state of electrolyte imbalance, or even taking a therapeutic dose of a particular drug.",
"affiliations": "1Institute of Forensic Medicine \"Milovan Milovanovic\",School of Medicine,University of Belgrade,Belgrade,Serbia.;2Department of Forensic Medicine,Clinical Centre of Montenegro,Podgorica,Montenegro.;3Department of Pathology,Centre for Pathology and Forensic Medicine,Clinical Centre of Montenegro,Podgorica,Montenegro.;4Department of Pharmacology and Clinical Pharmacology,School of Medicine, University of Montenegro,Podgorica,Montenegro.",
"authors": "Radnic|Bojana|B|;Radojevic|Nemanja|N|;Vucinic|Jelena|J|;Duborija-Kovacevic|Natasa|N|",
"chemical_list": "D000639:Amitriptyline; D002110:Caffeine; D000431:Ethanol; D016593:Terfenadine",
"country": "England",
"delete": false,
"doi": "10.1017/S1047951116001864",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "27(5)",
"journal": "Cardiology in the young",
"keywords": "Aortic stenosis; pro-arrhythmic agents; sudden death; young adults",
"medline_ta": "Cardiol Young",
"mesh_terms": "D000328:Adult; D000639:Amitriptyline; D001024:Aortic Valve Stenosis; D001145:Arrhythmias, Cardiac; D001344:Autopsy; D002110:Caffeine; D016757:Death, Sudden, Cardiac; D000431:Ethanol; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D015994:Incidence; D008297:Male; D054548:Montenegro; D012307:Risk Factors; D016593:Terfenadine; D055815:Young Adult",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "929-935",
"pmc": null,
"pmid": "27821197",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": "17206434;20381381;8956989;650346;22922550;12586277;22870741;1994662;22256934;20921449;11790933;7102517;10788818;4818133;6630761;18307620;22182983;1526078;22058665;9708660;14999113;3337000;21037046;7720786;7189084;16620542;8109548;12031739;2805263;7606309;7895601;1977935;3716982;21947676;8080594;21361120;11269621;2312954;4061271;22835221;14617564;6681930;8445813;8230644;7857739",
"title": "The association between pro-arrhythmic agents and aortic stenosis in young adults: is it sufficient to clarify the sudden unexpected deaths?",
"title_normalized": "the association between pro arrhythmic agents and aortic stenosis in young adults is it sufficient to clarify the sudden unexpected deaths"
} | [
{
"companynumb": "RS-VALIDUS PHARMACEUTICALS LLC-RS-2016VAL003128",
"fulfillexpeditecriteria": "1",
"occurcountry": "ME",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadd... |
{
"abstract": "BACKGROUND\nDrug shortages are common yet their impact on patient care and their commercial ramifications has not been adequately researched. In Australia a shortage of balsalazide (2012-2013) necessitated substitution with alternative 5-aminosalicylate (5-ASA) formulations for ulcerative colitis (UC).\n\n\nOBJECTIVE\nTo assess and compare the clinical and commercial sequelae of non-medical switching from balsalazide to another 5-ASA and/or return to balsalazide once supply resumed.\n\n\nMETHODS\nA prospective cohort study of patients on balsalazide for mild-moderate UC was conducted where, strictly due to the national shortage (November 2012- January 2013), were switched to alternative 5-ASA and/or then returned to balsalazide once supply resumed. Clinical (Partial Mayo), endoscopic (Mayo score) activity, adverse effects (to alternative 5-ASA) and percentage market share (of continuous 5-ASA users) from baseline (i.e., time of switching due to shortage) through to five years were assessed.\n\n\nRESULTS\nOf 31 patients switched due to the shortage, 12 (38.7%) resumed balsalazide immediately once supply resumed, 8 (25.8%) prompted by adverse effects to the alternative 5-ASA used. Three patients (9.7%) had documented symptomatic improvement, 15 (48.4%) were unchanged and 13 (41.9%) had symptomatic worsening vs baseline (P < 0.01), after switching to an alternative 5-ASA. At 3 and 5y post switch, overall 26/31 (83.9%) and 23/31 (74.2%) had remained continuously on any 5-ASA therapy respectively. Twelve (38.7%) and 11 (35.5%) patients remained on balsalazide continuously at three and five years respectively after drug supply returned, equating to a loss of market share (within 5-ASA class) of 45.2% and 38.7% respectively.\n\n\nCONCLUSIONS\nThis study of a balsalazide shortage in UC patients exemplifies the detrimental impact of a drug shortage on long term patient, disease and commercial outcomes.",
"affiliations": "Department of Gastroenterology, Eastern Health, Box Hill, Victoria 3128, Australia.;Department of Gastroenterology, Eastern Health, Box Hill, Victoria 3128, Australia.;Department of Gastroenterology, Eastern Health, Box Hill, Victoria 3128, Australia.",
"authors": "van Langenberg|Daniel R|DR|;Cheng|Richard Kai-Yuan|RK|;Garg|Mayur|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4291/wjgp.v11.i2.32",
"fulltext": "\n==== Front\nWorld J Gastrointest Pathophysiol\nWJGP\nWorld Journal of Gastrointestinal Pathophysiology\n2150-5330 Baishideng Publishing Group Inc \n\njWJGP.v11.i2.pg32\n10.4291/wjgp.v11.i2.32\nObservational Study\nOutcomes of a drug shortage requiring switching in patients with ulcerative colitis\nvan Langenberg Daniel R Department of Gastroenterology, Eastern Health, Box Hill, Victoria 3128, Australia\nEastern Health Clinical School, Monash University, Box Hill, Victoria 3128, Australia. daniel.van-langenberg@monash.edu\n Cheng Richard Kai-Yuan Department of Gastroenterology, Eastern Health, Box Hill, Victoria 3128, Australia\nDepartment of Gastroenterology, Redcliffe Hospital, Redcliffe, Queensland 4020, Australia\n Garg Mayur Department of Gastroenterology, Eastern Health, Box Hill, Victoria 3128, Australia\nEastern Health Clinical School, Monash University, Box Hill, Victoria 3128, Australia\nDepartment of Gastroenterology, Royal Melbourne Hospital, Parkville, Victoria 3052, Australia\n Author contributions: van Langenberg DR conceived and designed the work, plus contributed to the collection, analysis and interpretation of data and drafting of the manuscript; Cheng RKY contributed to the collection of data and to drafting the manuscript; Garg M contributed to the design and contributed to analysis and interpretation of data, plus drafting the manuscript; all authors approved the final version of the manuscript.\n\nCorresponding author: Daniel R van Langenberg, FRACP, MBBS, PhD, Associate Professor, Head of IBD, Gastroenterologist, Department of Gastroenterology, Eastern Health, 8 Arnold Street, Box Hill, Victoria 3128, Australia. daniel.van-langenberg@monash.edu\n\n\n12 4 2020 \n12 4 2020 \n11 2 32 42\n12 11 2019 4 3 2020 12 3 2020 ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.2020This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nDrug shortages are common yet their impact on patient care and their commercial ramifications has not been adequately researched. In Australia a shortage of balsalazide (2012-2013) necessitated substitution with alternative 5-aminosalicylate (5-ASA) formulations for ulcerative colitis (UC).\n\nAIM\nTo assess and compare the clinical and commercial sequelae of non-medical switching from balsalazide to another 5-ASA and/or return to balsalazide once supply resumed.\n\nMETHODS\nA prospective cohort study of patients on balsalazide for mild-moderate UC was conducted where, strictly due to the national shortage (November 2012- January 2013), were switched to alternative 5-ASA and/or then returned to balsalazide once supply resumed. Clinical (Partial Mayo), endoscopic (Mayo score) activity, adverse effects (to alternative 5-ASA) and percentage market share (of continuous 5-ASA users) from baseline (i.e., time of switching due to shortage) through to five years were assessed.\n\nRESULTS\nOf 31 patients switched due to the shortage, 12 (38.7%) resumed balsalazide immediately once supply resumed, 8 (25.8%) prompted by adverse effects to the alternative 5-ASA used. Three patients (9.7%) had documented symptomatic improvement, 15 (48.4%) were unchanged and 13 (41.9%) had symptomatic worsening vs baseline (P < 0.01), after switching to an alternative 5-ASA. At 3 and 5y post switch, overall 26/31 (83.9%) and 23/31 (74.2%) had remained continuously on any 5-ASA therapy respectively. Twelve (38.7%) and 11 (35.5%) patients remained on balsalazide continuously at three and five years respectively after drug supply returned, equating to a loss of market share (within 5-ASA class) of 45.2% and 38.7% respectively.\n\nCONCLUSION\nThis study of a balsalazide shortage in UC patients exemplifies the detrimental impact of a drug shortage on long term patient, disease and commercial outcomes.\n\nInflammatory bowel diseaseUlcerative colitisDrug supplyDrug shortagePatient outcomesMarket share\n==== Body\nCore tip: As a chronic disease, this study of a drug shortage in ulcerative colitis provides an excellent, novel insight into the short and long term effects of an sudden, unexpected nationwide drug shortage (in this case balsalazide) in patients previously in stable remission. The study highlights the importance of maintaining a seamless drug supply for both patients (given significant rates of disease worsening occurred, directly attributable to shortage), and drug manufacturers given the loss of market share engendered by even a short term drug shortage.\n\nINTRODUCTION\nDrug supply shortages are an insidious yet growing threat to the optimal medical management of chronic diseases, including ulcerative colitis (UC). Across many countries, healthcare settings and diseases, such shortages have been linked with patient deaths and significant morbidity[1,2]. Drug shortages may be defined by “a supply issue that affects the ability of preparation and/or dispensing of a drug such that it influences patient care and/or prescribers must use an alternative agent[3]”. They appear to be increasing for multiple reasons, including growing trends worldwide to operate drug supply chains on a just-in-time basis to maximise cost reduction and avoid excess inventory, brought about by lower profit margins due to the arrival of generics and other market competitive forces. Moreover, in most countries, there is no requirement for suppliers to report drug supply issues, often leading to clinicians and patients facing shortages with little or no warning. High cost drugs for relatively narrow indications in smaller markets appear more at risk of shortages, exemplified by the balsalazide shortage in Australia as studied here[4-6].\n\nOver a three month period from November 2012 to January 2013 inclusive, a nationwide shortage in the supply of balsalazide (Colazal, Colazide®) in Australia necessitated a blanket, non-medical substitution with alternative 5-ASA formulations in patients with UC. Balsalazide is a prodrug of the active metabolite, mesalazine, which is linked to a carrier molecule via an azo bond and released in the colon by bacterial azo-reduction[7]. The 5-aminosalicylic acid (5-ASA) agents as a class (including balsalazide) are standard and effective therapies for the induction and maintenance of remission in UC, particularly in mild to moderate disease. In the setting of few randomized head-to-head trials or real-world comparative studies of different oral 5-ASA preparations, the formulations are, pragmatically, considered to be similar in efficacy when adjusting for dose for both induction and maintenance of UC[8]. For instance, 6.75 g daily of balsalazide (equivalent to 2.34 g of mesalazine) was compared with a pH-dependent acrylic resin coated mesalazine formulation (Asacol®) in three randomized-controlled, double-blind studies[9-11], with no significant differences in the primary endpoints between these formulations at 8 wk.\n\nTherefore, this balsalazide shortage presented a unique opportunity to evaluate short and long term outcomes of a semi-controlled, unselected cohort of patients with UC in whom a non-medical switch in 5-ASA formulation was undertaken contemporaneously. Moreover, there are scant data regarding the short and long term implications of a drug shortage in patients with chronic diseases, including IBD. Hence, the aims of this prospective study were to assess the short and long term ramifications of a drug shortage imposed substitution of balsalazide to alternative 5-ASA formulations in patients with UC, in terms of: (1) Efficacy (including symptom-based, endoscopic activity and long-term outcomes); (2) Safety (including immediate adverse effects to alternative 5-ASA upon switching); and (3) The proportion of patients returning to the original product once supply resumed as a measure of loss of market share in a competitive drug category such as 5-ASA agents.\n\nMATERIALS AND METHODS\nA prospective, long term cohort study was undertaken of patients with a confirmed diagnosis of mild-moderate UC as per standard criteria, treated for a minimum of six months with balsalazide at specialist inflammatory bowel disease (IBD) Clinics at two Melbourne metropolitan hospitals, in whom switching to an alternative 5-ASA formulation (at the treating doctor’s discretion) was mandated by drug unavailability between November 1st 2012 to January 31st 2013. Patients who were switched from balsalazide to an alternative 5-ASA due to medical reasons, including intolerance, tablet burden or active disease were excluded from this study. After supply of balsalazide resumed, the occurrence of switching back to balsalazide was solely at the discretion and agreement of the patient and treating clinician.\n\nPatient demographics, disease characteristics (including Montreal Classification extent/severity of IBD[12]), biomarkers including C-reactive protein (CRP) and faecal calprotectin (where available), medication changes (including adverse effects and concomitant medications) and symptom-based disease activity (via partial Mayo score) were collected immediately at baseline pre-switch and then at multiple timepoints (3-6 mo at post-switch subsequent clinic review, then at 3 years and 5 years) after 5-ASA substitution. A balsalazide dose of 6-6.75 g was assumed to be equivalent to sulfasalazine or mesalazine 2-2.4 g as per the manufacturer’s product information documentation.\n\nEndoscopic data (via Mayo endoscopy score) were also collected at baseline (data included if endoscopy had occurred no more than 12 mo pre-switch), then post-switch (no less than 3 mo and no more than 12 mo from date of switch) and subsequently at three and five years (included if within six months in each case). A Mayo endoscopy score of 0 or 1 was deemed to represent endoscopic remission. Clinical remission was defined as a partial Mayo score of ≤ 2, where each subscore was ≤ 1. Patients with newly diagnosed ulcerative colitis in the preceding 12 mo prior November 1st 2012 were excluded from the analysis.\n\nThe impact on market share of balsalazide affected by the drug shortage was calculated as the proportion derived by the number of patients who were switched temporarily to an alternative 5-ASA before returning to balsalazide through to the three and five-year timepoints, divided by the total number of patients who, upon switching from balsalazide to an alternative 5-ASA, then remained on this or any alternative 5-ASA agent continuously to the respective timepoints.\n\nData were analyzed with GraphPad Prism version 7 (GraphPad software, La Jolla, United States 2018). Given the data were non-normally distributed and of relatively small sample size, non-parametric statistics were used. For continuous data, medians are presented and compared with Kruskal-Wallis (unpaired) or Wilcoxon (paired) tests. For categorical data, proportions were compared with Fisher exact tests. Patients without complete data at both baseline and five year follow-up timepoints were excluded from the study. A P < 0.05 was considered to be clinically significant. The statistical methods of this study were reviewed by Dr Danny Con, Biostatistician, Eastern Health. Ethics approval was obtained from the Eastern Health Office of Research and Ethics (LR 61/2015).\n\nRESULTS\nThirty-one patients with UC were switched from balsalazide to an alternative 5-ASA formulation specifically due to the balsalazide drug shortage. The majority of patients were switched from balsalazide to multi-matrix (MMX) mesalazine (28, 90.3%). Further characteristics of this cohort are shown in Table 1.\n\nTable 1 Characteristics of the patient cohort (n = 31) who were switched from balsalazide (due to shortage) to an alternative aminosalicylate formulation\n\nVariable\tPre-switch (baseline)\tPost-switch (at subsequent review)1\t\nAge (yr) (median, range)\t54 (20-79)\t\t\nMale sex (%)\t16 (51.6)\t\t\nDisease duration (yr) (median, range)\t10 (3-48)\t\t\nMontreal Classification, n (%)\t\t\t\nDisease extent\t\t\t\nProctitis (E1)\t4 (12.9)\t\t\nLeft sided colitis (E2)\t21 (67.7)\t\t\nExtensive colitis (E3)\t6 (19.4)\t\t\nDisease severity\t\t\t\nClinical remission (S0)\t14 (45.2)\t10 (32.2)\t\nMild (S1)\t16 (51.6)\t15 (48.4)\t\nModerate (S2)\t1 (3.2)\t6 (19.4)\t\nSevere (S3)\t0 (0.0)\t0 (0.0)\t\nEndoscopic (Mayo) subscore, n (%)\t\t\t\nMayo 0\t6 (19.4)\t13 (41.9)\t\nMayo 1\t9 (29.0)\t9 (29.0)\t\nMayo 2\t13 (41.9)\t5 (16.1)\t\nMayo 3\t3 (9.7)\t3 (9.7)\t\nEndoscopic remission (Mayo 0/1)\t15 (48.4)\t22 (71.0)\t\nAlternative 5-ASA formulation switched to\t\t\t\nMMX mesalazine\t28 (90.3)\t\t\nTime-dependent, ethylcellulose coated2\t2 (6.5)\t\t\nSulfasalazine\t1 (3.2)\t\t\nMedian balsalazide dose (g, range)\t5.3 (3.0-9.0)\t-\t\nMedian equivalent mesalazine dose (g, range)3\t2.1 (1.1-3.2)\t3.6 (2.0-4.8)\t\nConcurrent Medical therapy, n (%)\t\t\t\nNil other\t7 (22.6)\t\t\nTopical aminosalicylate\t10 (32.2)\t\t\nOral corticosteroid\t1 (3.2)\t\t\nAzathioprine/mercaptopurine\t14 (45.2)\t\t\nMethotrexate\t3 (9.7)\t\t\nAnti-TNF biologic\t0 (0.0)\t\t\nOther biologic\t0 (0.0)\t\t\n1 Median 3 mo after baseline–overall cohort data reported here (i.e., either on alternative aminosalicylate or had resumed balsalazide). \n\n2 Marketed as Mezavant® (Shire Pty Ltd) and Pentasa® (Ferring Pty Ltd) in Australia respectively. \n\n3 Based on Balsalazide Product Information[7].\n\nShort term outcomes post switch compared to baseline (pre-switch)\nCompared to baseline clinical (partial Mayo score) activity, three patients (9.7%) had documented symptomatic improvement (≥ 1 point reduction in partial Mayo score), 15 (48.4%) were unchanged and 13 (41.9%) had symptomatic worsening (≥ 1 point increase in partial Mayo score) (improvement vs worsening, P < 0.01, Fisher exact test) after switching from balsalazide to an alternative 5-ASA formulation.\n\nTwenty-six (83.9%) of the cohort had endoscopic assessment both within 12 mo prior and then within 12 mo after the switch. Of these, compared to baseline endoscopic activity (Mayo endoscopy score), 13 (50%) patients had similar or improved endoscopic activity and 13 (50%) had worsening of their endoscopic activity post switch (P = 1.0, Fisher exact test). There were no significant differences (pre to post-switch) in serum CRP [median difference 0 mg/L (-6, 108)], serum ALT [1.0 (-15, 61)], serum GGT [0.5 (-8, 507)] or serum white cell count [-0.5 (-3.0, 3.3)] (all tests +/−3 mo of switch, each P > 0.2, Wilcoxon tests).\n\nBased on the published dose equivalence of balsalazide compared to mesalazine[7], in all 31 patients there was an equal or increased effective mesalazine dose received after switching to the alternative 5-ASA formulation [median delta increase of 1.4 g (0, 3.2) mesalazine daily, P < 0.01 (Wilcoxon test)], Figure 1.\n\nFigure 1 Change in equivalent mesalazine dose with switch from balsalazide to alternative aminosalicylate agent.\n\nAdverse events with substitution of balsalazide to alternative 5-ASA agent during shortage\nAdverse events were reported by 8/31 (16.2%) patients, all documented within 2 wk after switching, and attributable to, the alternative 5-ASA agent. These included one or more of hepatotoxicity (n = 2), abdominal pain (n = 6), nausea (n = 1) and/or hypersensitivity reaction (n = 1). Of these patients with adverse events, all 8 (100%) had prompt resolution of symptoms upon cessation of alternative 5-ASA therapy. Then upon switching back to balsalazide once supply returned, all 8 continued on balsalazide without further adverse event/s during the remainder of the follow-up period (Figure 2).\n\nFigure 2 Flow chart depicting the switch to alternative aminosalicylate resulting from the balsalazide shortage, with adverse effect rate of 35.5% occurring immediately post-switch, which in all cases resolved upon return to balsalazide.\n\nLong term outcomes\nAt three and five years following the switch, overall 26/31 (83.9%) and 23/31 (74.2%) patients had remained continuously on any 5-ASA therapy respectively. Twelve (38.7%) patients switched back to balsalazide as soon as supply returned (within three months). All twelve (38.7%) remained on balsalazide at 3 years, with 11 patients (35.5%) on balsalazide at 5 years.\n\nCompared to the total number and accounting for the resultant attrition of those on continuous 5-ASA therapy, there was a loss of long-term market share of 45.2% and 38.7% at three and five years respectively after, and as a direct result of, the balsalazide shortage (Figure 3). Also, at each subsequent timepoint following the switch through to five years, there were no significant differences in the rates of clinical or endoscopic remission between those who continued on alternative 5-ASA therapy vs those who had switched but then returned to balsalazide as soon as supply returned (Figure 4A-B).\n\nFigure 3 Long term outcome of balsalazide drug shortage on market share through to five years follow-up (compared to persistence on alternative aminosalicylate therapy).\n\nFigure 4 Comparison of rates of Clinical remission and Endoscopic remission over multiple timepoints in those who switched to and remained on alternative aminosalicylate vs those who switched back and remained on balsalazide. A: Clinical remission; B: Endoscopic remission.\n\nFinally, there was no significant difference in rates of treatment escalation to immunomodulators or biologics, colectomy or mortality (all causes) between the two groups at both the 3 and 5-year follow-up timepoints. However, there was a higher rate of flares requiring hospitalization in those who switched from balsalazide then remained on an alternative 5-ASA (36.8 vs 0.0% at 5 years, P = 0.03, Fisher exact test), Table 2.\n\nTable 2 Long term cumulative outcomes including rates of treatment escalation, colectomy and mortality in those who continued on alternative aminosalicylate therapy (n = 19) vs those who switched but then returned to balsalazide as soon as supply returned (n = 12), n (%)\n\nOutcome (cumulative)\tPost-switch review (baseline), n (%)\tAs of 3y follow-up1, n (%)\tAs of 5y follow-up1, n = (%)\t\n\tAlternative 5-ASA2\tResumed alsalazide\tAlternative 5-ASA2\tResumed balsalazide\tAlternative 5-ASA2\tResumed balsalazide\t\nEscalated to immunomodulator\t14 (73.7)\t5 (41.7)\t16 (84.2)\t5 (41.7)\t16 (84.2)\t5 (41.7)\t\nEscalated to biologic\t0 (0)\t0 (0)\t3 (15.8)\t0 (0)\t6 (31.6)\t2 (16.7)\t\nHospitalised for flare3\t0 (0)\t0 (0)\t3 (15.8)\t0 (0)\t7 (36.8)a\t0 (0)a\t\nColectomy\t0 (0)\t0 (0)\t1 (5.3)\t0 (0)\t1 (5.3)\t0 (0)\t\nAll-cause mortality4\t0 (0)\t0 (0)\t2 (10.5)\t0 (0)\t2 (10.5)\t0 (0)\t\n1 Outcome occurring prior to or at timepoint. \n\n2 5-ASA: Aminosalicylae. \n\n3 First hospitalization counted for UC flare only. \n\n4 Both deaths in cohort were unrelated to ulcerative colitis (one due to sarcoma and one acute myocardial infarction). \n\na P < 0.05.\n\nDISCUSSION\nTo our knowledge, this study is the first to demonstrate the long-term ramifications of a drug shortage in a cohort of patients with inflammatory bowel disease. Mild-moderate UC is an archetypal chronic disease in which to examine the effect of a drug shortage given it is a lifelong, relapsing-remitting disease in typically young, otherwise healthy patients, where remission is achieved and maintained in a significant proportion by daily administration of oral drugs such as mesalazine or balsalazide, with a highly favourable risk: benefit ratio. Long-term stability of disease control and outcomes depend primarily on adherence, and therefore continuous supply, of the drug. Consequently, a drug shortage has the potential to exert multiple deleterious flow-on effects including a flare or worsening of disease with possible hospitalization or colectomy, as well as significant anxiety, psychological distress, and loss of work productivity. Hence, such a shortage poses a risk for not only the patient but health payers and the drug manufacturer.\n\nThe most striking finding of this study is perhaps the significant loss of balsalazide’s market share resulting from the shortage to competitor 5-ASA formulations of approximately 40% which persisted even to 5 years in this cohort. Given the sudden, unexplained nature of the drug shortage for both clinicians and patients with no advanced notification of return of supply, all patients were switched immediately to alternative 5-ASA formulations in order to maintain treatment continuity. Once balsalazide was again available, it is perhaps unsurprising that given the loss of confidence in drug supply that most patients chose to remain on the alternative 5-ASA therapy. This study therefore presents a warning to drug manufacturers that despite a relatively short-duration, once-off drug shortage, the effects on patient and clinician confidence in a product may be far more lasting, especially where similarly effective, competing formulations are available. Indeed, a sustained loss of 40% of prior market share as depicted in this study highlights financial risks to pharmaceutical companies as a result of suboptimal manufacture and supply-chain processes, especially in chronic diseases.\n\nIn this study there was no significant impact elicited in either clinical or endoscopic assessed disease activity on a per-group basis between those who remained on an alternative 5-ASA formulation post-switch and those who returned to balsalazide after drug supply returned, at each of the assessment timepoints to five years. Although this might imply the bioequivalence of the 5-ASA formulations, given the small sample size in this study no further conclusions can be made. It is important to reiterate that all switches were performed for non-medical reasons (i.e., shortage) only and those switched for other reasons such as intolerance, active disease, or tablet burden were excluded from the study. However, on a per-patient basis, a greater proportion of patients suffered a symptomatic worsening than improvement of their colitis at initial review post-switch (P < 0.01) and there was a higher rate of flares requiring hospitalization through to five years (37% vs 0%, P = 0.03) despite no differences in rates of treatment escalation between the groups. One may therefore hypothesise that for a given individual, not all oral aminosalicylate preparations are equal and due to reasons including disparate tablet/granule composition, delivery system, pharmacodynamics and phenotypic differences, switching between agents within class may result in improved/worsened disease control and/or adverse effects. Regardless, these data exemplify the potential clinical sequelae of a drug shortage, which hitherto has not been well characterized in previous studies[13-15].\n\nNotably, upon non-medical switching from balsalazide to an alternative 5-ASA formulation, approximately one-third of patients developed an adverse effect requiring drug cessation. This is a far higher proportion of adverse effects than typically seen in commencing 5-ASA agent/s in UC, and certainly higher than that reported in mesalazine registration trials[16,17]. Furthermore, many of the side effects appeared to be of idiosyncratic type (e.g., abdominal pain, Figure 2), occurred rapidly within 1-2 wk of commencement and all resolved upon cessation and recommencing balsalazide. It is plausible therefore that at least a proportion of these adverse effects might be explained by a nocebo effect– i.e., an effect occurring when negative expectations of the patient regarding a treatment cause the treatment to have a more negative effect than it otherwise would have, such as recently reported with the non-medical switching from originator to biosimilar infliximab in similar disease populations[18,19]. If so, this further illustrates the potential negative impact of a drug shortage on patients, especially in diseases like UC where psychological stress has been linked with flares and/or symptom provocation[20]. Another possible explanation is that, given the vast majority of patients were switched to MMX mesalazine, that this particular formulation might be the cause of adverse effects. Alternatively, the increase in side effects might have been explained by the almost universal increase in equivalent mesalazine dose received by patients switching to the alternative 5-ASA therapy (median increase of 1.6 g mesalazine), although multiple studies have demonstrated that adverse effects to mesalazine are not dose-dependent[21,22].\n\nThe authors acknowledge several limitations of this study, including the observational design and small sample size which limit the ability to make definitive conclusions given potential bias, or ascribe causality. However, this was an unselected, consecutive patient cohort who were all on the same treatment (balsalazide) prior to a non-medical therapeutic switch, were well phenotypically characterized (all mild-moderate UC), were all followed prospectively for five years and all treatments and disease (including endoscopic) assessments were recorded, thus alleviating much of the potential bias. Moreover, the vast majority (over 90%) were switched to MMX mesalazine upon shortage of balsalazide, further aiding uniformity. Other limitations of the study included that endoscopic and clinical assessment of disease activity prior to and post-switch was not performed at strictly uniform timepoints and faecal calprotectin testing was not routinely available for most patients during this study. Assessment by CRP was performed at the clinic visits by these patients, but CRP has known poor sensitivity in the assessment of disease activity in UC[23]. Finally, concomitant medications were not controlled in keeping with the “real world” nature of this cohort, however it should be noted that none of the patients were on biologic therapy at the time of drug shortage though a significant proportion were on concurrent immunomodulators.\n\nIn summary, this study has demonstrated the deleterious effects of a drug shortage in ulcerative colitis, with a higher than expected proportion of patients exhibiting a worsening of disease and/or significant side effects upon substitution of their maintenance agent balsalazide with an alternative in the same class. Furthermore, this study demonstrated the adverse commercial impact of a drug shortage for the manufacturer, with a 40% loss of market share persisting even to five years post-shortage. Despite enhanced globalization, supply chains and technological advances, drug shortages are increasingly common and relative low incidence chronic diseases such as IBD appear at higher risk. Hence, this study highlights the threat posed by drug shortages to patients, clinicians, healthcare payers and pharmaceutical companies alike, and the need to explore ways to minimise such occurrences in future.\n\nARTICLE HIGHLIGHTS\nResearch background\nDrug shortages appear to be occurring more frequently, yet their clinical impact and sequelae are not yet well described. Here, a nationwide drug shortage of balsalazide occurred over several months in 2012-3, necessitating a sudden switch to alternative aminosalicyclate formulations.\n\nResearch motivation\nIn this study the impact of this balsalazide shortage was intensively assessed in a well characterized population of patients with ulcerative colitis over a five year period to assess short and long term effects of a drug shortage. We hypothesized that this and similar drug shortages can have significant detrimental impacts on disease course and patient outcomes.\n\nResearch objectives\nThis study aimed to elucidate the short and long term ramifications of a drug shortage in ulcerative colitis patients on (1) efficacy (including symptom-based, and objective disease assessments); (2) safety (including immediate adverse effects occurring after switching to alternative agents); and (3) the proportion of patients returning to the original product once supply resumed as a measure of loss of market share. This comprehensive, holistic assessment of drug shortage-related outcomes sets a benchmark for further quantitative research in this field.\n\nResearch methods\nA prospective cohort study of patients on balsalazide for mild-moderate ulcerative colitis was conducted where, strictly due to the national shortage patients were switched to alternative 5-ASA and/or then returned to balsalazide once supply resumed. Clinical and disease activity assessments were performed at baseline pre-switch, then immediately and at 3 and 5 years after the drug shortage-imposed switch to assess short and long term sequelae.\n\nResearch results\nAlthough in stable remission at the time of the drug shortage, almost half of the patients when switched from balsalazide had documented clinical worsening at their subsequent review, including several reporting side effects to the alternative formulation. Only a minority of patients returned to balsalazide after drug supply returned, equating to a loss of market share (within the same class) of approximately 40% even to five years post-shortage in this cohort. These data highlight the importance of maintaining a seamless drug supply for both patients (given significant rates of disease worsening occurred, directly attributable to shortage), and drug manufacturers given the loss of market share engendered by even a short term drug shortage.\n\nResearch conclusions\nIn one of the first published studies of its kind to date, this study of a balsalazide shortage in UC patients exemplifies the detrimental impact of a drug shortage on long term patient, disease and commercial outcomes. Hence, patients, clinicians and drug manufacturers should be more aware and explore ways to address and minimize this growing problem worldwide.\n\nResearch perspectives\nFurther prospective, larger scale studies are needed to document the impacts of drug shortages in patients across multiple chronic and/or life-threatening diseases. By documenting the scope of this problem in this manner, hopefully long term solutions can then be instituted accordingly.\n\nInstitutional review board statement: This study was approved as a low-risk application by the Eastern Health Office for Human Research & Ethics.\n\nInformed consent statement: Patient consent was not deemed to be required for this non-interventional observational study using deidentified data.\n\nConflict-of-interest statement: The authors have no conflicts of interest to declare.\n\nSTROBE statement: The authors have read the STROBE Statement-checklist of items, and the manuscript was prepared and revised according to the STROBE Statement-checklist of items.\n\nManuscript source: Invited Manuscript\n\nCorresponding Author's Membership in Professional Societies: Gastroenterology and hepatology.\n\nPeer-review started: November 12, 2019\n\nFirst decision: December 23, 2019\n\nArticle in press: March 12, 2020\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: Australia\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): 0\n\nGrade C (Good): C, C\n\nGrade D (Fair): D\n\nGrade E (Poor): 0\n\nP-Reviewer: de Silva AP, Chiba T, Sikiric P S-Editor: Wang J L-Editor: A E-Editor: Qi LL\n\nData sharing statement\nNot applicable.\n==== Refs\n1 Fox ER Sweet BV Jensen V Drug shortages: a complex health care crisis Mayo Clin Proc 2014 89 361 373 24582195 \n2 Pauwels K Simoens S Casteels M Huys I Insights into European drug shortages: a survey of hospital pharmacists PLoS One 2015 10 e0119322 25775406 \n3 Fox ER McLaughlin MM ASHP guidelines on managing drug product shortages Am J Health Syst Pharm 2018 75 1742 1750 30061155 \n4 Pauwels K Huys I Casteels M Simoens S Drug shortages in European countries: a trade-off between market attractiveness and cost containment? BMC Health Serv Res 2014 14 438 25257912 \n5 Fox ER Tyler LS Potential Association between Drug Shortages and High-Cost Medications Pharmacotherapy 2017 37 36 42 27891635 \n6 Schweitzer SO How the US Food and Drug Administration can solve the prescription drug shortage problem Am J Public Health 2013 103 e10 e14 \n7 Colazide Product Information 2017 [updated 2017 March 31st] Available from: https://www.fresenius-kabi.com/au/documents/Colazide_PI.pdf \n8 Feagan BG Macdonald JK Oral 5-aminosalicylic acid for maintenance of remission in ulcerative colitis Cochrane Database Syst Rev 2012 10 CD000544 23076890 \n9 Pruitt R Hanson J Safdi M Wruble L Hardi R Johanson J Koval G Riff D Winston B Cross A Doty P Johnson LK Balsalazide is superior to mesalamine in the time to improvement of signs and symptoms of acute mild-to-moderate ulcerative colitis Am J Gastroenterol 2002 97 3078 3086 12492193 \n10 Levine DS Riff DS Pruitt R Wruble L Koval G Sales D Bell JK Johnson LK A randomized, double blind, dose-response comparison of balsalazide (6.75 g), balsalazide (2.25 g), and mesalamine (2.4 g) in the treatment of active, mild-to-moderate ulcerative colitis Am J Gastroenterol 2002 97 1398 1407 12094857 \n11 Green JR Lobo AJ Holdsworth CD Leicester RJ Gibson JA Kerr GD Hodgson HJ Parkins KJ Taylor MD Balsalazide is more effective and better tolerated than mesalamine in the treatment of acute ulcerative colitis. The Abacus Investigator Group Gastroenterology 1998 114 15 22 9428213 \n12 Kobayashi T Tao T Grabarek Z Gergely J Collins JH Cross-linking of residue 57 in the regulatory domain of a mutant rabbit skeletal muscle troponin C to the inhibitory region of troponin I J Biol Chem 1991 266 13746 13751 1856208 \n13 Nonzee NJ Luu TH The Drug Shortage Crisis in the United States: Impact on Cancer Pharmaceutical Safety Cancer Treat Res 2019 171 75 92 30552658 \n14 Hedlund NG Isgor Z Zwanziger J Rondelli D Crawford SY Hynes DM Powell LM Drug Shortage Impacts Patient Receipt of Induction Treatment Health Serv Res 2018 53 5078 5105 30198560 \n15 Ralls MW Blackwood RA Arnold MA Partipilo ML Dimond J Teitelbaum DH Drug shortage-associated increase in catheter-related blood stream infection in children Pediatrics 2012 130 e1369 e1373 23045557 \n16 Kruis W Schreiber S Theuer D Brandes JW Schütz E Howaldt S Krakamp B Hämling J Mönnikes H Koop I Stolte M Pallant D Ewald U Low dose balsalazide (1.5 g twice daily) and mesalazine (0.5 g three times daily) maintained remission of ulcerative colitis but high dose balsalazide (3.0 g twice daily) was superior in preventing relapses Gut 2001 49 783 789 11709512 \n17 D'Haens G Hommes D Engels L Baert F van der Waaij L Connor P Ramage J Dewit O Palmen M Stephenson D Joseph R Once daily MMX mesalazine for the treatment of mild-to-moderate ulcerative colitis: a phase II, dose-ranging study Aliment Pharmacol Ther 2006 24 1087 1097 16984503 \n18 Bakalos G Zintzaras E Drug Discontinuation in Studies Including a Switch From an Originator to a Biosimilar Monoclonal Antibody: A Systematic Literature Review Clin Ther 2019 41 155 173.e13 30551802 \n19 Kristensen LE Alten R Puig L Philipp S Kvien TK Mangues MA van den Hoogen F Pavelka K Vulto AG Non-pharmacological Effects in Switching Medication: The Nocebo Effect in Switching from Originator to Biosimilar Agent BioDrugs 2018 32 397 404 30269270 \n20 Mawdsley JE Rampton DS Psychological stress in IBD: new insights into pathogenic and therapeutic implications Gut 2005 54 1481 1491 16162953 \n21 Ogata H Yokoyama T Mizushima S Hagino A Hibi T Comparison of efficacy of once daily multimatrix mesalazine 2.4 g/day and 4.8 g/day with other 5-aminosalicylic acid preparation in active ulcerative colitis: a randomized, double-blind study Intest Res 2018 16 255 266 29743838 \n22 Fockens P Mulder CJ Tytgat GN Blok P Ferwerda J Meuwissen SG Tuynman HA Dekker W Gasthuis K van Hees PA Comparison of the efficacy and safety of 1.5 compared with 3.0 g oral slow-release mesalazine (Pentasa) in the maintenance treatment of ulcerative colitis. Dutch Pentasa Study Group Eur J Gastroenterol Hepatol 1995 7 1025 1030 8680900 \n23 Lewis JD The utility of biomarkers in the diagnosis and therapy of inflammatory bowel disease Gastroenterology 2011 140 1817 1826.e2 21530748\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2150-5330",
"issue": "11(2)",
"journal": "World journal of gastrointestinal pathophysiology",
"keywords": "Drug shortage; Drug supply; Inflammatory bowel disease; Market share; Patient outcomes; Ulcerative colitis",
"medline_ta": "World J Gastrointest Pathophysiol",
"mesh_terms": null,
"nlm_unique_id": "101547471",
"other_id": null,
"pages": "32-42",
"pmc": null,
"pmid": "32318313",
"pubdate": "2020-04-12",
"publication_types": "D016428:Journal Article",
"references": "24582195;21530748;27891635;30061155;30198560;25257912;30552658;30269270;25775406;23045557;12094857;29743838;9428213;30551802;11709512;23488502;8680900;12492193;23076890;1856208;16162953;16984503",
"title": "Outcomes of a drug shortage requiring switching in patients with ulcerative colitis.",
"title_normalized": "outcomes of a drug shortage requiring switching in patients with ulcerative colitis"
} | [
{
"companynumb": "AU-SHIRE-ALL1-2013-06802",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": "1",
... |
{
"abstract": "A 78-year-old man complained of dysphagia. Gastrointestinal endoscopy showed a Type 2 tumor in the lower esophagus and a Type 0-Ⅱa lesion in the posterior wall of the upper gastric body. An enhanced CT scan showed several swollen abdominal and cervical lymph nodes as well as bilateral lung multiple nodules, suggesting distant metastasis. We diagnosed the patient with double cancers consisting of an unresectable advanced esophageal squamous cell carcinoma with multiple lymph nodes and lung metastases(Lt, cT3N4M1, cStage Ⅳb)and early gastric cancer(U, post, cType 0-Ⅱa, cT1N0M0, cStageⅠ). On day 4 of the first course of chemotherapy(docetaxel plus cisplatin plus 5-FU: DCF), a high fever was observed. A chest CT scan revealed suspected mediastinitis and right pyothorax due to perforation by the esophageal cancer. Thoracoscopic mediastinal drainage was immediately performed. CT-guided abscess drainage was added for a residual abscess in the right thoracic cavity on day 10 after drainage surgery. The patient's general condition improved, and he was discharged on 24th postoperative day. The patient was able to reinstitute and continue DCF therapy until disease progression.",
"affiliations": "Dept. of Surgery, Kansai Rosai Hospital.",
"authors": "Fukuyama|Kaoru|K|;Takeno|Atsushi|A|;Murakami|Kohei|K|;Kawai|Kenji|K|;Sakamoto|Takuya|T|;Inatome|Junichi|J|;Naito|Atsushi|A|;Katsura|Yoshiteru|Y|;Ohmura|Yoshiaki|Y|;Kagawa|Yoshinori|Y|;Masuzawa|Toru|T|;Egawa|Chiyomi|C|;Takeda|Yutaka|Y|;Murata|Kohei|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "45(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D004322:Drainage; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D006801:Humans; D008297:Male; D008480:Mediastinitis",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2402-2404",
"pmc": null,
"pmid": "30692478",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Successful Drainage for Mediastinitis during Chemotherapy for Unresectable Advanced Esophageal Cancer.",
"title_normalized": "a case of successful drainage for mediastinitis during chemotherapy for unresectable advanced esophageal cancer"
} | [
{
"companynumb": "JP-ACCORD-107686",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Paraplegia following spinal injury is a rare complication subsequent to the administration of intrathecal chemotherapy; however, it is also one of the rare clinical features of central nervous system leukemia (CNSL). Distinguishing between the two is extremely important. The present study reports the case of a 46-year-old man who was diagnosed with acute lymphoblastic leukemia and subsequently achieved remission in the blood and bone marrow following the initial course of chemotherapy. However, the patient developed a sudden onset of paraplegia and urinary retention due to spinal cord infiltration of leukemia cells following the administration of intrathecal methotrexate and cytarabine. The paraplegia was initially reversible. However, a few weeks later, the patient developed irreversible paraplegia due to a complication of the intrathecal administration of chemotherapy (methotrexate and cytarabine arabinoside). The patient gave up further treatment in May 2013 and succumbed to the disease in June 2013.",
"affiliations": "Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China.;Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China.;Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China.;Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China.;Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China.;Department of Hematology, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, P.R. China.",
"authors": "Pan|Ying|Y|;Wang|Chunhuai|C|;Wang|Huiping|H|;Tao|Qianshan|Q|;Xiong|Shudao|S|;Zhai|Zhimin|Z|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2016.4519",
"fulltext": null,
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"issn_linking": "1792-1074",
"issue": "11(6)",
"journal": "Oncology letters",
"keywords": "B-cell acute lymphocytic leukemia; chemotherapy; transverse myelopathy",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "4066-4068",
"pmc": null,
"pmid": "27313742",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": "18308251;3455842;2728081;25408936;17304378;15251979;8321259;11806983;577895;11873541;3214264;810575;25408861;946593;24156466",
"title": "Transverse myelopathy occurring with intrathecal administration of methotrexate and cytarabine chemotherapy: A case report.",
"title_normalized": "transverse myelopathy occurring with intrathecal administration of methotrexate and cytarabine chemotherapy a case report"
} | [
{
"companynumb": "CN-MYLANLABS-2016M1026403",
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"abstract": "We herein report a patient with a history of rheumatoid arthritis treated with methotrexate, which caused methotrexate-associated lymphoproliferative disorder and obstructive jaundice due to an enlarged lymph node. The obstructive jaundice was treated with endoscopic biliary stenting. A histopathological examination revealed features of Hodgkin's lymphoma, and chemotherapy with brentuximab vedotin was administered. Cholangiography and duodenoscopy after four rounds of chemotherapy revealed a choledochoduodenal fistula that developed in response to chemotherapy. It should be noted that, in cases of lymphoma infiltrating the gastrointestinal wall, fistulae can occur because of rapid regression due to regimens comprising monoclonal antibodies, such as rituximab and brentuximab vedotin.",
"affiliations": "Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Japan.;Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Japan.;Integrated Clinical Education Center, Kyoto University Hospital, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Japan.;Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Japan.",
"authors": "Eso|Yuji|Y|;Uza|Norimitsu|N|;Shirakawa|Kotaro|K|;Sawada|Kenji|K|;Katsuragi|Kentaro|K|;Matsuura|Minoru|M|;Seno|Hiroshi|H|",
"chemical_list": "D018796:Immunoconjugates; D000079963:Brentuximab Vedotin; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.0557-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2952696110.2169/internalmedicine.0557-17Case ReportCholedochoduodenal Fistula during Chemotherapy with Brentuximab Vedotin for Methotrexate-associated Lymphoproliferative Disorder Eso Yuji 1Uza Norimitsu 1Shirakawa Kotaro 2Sawada Kenji 1Katsuragi Kentaro 3Matsuura Minoru 1Seno Hiroshi 1\n1 Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Japan\n2 Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, Japan\n3 Integrated Clinical Education Center, Kyoto University Hospital, JapanCorrespondence to Dr. Yuji Eso, yujieso@kuhp.kyoto-u.ac.jp\n\n9 3 2018 1 8 2018 57 15 2203 2207 20 11 2017 9 1 2018 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).We herein report a patient with a history of rheumatoid arthritis treated with methotrexate, which caused methotrexate-associated lymphoproliferative disorder and obstructive jaundice due to an enlarged lymph node. The obstructive jaundice was treated with endoscopic biliary stenting. A histopathological examination revealed features of Hodgkin's lymphoma, and chemotherapy with brentuximab vedotin was administered. Cholangiography and duodenoscopy after four rounds of chemotherapy revealed a choledochoduodenal fistula that developed in response to chemotherapy. It should be noted that, in cases of lymphoma infiltrating the gastrointestinal wall, fistulae can occur because of rapid regression due to regimens comprising monoclonal antibodies, such as rituximab and brentuximab vedotin. \n\ncholedochoduodenal fistulamethotrexate-associated lymphoproliferative disorderrheumatoid arthritisbrentuximab vedotin\n==== Body\nIntroduction\nCholedochoduodenal fistula (CDF) is a relatively rare condition involving an abnormal communication between the common bile duct (CBD) and duodenum. The most common etiologies of CDF are duodenal ulcer, carcinoma of the duodenum or bile duct, and iatrogenic injury due to a self-expandable metallic stent (1-6). However, CDFs associated with lymphoma treatment are rare.\n\nWe herein report a rare case of CDF that occurred during chemotherapy with brentuximab vedotin for methotrexate-associated lymphoproliferative disorder (MTX-LPD).\n\nCase Report\nAn 83-year-old man was admitted to our hospital to undergo cholangiography. He had a history of rheumatoid arthritis and had been taking methotrexate (MTX, 8 mg per week) for six years. After developing multiple lymphadenopathy 11 months earlier, he was diagnosed with MTX-LPD, prompting the immediate withdrawal of MTX. Subsequently, his multiple lymphadenopathy partially resolved. However, he developed obstructive jaundice 2 months later because of a 40-mm mass adjacent to the CBD. Fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) demonstrated the uptake of 18F-FDG by the mass (Fig. 1). A histopathological examination of the mass obtained via an endoscopic ultrasonography-guided fine-needle aspiration biopsy showed atypical lymphocytic infiltration. An immunohistological analysis was difficult because of the insufficient volume of the sample.\n\nFigure 1. Fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography scan showing the uptake of 18F-FDG by the mass, adjacent to the common bile duct (white arrowheads).\n\nThe obstructive jaundice was treated with percutaneous transhepatic biliary drainage and endoscopic biliary stenting, and four rounds of chemotherapy with rituximab were administered. However, his multiple lymphadenopathy did not improve. Therefore, an excisional biopsy of the left supraclavicular lymph node was performed. A histopathological analysis revealed Reed-Sternberg cells with immunohistological positivity for CD30, PAX5, IMP3, EBER, and Ki-67 (Fig. 2). He was therefore diagnosed with MTX-LPD with Hodgkin's lymphoma-like features, and rituximab was switched to brentuximab vedotin (AdcetrisⓇ, Takeda Pharmaceutical, Tokyo, Japan), an antibody-drug conjugate directed against CD30. 18F-FDG-PET after four rounds of chemotherapy with brentuximab vedotin revealed a markedly reduced mass (Fig. 3). Therefore, removal of the biliary drainage tubes was planned.\n\nFigure 2. (a) A histopathologic examination of the resected the left supraclavicular lymph node (Hematoxylin and Eosin staining, ×200). (b-f) Immunohistochemistry findings of the lymph node. The neoplastic cells are positive for CD30 (b), PAX-5 (c), IMP3 (d), EBER (e), and Ki-67 (f), which is consistent with methotrexate-associated lymphoproliferative disorder with Hodgkin’s lymphoma-like features (×200).\n\nFigure 3. Fluorine-18-fluorodeoxyglucose positron emission tomography findings after four rounds of chemotherapy with brentuximab vedotin revealing a markedly reduced mass (white arrowheads).\n\nPercutaneous transhepatic cholangiography showed outflow of the contrast dye from the CBD to the duodenum (Fig. 4a). Duodenoscopy revealed the exposure of the side wall of the stent, indicating a CDF due to the response to chemotherapy (Fig. 4b). Drainage tubes were removed because the bile was thought to smoothly flow through the CDF. After removal of the tubes, obstructive jaundice did not recur, and the patient was discharged on day 14 of hospitalization. Two additional rounds of chemotherapy with brentuximab vedotin were administered at an outpatient clinic.\n\nFigure 4. (a) Percutaneous transhepatic cholangiography showing outflow of the contrast dye from the common bile duct to the duodenum (white arrow). (b) Duodenoscopy revealing the exposure of the side wall of the stent, indicating a choledochoduodenal fistula.\n\nOne month after discharge, the patient visited the emergency department of our hospital with a chief complaint of melena. Emergent gastroduodenoscopy revealed no active bleeding. However, the accumulation of blood was found in the duodenum, and hemorrhaging from the fistula was highly suspected (Fig. 5a). Angiography did not identify active contrast medium extravasation (Fig. 5b). However, contrast-enhanced computed tomography (CT) suggested that the gastroduodenal artery (GDA), which was adjacent to the fistula, was the source of the bleeding (Fig. 5c). Therefore, transcatheter arterial embolization (TAE) using seven coils for the GDA was performed to prevent re-bleeding. Angiography after TAE confirmed the complete occlusion of the GDA (Fig. 5d). The patient recovered and was discharged 15 days after TAE. 18F-FDG-PET one month after TAE revealed the progression of MTX-LPD, including re-enlargement of the mass adjacent to the CBD (Fig. 6). Therefore, brentuximab vedotin was switched to nivolumab (OpdivoⓇ, Ono Pharmaceutical, Osaka, Japan), an anti-programmed death-1 receptor antibody and three rounds of chemotherapy with nivolumab were administered.\n\nFigure 5. (a) Duodenoscopy revealing a visible vessel in the fistula, which was suspected to be the source of bleeding (white arrow). (b) The angiogram did not identify active contrast medium extravasation from the gastroduodenal artery (GDA, black arrow). (c) A contrast-enhanced tomography scan showing that the GDA (white arrowhead) was adjacent to the fistula (white arrow), suggesting that the GDA was the source of bleeding. (d) An angiogram after embolization confirming the complete occlusion of the GDA (black arrowhead).\n\nFigure 6. Fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography findings showing re-enlargement and the uptake of 18F-FDG by the mass adjacent to the common bile duct (white arrowheads).\n\nThe patient was admitted to the emergency department again with hematemesis. The last course of chemotherapy with nivolumab was administered 13 days before presentation. Blood transfusion and emergent CT were planned; however, he suddenly developed hemorrhagic shock after massive hematemesis followed by asystole and expired despite resuscitative efforts. An autopsy revealed enlarged lymph nodes infiltrating the duodenal wall and fistula formation, which were consistent with the source of bleeding.\n\nDiscussion\nMTX-LPD is a rare but critical complication in patients treated with MTX. MTX-LPD is categorized as an iatrogenic immunodeficiency-associated LPD in the recent World Health Organization classification of lymphoid neoplasms. In many cases, spontaneous regression is achieved after MTX withdrawal, especially in cases of peripheral Epstein-Barr virus-DNA positivity, non-diffuse large B-cell lymphoma-type MTX-LPD, and the early recovery of the absolute lymphocyte count (7-9). However, in many cases of diffuse large B-cell lymphoma-type MTX-LPD, systemic chemotherapy is required (7,8).\n\nCDF involves an abnormal passage between the CBD and duodenum. The most common etiologies of CDF are duodenal ulcer, carcinoma of the duodenum or bile duct, and iatrogenic injury due to a self-expandable metallic stent (1-6). However, CDF associated with treatment of lymphoma is rare, and only one case of non-Hodgkin's lymphoma of the duodenum treated with cyclophosphamide, vincristine, hydrocortisone, and doxorubicin has been reported (10). In cases of lymphoma infiltrating the gastrointestinal wall, gastrointestinal fistulae can occur as a result of rapid regression due to systemic chemotherapy. Regimens comprising monoclonal antibodies, such as rituximab and brentuximab vedotin, can lead to an increased incidence of fistula formation due to the potency of the treatment (11). In the present case, the rapid regression of an enlarged lymph node adjacent to both the duodenal wall and CBD was thought to have resulted in CDF formation and the first instance of hemorrhaging. The association between re-bleeding and the effect of nivolumab was unknown because the therapeutic effect of nivolumab was not assessed until the patient had died of hemorrhagic shock. However, based on the autopsy findings, the effect of nivolumab was suspected to have been relatively slight at that moment, and the second episode of hemorrhaging was likely caused by tumor progression.\n\nIn conclusion, it should be noted that, in cases of lymphoma infiltrating the duodenal wall, the development of CDF or even of fatal hemorrhaging can occur after chemotherapy, especially with regimens containing monoclonal antibodies, such as rituximab and brentuximab vedotin.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Wong WM , Hu WH , Lai KC \nImages of interest. Hepatobiliary and pancreatic: Choledochoduodenal fistula secondary to duodenal ulcer disease . J Gastroenterol Hepatol \n19 : 829 , 2004 .15209635 \n2. B S B , Kar A , Dutta M , et al \nA case of choledochoduodenal fistula - an unusual case report . Clin Case Rep \n5 : 1462 -1464 , 2017 .28878904 \n3. Lin CT , Hsu KF , Yu JC , et al \nCholedochoduodenal fistula caused by cholangiocarcinoma of the distal common bile duct . Endoscopy \n41 : E319 -E320 , 2009 .19921610 \n4. Williamson JB , Draganov PV \nCholedochoduodenal fistula after biliary metallic stent placement for pancreatic cancer . Dig Endosc \n26 : 292 , 2014 .24237310 \n5. Ogawa T , Horaguchi J , Fujita N \nPatent choledochoduodenal fistula created by endosonography-guided biliary drainage after migration of a metallic stent . Dig Endosc \n25 : 84 -85 , 2013 .23286262 \n6. Chaudhari D , Saleem A , Murthy R , et al \nCholedochoduodenal fistula after biliary placement of a self-expanding metallic stent for palliation of pancreatic cancer . Endoscopy \n45 : E77 , 2013 .23526528 \n7. Ichikawa A , Arakawa F , Kiyasu J , et al \nMethotrexate/iatrogenic lymphoproliferative disorders in rheumatoid arthritis: histology, Epstein-Barr virus, and clonality are important predictors of disease progression and regression . Eur J Haematol \n91 : 20 -28 , 2013 .23560463 \n8. Gion Y , Iwaki N , Takata K , et al \nClinicopathological analysis of methotrexate-associated lymphoproliferative disorders: comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types . Cancer Sci \n108 : 1271 -1280 , 2017 .28380678 \n9. Takanashi S , Aisa Y , Ito C , et al \nClinical characteristics of methotrexate-associated lymphoproliferative disorders: relationship between absolute lymphocyte count recovery and spontaneous regression . Rheumatol Int \n37 : 1629 -1633 , 2017 .28676912 \n10. Scott J , Spencer JA , MacLennan KA \nCholedochoduodenal fistula complicating non-Hodgkin's lymphoma of the duodenum during chemotherapy . Clin Radiol \n56 : 508 -510 , 2001 .11428804 \n11. Palmowski M , Zechmann C , Satzl S , et al \nLarge gastrosplenic fistula after effective treatment of abdominal diffuse large-B-cell lymphoma . Ann Hematol \n87 : 337 -338 , 2008 .17929016\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(15)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "brentuximab vedotin; choledochoduodenal fistula; methotrexate-associated lymphoproliferative disorder; rheumatoid arthritis",
"medline_ta": "Intern Med",
"mesh_terms": "D000369:Aged, 80 and over; D001172:Arthritis, Rheumatoid; D000079963:Brentuximab Vedotin; D006801:Humans; D018796:Immunoconjugates; D041781:Jaundice, Obstructive; D008232:Lymphoproliferative Disorders; D008297:Male; D008727:Methotrexate",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "2203-2207",
"pmc": null,
"pmid": "29526961",
"pubdate": "2018-08-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "28676912;23526528;23560463;24237310;28380678;23286262;19921610;28878904;17929016;15209635;11428804",
"title": "Choledochoduodenal Fistula during Chemotherapy with Brentuximab Vedotin for Methotrexate-associated Lymphoproliferative Disorder.",
"title_normalized": "choledochoduodenal fistula during chemotherapy with brentuximab vedotin for methotrexate associated lymphoproliferative disorder"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2018R1-184105",
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"activesubstancename": "METHOTREXATE"
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{
"abstract": "Patients with etoposide/platinum-refractory extensive disease (ED) small-cell lung cancer (SCLC) have a dismal prognosis. We aimed to evaluate the efficacy and safety of pembrolizumab and paclitaxel combination therapy in these patients.\n\n\n\nIn this multi-center, phase II study, ED-SCLC patients who showed progression after etoposide/platinum chemotherapy received paclitaxel 175 mg/m2 every 3 weeks for up to six cycles. Pembrolizumab 200 mg was added from the second cycle and continued until disease progression or unacceptable toxicity. The primary endpoint was the objective response rate (ORR) and the secondary endpoints were progression-free survival (PFS), overall survival (OS), safety, and biomarker analyses including programmed death-ligand 1 (PD-L1) expression, next-generation sequencing, and flow cytometric analysis of peripheral blood cells.\n\n\n\nOf the 26 patients enrolled, the confirmed ORR was 23.1% (95%CI: 6.9%-39.3%); complete response: 3.9%, confirmed partial response [PR]: 19.2%, stable disease: 57.7%, progressive disease: 7.7%, and not evaluable: 11.5%. Including 4 cases of unconfirmed PRs, 38.5% of patients were responding and the disease control rate was 80.7%. The median PFS and OS were 5.0 months (95% CI: 2.7-6.7) and 9.1 months (95% CI: 6.5-15.0), respectively. The grade 3 or 4 adverse events observed included febrile neutropenia (7.7%), neutropenia (7.7%), asthenia (7.7%), hyponatremia (7.7%), and type I diabetes (7.7%). Targeted gene sequencing identified no specific genetic alterations correlated with the treatment, except for theMET copy number gain (PFS 10.5 versus 3.4 months, p = 0.019).\n\n\n\nPembrolizumab and paclitaxel combination therapy showed a moderate activity with acceptable toxicity in patients with refractory ED-SCLC.",
"affiliations": "Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul, Republic of Korea. Electronic address: bhumsuk@snu.ac.kr.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.;Theragen Etex Bioinstitute, NGS Genome Division, Suwon, Republic of Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.;Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul, Republic of Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea; Cancer Research Institute, Seoul National University, Seoul, Republic of Korea.",
"authors": "Kim|Yu-Jung|YJ|;Keam|Bhumsuk|B|;Ock|Chan-Young|CY|;Song|Sanghoon|S|;Kim|Miso|M|;Kim|Se Hyun|SH|;Kim|Ki Hwan|KH|;Kim|Jin-Soo|JS|;Kim|Tae Min|TM|;Kim|Dong-Wan|DW|;Lee|Jong Seok|JS|;Heo|Dae Seog|DS|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; C582435:pembrolizumab; D017239:Paclitaxel",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2019.08.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "136()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Paclitaxel; Pembrolizumab; Small-cell lung cancer",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D011379:Prognosis; D012008:Recurrence; D055752:Small Cell Lung Carcinoma; D016896:Treatment Outcome",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "122-128",
"pmc": null,
"pmid": "31494530",
"pubdate": "2019-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase II study of pembrolizumab and paclitaxel in patients with relapsed or refractory small-cell lung cancer.",
"title_normalized": "a phase ii study of pembrolizumab and paclitaxel in patients with relapsed or refractory small cell lung cancer"
} | [
{
"companynumb": "KR-HQ SPECIALTY-KR-2019INT000272",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
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{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
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{
"abstract": "OBJECTIVE\nTo describe clinical and molecular characteristics of an outbreak due to metallo-β-lactamases (MBLs) producing Klebsiella pneumoniae collected at Charles Nicolle Hospital of Tunis and to analyze the impact of outer membrane porin (OMP) loss on carbapenem resistance levels.\n\n\nMETHODS\nBetween 2010 and 2015, 178 carbapenem-resistant Enterobacteriaceae were isolated. Screening for MBL production was performed using combined disk diffusion method, with imipenem and ethylene diamine tetraacetic acid (EDTA) as inhibitors. Resistance genes and virulence factors were identified by polymerase chain reaction (PCR) and sequencing. Genotyping was performed by pulsed-field gel electrophoresis and multilocus sequence typing. Genetic environment of carbapenemase genes was determined by PCR mapping. Conjugation assays were performed, and plasmids were assigned to incompatibility groups by PCR-based replicon typing. OMPs were profiled by sodium dodecyl sulfate-polyacrilamide gel electrophoresis, and porin genes were sequenced.\n\n\nRESULTS\nNineteen K. pneumoniae (10.6%) showing MBL activity were isolated from patients hospitalized on four different wards. NDM-1 was the only MBL identified, in association with blaOXA-48. All strains lacked at least one OMP, and carbapenem resistance levels were remarkably elevated in strains lacking OmpK35 and OmpK36. blaNDM-1 was located in IncFIA-type conjugative plasmid, with the same genetic context in all strains. The epidemiological diffusion of blaNDM-1 was due to two clones, one major clone belonging to sequence type (ST) 147 (n = 16) and the other clone belonging to ST307 (n = 3).\n\n\nCONCLUSIONS\nThis study describes an outbreak of NDM-1-producing K. pneumoniae strains, isolated from a Tunisian hospital, caused by two clones belonging to ST147 and ST307; and highlights the role of OMPs loss, in combination with β-lactamase expression, in conferring high carbapenem resistance.",
"affiliations": "1 Faculty of Medicine of Tunis-LR99ES09 Research Laboratory of Antimicrobial Resistance, University of Tunis El Manar , Tunis, Tunisia .;3 Service of Microbiology, University Hospital Marqués de Valdecilla-IDIVAL , Santander, Spain .;1 Faculty of Medicine of Tunis-LR99ES09 Research Laboratory of Antimicrobial Resistance, University of Tunis El Manar , Tunis, Tunisia .;3 Service of Microbiology, University Hospital Marqués de Valdecilla-IDIVAL , Santander, Spain .;1 Faculty of Medicine of Tunis-LR99ES09 Research Laboratory of Antimicrobial Resistance, University of Tunis El Manar , Tunis, Tunisia .;1 Faculty of Medicine of Tunis-LR99ES09 Research Laboratory of Antimicrobial Resistance, University of Tunis El Manar , Tunis, Tunisia .;1 Faculty of Medicine of Tunis-LR99ES09 Research Laboratory of Antimicrobial Resistance, University of Tunis El Manar , Tunis, Tunisia .;4 Department of Bacteriology, Medical School, University Pierre et Marie Curie , Paris, France .;4 Department of Bacteriology, Medical School, University Pierre et Marie Curie , Paris, France .;1 Faculty of Medicine of Tunis-LR99ES09 Research Laboratory of Antimicrobial Resistance, University of Tunis El Manar , Tunis, Tunisia .;1 Faculty of Medicine of Tunis-LR99ES09 Research Laboratory of Antimicrobial Resistance, University of Tunis El Manar , Tunis, Tunisia .;1 Faculty of Medicine of Tunis-LR99ES09 Research Laboratory of Antimicrobial Resistance, University of Tunis El Manar , Tunis, Tunisia .;3 Service of Microbiology, University Hospital Marqués de Valdecilla-IDIVAL , Santander, Spain .",
"authors": "Hamzaoui|Zaineb|Z|;Ocampo-Sosa|Alain|A|;Maamar|Elaa|E|;Fernandez Martinez|Marta|M|;Ferjani|Sana|S|;Hammami|Samia|S|;Harbaoui|Sarra|S|;Genel|Nathalie|N|;Arlet|Guillaume|G|;Saidani|Mabrouka|M|;Slim|Amine|A|;Boutiba-Ben Boubaker|Ilhem|I|;Martinez-Martinez|Luis|L|",
"chemical_list": "D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; C119261:OmpK35 porin, Klebsiella pneumoniae; C092233:OmpK36 protein, Klebsiella pneumoniae; D018272:Porins; D015378:Imipenem; D001618:beta-Lactamases; C552864:beta-lactamase NDM-1; C063912:carbapenemase",
"country": "United States",
"delete": false,
"doi": "10.1089/mdr.2017.0165",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-6294",
"issue": "24(8)",
"journal": "Microbial drug resistance (Larchmont, N.Y.)",
"keywords": "Klebsiella pneumoniae; New Delhi metallo-β-lactamase; carbapenem-resistant Enterobacteriaceae; carbapenemases; epidemiology; outer membrane porin",
"medline_ta": "Microb Drug Resist",
"mesh_terms": "D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D015780:Carbapenems; D004196:Disease Outbreaks; D006801:Humans; D015378:Imipenem; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008826:Microbial Sensitivity Tests; D010957:Plasmids; D018272:Porins; D014416:Tunisia; D001618:beta-Lactamases",
"nlm_unique_id": "9508567",
"other_id": null,
"pages": "1137-1147",
"pmc": null,
"pmid": "29373087",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An Outbreak of NDM-1-Producing Klebsiella pneumoniae, Associated with OmpK35 and OmpK36 Porin Loss in Tunisia.",
"title_normalized": "an outbreak of ndm 1 producing klebsiella pneumoniae associated with ompk35 and ompk36 porin loss in tunisia"
} | [
{
"companynumb": "TN-BAYER-2018-213821",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
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"drugadditional": null,
... |
{
"abstract": "The incidence of tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is 10-40 times higher than that in the general population, which ranges from 0.1% to 5.5%. However, the clinical features of TB among allo-HSCT recipients in Japan remain unknown. We retrospectively analyzed the incidence of TB and the clinical features of culture-positive TB among allo-HSCT recipients at our hospital between 2002 and 2018. Of 1,047 recipients, 5 (0.4%) developed pulmonary TB (with an incidence rate of 472 per 100,000 population) at a median of 1,730 (range: 586-2,526) days after allo-HSCT. Three patients had chronic graft-versus-host disease upon the onset of TB, which was well-controlled with tacrolimus and/or steroid. Three of five patients completed TB treatment, and the disease did not flare up after therapy completion. The incidence of TB was higher in allo-HSCT recipients than in the general population (0.01%, with an incidence rate of 12.3 per 100,000 population). Therefore, TB should be considered a late complication among allo-HSCT recipients.",
"affiliations": "Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Department of Infection Control, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.;Hematology Division, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital.",
"authors": "Adachi|Hiroto|H|;Sekiya|Noritaka|N|;Kambara|Yasuhiro|Y|;Atsuta|Yuya|Y|;Otsuka|Yuki|Y|;Konuma|Ryosuke|R|;Suzaki|Ken|K|;Wada|Atsushi|A|;Kishida|Yuya|Y|;Uchibori|Yusuke|Y|;Mukae|Junichi|J|;Shingai|Naoki|N|;Toya|Takashi|T|;Shimizu|Hiroaki|H|;Najima|Yuho|Y|;Kobayashi|Takeshi|T|;Sakamaki|Hisashi|H|;Ohashi|Kazuteru|K|;Doki|Noriko|N|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.62.239",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "62(4)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Allogeneic hematopoietic stem cell transplantation; Mycobacterium tuberculosis",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007564:Japan; D012189:Retrospective Studies; D014376:Tuberculosis",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "239-244",
"pmc": null,
"pmid": "33967146",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical features of tuberculosis among allogeneic hematopoietic stem cell transplantation recipients.",
"title_normalized": "clinical features of tuberculosis among allogeneic hematopoietic stem cell transplantation recipients"
} | [
{
"companynumb": "JP-SA-2021SA182633",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugadditional": "3",
"drug... |
{
"abstract": "The safety and tolerability of everolimus has been evaluated in a randomized, phase II trial, comparing 3 doses of everolimus to a placebo, in association with cyclosporine and corticosteroids, after liver transplantation. There were no significant differences between groups in the rates of the composite end point (graft failure, biopsy-proven acute rejection, graft loss, death, or loss to follow-up) or its individual components. Although there were lower rates of treated acute rejection and mortality with the higher dosages (2 and 4 mg/day), these did not reach statistical significance. Interestingly, freedom from rejection correlated with trough blood levels of everolimus: patients with levels of 3 ng/mL or less had rejection rates 3-fold higher than patients with levels exceeding 3 ng/mL. All graft losses and most deaths were associated with typical posttransplant complications, not with study medication and not due to hepatic artery thrombosis. There were no clear dose-related differences among groups for hematology parameters. After transplantation, renal function declined to a similar extent in all 4 groups. The overall incidence of infection was comparable between groups (61-77%). Although the interpretation of the results of this trial is hampered by the small sample sizes of patient groups (about 30 in each group) and the high dropout rates (about 50%), this study suggests that everolimus is an effective immunosuppressive agent with an acceptable patient tolerance and safety profile after liver transplantation.",
"affiliations": "Unité de Transplantation Hépatique, Hôpital Cochin, 27, rue du Fbg St-Jacques, Paris, France. Yvon.calmus@cch.aphp.fr",
"authors": "Calmus|Y|Y|;Durrbach|A|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D010919:Placebos; D016572:Cyclosporine; D000068338:Everolimus; C546842:MTOR protein, human; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus",
"country": "France",
"delete": false,
"doi": "10.1016/S0399-8320(09)73161-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0399-8320",
"issue": "33 Suppl 4()",
"journal": "Gastroenterologie clinique et biologique",
"keywords": null,
"medline_ta": "Gastroenterol Clin Biol",
"mesh_terms": "D016572:Cyclosporine; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000068338:Everolimus; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D047908:Intracellular Signaling Peptides and Proteins; D016031:Liver Transplantation; D010919:Placebos; D017346:Protein Serine-Threonine Kinases; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases",
"nlm_unique_id": "7704825",
"other_id": null,
"pages": "S247-52",
"pmc": null,
"pmid": "20004330",
"pubdate": "2009-11",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Everolimus de novo in liver transplantation.",
"title_normalized": "everolimus de novo in liver transplantation"
} | [
{
"companynumb": "NVSC2019FR079993",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Methyl-CpG-binding protein 2 (MECP2) deleterious variants, which are responsible for Rett syndrome in girls, are involved in a wide spectrum of developmental disabilities in males. A neuropsychiatric phenotype without intellectual disability is uncommon in patients with MECP2 deleterious variants. We report on two dizygotic twins with an MECP2-related psychiatric disorder without intellectual disability. Neuropsychological and psychiatric phenotype assessments were performed, and a genetic analysis was carried out. Both patients fulfilled the Pervasive Developmental Disorder criteria on Autism Diagnostic Observation Schedule and Asperger syndrome criteria on Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV). One patient developed early-onset schizophrenia (DSM-IV criteria) with two acute psychotic episodes, the latest one following corticosteroids and sodium valproate intake, with major hyperammonemia. A novel MECP2 gene transversion c.491 G>T [p.(Ser164Ile)] was found in both twins. Pathogenicity of this variant was considered on the basis of strong clinical and molecular data. The underlying molecular basis of neuropsychiatric disorders may have important consequences on genetic counseling and therapeutic strategies.",
"affiliations": "aClaude Bernard Lyon 1 University bInstitute of Cognitive Science, CNRS UMR 5304 cFrench National Reference Center for Rare Diseases with Intellectual Disability dReference Center on Learning Disabilities, Pediatric Functional Rehabilitation Department, Escale, Women Mothers and Children Hospital eDepartment of Child Psychiatry, Neurological Hospital fDepartment of Medical Genetics, Lyon University Hospital gCNRS UMR 5292, INSERM U1028, CNRL hDepartment of Child Psychiatry, Saint Jean de Dieu Hospital, Lyon, France.",
"authors": "Curie|Aurore|A|;Lesca|Gaëtan|G|;Bussy|Gérald|G|;Manificat|Sabine|S|;Arnaud|Valérie|V|;Gonzalez|Sibylle|S|;Revol|Olivier|O|;Calender|Alain|A|;Gérard|Daniel|D|;des Portes|Vincent|V|",
"chemical_list": "C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2",
"country": "England",
"delete": false,
"doi": "10.1097/YPG.0000000000000165",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0955-8829",
"issue": "27(3)",
"journal": "Psychiatric genetics",
"keywords": null,
"medline_ta": "Psychiatr Genet",
"mesh_terms": "D020817:Asperger Syndrome; D001321:Autistic Disorder; D002648:Child; D020022:Genetic Predisposition to Disease; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D051783:Methyl-CpG-Binding Protein 2; D009154:Mutation; D020125:Mutation, Missense; D012559:Schizophrenia; D012561:Schizophrenia, Childhood",
"nlm_unique_id": "9106748",
"other_id": null,
"pages": "105-109",
"pmc": null,
"pmid": "28230711",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Asperger syndrome and early-onset schizophrenia associated with a novel MECP2 deleterious missense variant.",
"title_normalized": "asperger syndrome and early onset schizophrenia associated with a novel mecp2 deleterious missense variant"
} | [
{
"companynumb": "FR-BION-006076",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VALPROIC ACID"
},
"drugadditional": "1",
"drug... |
{
"abstract": "Vertebral aspergillosis is a rare infectious disease with a high mortality rate. We herein report a 70-year-old woman with acute myelogenous leukemia with myelodysplasia-related changes, nontuberculous mycobacteriosis, and bronchiectasis who presented with a fever and cough. Her clinical symptoms and laboratory test results suggested febrile neutropenia and pneumonia. However, her clinical course was further complicated by lower extremity weakness. Magnetic resonance imaging of the spine showed consolidation contiguously spreading toward the epidural space between the T4 and T5. Cytological testing of the pleural effusion revealed Aspergillus fumigatus. We also review and summarize previously reported cases of vertebral aspergillosis in Japan.",
"affiliations": "Division of Hematology, Shonan Kamakura General Hospital, Japan.;Division of Hematology, Shonan Kamakura General Hospital, Japan.;Division of Hematology, Shonan Kamakura General Hospital, Japan.;Division of Hematology, Shonan Kamakura General Hospital, Japan.;Division of Hematology, Shonan Kamakura General Hospital, Japan.;Division of Hematology, Shonan Kamakura General Hospital, Japan.",
"authors": "Ono|Ryohei|R|;Sato|Shuku|S|;Okada|Satomi|S|;Kanbe|Emiko|E|;Tanaka|Eri|E|;Tamai|Yotaro|Y|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.1135-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2987728210.2169/internalmedicine.1135-18Case ReportInvasive Pulmonary Aspergillosis in the Epidural Space in a Patient with Acute Myelogenous Leukemia with Myelodysplasia-related Changes: A Case Study and Literature Review of Vertebral Aspergillosis in Japan Ono Ryohei 1Sato Shuku 1Okada Satomi 1Kanbe Emiko 1Tanaka Eri 1Tamai Yotaro 1\n1 Division of Hematology, Shonan Kamakura General Hospital, JapanCorrespondence to Dr. Ryohei Ono, ryohei_ono_0820@yahoo.co.jp\n\n6 6 2018 1 11 2018 57 21 3205 3212 5 3 2018 3 4 2018 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Vertebral aspergillosis is a rare infectious disease with a high mortality rate. We herein report a 70-year-old woman with acute myelogenous leukemia with myelodysplasia-related changes, nontuberculous mycobacteriosis, and bronchiectasis who presented with a fever and cough. Her clinical symptoms and laboratory test results suggested febrile neutropenia and pneumonia. However, her clinical course was further complicated by lower extremity weakness. Magnetic resonance imaging of the spine showed consolidation contiguously spreading toward the epidural space between the T4 and T5. Cytological testing of the pleural effusion revealed Aspergillus fumigatus. We also review and summarize previously reported cases of vertebral aspergillosis in Japan. \n\nvertebral aspergillosisAML/MRCreviewaspergillus fumigatusepidural mass\n==== Body\nIntroduction\nInvasive pulmonary aspergillosis generally occurs in patients with severe immunodeficiency and can be a major cause of morbidity and mortality (1). Aspergillus osteomyelitis is a debilitating and severe form of invasive aspergillosis, but it is extremely rare with a high mortality rate (2,3). Vinas et al. (4) and Studemeister et al. (5) reviewed the literature on 41 and 21 previous aspergillus vertebral osteomyelitis cases, respectively. However, only Japanese reports of vertebral aspergillosis cases have been published, and we found none of these Japanese case reports in the English literature. We searched PubMed and Japana Centra Revuo Medicina (Igaku-Chuo-Zasshi), which is a database for Japanese medical journals, to identify case reports of vertebral aspergillosis in Japan and found 27 cases reported from 1972 to 2017 (6-31).\n\nWe herein report a rare case of invasive pulmonary aspergillosis spreading to the epidural space in a patient with acute myelogenous leukemia with myelodysplasia-related changes (AML/MRC). Previously reported cases of vertebral aspergillosis in Japan were also reviewed and summarized.\n\nCase Report\nA 70-year-old Japanese woman presented with a fever and chronic cough that had developed 1 week before admission. She had been diagnosed with nontuberculous mycobacteriosis of Mycobacterium avium and bronchiectasis with chronic cough at 30 years of age and AML/MRC 20 months earlier. She was subsequently treated with a cycle of low-dose cytarabine, aclarubicin hydrochloride, and granulocyte colony-stimulating factor (CAG regimen) along with 15 cycles of azacitidine regimen. The azacitidine regimen had been performed seven days earlier, and a slight fever was noted. Her familial history was unremarkable.\n\nThe patient was slightly drowsy upon arrival, but her Glasgow Coma Score was 15. Her blood pressure, pulse, body temperature, and respiratory rate were 84/53 mmHg, 92 beats/min, 37.1°C, and 22 cycles/min, respectively. Her height and weight were 156.0 cm and 36.8 kg, respectively. A physical examination revealed conjunctival pallor, furry tongue, generalized purpura, and coarse crackles at the right upper lobe. Her extremities were warm. Laboratory studies demonstrated pancytopenia and elevation of C-reactive protein (CRP) levels. In addition, serum β-D-glucan (measured by the kinetic colorimetric assay called Fungitec G-Test MK) and aspergillus antigen levels were elevated (Table 1). A sputum culture was only positive for Staphylococcus epidermidis, which is a normal flora species.\n\nTable 1. Summary of Laboratory Data upon Admission.\n\nHematology\t\tBlood chemistry\t\nWBC\t100\t/μL\t\tTP\t5.1\tg/dL\t\nNeutro\t14.3\t%\t\tAlb\t2.0\tg/dL\t\nLym\t78.6\t%\t\tAST\t12\tU/L\t\nMono\t7.1\t%\t\tALT\t40\tU/L\t\nRBC\t255\t104/μL\t\tLDH\t116\tU/L\t\nHb\t7.4\tg/dL\t\tALP\t621\tU/L\t\nHt\t21.5\t%\t\tT-Bil\t1.1\tmg/dL\t\nMCV\t84.3\tfL\t\tBUN\t21.4\tmg/dL\t\nPlt\t0.6\t104/μL\t\tCre\t0.66\tmg/dL\t\n\t\t\t\tNa\t133\tmEq/L\t\n\t\t\t\tK\t3.4\tmEq/L\t\n\t\t\t\tCl\t97\tmEq/L\t\n\t\t\t\tCa\t8.8\tmg/dL\t\n\t\t\t\tMg\t1.7\tmg/dL\t\n\t\t\t\tIP\t4.0\tmg/dL\t\n\t\t\t\tFerritin\t4,371\tng/mL\t\n\t\t\t\tCRP\t34.3\tmg/dL\t\n\t\t\t\tProcalcitonin\t9.2\tng/mL\t\n\t\t\t\tβ-D-glucan\t36.5\tpg/mL\t\n\t\t\t\tAspergillus antigen (cutoff index; 0-0.4)\t0.5\t\t\nWBC: white blood cells, Neutro: neutrophils, Lym: lymphocytes, Mono: monocytes, RBC: red blood cells, Hb: hemoglobin, Ht: hematocrit, MCV: mean cell volume, Plt: platelets, TP: total protein, Alb: albumin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: Alkaline phosphatase, T-Bil: total bilirubin, BUN: blood-urea-nitrogen, Cre: creatinine, CRP: C-reactive protein\n\nChest roentgenogram and computed tomography (CT) of the chest showed consolidation with lesions in right S3 and S6 and left S3, S4, and S6 (Fig. 1, 2). The right S6 lesion was located at the level of the T5 vertebra. The patient was initially diagnosed with febrile neutropenia, bilateral pneumonia, and oral candida infection, which were treated with the granulocyte-colony stimulating factor cefepime (CFPM) 4 g/day and liposomal amphotericin B (L-AMB) 2.5 mg/kg/day. On day 2, Pseudomonas aeruginosa was detected in the patient’s blood culture, and the fever had not abated. Antibiotic therapy was escalated to meropenem (MEPM) 3 g/day based on the results of the antibiogram on day 4. However, on the same day, she complained of right lower leg weakness, although she was able to walk. On day 6, she developed right hemiplegia and left thermal hypoalgesia in the T6 level, presenting as Brown-Sequard syndrome-like symptoms.\n\nFigure 1. Chest roentgenogram showing bilateral infiltrations.\n\nFigure 2. Computed tomography image of the chest showing the consolidation with lesions at the right upper and lower lobe, left lingular lobe, and lower lobe (red arrows).\n\nHer brain CT findings were unremarkable. Magnetic resonance imaging (MRI) of the thoracic and lumbar spine showed that consolidation was contiguously spreading toward the epidural space at the level between the T4 and T5 (Fig. 3). Although radiological findings demonstrated discitis, osteomyelitis, and an epidural mass at the same levels, the patient was not given surgical treatment due to her poor condition. On day 7, the patient developed paraplegia, absent bilateral lower tendon reflexes, and bladder and rectal disturbance; thus, contrast CT of the chest and abdomen was performed (Fig. 4). The results showed bilateral hydronephrosis, intestinal gas accumulation, and an infiltrative epidural tumor secondary to pulmonary consolidation. We immediately performed CT-guided thoracentesis from the back to examine the tumor in right S6 (Fig. 5), and cytology of the right pleural effusion and the mass detected the presence of Aspergillus fumigatus, which was confirmed based on the morphology and real-time polymerase chain reaction for A. fumigatus DNA (geniQⓇ; KITASATO-OTSUKA Biomedical Assay Laboratories Company, Sagamihara, Japan) (5,000 copies/mL, normal range: <40 copies/mL) (Fig. 6).\n\nFigure 3. Magnetic resonance imaging of the thoracic and lumbar spine showing the consolidation (red arrows) contiguously spreading toward the epidural space at the level of T4 and T5: (a) T1-weighted image on an axial view. (b) T1-weighted image on a sagittal view. (c) T2-weighted image on an axial view. (d) T2-weighted image on a coronal view.\n\nFigure 4. Contrast CT of the chest and abdomen showing bilateral hydronephrosis (a, c), intestinal gas accumulation (b), and the epidural mass (d).\n\nFigure 5. CT-guided thoracentesis from the back into the mass in right S6.\n\nFigure 6. The results of cytology of patient’s pleural effusion showing Aspergillus fumigatus (left: Papanicolaou stain, right: Grocott’s methenamine silver stain; ×1,000).\n\nA diagnosis of vertebral aspergillosis was made, so micafungin (MCFG) 200 mg/day was added, and the dose of L-AMB was increased to 4.0 mg/kg/day on day 8. On day 9, drainage tubes were inserted under CT-guided thoracentesis, and saline perfusion was also performed using drainage tubes. Intravenous voriconazole (VRCZ) 6 mg/kg was administered every 12 hours on day 10 instead of L-AMB and MCFG and subsequently decreased to 4 mg/kg twice daily, but the patient died 14 days after hospital admission due to uncontrolled infection and multiple organ failure, including disseminated intravascular coagulation. During the hospitalization, the patient’s pancytopenia, elevated CRP, and fever never improved (Fig. 7). Catheter tip cultures of drainage tubes were also positive for A. fumigatus.\n\nFigure 7. The clinical course of the patient. CFPM: Cefepime, CRP: C-reactive protein, L-AMB: Liposomal amphotericin B, MCFG: Micafungin, MEPM: Meropenem, VRCZ: Voriconazole\n\nDiscussion\nAspergillus spp. have emerged as major causes of morbidity and mortality in immunocompromised hosts. Patients with osteomyelitis caused by Aspergillus spp. had an overall mortality rate of 25% (2). However, patients with vertebral osteomyelitis had lower mortality rates (4). The major clinical features of the 27 previously reported cases of vertebral aspergillosis in Japan and our case are summarized in Table 2 (6-31).\n\nTable 2. Literature Review of Vertebral Aspergillosis Reported in Japan.\n\nCase\tReference/\nyear\tAge \n(years)\tSex\tAspergillus\n\nspecies\tPresentation\tPredisposing factor(s)\tInfectious route\tParalysis\tSpine \nlevel\tRadiological \nfinding(s)\tAntifungal \ntreatment\tSurgical treatment\tOutcome\t\n1\t[6], 1972\t38\tF\t\nfumigatus\n\tNeck pain, back pain\tTuberculosis, empyema, pulmonary aspergillosis\tND\tNo\tC5-L2\tDiscitis, osteomyelitis\tND\tPosterior spinal fusion\tAlive\t\n2\t[7], 1978\t53\tM\tND\tChest pain, fever\tTuberculosis, steroid user\tContiguous spread\tYes\tT3-T7\tDiscitis, osteomyelitis, epidural mass\tND\tLaminectomy\tDeath\t\n3\t[8], 1981\t57\tM\t\nfumigatus\n\tChest pain, back pain\tTuberculosis (lobectomy)\tHematogenous\tNo\tC6-L3\tDiscitis, osteomyelitis\tAMPH-B\tNone\tAlive\t\n4\t[9], 1987\t62\tM\t\nfumigatus\n\tBack pain\tTuberculosis\tContiguous spread\tYes\tT6-T7\tEpidural mass\tAMPH-B, 5-FC\tLaminectomy\tDeath\t\n5\t[10], 1989\t13\tM\t\nfumigatus\n\tBack pain\tChronic granulomatous disease\tContiguous spread\tYes\tC6-T4\tDiscitis, osteomyelitis, epidural mass\tND\tAnterior spinal fusion, debridement\tDeath\t\n6\t[11], 1991\t71\tM\tND\tLower extremity weakness\tTuberculosis, alcoholic liver failure\tContiguous spread\tYes\tT4-T5\tEpidural mass\tND\tLaminectomy\tDeath\t\n7\t[12], 1992\t71\tM\t\nfumigatus\n\tChest pain, back pain, lower extremity weakness\tTuberculosis, alcoholic liver failure\tContiguous spread\tYes\tT4\tEpidural mass\tMCZ\tLaminectomy\tDeath\t\n8\t[13], 1992\t63\tM\t\nfumigatus\n\tLower extremity weakness, incontinence\tTuberculosis, pulmonary aspergillosis\tContiguous spread\tYes\tT2-T5\tDiscitis, osteomyelitis, epidural mass\tMCZ\tNone\tDeath\t\n9\t[14], 1994\t56\tM\tND\tLower extremity weakness, back pain\tLung cancer (lobectomy+radiation)\tContiguous spread\tYes\tT3-T5\tOsteomyelitis, epidural mass\tFLCZ\tPosterior spinal fusion\tDeath\t\n10\t[15], 1995\t47\tF\tND\tLow back pain\tAcute lymphocytic leukemia (chemotherapy, steroid user)\tHematogenous\tNo\tL4-S1\tDiscitis\tAMPH-B, MCZ\tLaminectomy, debridement\tAlive\t\n11\t[16], 1996\t53\tF\t\nfumigatus\n\tChest pain, extremity weakness\tTuberculosis\tContiguous spread\tYes\tT5\tOsteomyelitis, epidural mass\tND\tNone\tDeath\t\n12\t[17], 1997\t53\tM\t\nfumigatus\n\tBack pain, lower extremity weakness, dysuria\tTuberculosis (thoracoplasty)\tHematogenous\tYes\tT11-L2\tDiscitis, osteomyelitis, epidural mass\tAMPH-B, FLCZ\tLaminectomy, debridement\tAlive\t\n13\t[18], 1998\t8\tF\tND\tLower extremity weakness, dysuria, back pain\tChronic granulomatous disease, pneumonia\tContiguous spread\tYes\tT2-T5\tEpidural mass, osteomyelitis, discitis\tITCZ, FLCZ, AMPH-B\tLaminectomy\tDeath\t\n14\t[19], 1998\t41\tF\tND\tBack pain, lower extremity numbness\tAcute lymphocytic leukemia\tHematogenous\tYes\tL4-S1\tOsteomyelitis, epidural mass\tAMPH-B\tLaminectomy, debridement\tAlive\t\n15\t[19], 1998\t54\tF\t\nfumigatus\n\tBack pain, lower extremity weakness\tThrombocytopenic purpura, steroid user\tContiguous spread\tYes\tT7-T9\tDiscitis, osteomyelitis, epidural mass\tND\tNone\tDeath\t\n16\t[20], 2000\t70\tM\tND\tRight lower extremity weakness, back pain\tAcute lymphocytic leukemia\tContiguous spread\tYes\tND\tOsteomyelitis\tND\tNone\tDeath\t\n17\t[21], 2000\t67\tM\tND\tLow back pain, lower extremity pain\tTuberculosis (thoracoplasty)\tHematogenous\tYes\tT11-L2\tOsteomyelitis, epidural mass\tND\tLaminectomy, debridement\tDeath\t\n18\t[22], 2000\t68\tM\tND\tLower extremity weakness\tTraumatic pleurisy (thoracoplasty), diabetes mellitus, pulmonary aspergillosis\tND\tYes\tT9-T10\tDiscitis,epidural mass\tFLCZ, AMPH-B\tCostotransversectomy, laminectomy, debridement\tAlive\t\n19\t[23], 2003\t61\tM\tND\tLower extremity weakness\tND\tND\tYes\tT6-T7\tDiscitis, osteomyelitis, epidural mass\tND\tLaminectomy, debridement\tDeath\t\n20\t[24], 2003\t75\tF\tND\tLower extremity weakness\tImmune thrombocytopenic purpura, steroid user, diabetes mellitus\tHematogenous\tYes\tT10\tEpidural mass, compression fracture\tFLCZ, ITCZ\tLaminectomy, debridement\tAlive\t\n21\t[25], 2007\t77\tM\tND\tLower extremity weakness, dysuria\tLung cancer (lobectomy+radiation), pulmonary aspergillosis\tContiguous spread\tYes\tT3-T4\tDiscitis, osteomyelitis, epidural mass\tVRCZ, MCFG\tLaminectomy, posterior spinal fusion\tAlive\t\n22\t[26], 2009\t64\tM\t\nfumigatus\n\tLower extremity weakness\tRetrobulbar optic neuritis, steroid user, hepatitis C\tHematogenous\tYes\tT8-T9\tDiscitis, osteomyelitis, epidural mass\tVRCZ, AMPH-B\tNone\tDeath\t\n23\t[27], 2012\t70\tF\tND\tLow back pain\tNeutropenia, steroid user\tHematogenous\tNo\tL4-L5\tDiscitis\tVRCZ\tDiscectomy\tAlive\t\n24\t[28], 2013\t60\tM\tND\tChest pain, back pain, extremity weakness\tLung cancer (lobectomy+radiation), pulmonary aspergillosis\tContiguous spread\tYes\tSpine\tOsteomyelitis, epidural mass\tMCFG, L-AMB\tLaminectomy, debridement\tDeath\t\n25\t[29], 2013\t60\tM\tND\tRight lower extremity weakness\tLung cancer (lobectomy+radiation), pulmonary aspergillosis\tContiguous spread\tYes\tT5-T6\tEpidural mass\tND\tLaminectomy, debridement\tDeath\t\n26\t[30], 2015\t73\tM\tND\tBack pain\tLung cancer (radiation), pulmonary aspergillosis\tContiguous spread\tNo\tT2\tOsteomyelitis\tVRCZ, MCFG\tNone\tAlive\t\n27\t[31], 2017\t72\tM\tND\tLow back pain, muscle weakness\tOpen vertebral fracture (Th12; debridement)\tDirect inoculation (wound infection)\tYes\tT11-T12\tDiscitis\tND\tAnterior spinal fusion\tAlive\t\n28\tOno (our case) 2018\t70\tF\t\nfumigatus\n\tFever, lower extremity weakness\tAML/MRC, nontuberculous mycobacteriosis, bronchiectasis, steroid user\tContiguous spread\tYes\tT4-T5\tDiscitis, osteomyelitis, epidural mass\tVRCZ, MCFG\tNone\tDeath\t\nND: Not described, MCZ: Miconazole, MCFG: Micafungin, L-AMB: Liposomal amphotericin B, VRCZ: Voriconazole, AMPH-B: Amphotericin B, ITCZ: Itraconazole, FLCZ: Fluconazole, 5-FC: 5-Fluorocytosine\n\nThe mean age of the population ± standard deviation was 58.1 ± 16.4 years (range, 8-77 years), of which 19 were men and 9 women. Young patients with chronic granulomatous disease were described in two cases out of the 28 cases of vertebral aspergillosis. A. fumigatus was detected in 11 cases (39%), but the Aspergillus spp. detected in the other cases were not described in detail. The most common presenting symptom of vertebral aspergillosis was extremity weakness (68%), followed by back pain (61%), chest pain (18%), urinary problems such as incontinence or dysuria (14%), a fever (7%), and neck pain (4%). Throughout the process, neurological deficit as a sign of paralysis was finally noted in 23 cases (82%).\n\nCauses of vertebral aspergillosis can be divided into three main categories. Direct inoculation related to trauma, spinal surgery, or epidural injection occurs rarely and manifests generally within months after the procedure, while contiguous spread from pulmonary disease mainly affects the thoracic spine. Hematogenous infection occurs generally in immunosuppressed patients. A previous study reported that about half of patients acquired the infection by a presumed hematogenous route (5). However, in Japan, 16 cases (57%) acquired the infection by a presumed contiguous spread. This is due to the high prevalence of tuberculosis and lung cancer in Japan, which is a tuberculosis middle-burden country (32). Our study reported 10 cases of tuberculosis (36%) and 5 cases of lung cancer with surgical and radiation treatment (18%) as predisposing factors, respectively. Usually, patients with chronic lung disease are prone to Aspergillus colonization and infection. Patients infected with nontuberculous mycobacteriosis may have coexisting lung disease, such as bronchiectasis or chronic obstructive pulmonary disease. Although our case had a history of nontuberculous mycobacteriosis and bronchiectasis, a recent study showed that patients with bronchiectasis and nontuberculous mycobacterial disease have a higher prevalence of coexisting Aspergillus-related lung disease than those with bronchiectasis and without nontuberculous mycobacteria (33). Therefore, nontuberculous mycobacterial disease or bronchiectasis should be considered risk factors for vertebral aspergillosis. The hematogenous spread was observed in 8 cases (29%), but only 1 (4%) of these cases was due to wound infection by direct inoculation.\n\nThe thoracic vertebrae were the most frequent sites of infection (82.1%), while the lumbar vertebrae and cervical spine were involved in 25.0% and 10.7% of the cases, respectively. The thoracic vertebrae are easily affected by contiguous spread arising from pulmonary diseases. Most patients presented with discitis or osteomyelitis at one or more levels of the cervical, thoracic, or lumbar spine. Epidural mass was reported in 21 cases (75%). Since the radiological findings are nonspecific, the definitive diagnosis of vertebral aspergillosis requires the isolation of the organism from bone specimens obtained by a needle biopsy or open biopsy or from aspirate of adjacent fluid collection (4). Our study suggested that CT-guided thoracentesis may be an effective way of obtaining specimens.\n\nA total of 17 patients (61%) were treated with antifungal agents, while 20 patients (71%) received surgical treatments. The overall mortality rate was 61%, and the recovery rate was 39%. About 7 of the 11 patients who survived from vertebral aspergillosis were given both surgical and antifungal treatments. The penetration of antifungal agents in bone tissues is controversial. Denes et al. reported VRCZ may have a role in managing infection at the bone since the concentration of the VRCZ was high in the bone (34). However, the amphotericin concentrations were found to be high in the bone marrow of dogs and rabbits following the administration of any of the currently available formulations, including L-AMB. No data are available for MCFG, although this has been used to treat a few patients with bone/joint infections, in combination with amphotericin (35).\n\nIn summary, our review of reported cases of vertebral aspergillosis in Japan suggested that patients with a history of pulmonary diseases such as tuberculosis, including nontuberculous mycobacteriosis, bronchiectasis, or lung cancer treated with surgery or radiology, should be screened for aspergillosis. If such patients develop extremity weakness or back pain, MRI of the spine should be performed to diagnose vertebral aspergillosis. CT-guided thoracentesis should be considered in order to identify the cytology. Antifungal therapy in combination with surgical treatment should be given to treat serious and life-threatening infections as the condition allows.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Reichenberger F , Habicht JM , Gratwohl A , Tamm M \nDiagnosis and treatment of invasive pulmonary aspergillosis in neutropenic patients . Eur Respir J \n19 : 743 -755 , 2002 .11999005 \n2. Gabrielli E , Fothergill AW , Brescini L , et al \nOsteomyelitis caused by Aspergillus species: a review of 310 reported cases . Clin Microbiol Infect \n20 : 559 -565 , 2014 .24303995 \n3. Li Y , Cen Y , Luo Y , Zhu Z , Min S , Chen X \nAspergillus vertebral osteomyelitis complicating pulmonary granuloma in an immunocompetent adult . Med Princ Pract \n25 : 394 -396 , 2016 .26667988 \n4. Vinas FC , King PK , Diaz FG \nSpinal aspergillus osteomyelitis . Clin Infect Dis \n28 : 1223 -1229 , 1999 .10451157 \n5. Studemeister A , Stevens DA \nAspergillus vertebral osteomyelitis in immunocompetent hosts: role of triazole antifungal therapy . Clin Infect Dis \n52 : e1 -e6 , 2011 .21148508 \n6. Kawata T , Shimomura M , Waku K , Okuda Y , Sawamura K , Koh Y \nA case report of disseminated aspergillosis involving vertebrae . Cent Jpn J Orthop Traumat \n15 : 690 -691 , 1972 (in Japanese).\n7. Fukushima N , Doi A , Fujii K \nA case of autopsy of aspergillus pleuritis spreading to the thoracicus . The Medical Journal of the Fraternity Memorial Hospital \n10 : 132 -140 , 1978 (in Japanese).\n8. Maki Y , Hayashi N , Minagawa H , Yagi K \nA case of vertebral aspergillosis with the difficulty of diagnosis and treatment . Tohoku Archives of Orthopaedic Surgery and Traumatology \n24 : 110 -111 , 1981 (in Japanese).\n9. Ito S , Muro T , Nishikimi J , et al \nA case report of Aspergillus fumigatus spondylitis of the thoracic spine . Seikei Saigai Geka \n30 : 1729 -1733 , 1987 (in Japanese).\n10. Hitomi S , Miyamoto T , Sakakibara K , et al \nA case report of Aspergillus osteomyelitis of the spine . Orthopedic Surgery \n40 : 239 -244 , 1989 (in Japanese).\n11. Shibata M \nAspergillus spinal epidural abscess: an autopsy case report . The Journal of the Japan Spine Research Society \n2 : 281 , 1991 (in Japanese).\n12. Kumeta Y , Mimura M , Shibata M , Hattori A , Kanaya N , Namiki A \nA case of pulmonary and spinal aspergillosis with chest and back pain . Pain Clinic \n13 : 215 -218 , 1992 (in Japanese).\n13. Hamaya K , Nose S , Muguruma M , Nakagawa M , Yasuda H \nAspergillosis involving the thoracic spinal cord - an autopsy case . No To Shinkei \n44 : 1025 -1028 , 1992 (in Japanese, Abstract in English).1296715 \n14. Uchida K , Nagano K , Nishihara N , Nakahara S , Matsui Y , Edashige K \nFour cases of fungal vertebral osteomyelitis . Journal of the Chugoku-Shikoku Orthopaedic Association \n6 : 479 -485 , 1994 (in Japanese, Abstract in English).\n15. Kawamura M , Takeuchi J , Hatta Y , et al \nAspergillus lumbar discitis in a patient with acute lymphoblastic leukemia following induction therapy . Jpn J Clin Hematol \n36 : 206 -211 , 1995 (in Japanese, Abstract in English).\n16. Akutsu K , Goto H , Sakurada S , et al \nA case of invasive pulmonary aspergillosis accompanied with aspergillus meningitis . Kansenshogaku Zasshi (J Jpn Assoc Infect Dis) \n70 : 637 -641 , 1996 (in Japanese, Abstract in English).\n17. Kageyama M , Adachi K , Ebihara A , et al \nAspergillus spondylitis: a case report . Kanagawa J Orthop Traumatol \n10 : 35 -38 , 1997 (in Japanese).\n18. Katagiri M , Agematsu K , Yabuhara A , et al \nA case of chronic granulomatous disease with myeloparalysis caused by the infiltration from aspergillus pneumonia . Japanese Journal of Pediatric Medicine \n30 : 561 -566 , 1998 (in Japanese).\n19. Okawa A , Masubuchi H , Shimakura Y , et al \nAspergillus infection of the spine: report of two cases . Kanto Journal of Orthopedics and Traumatology \n29 : 391 -396 , 1998 (in Japanese).\n20. Tamano K , Yoshizumi Y , Imada K , et al \nA case of aspergillus spondylitis . Cent Jpn J Orthop Traumat \n43 : 1338 -1339 , 2000 (in Japanese).\n21. Chino K , Fujiwara S , Kanazawa H , Okuda T , Oyama T \nA case report of aspergillus spondylitis of the spine . J Jpn Soc Bone Jt Infect \n14 : 149 -153 , 2000 (in Japanese).\n22. Mizuno K , Nakai O , Matsuoka T , et al \nA case of aspergillus osteomyelitis . The Journal of the Japan Medical Society of Paraplegia \n13 : 82 -83 , 2000 (in Japanese).\n23. Toyoda K , Taguchi T , Kaneko K , Katou Y , Kawai S \nThe study of fungal spondylitis . Journal of the Western Japanese Research Society for Spine \n29 : 3 -6 , 2003 (in Japanese).\n24. Hoshino K , Momota Y , Morio Y , Nagashima H \nA case report of aspergillus epidural abscess of thoracic spine . Journal of the Western Japanese Research Society for Spine \n29 : 7 -10 , 2003 (in Japanese).\n25. Sagara T , Akasaki K , Kimura M , et al \nAspergillus spondylitis with paraplegia: a case report . Orthopaedics and Traumatology \n56 : 581 -584 , 2007 (in Japanese, Abstract in English).\n26. Saisu A , Odaka M , Hirata K \nA case of aspergillosis developing orbital apex syndrome followed by spondylitis . Neurological Medicine \n70 : 397 -401 , 2009 (in Japanese, Abstract in English).\n27. Kusaka S , Iizuka H , Nishiyama S , et al \nCase report: chronic neutropenia with variegated infectious symptoms . Nihon Naika Gakkai Zasshi (J Jpn Soc Int Med) \n101 : 150 -153 , 2012 (in Japanese).\n28. Nakamura A , Uemura T , Takakuwa O , et al \nA case of chronic necrotizing pulmonary aspergillosis presenting as transverse myelitis due to the epidural abscess during the treatment . Kansenshogaku Zasshi (J Jpn Assoc Infect Dis) \n87 : 315 -316 , 2013 (in Japanese).\n29. Suzuki N , Fukuoka M , Mizutani J , Otsuka S , Otsuka T \nAspergillus spondylitis directly infiltrated from lung aspergilloma with paraparesia . Cent Jpn J Orthop Traumat \n56 : 1243 -1244 , 2013 (in Japanese).\n30. Nanjo Y , Sasaki S \nA case of aureus type pulmonary aspergillosis directly infiltrating into the spine . Kansenshogaku Zasshi (J Jpn Assoc Infect Dis) \n89 : 338 , 2015 (in Japanese).\n31. Shimozaki K , Takagi Y , Yamada H , et al \nA case of fungal spondylitis in a patient with open fractures of thoracic vertebrae . Cent Jpn J Orthop Traumat \n60 : 227 , 2017 (in Japanese).\n32. Ohmori M , Ishikawa N , Yoshiyama T , Uchimura K , Aoki M , Mori T \nCurrent epidemiological trend of tuberculosis in Japan . Int J Tuberc Lung Dis \n6 : 415 -423 , 2002 .12019917 \n33. Kunst H , Wickremasinghe M , Wells A , Wilson R \nNontuberculous mycobacterial disease and Aspergillus-related lung disease in bronchiectasis . Eur Respir J \n28 : 352 -357 , 2006 .16611651 \n34. Denes E , Boumediene A , Durox H , et al \nVoriconazole concentrations in synovial fluid and bone tissues . J Antimicrob Chemother \n59 : 818 -819 , 2007 .17329266 \n35. Felton T , Troke PF , Hope WW \nTissue penetration of antifungal agents . Clin Microbiol Rev \n27 : 68 -88 , 2014 .24396137\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(21)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "AML/MRC; aspergillus fumigatus; epidural mass; review; vertebral aspergillosis",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D001232:Aspergillus fumigatus; D003371:Cough; D004824:Epidural Space; D005260:Female; D005334:Fever; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis; D007564:Japan; D015470:Leukemia, Myeloid, Acute; D008279:Magnetic Resonance Imaging; D009190:Myelodysplastic Syndromes; D011014:Pneumonia; D013122:Spinal Diseases",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3205-3212",
"pmc": null,
"pmid": "29877282",
"pubdate": "2018-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "26667988;11999005;1296715;7783323;12019917;10451157;24303995;8741716;17329266;21148508;24396137;22413471;16611651",
"title": "Invasive Pulmonary Aspergillosis in the Epidural Space in a Patient with Acute Myelogenous Leukemia with Myelodysplasia-related Changes: A Case Study and Literature Review of Vertebral Aspergillosis in Japan.",
"title_normalized": "invasive pulmonary aspergillosis in the epidural space in a patient with acute myelogenous leukemia with myelodysplasia related changes a case study and literature review of vertebral aspergillosis in japan"
} | [
{
"companynumb": "PHHY2018JP163834",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CEFEPIME HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nAlthough ocular side effects of topiramate are common, neuroophthalmologic manifestations such as blepharospasm, myokymia and oculogyric crisis are scarcely reported.\n\n\nMETHODS\nWe present a serie of 8 patients with migraine who developed eyelid myokymia after treatment with topiramate. We reviewed all patients with migraine treated with topiramate attending the headache outpatient clinic of our hospital from January 2008 to December 2012.\n\n\nRESULTS\nDuring the study period, a total of 140 patients with migraine were treated with topiramate in our headache clinic. Eight presented eyelid myokymia after beginning treatment with topiramate (5,7%). Topiramate was stopped and myokymia disappeared in all patients, it was prescribed again and eyelid myokymia reappeared with their previous characteristics in all patients.\n\n\nCONCLUSIONS\nEyelid myokymia is an underreported side-effect of topiramate in patients with migraine, of unknown cause, so that in future, further studies are need to examine whether patients with migraine are predisposed or not to this adverse effect.",
"affiliations": "Department of Neurology, Hospital General Universitario Virgen De La Salud, Elda, Spain.;Department of Neurology, Hospital General Universitario De Alicante, Alicante, Spain.;Department of Neurology, Hospital Verge Dels Lliris, Alcoi, Spain.;Department of Neurology, Hospital General Universitario Virgen De La Salud, Elda, Spain.;Department of Neurology, Hospital General Universitario Virgen De La Salud, Elda, Spain.;Department of Neurology, Hospital General Universitario Virgen De La Salud, Elda, Spain.;Department of Neurology, Hospital General Universitario Virgen De La Salud, Elda, Spain.",
"authors": "Medrano-Martínez|V|V|;Pérez-Sempere|A|A|;Moltó-Jordá|J M|JM|;Fernández-Izquierdo|S|S|;Francés-Pont|I|I|;Mallada-Frechin|J|J|;Piqueras-Rodríguez|L|L|",
"chemical_list": "D000077236:Topiramate; D005632:Fructose",
"country": "Denmark",
"delete": false,
"doi": "10.1111/ane.12395",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-6314",
"issue": "132(2)",
"journal": "Acta neurologica Scandinavica",
"keywords": "eyelid myokymia; isolated myokymia; migraine; neuro-ophthalmologic manifestations; ocular side effects; topiramate",
"medline_ta": "Acta Neurol Scand",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D005143:Eyelids; D005260:Female; D005632:Fructose; D006801:Humans; D008297:Male; D008875:Middle Aged; D008881:Migraine Disorders; D020385:Myokymia; D000077236:Topiramate",
"nlm_unique_id": "0370336",
"other_id": null,
"pages": "143-6",
"pmc": null,
"pmid": "25828425",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Eyelid myokymia in patients with migraine taking topiramate.",
"title_normalized": "eyelid myokymia in patients with migraine taking topiramate"
} | [
{
"companynumb": "ES-LUPIN PHARMACEUTICALS INC.-2015-02491",
"fulfillexpeditecriteria": "2",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional... |
{
"abstract": "PH is a rare condition with high mortality rate after pediatric HSCT. As clinical presentation is non-specific and may mimic other conditions, a high degree of suspicion is required for diagnosis. Here, we present a patient with stage-IV neuroblastoma who developed PAH after autologous HSCT. After exclusion of other causes of PH, we regarded that this condition was secondary to HSCT.",
"affiliations": "Division of Pediatric Oncology, Ankara Children's Hematology and Oncology Education and Research Hospital, Ankara, Turkey.;Division of Pediatric Cardiology, Ankara Children's Hematology and Oncology Education and Research Hospital, Ankara, Turkey.;Division of Pediatric Cardiology, Ankara Children's Hematology and Oncology Education and Research Hospital, Ankara, Turkey.;Division of Pediatric Cardiology, Ankara Children's Hematology and Oncology Education and Research Hospital, Ankara, Turkey.;Division of Pediatric Oncology, Ankara Children's Hematology and Oncology Education and Research Hospital, Ankara, Turkey.;Division of Pediatric Cardiology, Ankara Children's Hematology and Oncology Education and Research Hospital, Ankara, Turkey.;Division of Bone Marrow Transplantation Unit, Ankara Children's Hematology and Oncology Education and Research Hospital, Ankara, Turkey.;Division of Bone Marrow Transplantation Unit, Ankara Children's Hematology and Oncology Education and Research Hospital, Ankara, Turkey.",
"authors": "Özyörük|Derya|D|;Kibar|Ayşe Esin|AE|;Sürücü|Murat|M|;Azak|Emine|E|;Emir|Suna|S|;Çetin|İbrahim İlker|İİ|;Tunç|Bahattin|B|;Özbek|Namık Yaşar|NY|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12576",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "19(7)",
"journal": "Pediatric transplantation",
"keywords": "children; hematopoietic stem cell transplantation; pulmonary hypertension",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D002675:Child, Preschool; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D009367:Neoplasm Staging; D009447:Neuroblastoma; D014182:Transplantation, Autologous",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "E185-8",
"pmc": null,
"pmid": "26282574",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pulmonary arterial hypertension in a child with stage-IV neuroblastoma after autologous hematopoietic stem cell transplantation and review of the literature.",
"title_normalized": "pulmonary arterial hypertension in a child with stage iv neuroblastoma after autologous hematopoietic stem cell transplantation and review of the literature"
} | [
{
"companynumb": "TR-OTSUKA-2015_015912",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MELPHALAN"
},
"drugadditional": null,
"... |
{
"abstract": "We observed opioid-related respiratory depression in a patient receiving tramadol via patient-controlled analgesia. Predisposing factors were the patient's genetic background and renal impairment. Complete recovery occurred after naloxone administration, thus confirming opioid intoxication. Analysis of the patient's genotype revealed a CYP2D6 gene duplication resulting in ultra-rapid metabolism of tramadol to its active metabolite (+)O-desmethyltramadol. Concomitant renal impairment resulting in decreased metabolite clearance enhanced opioid toxicity. This genetic CYP2D6 variant is particularly common in specific ethnic populations and should be a future diagnostic target whenever administration of tramadol or codeine is anticipated, as both drugs are subject to a comparable CYP2D6-dependent metabolism.",
"affiliations": "Department of Anesthesiology and Intensive Care Medicine, University of Bonn, Sigmund-Freud-Str. 25, 53105 Bonn, Germany. ulrike.stamer@ukb.uni-bonn.de",
"authors": "Stamer|Ulrike M|UM|;Stüber|Frank|F|;Muders|Thomas|T|;Musshoff|Frank|F|",
"chemical_list": "D000701:Analgesics, Opioid; D014147:Tramadol; D019389:Cytochrome P-450 CYP2D6",
"country": "United States",
"delete": false,
"doi": "10.1213/ane.0b013e31817b796e",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2999",
"issue": "107(3)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D000368:Aged; D000698:Analgesia; D000701:Analgesics, Opioid; D019389:Cytochrome P-450 CYP2D6; D020440:Gene Duplication; D005786:Gene Expression Regulation; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D008297:Male; D010597:Pharmacogenetics; D012119:Respiration; D012131:Respiratory Insufficiency; D014147:Tramadol",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "926-9",
"pmc": null,
"pmid": "18713907",
"pubdate": "2008-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Respiratory depression with tramadol in a patient with renal impairment and CYP2D6 gene duplication.",
"title_normalized": "respiratory depression with tramadol in a patient with renal impairment and cyp2d6 gene duplication"
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"companynumb": "DE-BAUSCH-BL-2018-018369",
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"abstract": "OBJECTIVE\nCompared to intravenous taxane chemotherapy, newer orally-available and/or less toxic agents for metastatic castration-resistant prostate cancer (MCRPC) may be associated with higher likelihood of starting treatment in patients with adverse prognostic features and limited life expectancy. To test this hypothesis, we analyzed the rates of treatment initiation during the last 30 days of life in a real-world cohort of men with MCRPC.\n\n\nMETHODS\nThis was a retrospective analysis of 146 patients.\n\n\nRESULTS\nSeven patients (5%) who started any systemic treatment during the last 30 days of life were identified. The likelihood of treatment initiation in the last 30 days of life correlated significantly with the number of lines of systemic treatment (higher risk for previously treated patients) and non-use of bone-targeted agents.\n\n\nCONCLUSIONS\nInitiation of systemic therapy in the last 30 days of life was uncommon. This endpoint might complement other quality-of-care indicators.",
"affiliations": "Department of Clinical Medicine, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway carsten.nieder@nlsh.no.;Department of Oncology and Palliative Medicine, Nordland Hospital, Bodø, Norway.;Department of Oncology and Palliative Medicine, Nordland Hospital, Bodø, Norway.;Department of Oncology and Palliative Medicine, Nordland Hospital, Bodø, Norway.;Department of Oncology and Palliative Medicine, Nordland Hospital, Bodø, Norway.;Department of Clinical Medicine, Faculty of Health Sciences, UiT - The Arctic University of Norway, Tromsø, Norway.",
"authors": "Nieder|Carsten|C|;Haukland|Ellinor|E|;Mannsåker|Bård|B|;Pawinski|Adam|A|;Yobuta|Rosalba|R|;Norum|Jan|J|",
"chemical_list": "D001952:Bridged-Ring Compounds; D043823:Taxoids; D000077143:Docetaxel; C080625:taxane",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.13116",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "39(1)",
"journal": "Anticancer research",
"keywords": "Palliative chemotherapy; docetaxel; prognostic factors; prostate cancer; quality-of-care; systemic therapy",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000368:Aged; D001952:Bridged-Ring Compounds; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D043823:Taxoids; D013727:Terminal Care; D016896:Treatment Outcome",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "335-340",
"pmc": null,
"pmid": "30591477",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Initiation of Systemic Therapy During the Last 30 Days of Life in Patients With Metastatic Castration-resistant Prostate Cancer.",
"title_normalized": "initiation of systemic therapy during the last 30 days of life in patients with metastatic castration resistant prostate cancer"
} | [
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"activesubstancename": "DOCETAXEL"
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{
"abstract": "Neuroleptic malignant syndrome (NMS) is a neurological emergency rarely encountered in clinical practice but with a high mortality rate. Cases associated with atypical antipsychotic use or termination of dopamine agonists have been seen in recent years. The purpose of this study was to assess the presence of risk factors for mortality by investigating all clinical and laboratory characteristics of cases with NMS.\nThis descriptive, cross-sectional study retrospectively investigated all clinical and laboratory characteristics by scanning the ICD-10 codes of patients presenting to the XXXX Faculty of Medicine Emergency Department and diagnosed with NMS between 2006 and 2016. Patients were divided into surviving and non-surviving groups, and the data elicited were subjected to statistical comparisons.\nThe mean age of the 18 patients diagnosed with NMS was 46.9 ± 4.8 years, and 50% were women. In addition to antipsychotics among the drugs leading to NMS, the syndrome also developed as a result of levodopa withdrawal in three patients and metoclopramide use in one patient. Statistically significant differences were determined between the surviving and non-surviving patients in terms of blood pressure, blood urea nitrogen (BUN), creatine kinase (CK) and mean platelet volume (MPV) values (p ≤ 0.05).\nIn this study the most common agent that cause NMS was atypical antipsychotics. Also advanced age, increased blood pressure and serum CK, BUN and MPV values were identified as potential risk factors for mortality in NMS.",
"affiliations": "Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Fatih Public Hospital, Department of Emergency Medicine, Trabzon, Turkey.;Giresun University, Faculty of Medicine, Department of Emergency Medicine, Giresun, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Psychiatry, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkey.;Dokuz Eylül University, Faculty of Medicine, Department of Pharmacology, İzmir, Turkey.",
"authors": "Sahin|Aynur|A|;Cicek|Mustafa|M|;Gonenc Cekic|Ozgen|O|;Gunaydin|Mucahit|M|;Aykut|Demet Saglam|DS|;Tatli|Ozgur|O|;Karaca|Yunus|Y|;Arici|Mualla Aylin|MA|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.tjem.2017.10.001",
"fulltext": "\n==== Front\nTurk J Emerg MedTurk J Emerg MedTurkish Journal of Emergency Medicine2452-2473Elsevier S2452-2473(17)30158-910.1016/j.tjem.2017.10.001Original ArticleA retrospective analysis of cases with neuroleptic malignant syndrome and an evaluation of risk factors for mortality Sahin Aynur dr-aynursahin@hotmail.coma∗Cicek Mustafa aGonenc Cekic Ozgen bGunaydin Mucahit cAykut Demet Saglam dTatli Ozgur aKaraca Yunus aArici Mualla Aylin ea Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, Trabzon, Turkeyb Fatih Public Hospital, Department of Emergency Medicine, Trabzon, Turkeyc Giresun University, Faculty of Medicine, Department of Emergency Medicine, Giresun, Turkeyd Karadeniz Technical University, Faculty of Medicine, Department of Psychiatry, Trabzon, Turkeye Dokuz Eylül University, Faculty of Medicine, Department of Pharmacology, İzmir, Turkey∗ Corresponding author. Karadeniz Technical University, Faculty of Medicine, Department of Emergency Medicine, 61080, Trabzon, Turkey.Karadeniz Technical UniversityFaculty of MedicineDepartment of Emergency MedicineTrabzon61080Turkey dr-aynursahin@hotmail.com27 11 2017 12 2017 27 11 2017 17 4 141 145 13 7 2017 26 9 2017 5 10 2017 Copyright © 2017 The Emergency Medicine Association of Turkey. Production and hosting by Elsevier B.V. on behalf of the Owner.2017The Emergency Medicine Association of TurkeyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Objective\nNeuroleptic malignant syndrome (NMS) is a neurological emergency rarely encountered in clinical practice but with a high mortality rate. Cases associated with atypical antipsychotic use or termination of dopamine agonists have been seen in recent years. The purpose of this study was to assess the presence of risk factors for mortality by investigating all clinical and laboratory characteristics of cases with NMS.\n\nMaterial and methods\nThis descriptive, cross-sectional study retrospectively investigated all clinical and laboratory characteristics by scanning the ICD-10 codes of patients presenting to the XXXX Faculty of Medicine Emergency Department and diagnosed with NMS between 2006 and 2016. Patients were divided into surviving and non-surviving groups, and the data elicited were subjected to statistical comparisons.\n\nResults\nThe mean age of the 18 patients diagnosed with NMS was 46.9 ± 4.8 years, and 50% were women. In addition to antipsychotics among the drugs leading to NMS, the syndrome also developed as a result of levodopa withdrawal in three patients and metoclopramide use in one patient. Statistically significant differences were determined between the surviving and non-surviving patients in terms of blood pressure, blood urea nitrogen (BUN), creatine kinase (CK) and mean platelet volume (MPV) values (p ≤ 0.05).\n\nConclusion\nIn this study the most common agent that cause NMS was atypical antipsychotics. Also advanced age, increased blood pressure and serum CK, BUN and MPV values were identified as potential risk factors for mortality in NMS.\n==== Body\n1 Introduction\nNeuroleptic malignant syndrome (NMS) is a life-threatening neurological emergency that occurs following use of neuroleptic drugs and other dopamine antagonists or termination of a dopamine agonist and characterized by altered mental state, fever, rigidity and autonomic dysfunction. Although typical neuroleptics exhibiting an antagonist effect on dopamine receptors are frequently involved in the etiology, there are also reports in the literature of cases of NMS caused by drugs from various different groups.1, 2 Diagnostic criteria are used to overcome the diagnostic difficulty in NMS (Table 1).3 There are no specific laboratory findings used in diagnosis, but in addition to increasing creatine kinase (CK) associated with muscle destruction, accompanying leukocytosis, increased serum aminotransferases (AST and ALT), electrolyte anomalies (hyperkalemia, hypo-hypernatremia or hypocalcemia), increased lactate dehydrogenase (LDH) and metabolic acidosis may be seen.4Table 1 Diagnostic criteria for NMS.\n\nTable 1Criteria\tCharacteristics\tAt least\t\nHistory of drug use\t- Use of one antipsychotic\n\n- Use of one dopamine antagonist\n\n- Recent termination of treatment with one dopamine agonist\n\n\t1\t\nMajor criteria\t- Hyperthermia (37.5° or above)\n\n- Muscular rigidity,\n\n- Creatine kinase (CK) levels over 3 times above normal\n\n\t2\t\nMinor criteria\t- Altered mental state,\n\n- Extrapyramidal findings, Autonomic instability,\n\n- Respiration problems,\n\n- Leukocytosis\n\n\t4\t\n\n\nThe first stage in the treatment of NMS is to stop the agent responsible or to resume the discontinued dopamine agonist. In the second stage, intensive supportive therapy is applied. Dantrolene, a centrally acting muscle relaxant recommended for specific therapy but lacking sufficient levels of evidence for its efficacy, and the dopamine agonist bromocriptine and amantadine are pharmacological agents capable of use in addition to supportive therapy.5, 6 Mortality rates associated with complications of NMS, such as rhabdomyolysis, acute kidney failure, respiratory failure, cardiovascular collapse, aspiration pneumonia and disseminated intravascular coagulation, approach 50%, but this decreases to approximately 5% with adequate supportive therapy in cases without complications.7 Early commencement of treatment through early diagnosis in emergency departments and the determination of prognostic factors affecting mortality are therefore important in terms of survival. Since the incidence of NMS in the community is low, evidence-based data concerning the epidemiology and clinical and pharmacological risk factors are limited. Our purpose was therefore to evaluate the epidemiological and clinical characteristics of patients diagnosed with NMS in our hospital and, in particular, to identify prognostic factors capable of affecting mortality by comparing the clinical and laboratory features of death and survived cases.\n\n2 Materials and methods\nIn this cross-sectional, descriptive study, following receipt of ethical committee approval, patients aged 18 or over presenting to the Karadeniz Technical University Faculty of Medicine Emergency Department in 2006–2016 and diagnosed with NMS were identified by scanning their ICD-10 codes from the hospital computer software system, and patient files obtained from the archive were examined retrospectively. Cases with incorrect ICD-10 entries and patients with incomplete record data were excluded. Patients' ICD-10 diagnoses were confirmed on the bases of the NMS criteria shown in Table 1. The diagnosis of NMS was made in the presence of at least two of the major and four minor diagnostic criteria. Cases' demographic characteristics, existing diseases, clinical and laboratory findings, all drugs used, lengths of stay in hospital and survival were evaluated. Cases were divided into two groups on the bases of clinical outcomes death and recovery. All data were transferred to and analyzed on IBM Statistical Package for the Social Sciences 23.0 (IBM SPSS Inc., Chicago, IL, USA) software. The Mann Whitney U test was used to compare the two groups' non-parametric data, and p values ≤ 0.05 were regarded as statistically significant.\n\n3 Results\nRecords were available for all 18 patients diagnosed with NMS among the 505,520 patients presenting to the emergency department in 2006–2016. According to our records, the rate of NMS among patients presenting to our hospital in the previous 10 years was 0.004%.\n\nThe distribution of patients' clinical characteristics is shown in Table 2, Table 3. Half of the patients were women, and the general median age was 43.5 (IQR, 30.2–67.2). The most common existing chronic diseases among the patients were schizophrenia at 27.8% (n = 5), Parkinson's disease at 22.2% (n = 4), and mental retardation at 16.7% (n = 3), with lower incidences of substance dependence, dementia, bipolar disorder, acute psychosis and delirium. A history of use of two or more drugs was present in 88.9% (n = 16) of cases, and of antipsychotic drug use in 77.8% (n = 14). Drug use was at therapeutic doses in all NMS cases. The most common antipsychotic agents used by NMS patients were atypical antipsychotic agents (78.6%, n = 11).Table 2 Characteristics of NMS cases.\n\nTable 2No.\tAge, sex (M: Male, F: Female)\tDisease\tDrugs used\tTA (mmHg)\tPulse (min)\tTemperature (°C)\tGCS\tClinical symptoms and findings\tOutcome\tLength of stay in hospital (Day)\tCauses of death\t\n1\t47, F\tSchizophrenia\tAlprazolam, quetiapine, aripiprazole, paliperidone\t164/123\t113\t38.6\t8\tMuscular rigidity, sweating, dysphagia, tremor, incontinence, altered consciousness, mutism\tDeath\t10\tSepsis\t\n2\t75, M\tSchizophrenia\tBiperiden, mirtazapine, paroxetine, amisulpride, clozapine, risperidone\t160/140\t170\t39.0\t9\tMuscular rigidity, sweating, dysphagia, tremor, incontinence, altered consciousness, mutism\tDeath\t2\tRespiratory failure\t\n3\t76, F\tParkinson\tLevodopa (withdrwal), pramipexole, gabapentin, paroxetine, amitriptyline\t180/100\t140\t39.3\t10\tMuscular rigidity, sweating, tremor, altered consciousness, mutism\tDeath\t42\tSepsis\t\n4\t42, M\tMental retardation\tBiperiden, olanzapine\t170/100\t117\t38.4\t12\tMuscular rigidity, sweating, tremor, altered consciousness\tRecovery\t32\t\t\n5\t43, F\tBipolar disorder\tBiperiden, amitriptyline, lithium, phenothiazine, chlorpromazine, quetiapine\t90/60\t122\t39.1\t11\tMuscular rigidity, sweating, tremor, altered consciousness, mutism\tRecovery\t19\t\t\n6\t64, F\tBipolar disorder\tValproic acid, lorazepam, haloperidol, quetiapine, olanzapine\t140/80\t108\t38.0\t13\tMuscular rigidity, tremor, altered consciousness,\tRecovery\t11\t\t\n7\t20, F\tMental retardation\tRisperidone, quetiapine\t110/80\t80\t39.0\t11\tMuscular rigidity, dysphagia, tremor, incontinence altered consciousness, mutism\tRecovery\t47\t\t\n8\t44, M\tSchizophrenia\n+Substance dependence\tAmisulpride\t120/70\t84\t38.6\t12\tMuscular rigidity, sweating, tremor, altered consciousness, mutism\tRecovery\t31\t\t\n9\t18, F\tSchizophrenia\n+acute psychosis\tClonazepam, amisulpride, olanzapine\t100/80\t112\t38.2\t12\tMuscular rigidity, sweating, tremor, altered consciousness, mutism\tRecovery\t22\t\t\n10\t32, M\tSubstance dependence\tLorazepam, quetiapine\t110/70\t92\t38\t8\tMuscular rigidity, sweating, altered consciousness, mutism\tRecovery\t54\t\t\n11\t25, M\tMental retardation\tLorazepam, amisulpride\t140/90\t88\t37.9\t13\tMuscular rigidity, sweating, dysphagia, altered consciousness, mutism\tRecovery\t19\t\t\n12\t40, F\tSchizophrenia\tBiperiden, mirtazapine, olanzapine\t100/60\t130\t38.5\t13\tAltered consciousness mutism\tRecovery\t92\t\t\n13\t46, M\tDelirium\tHaloperidol, olanzapine\t145/90\t125\t38.5\t12\tsweating, dysphagia, incontinence, altered consciousness, mutism\tRecovery\t8\t\t\n14\t23, K\tAcute psychosis\tLorazepam, quetiapine, risperidone\t160/90\t140\t39.0\t11\tMuscular rigidity, tremor, altered consciousness, mutism\tRecovery\t33\t\t\n15\t32,M\tNo characteristic\tMetoclopramide\t140/100\t120\t40.0\t10\tMuscular rigidity, sweating, dysphagia, tremor, incontinence, altered consciousness, mutism\tRecovery\t20\t\t\n16\t79, M\tDementia\n+Parkinson\n+Alzheimer\tLevodopa (withdrwal), pramipexole\t150/100\t112\t38.2\t12\tMuscular rigidity, sweating, dysphagia, altered consciousness, mutism\tRecovery\t10\t\t\n17\t74, F\tParkinson\tLevodopa, paroxetine, quetiapine\t150/100\t81\t37.7\t10\tMuscular rigidity, sweating, dysphagia, tremor, altered consciousness, mutism\tRecovery\t11\t\t\n18\t65, M\tParkinson\tLevodopa (withdrwal), paroxetine\t90/50\t144\t40.0\t7\tMuscular rigidity, sweating, dysphagia, altered consciousness, mutism\tRecovery\t9\t\t\nTable 3 Distribution of clinical symptoms and findings in NMS cases.\n\nTable 3\tn\t%\t\tn\t%\t\nHyperthermia\t18\t100.0\tTremor\t11\t61.1\t\nMuscular rigidity\t17\t94.4\tDysphagia\t10\t55.6\t\nAltered consciousness\t15\t83.3\tHypertension\t9\t50.0\t\nSweating\t15\t83.3\tIncontinence\t5\t27.8\t\nMutism\t15\t83.3\tHypotension\t3\t16.7\t\nTachycardia\t13\t72.2\tTremor\t11\t61.1\t\n\n\nIn addition to antipsychotic drugs such as quetiapine, clozapine, risperidone, amisulpride, and haloperidol, the medications leading to the development of NMS also included drugs affecting the central nervous system, such as paroxetine, amitriptyline and lithium. NMS developed following discontinuation of levodopa in three cases and use of metoclopramide in one case (Table 2). Among the three fatal cases of NMS, two cases used more than one neuroleptic agents and a 76-year-old woman with Parkinson's disease used no neuroleptic medication, but NMS developed in association with withdrawal of levodopa and multi-drug use consisting of amitriptyline, pramipexole, gabapentin and paroxetine.\n\nWhen the death (n = 3) and recovery (n = 15) groups were compared in terms of clinical and laboratory characteristics, statistically significant differences were observed in terms of age, systolic and diastolic blood pressure, blood urea nitrogen (BUN), serum creatine kinase (CK) and mean platelet volume (MPV) values (Table 4) (p ≤ 0.05).Table 4 Clinical and laboratory findings of groups in NMS.\n\nTable 4\tGroups\tp\t\nDeath (n = 3)\tRecovery (n = 15)\t\nClinical characteristics (MD, Min-max)\t\nAge\t75 (47–76)\t42 (18–79)\t0.05\t\nGCS\t9 (8–10)\t12 (7–13)\t0.054\t\nHearth rate (bpm)\t140 (113–170)\t112 (80–144)\t0.097\t\nSBP (mmHg)\t164 (160–180)\t140 (90–170)\t0.01\t\nDBP (mmHg)\t123 (100–140)\t80 (50–100)\t0.01\t\nTemperature (C°)\t39 (38.6–39.3)\t38.5 (38–40)\t0.191\t\nLength of hospital stay (Day)\t10 (2–42)\t20 (8–92)\t0.34\t\nLaboratory findings (MD, Min-max)\t\nGlucose\nNR:74-110 mg/dL\t139 (108–155)\t117 (73–349)\t0.514\t\nBUN\nNR:6-20 mg/dL\t42 (27–71)\t18 (7–35)\t0.024\t\nCre\nNR:0.5-0.9 mg/dL\t1.36 (0.91–2.2)\t0.7 (0.39–1.70)\t0.137\t\nCK\nNR:38-176 U/L\t5543 (2702–10343)\t1720 (700–3496)\t0.021\t\nAST\nNR:0-35 U/L\t75 (56–94)\t74 (70–118)\t0.374\t\nALT\nNR: 0-45 U/L\t54 (3–106)\t54 (29–94)\t0.373\t\nTroponin\nNR: < 14 ng/mL\t88.7 (47–538)\t40 (4.2–321)\t0.930\t\nMyoglobin\nNR: 0-85 ng/mL\t983 (870–3000)\t511 (32–3147)\t0.311\t\nCK-MB\nNR: 0 - 4.8 U/L\t16.1 (5.5–25.8)\t8.7 (2.2–181)\t0.638\t\nLactate\nNR: 4.5-19.8 mg/dL\t15.5 (11–20)\t7.78 (7–10.24)\t0.064\t\nLDH\nNR:122-222 U/L\t620 (384–669)\t403 (165–620)\t0.097\t\nWBC\nNR:4800-10800 per μL\t15,900 (14,027–22,270)\t10,000 (1000–26,200)\t0.260\t\nHemoglobin\nNR:12-17 g/dL\t13.5 (10.1–16)\t12.6 (9–15.7)\t0.406\t\nPlatelet\nNR:130-400 x 103/μL\t162 (154–327)\t230 (51–474)\t0.767\t\nMPV\nNR: 7.4-11 fL\t13 (10.3–13.8)\t8.7 (6.2–11.5)\t0.021\t\nRDW\nNR: 11.6-16.5(%)\t14.3 (13.3–16.1)\t14.2 (12.3–21.5)\t0.767\t\nNLR\t11.2 (3–27.9)\t7.5 (1–32.3)\t0.514\t\nAccording to Mann Whitney U test.\n\nAbbreviations (MD: Median, Min: Minimum, Max: Maximum, NR: Normal Range, GCS: Glasgow Coma Scale, SBP: Systolic Blood Pressure, DBP: Diastolic Blood Pressure, BUN: Blood Urea Nitrogen, Cre: Creatinine AST: Aspartate Aminotranferase, ALT: Alanine Aminotranferase WBC: White Blood Cell, CK: Creatine Kinase, LDH: Lactate Dehydrogenase, MPV: Mean Platelet Volume, RDW: Red Cell Distribution Width, NLR: Neutrophil Lymphocyte Ratio).\n\n\n\n4 Discussion\nOur study is one of the largest cohort of NMS patients from Turkey. According to results of this study, both neuroleptic and non-neuroleptic drug use were the causes of NMS. Contrary to common belief, atypical antipsychotic drug use was most commonly observed as the cause of NMS in this study, and also we found that advanced age and high CK, BUN and MPV values can be potential risk factors for mortality.\n\nFactors such as age and sex affect the incidence of NMS in addition to various clinical and pharmacological factors. The incidence of NMS among neuroleptic users therefore ranges between 0.024% and 3%.8, 9 There are several reasons for this, such as the population selected and the different diagnostic criteria used. Since ICD-10 coding of subjects using neuroleptics was not possible in our hospital's data recording system we determined the rate as a proportion among all populations. There is no consensus in the literature concerning gender as a potential risk factor for NMS, although the general opinion in the 1980s was that it is more common in males, the reason being the denser muscle mass in men and the clinical manifestation (muscular rigidity and fever secondary to hypermetabolism) being more visible than in women. In contrast, a meta-analysis by Gurrera et al. from 2017 concluded that NMS appeared equally in males and females, but more commonly in young adults.10 Women represented 50% of the cases in our study, and patients' mean age was also compatible with the previous literature.8\n\nSudden interruption of dopamine reduction is an important agent in the molecular mechanism of the development of NMS. This may result from termination of dopaminergic agent use with dopamine receptor antagonism mediated by neuroleptic or other pharmacological agents.4 Although typical neuroleptics are the most commonly implicated pharmacological agents in the literature, examination of the cases in our study revealed metoclopramide use in one and multiple pharmacological agent use in others, and the level of atypical antipsychotics use was higher compared to other drugs.11, 12, 13 The reason atypical antipsychotics are preferred by psychiatrists that they are superior to typical antipsychotics at side effects.\n\nNMS may be difficult to diagnose since it begins with non-specific symptoms in the early period, such as unexplained tremor, muscular cramps, anxiety, confusion, agitation or catatonia, rather than the principal symptoms and findings such as fever, rigidity, mental state alterations and autonomic instability.4 In one case-controlled study, Berardi et al. particularly described psychomotor agitation, confusion, disorganized behavioral findings, and extrapyramidal findings as potential clinical risk factors for the development of NMS.14 Although there is evidence that the antidopaminergic effect of pharmacological agents is the mechanism underlying clinical and laboratory findings emerging in NMS, there are question marks concerning the mechanism by which agents with no effect on dopamine receptors give rise to the clinical manifestation.15, 16 Analysis of the clinical characteristics of the cases in our study revealed no atypical findings other than mutism, dysphagia and incontinence, in addition to the classic findings. Hyperthermia and altered consciousness were determined in all patients and muscular rigidity was observed at a high level.\n\nThere are no 100% specific laboratory findings in NMS, although serum CK elevation increasing in association with muscular rigidity accompanies clinical findings. Serum CK levels exceeding 1000 IU/L and rising are generally correlated with severity of disease and prognosis.17, 18 Other non-specific findings seen in NMS include metabolic acidosis, leukocytosis, increased lactate dehydrogenase and aminotransferases and electrolyte anomalies (hypocalcemia, hypomagnesemia, hypo-hypernatremia and hyperkalemia).19 The findings of this study correlated with literature.\n\nPrognosis varies depending on the presence of complications such as rhabdomyolysis, renal failure, aspiration pneumonia, sepsis and pulmonary embolism. The mortality rate in NMS irrespective of early diagnosis and treatment is 5–20%, but this rises to 70% in the presence of complications.20, 21, 22 In this study, the mortality rate in patients diagnosed with NMS was approximately 17%. Shalev et al. evaluated 202 cases of NMS-associated mortality and identified rhabdomyolysis, myoglobinuria and renal failure as powerful predictors of mortality.7 Additionally, septic shock and respiratory and cardiac failure associated with infections developing secondary to hospitalization have also been reported as important risk factors for mortality.4 When we compared cases of death and recovery groups in terms of outcomes, age and blood pressure were statistically significantly higher in the death group. Advanced age and high blood pressure may therefore be interpreted as factors potentially affecting mortality. When death and recovery groups were compared in terms of laboratory values, CK, BUN and MPV values were statistically significantly higher in the death group. These findings support the idea that rhabdomyolysis and renal function impairment are important risk factors in terms of poor outcome. MPV values are involved in many studies as a current prognostic marker recently. Previous studies have linked MPV elevation with both poor prognosis and infarction area, particularly in patients with ischemic and hemorrhagic stroke, coronary artery disease and acute coronary syndrome.23 There is no study performed relationship between NMS and MPV values. The mechanism involved in this significant elevation observed in fatal cases of NMS is unclear, and further clinical studies involving larger case numbers regarding its potential predictive value for prognosis are needed.\n\n5 Limitations\nThere are limitations in this study. Due to the clinical rarity of NMS and the hospital's computerized database going back only 10 years, we were only able to access data for patients with entered ICD-10 diagnoses. The retrospective nature of the study also limited our access to all the information in the patient files.\n\n6 Conclusion\nIn conclusion, despite being a rare disease, NMS is a life-threatening condition in terms of clinical course and outcome that develops in association with neuroleptic and non-neuroleptic drug use. Atypical antipsychotic drug use was most commonly observed in the NMS cases assessed in this study, and advanced age and high CK, BUN and MPV values may be potential risk factors for mortality.\n\nGrant\nNo.\n\nConflict of interests statement\nThe authors declare that they have no significant competing financial, professional or personal interests that might have influenced the performance or presentation of the work described in this manuscript.\n\nPeer review under responsibility of The Emergency Medicine Association of Turkey.\n==== Refs\nReferences\n1 Adnet P. Lestavel P. Krivosic-Horber R. Neuroleptic malignant syndrome BJA Br J Anaesth 85 2000 129 135 10928001 \n2 Gurrera R.J. Mortillaro G. Velamoor V. A validation study of the international consensus diagnostic criteria for neuroleptic malignant syndrome J Clin Psychopharmacol 37 2017 67 71 28027111 \n3 Neuroleptic malignant syndrome. POISINDEX® Database. Micromedex solutions [Internet]. Ann Arbor, MI: Truven Health Analytics 2017, Inc. Available from: http://www.micromedexsolutions.com.\n4 Oruch R. Pryme I.F. Engelsen B.A. Neuroleptic malignant syndrome: an easily overlooked neurologic emergency Neuropsychiatr Dis Treat 13 2017 161 175 28144147 \n5 Sakkas P. Davis J.M. Janicak P.G. Drug treatment of the neuroleptic malignant syndrome Psychopharmacol Bull 27 1991 381 384 1685592 \n6 Rosebush P.I. Stewart T. Mazurek M.F. The treatment of neuroleptic malignant syndrome. Are dantrolene and bromocriptine useful adjuncts to supportive care? Br J Psychiatry 159 1991 709 712 1843801 \n7 Shalev A. Hermesh H. Munitz H. Mortality from neuroleptic malignant syndrome J Clin Psychiatry 50 1989 18 25 \n8 Gurrera R.J. Simpson J.C. Tsuang M.T. Meta-analytic evidence of systematic bias in estimates of neuroleptic malignant syndrome incidence Compr Psychiatry 48 2007 205 211 17292713 \n9 Al Owesie R.M. Robert A.A. Delirium followed by neuroleptic malignant syndrome in rehabilitation setting. Is it anger reaction before discharge Pan Afr Med J 15 2013 26 24009802 \n10 Gurrera R.J. A systematic review of sex and age factors in neuroleptic malignant syndrome diagnosis frequency Acta Psychiatr Scand 135 2017 398 408 28144982 \n11 Chandran G.J. Mikler J.R. Keegan D.L. Neuroleptic malignant syndrome: case report and discussion CMAJ 169 2003 439 442 12952806 \n12 Strawn J.R. Keck P.E. Jr. Caroff S.N. Neuroleptic malignant syndrome Am J Psychiatry 164 2007 870 876 17541044 \n13 Seitz D.P. Gill S.S. Neuroleptic malignant syndrome complicating antipsychotic treatment of delirium or agitation in medical and surgical patients: case reports and a review of the literature Psychosomatics 50 2009 8 15 19213967 \n14 Berardi D. Amore M. Keck P.E. Jr. Clinical and pharmacologic risk factors for neuroleptic malignant syndrome: a case-control study Biol Psychiatry 44 1998 748 754 9798079 \n15 Yildirim V. Direk M.C. Gunes S. Neuroleptic malignant syndrome associated with valproate in an adolescent Clin Psychopharmacol Neurosci 15 2017 76 78 28138117 \n16 Ananth J. Aduri K. Parameswaran S. Neuroleptic malignant syndrome: risk factors, pathophysiology, and treatment Acta Neuropsychiatr 16 2004 219 228 26984310 \n17 Pelonero A.L. Levenson J.L. Pandurangi A.K. Neuroleptic malignant syndrome: a review Psychiatr Serv 49 1998 1163 1172 9735957 \n18 Bristow M.F. Kohen D. Neuroleptic malignant syndrome Br J Hosp Med 55 1996 517 520 8732227 \n19 Wijdicks E. Neuroleptic malignant syndrome. In: UpToDate, Aminoff M (Ed.). UpToDate, Waltham, MA. (Accessed on May 30, 2014). Available from: http://www.uptodate.com.\n20 Kasantikul D. Kanchanatawan B. Neuroleptic malignant syndrome: a review and report of six cases J Med Assoc Thai 89 2006 2155 2160 17214072 \n21 Tural U. Onder E. Clinical and pharmacologic risk factors for neuroleptic malignant syndrome and their association with death Psychiatry Clin Neurosci 64 2010 79 87 20416027 \n22 Nakamura M. Yasunaga H. Miyata H. Mortality of neuroleptic malignant syndrome induced by typical and atypical antipsychotic drugs: a propensity-matched analysis from the Japanese Diagnosis Procedure Combination database J Clin Psychiatry 73 2012 427 430 22154901 \n23 Mayda-Domac F. Misirli H. Yilmaz M. Prognostic role of mean platelet volume and platelet count in ischemic and hemorrhagic stroke J Stroke Cerebrovasc Dis 19 2010 66 72 20123229\n\n",
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"title": "A retrospective analysis of cases with neuroleptic malignant syndrome and an evaluation of risk factors for mortality.",
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"abstract": "Ovarian cancer rarely metastasizes to the brain. If it does, it is more likely to occur with advanced stage carcinomas, more than one year after diagnosis, and rarely presents as a single lesion. Early detection, treatment, and close follow-up is essential to optimize prognosis and prevent long-term disability. This case presents a 54-year-old female with a previously diagnosed & treated stage 1a, grade 3 ovarian cancer who presented with a complaint of persistent headache. Imaging demonstrated a singular brain lesion. She underwent mass resection with pathology consistent with metastatic ovarian cancer. This was only 18 months after her primary diagnosis, demonstrating the importance of close surveillance and heightened awareness of metastatic disease.",
"affiliations": "Ascension Providence Hospital, Department of Obstetrics & Gynecology, Southfield, MI, United States.;School of Medicine, St. George's University, True Blue, Grenada.;Ascension Providence Hospital, Department of Obstetrics & Gynecology, Southfield, MI, United States.",
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"fulltext": "\n==== Front\nGynecol Oncol RepGynecol Oncol RepGynecologic Oncology Reports2352-5789Elsevier S2352-5789(20)30006-010.1016/j.gore.2020.100540100540Case ReportMetastatic brain disease in early stage ovarian cancer: A case report Halassy Sophia shalassy@gmail.comab⁎Au Katrina cChobanian Nishan aba Ascension Providence Hospital, Department of Obstetrics & Gynecology, Southfield, MI, United Statesb Michigan State University, East Lansing, MI, United Statesc School of Medicine, St. George’s University, True Blue, Grenada⁎ Corresponding author. shalassy@gmail.com30 1 2020 5 2020 30 1 2020 32 10054010 11 2019 14 1 2020 27 1 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Patient with history of early stage ovarian cancer with singular brain lesion.\n\n• Head imaging with finding of mass effect and edema requiring surgical intervention.\n\n• Ovarian cancer metastasizes locally and rarely to the brain.\n\n• Brain metastases commonly are multiple, and rarely singular.\n\n• The most significant risk factor for brain metastasis includes advanced stage disease.\n\n\n\nOvarian cancer rarely metastasizes to the brain. If it does, it is more likely to occur with advanced stage carcinomas, more than one year after diagnosis, and rarely presents as a single lesion. Early detection, treatment, and close follow-up is essential to optimize prognosis and prevent long-term disability. This case presents a 54-year-old female with a previously diagnosed & treated stage 1a, grade 3 ovarian cancer who presented with a complaint of persistent headache. Imaging demonstrated a singular brain lesion. She underwent mass resection with pathology consistent with metastatic ovarian cancer. This was only 18 months after her primary diagnosis, demonstrating the importance of close surveillance and heightened awareness of metastatic disease.\n\nKeywords\nEarly stage ovarian cancerBrain metastasisEarly metastatic disease\n==== Body\n1 Introduction\nIn 2018, there was predicted to be approximately 22,240 new cases of ovarian cancer and 14,070 ovarian cancer deaths in the US (Torre et al., 2018). Epithelial ovarian cancer is the most common type of ovarian cancer and the one of the most common causes of gynecological cancer related deaths (Jayson et al., 2014). One quarter of all ovarian cancers are diagnosed at stage I (Torre et al., 2018). The incidence of brain metastases in ovarian cancer is estimated to be between 0.29 and 5% and often coincide with extracranial metastasis (Ushijima, 2010, Pectasides, 2006). More commonly, brain metastasis occurs in stage III and stage IV and are histologically grade 3 (Pectasides, 2006). We present a rare case of a patient with stage IA, grade III endometrioid ovarian cancer who developed a single brain metastatic lesion (See Scheme 1a, Scheme 1b, Scheme 2, Scheme 3, Scheme 4).Scheme 1a CT image demonstrating 2.4 × 2.4 cm singular lesion with surrounding edema in left frontal lobe in coronal view.\n\nScheme 1b CT image demonstrating 2.4 × 2.4 cm singular lesion with surrounding edema in left frontal lobe in sagittal view.\n\nScheme 2 T2-weighted MRI demonstrating heterogeneously enhancing circumscribed 2.5 cm mass within the left anterior frontal region with extensive vasogenic edema, mass-effect and midline shift in coronal view.\n\nScheme 3 T1-weighted MRI demonstrating heterogeneously enhancing circumscribed 2.5 cm mass within the left anterior frontal region with extensive vasogenic edema, mass-effect and midline shift in coronal view.\n\nScheme 4 Histologic comparison of ovarian primary tumor (right) and brain metastasis (left), medium magnification. Arrows highlight papillary epithelial tufts present. Insets (high magnification) demonstrate similar nuclear features in the tumors.\n\n\n\n2 Case\nThe patient is a 54-year-old G3 P2-0-1-2 with significant past medical history of endometrioid ovarian cancer (stage Ia, grade 3) who presented to the emergency department with a primary complaint of left-sided headache. She had been experiencing retro-orbital headaches for the last several months without other neurological deficits. Review of systems was otherwise negative.\n\nHer physical examination was within normal limits. Due to the persistent nature of the patient's symptoms and significant history, a head CT was performed. This demonstrated a left frontal 2.4 × 2.4 cm lobe mass with surrounding edema. An MRI was subsequently performed which demonstrated a heterogeneously enhancing circumscribed 2.5 cm mass within the left anterior frontal region with extensive vasogenic edema, mass-effect and midline shift. A CT of the chest, abdomen, and pelvis were negative for any metastatic disease.\n\nThe patient underwent menopause at age 49 with menarche at 13. She had 2 healthy pregnancies. She never used tobacco, did not have any history of hormonal replacement therapy and had no significant family history. As previously mentioned, the patient did have a recent history of endometrioid ovarian cancer (stage Ia, grade 3). After surgical intervention (total abdominal hysterectomy, bilateral salpingo-oophorectomy, lymph node dissection, appendectomy, and omentectomy), the patient underwent 6 cycles of Paclitaxel (Taxol) and Carboplatin (Carbo). She declined any genetic or germline mutation testing. The patient did follow-up as directed with her gynecological oncologist. Other than a complaint of headache, the patient did not have any other significant symptoms or findings during these visits. The patient had undergone a head CT and PET/CT skull in the interval between her surgical intervention and current presentation. No abnormalities were found.\n\nShe was admitted to the hospital with continued close monitoring. She was started on intravenous steroid therapy along with antiseizure medications. A serum CA-125 was 7 unit/mL, which was unchanged from baseline and both 6 and 12 months before. The patient underwent a left stereotactic frontal craniotomy with resection of an intradural, intra-axial mass 4 days after admission. The patient tolerated the procedure well and was transferred to the neurology ICU for postoperative management.\n\nHer postoperative course was complicated by an episode of questionable loss of consciousness. A repeat brain MRI demonstrated edema. No acute intracranial process was noted. An echocardiogram was performed and was significant for a large size (1.8 × 1.5 cm), nonmobile, echogenic mass attached to the right atrial wall. Prophylactic anticoagulation was started. A lower extremity duplex study was negative. A repeat chest CT scan was positive for a left lower lobe branch small pulmonary artery embolism. There was no evidence of right heart strain. Daily head CTs were performed and on postoperative day 5, increased hemorrhage was noted and IV anticoagulation was halted. A transesophageal echocardiogram was obtained and demonstrated a large 4.6 × 2.1 cm echogenic broad-based mass adherent to the right atrial wall. This was most consistent with a thrombus however malignancy was still unable to be ruled out.\n\nThe final pathology of the left frontal mass was significant for metastatic poorly differentiated adenocarcinoma. This lesion was similar to some of the poorly differentiated foci of the ovarian carcinoma. The patient remained stable and was discharged 14 days after initial presentation. Further management included brain radiation therapy with four cycles of Carbo/Taxol adjuvant chemotherapy.\n\n3 Discussion\nEndometrioid ovarian cancer makes up only 10% of epithelial ovarian cancer (Torre et al., 2018). This subtype is often diagnosed at stage I (59%) (Torre et al., 2018), as seen in our patient. This patient had developed one of the rarer epithelial ovarian cancers, endometrioid subtype, but was diagnosed as stage IA (defined as limited to one ovary or fallopian tube) which is more common in this subtype (59%) (Torre et al., 2018, Javadi et al., 2016). Treatment for stage I ovarian cancer includes surgery to remove adnexa on the side of the tumor, resection of the contralateral adnexa, hysterectomy, resection of greater omentum, retroperitoneal lymph node dissection and peritoneal biopsy (Hirose et al., 2018). Given that this patient’s tumor was poorly differentiated (grade 3(Javadi et al., 2016), despite stage Ia, she received 6 cycles of Carbo/Taxol. The survival rate of women with stage I epithelial ovarian cancer is 92% (versus 17–28% in advanced stages) (Doubeni et al., 2016), with recurrence of 20–25% in stage I (Ushijima, 2010). Histological grade of the tumor is the most important prognostic indicator in disease-free survival (Javadi et al., 2016).\n\nBrain metastases is rare in ovarian cancer with the incidence estimated to be between 0.29 and 5% with evidence of other sites of metastasis prior to this time (Ushijima, 2010, Pectasides, 2006). These patients usually have more advanced stage of disease (Pectasides, 2006). This patient was unique because the early stage of her cancer and no other confirmed metastatic sites. A retrospective study done by Kolomainen et al. found that the stage of the disease had little effect on the time to brain metastasis (Kolomainen et al., 2002). Brain metastasis often occurs late in the course of the disease and patients will present with CNS symptoms only (Kolomainen et al., 2002). Our patient presented 18 months after initial diagnosis and her only significant symptoms were headache, fatigue and drowsiness. To the authors’ knowledge, there has only been one similar case report that described a patient who presented with symptoms of increased intracranial pressure and was found to have a brain lesion with ovarian origin (Matsunami et al., 1999). On laparoscopic examination, there was no evidence of locally invasive disease and the carcinoma would have otherwise been categorized as stage IA (Matsunami et al., 1999).\n\nSingle site brain metastases are less common than multiple brain metastases, potentially ranging from 35% to 46% of cases and are most commonly seen in the cerebral hemisphere (Pectasides, 2006). In a review by Pectasides et al., there was no difference in the development of brain metastasis between the histological subtypes of ovarian cancer (Pectasides, 2006).\n\nThere has been some discussion on the impact of platinum-based chemotherapy on the blood brain barrier, allowing for brain metastasis, however, it appears to be controversial and requires further study (Pectasides, 2006, Pietzner et al., 2009). Our patient had completed her chemotherapy regimen prior and it could have contributed to the development of brain metastasis. Although further study could be warranted, it would be difficult to study the effects of chemotherapy on brain metastasis in this subset of patients since diagnosing early stages of ovarian cancer is uncommon, many may not have received chemotherapy treatment, and the incidence of brain metastasis is low.\n\nPatients with brain metastasis benefit from aggressive combined treatment with external whole brain radiation and surgery with or without chemotherapy compared to those who were treated using single treatment modalities, especially in patients that have no evidence of disease at other sites (Anupol et al., 2002, Cohen et al., 2004). Corticosteroids are used in the treatment of brain metastasis however, their use is purely palliative and has no survival benefit (Pietzner et al., 2009). Positive prognostic factors for patients that have brain metastasis include younger age at diagnosis of both the primary tumor and the brain metastasis, lower grade of primary tumor and higher functional status (Pakneshan et al., 2014). In this case, the patient was diagnosed at a later age and her brain functionality is still intact, leading to the increased likelihood that she will have a positive prognosis despite this newly developed brain metastasis.\n\n4 Conclusion\nThe risk of metastatic brain lesions from ovarian cancer is positively correlated with advanced stage disease. Time to metastasis has no such association and typically occurs more than one year after diagnosis. Other proposed associations include genetic mutations and chemotherapeutic drugs. The risk of a single metastatic brain lesion after diagnosis of stage Ia, grade 3 ovarian cancer is minimal, especially when the patient does not have a history of any known risk factors. However, when a patient with a history of ovarian cancer presents with constant headache, there should be consideration for metastasis, regardless of the stage of the disease. Imaging can aid to direct further intervention. While the overall prognosis of this patient is good, further surveillance will be essential.\n\nAuthor contribution\nSophia Halassy: Manuscript drafting and editing, Katrina Au: Review of literature, Nishan Chobanian: Editing\n\nDeclaration of Competing Interest\nThe authors declared that there is no conflict of interest.\n==== Refs\nReferences\nTorre L.A. Trabert B. DeSantis C.E. Ovarian cancer statistics, 2018 CA Cancer J. Clin. 68 4 2018 284 296 29809280 \nJayson G.C. Kohn E.C. Kitchener H.C. Ledermann J.a. Ovarian cancer Lancet 384 9951 2014 1376 1388 24767708 \nUshijima K. Treatment for recurrent ovarian cancer – At first relapse J. Oncol. 2010 \nPectasides D. Brain metastases from epithelial ovarian cancer: a review of the literature Oncologist 11 3 2006 252 260 16549809 \nJavadi Sanaz Ganeshan Dhakshina M. Qayyum Aliya Iyer Revathy B. Bhosale Priya Ovarian cancer, the revised FIGO staging system, and the role of imaging Am. J. Roentgenol. 206 6 2016 1351 1360 27042752 \nHirose S. Tanabe H. Nagayoshi Y. Retrospective analysis of sites of recurrence in stage I epithelial ovarian cancer J. Gynecol. Oncol. 29 3 2018 \nDoubeni C.A. Doubeni A.R.B. Myers A.E. Diagnosis and management of ovarian cancer Am. Fam. Physician 93 11 2016 937 944 27281838 \nKolomainen, D.F. Larkin, J.M.G. Badran M. et al. Epithelial Ovarian Cancer Metastasizing to the Brain: A Late Manifestation of the Disease With an Increasing Incidence. Vol 20. 2002.\nMatsunami K. Imai A. Tamaya T. Takagi Hiroshi Noda K. Brain metastasis as first manifestation of ovarian cancer Eur. J. Obstet. Gynecol. Reprod. Biol. 82 1 1999 81 83 10192491 \nPietzner K. Oskay-Oezcelik G. El Khalfaoui K. Boehmer D. Lichtenegger W. Sehouli J. Brain metastases from epithelial ovarian cancer: Overview and optimal management Anticancer Res. 29 2009 2793 2798 19596963 \nAnupol N. Ghamande S. Odunsi K. Driscoll D. Lele S. Evaluation of prognostic factors and treatment modalities in ovarian cancer patients with brain metastases Gynecol. Oncol. 85 3 2002 487 492 12051879 \nCohen Z.R. Suki D. Weinberg J.S. Brain metastases in patients with ovarian carcinoma: prognostic factors and outcome J. Neurooncol. 66 3 2004 313 325 15015663 \nPakneshan S. Safarpour D. Tavassoli F. Jabbari B. Brain metastasis from ovarian cancer: A systematic review J. Neurooncol. 119 1 2014 1 6 24789253\n\n",
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"abstract": "Background Amiodarone is an iodine-rich medication used to treat maternal and fetal arrhythmias, with known effects on thyroid hormone homeostasis. Case presentation We describe a case of transient neonatal hypothyroidism following a short prenatal course of maternal amiodarone therapy resulting in neonatal TSH elevations exceeding those reported in the available literature.",
"affiliations": "Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Johns Hopkins University School of Medicine, Baltimore, MD, USA.",
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"title": "Transient neonatal hypothyroidism following a short course of maternal amiodarone therapy.",
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"abstract": "Primary penile lymphoma presenting with priapism as the initial symptom is extremely rare. In total, <10 cases have been previously reported. The diagnosis can be difficult and patients often develop metastasis. The current study reports the case of a 48-year-old male, who presented with a one-month history of painless priapism. On admission to Yantai Yuhuangding Hospital Affiliated to Qingdao University (Yantai, China), examination revealed an erect penis, enlarged lymph nodes in the bilateral inguinal and swelling in the thighs. A biopsy was taken from the right inguinal lymph node and the pathological diagnosis confirmed a diffuse large B-cell type of non-Hodgkin's lymphoma, while an enhanced computed tomography scan of the chest revealed evidence of the invasion of malignant lymphoma cells. Priapism disappeared two days following the completion of the first cycle of chemotherapy with the E-CHOP regimen (cyclophosphamide, vincristine, prednisone, epirubicin and etoposide); however, evidence of brain metastases was observed one month later, which was confirmed by magnetic resonance imaging. The patient received cranial radiotheraphy and systemic treatment for cerebral edema. The patient did not respond well to treatment and succumbed to the disease three months following the initial diagnosis of lymphoma. Lymphoma may be difficult to diagnose, depending on the initial symptoms; therefore, the patient history must be carefully assessed so as to determine an early diagnosis and prevent metastasis, thus improving the prognostic outcome.",
"affiliations": "Department of Oncology, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264000, P.R. China.;Division of Graduate Education, Dalian Medical University, Dalian, Liaoning 116027, P.R. China.;Central Laboratory, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264000, P.R. China.;Central Laboratory, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264000, P.R. China.;Department of Oncology, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264000, P.R. China.;Department of Oncology, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264000, P.R. China.;Department of Oncology, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264000, P.R. China ; Central Laboratory, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264000, P.R. China.",
"authors": "Gong|Zhaohua|Z|;Zhang|Ying|Y|;Chu|Hongjin|H|;Lian|Peiwen|P|;Zhang|Liangming|L|;Sun|Ping|P|;Chen|Jian|J|",
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"fulltext": "\n==== Front\nOncol LettOncol LettOLOncology Letters1792-10741792-1082D.A. Spandidos 10.3892/ol.2014.2488ol-08-05-1929ArticlesPriapism as the initial symptom of primary penile lymphoma: A case report GONG ZHAOHUA 1ZHANG YING 2CHU HONGJIN 3LIAN PEIWEN 3ZHANG LIANGMING 1SUN PING 1CHEN JIAN 131 Department of Oncology, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264000, P.R. China2 Division of Graduate Education, Dalian Medical University, Dalian, Liaoning 116027, P.R. China3 Central Laboratory, Yantai Yuhuangding Hospital Affiliated to Qingdao University, Yantai, Shandong 264000, P.R. ChinaCorrespondence to: Dr Jian Chen, Department of Oncology, Yantai Yuhuangding Hospital Affiliated to Qingdao University, 20 Yuhuangding West Road, Yantai, Shandong 264000, P.R. China, E-mail: chenjianyt@163.com11 2014 28 8 2014 28 8 2014 8 5 1929 1932 06 5 2014 25 6 2014 Copyright © 2014, Spandidos Publications2014This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.Primary penile lymphoma presenting with priapism as the initial symptom is extremely rare. In total, <10 cases have been previously reported. The diagnosis can be difficult and patients often develop metastasis. The current study reports the case of a 48-year-old male, who presented with a one-month history of painless priapism. On admission to Yantai Yuhuangding Hospital Affiliated to Qingdao University (Yantai, China), examination revealed an erect penis, enlarged lymph nodes in the bilateral inguinal and swelling in the thighs. A biopsy was taken from the right inguinal lymph node and the pathological diagnosis confirmed a diffuse large B-cell type of non-Hodgkin’s lymphoma, while an enhanced computed tomography scan of the chest revealed evidence of the invasion of malignant lymphoma cells. Priapism disappeared two days following the completion of the first cycle of chemotherapy with the E-CHOP regimen (cyclophosphamide, vincristine, prednisone, epirubicin and etoposide); however, evidence of brain metastases was observed one month later, which was confirmed by magnetic resonance imaging. The patient received cranial radiotheraphy and systemic treatment for cerebral edema. The patient did not respond well to treatment and succumbed to the disease three months following the initial diagnosis of lymphoma. Lymphoma may be difficult to diagnose, depending on the initial symptoms; therefore, the patient history must be carefully assessed so as to determine an early diagnosis and prevent metastasis, thus improving the prognostic outcome.\n\npriapismprimary penile lymphomametastasis\n==== Body\nIntroduction\nPrimary penile lymphoma presenting with priapism as the initial symptom is extremely rare, with few cases reported worldwide. Penile cancer accounts for only 0.4–0.6% of all malignancies in the developed world (1), and the involvement of lymphoma is even more rare. The first case of primary malignant lymphoma of the penis was reported in 1962 (2), and few cases have been reported since. The most common subtype is diffuse large B-cell lymphoma (3). The diagnosis of rare lymphoma is difficult and may be delayed without specific symptoms and thus, treatment of this lesion remains controversial. Chemotherapy is the main treatment adminstered, however, immunotherapy, radiotherapy and penile preservation have all been reported (3,4) and a combined treatment modality is usually recommended (5). The current study reports a patient diagnosed with primary malignant penile lymphoma, with metastasis in the lungs and brain, and poor prognosis. The diagnosis was confirmed by biopsy, and enhanced CT of chest revealed evidence of pulmonary and brain metastasis. Written informed consent was obtained from the patient.\n\nCase report\nA 48-year-old male presented to Yantai Yuhuanding Hospital Affiliated to Qingdao University (Yantai, China) with a one-month history of painless priapism associated with chest congestion and shortness of breath. The patient had a history of type II diabetes. Physical examination revealed a swollen penis, enlarged inguinal lymph nodes, swelling in the thighs and varicose veins, which were visible in the lower limbs. No fever, night sweats or weight loss were observed in the month prior to patient referral, and no symptoms of ulceration, difficulty in urination or complaint of any epidermal changes were observed; therefore, no systemic symptoms of lymphoma were presented. Norepinephrine was administered, however, detumescence did not occur. The B-mode ultrasound examination of the rectum and perineum and the arteriography revealed no apparent arteriovenous fistula. An abdominal and pelvic computed tomography (CT) scan showed multiple node involvement, including the aortoiliac vessels, neck of the bladder, seminal vesicle, prostate gland and bilateral inguinal area. A biopsy was taken from the right inguinal lymph node (1.5×1.5 cm) and immunohistochemical analysis with markers confirmed that the lymphoma cells were CD20++, CD3−, CD10−, MuM1− and bcl-6−, corresponding with non-Hodgkin’s lymphoma (Fig. 1). The degree of staining was calculated using the following scale: −, positive staining of cancerous cells was observed in <25% of the cells; +, positive staining of cancerous cells was observed in >25% but <50% of the cells; ++, positive staining of the cancerous cells was observed in >50% but <75% of the cells (6). Based on these observations, the diagnosis of diffuse large B-cell lymphoma (DLBCL) was determined.\n\nOne week following admission, the patient complained of chest congestion; an enhanced CT scan revealed the invasion of malignant lymphoma cells to the lungs, and pericardial and bilateral pleural effusion was also identified (Fig. 2); however, at this stage, the possibility of fungal infection was not excluded. The E-CHOP regimen was administered (1.2 mg cyclophosphamide, day one; 2 mg vincristine, 60 mg epirubicin, days one to two; 100 mg prednisolone, days one to five; and 0.1 mg etoposide, days one to five). After four days, chest congestion, edema in the limbs and priapism were moderately relieved. A further histology of the lung by a needle biopsy revealed lymphoma cell infusion. Treatment for the decreased white blood cell count (0.56×109 cells/l; normal range, 4–10×109 cells/l) was administered during the second course of chemotherapy. The patient was continuously treated with systemic chemotherapy with the E-CHOP regimen. Concomitantly, symptomatic treatment to relieve airway spasms was administered. The patient tolerated the entire course of chemotherapy well, and the priapism was alleviated two days following the completion of one cycle of E-CHOP therapy. The enlarged bilateral inguinal lymph nodes were non-palpable at the time of completion.\n\nOn day 14 following admission, the patient was unresponsive to external stimuli and suffered an epileptic seizure. The results of the laboratory evaluations were as follows: Blood ammonia levels, 18 μmol/l (normal range, 20–60 μmol/l); blood ketone bodies, negative; and blood sugar levels, 17.27 mmol/l (normal range, 3.9–7.5 mmol/l); therefore, DKA and hepatic encephalopathy were ruled out. A cranio-cerebral magnetic resonance imaging scan revealed an anomaly in the rear of the anterior and posterior pituitary, suggesting possible cranial nerve nuclei involvement and infiltration (Fig. 3). The patient was subjected to radiotherapy when brain metastasis was identified. Systemic treatment for cerebral edema (dehydration) and nutrition following severe epileptic seizures were also administered. The final diagnosis was stage IV diffuse large B-cell non-Hodgkin’s lymphoma with metastasis to the brain and lungs, according to the Ann Arbor-Cotswolds staging classification (7). The patient succumbed to the disease three months following the initial diagnosis of lymphoma.\n\nDiscussion\nPriapism is defined as an involuntary, usually painful, prolonged penile erection unrelated to sexual stimulation (8). It is most commonly caused by hematological disorders such as sickle cell anemia; however, other causes include neurological damage, trauma, infection, malignancy, erectile dysfunction drugs, such as papaverine and alprostadil, and metabolic disturbances (9). The presentation of penile lymphoma varies, with symptoms including indurated papules, nodules, ulcers and diffuse penile swelling (10). Primary penile lymphoma is extremely rare and difficult to diagnose, and patient history must be carefully assessed. In order to determine an accurate diagnosis, a full physical examination, radiological imaging studies, excision biopsy and immunohistochemical analysis must be conducted. Reports have been published describing this malignancy with common phenotypes including nodules, ulceration or penile enlargement, all of which are similar to other soft tissue tumors and, therefore, lead to the condition being difficult to diagnose (3). However, priapism as the initial symptom of lymphoma is extremely rare. To the best of our knowledge, only four cases of primary penile lymphoma have been reported presenting with priapism as the initial symptom (11–13). The pathological studies demonstrated that all cases were diffuse large DLBCL, which is the most common subtype of lymphoma at this anatomical site (14).\n\nIn the current study, the 48-year-old male initially presented with priapism, which was followed by enlargement of the lymph node. The pathological studies confirmed the diagnosis of malignant penile lymphoma and treatment with the E-CHOP regimen led to the remission of the physiological symptoms; however, the patient later developed metastasis in the lungs and brain. This indicated a poor prognosis for DLBCL, the most common subtype of non-Hodgkin’s lymphoma. DLBCL is aggressive and is associated with a wide range of clinical manifestations at all ages; however, patients with the condition may undergo complete remission with appropriate treatment (11,12,15,16). It was speculated that priapism in lymphoma is caused by tumor cells infiltrating the penile cavernous tissue, which causes venous obstruction and priapism (10). Priapism caused by tumor cell infiltration is usually associated with congestion and swelling in the body of penis. Additionally, priapism as the initial manifestation has been reported in leukemia, which is also a malignant hematological disease. Often, priapism subsides after two to seven days of chemotherapy; however, occasionally it is caused by tumor lysis syndrome in leukemia, where the condition occurs following chemotherapy (13,17). To achieve an improved outcome in cases where the original diagnostic evidence is limited or current treatment failed, the possibility of lymphoma must be investigated. Furthermore, it has been suggested that levels of soluble interleukin-2 receptor may serve as a potential prognostic marker for the low complete response rates in DLCBL (16,18).\n\nTo date, the preferred treatment for DLCBL includes excision, radiotherapy, and chemotherapy; however, no standard treatment modality has been established (16). Although early-stage localized lymphoma is potentially curable with localized therapy and has a good prognosis, the anatomical resection and radiotherapy may cause local morbidity. The E-CHOP regimen alone, or combined with rituximab, which is a chimeric monoclonal antibody against the CD20 B-cell antigen, has become the current recommended treatment for DLBCL. In the majority of reported cases, following chemotherapy treatment, complete resolution of the disease was observed for between four months and six years (10,15,19–26). However mortalities due to this malignancy have also been reported (21).\n\nIn conclusion, the current study reports the case of a 48-year-old male with primary penile lymphoma, presenting with a one-month history of priapism due to large DLBCL cell infiltration, which also affected the lungs and cranial nervous system. The diagnosis was prolonged as the initial manifestation of the disease was extremely rare. The E-CHOP chemotherapy regimen was the selected treatment modality in this case, considering the patient’s relatively young age, due to the vigorous nature of the therapy. However, the prognosis was poor due to the advanced stage of the invasion and disseminated lymphoma cells. This case report may increase understanding with regard to the specific aetiology and pathogenesis of this disease and may prevent misdiagnosis by clinicians. Non-Hodgkin’s lymphoma may be difficult to diagnose based on the initial symptoms presented by patients. Thus, early recognition and appropriate clinical management are required. Further clinical studies are required to identify a standard treatment for this malignancy.\n\nAcknowledgements\nThis study was supported by the Shandong Doctoral Program fund (grant no. 2008BS02012) and the Yantai Science and Technology Program (grant no. 2009155-3).\n\nFigure 1 Biopsy taken from the right inguinal lymph node showing (A) diffused infiltration of atypical neoplastic lymphocytes with primitive nuclear morphology, visible nucleoli and little cytoplasm. The cells exhibited positive immunoreactivity for CD20. (B) Biopsy of the lung revealed diffused infiltration of atypical neoplastic lymphocytes by hematoxylin and eosin staining. Original magnification, ×200.\n\nFigure 2 Transaxial computed tomography images of the chest showing infiltration of the lungs (A) prior to chemotherapy. The bilateral lungs had a large area with a dark appearance, and mediastinal lymph nodes were visible.(B) Transaxial computed tomography images of the chest following chemotherapy.\n\nFigure 3 Magnetic resonance imaging scans show cranial nerve nuclei involvement of lymphomatic metastasis. The bilateral cerebral hemisphere cortex had (A and B) marginally long T1 and (C) long T2 signal changes, and cerebral fissure was not apparent. Bilateral basal ganglia had hyperintense T1 and T2 signals. (D) Fluid attenuated inversion recovery showed enhanced signal, whereas (E) diffusion weighted imaging exhibited a slightly low signal on the right. No apparent enhancement of the signal was observed following the injection of the contrast agent.\n==== Refs\nReferences\n1 Bleeker MC Heideman DA Snijders PJ Penile cancer: epidemiology, pathogenesis and prevention World J Urol 27 141 150 2009 18607597 \n2 Oomura J Ookita K Takenaka M Yamada S Primary reticulosarcoma of the penis. Report of a case Hinyokika Kiyo 8 53 542 1962 (In Japenese) \n3 Chu L Mao W Curran Vikramsingh K Primary malignant lymphoma of the glans penis: a rare case report and review of the literature Asian J Androl 15 571 572 2013 23644872 \n4 Delicato G Baffigo G Bianchi D Conservative therapy in two cases of non-Hodgkin lymphoma of the penis: Case reports with review of the literature World J Oncol 3 37 38 2012 \n5 Arena F di Stefano C Peracchia G Primary lymphoma of the penis: diagnosis and treatment Eur Urol 39 232 235 2001 11223685 \n6 Vardiman JW Thiele J Arber DA The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes Blood 114 937 951 2009 19357394 \n7 Izumi T Ozawa K Clinical classification of non-Hodgkin’s lymphoma Nihon Rinsho 58 598 601 2000 (In Japenese) 10741131 \n8 Salonia A Eardley I Giuliano F European Association of Urology guidelines on priapism Eur Urol 65 480 489 2014 24314827 \n9 Van der Horst C Stuebinger H Seif C Priapism - etiology, pathophysiology and management Int Braz J Urol 29 391 400 2003 15745583 \n10 Kim HY Oh SY Lee S Primary penile diffuse large B cell lymphoma treated by local excision followed by rituximab-containing chemotherapy Acta Haematol 120 150 152 2008 19039206 \n11 Guo Y Bai RJ Gao S FDG PET/CT detects malignant lymphoma invading the penis Clin Nucl Med 36 e204 206 2011 22064111 \n12 Madeb R Rub R Erlich N Hegarty PK Yachia D Long standing priapism as presentation of lymphoma Am J Hematol 82 87 2007 17078020 \n13 Hamamoto S Tozawa K Nishio H Kawai N Kohri K Successful treatment of primary malignant lymphoma of the penis by organ-preserving rituximab-containing chemotherapy Int J Clin Oncol 17 181 184 2012 21710157 \n14 Sun J Medeiros LJ Lin P Lu G Bueso-Ramos CE You MJ Plasmablastic lymphoma involving the penis: a previously unreported location of a case with aberrant CD3 expression Pathology 43 54 57 2011 21240066 \n15 Wei CC Peng CT Chiang IP Wu KH Primary B cell non-hodgkin lymphoma of the penis in a child J Pediatr Hematol Oncol 28 479 480 2006 16825998 \n16 Marks D Crosthwaite A Varigos G Ellis D Morstyn G Therapy of primary diffuse large cell lymphoma of the penis with preservation of function J Urol 139 1057 1058 1988 3361644 \n17 Asakura H Nakazono M Masuda T Yamamoto T Tazaki H Priapism with malignant lymphoma: a case report Hinyokika Kiyo 35 1811 1814 1989 (in Japanese) 2481974 \n18 Arena F di Stefano C Peracchia G Barbieri A Cortellini P Primary lymphoma of the penis: diagnosis and treatment Eur Urol 39 232 235 2001 11223685 \n19 Delicato G Baffigo G Bianchi D Farullo G Signore S Tartaglia E Corvese F Ferdinandi V Conservative therapy in two cases of non-Hodgkin lymphoma of the penis: Casereports with review of the literature World J Oncol 3 37 38 2012 \n20 Carter RD Smith R Alpern HD Healey BM Primary lymphoma of the penis with rationale of treatment Int Urol Nephrol 24 521 525 1992 1459829 \n21 el-Sharkawi A Murphy J Primary penile lymphoma: the case for combined modality therapy Clin Oncol (R Coll Radiol) 8 334 335 1996 8934056 \n22 Gallardo F Pujol RM Barranco C Salar A Progressive painless swelling of glans penis: uncommon clinical manifestation of systemic non-Hodgkin’s lymphoma Urology 73 e3 e5 2009 18571702 \n23 Wang HT Lo YS Huang JK Primary lymphoma of the penis J Chin Med Assoc 66 379 381 2003 12889509 \n24 Pomara G Cuttano MG Tripodo C Carlino F Selli C Primary T-cell rich B-cell lymphoma of the penis: a first case BJU Int 91 889 2003 12780856 \n25 Hashine K Akiyama M Sumiyoshi Y Primary diffuse large cell lymphoma of the penis Int J Urol 1 189 190 1994 7627859 \n26 Terada T Shirakashi Y Sugiura M T-cell lymphoma of the penis as the first manifestation of adult T-cell lymphoma/leukemia Int J Dermatol 51 973 975 2012 22788817\n\n",
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"title": "Priapism as the initial symptom of primary penile lymphoma: A case report.",
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"abstract": "BACKGROUND\nChronic renal failure is strongly associated with poor pregnancy outcome. Women dependent on hemodialysis before conception rarely achieve a successful live birth.\n\n\nMETHODS\nA 31-year-old multiparous Turkish woman was scheduled for cesarean section under spinal anesthesia at 37 weeks and five days' gestation because of hemorrhage due to secondary placenta previa. Spinal anesthesia with 8 mg of hyperbaric bupivacaine was successfully performed. Invasive blood pressure, central venous pressure, and heart rate were stable during the surgery. The mother returned to regular hemodialysis on the first postoperative day.\n\n\nCONCLUSIONS\nPregnancy is uncommon in women with chronic renal failure requiring chronic dialysis. Rates of maternal hypertension, pre-eclampsia, anemia, and infection in the pregnant chronic dialysis patient are high. However, our findings suggest that with careful, close, and effective monitoring preoperatively and intraoperatively, spinal anesthesia can be safely performed for cesarean section in patients undergoing hemodialysis.",
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"title": "Safe spinal anesthesia in a woman with chronic renal failure and placenta previa.",
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"abstract": "To describe a case of rapid keratitis and corneal perforation after epithelium off collagen cross-linking.\nWe report a case of a 17-year-old male who underwent collagen cross-linking with the protocol and device approved by the United States Food and Drug Administration (FDA) that developed a corneal infiltrate 3 days after the procedure. He later developed corneal thinning and perforation on day 5 requiring the use of cyanoacrylate glue and a Kontur lens. Despite initial improvement in the infiltrate with fortified antibiotics he later had leakage of aqueous around the glue and a flat chamber requiring an emergent penetrating keratoplasty on postoperative day 16.\nWhile collagen cross-linking has been very effective for treating keratoconus and is being recommended more frequently since FDA approval in the United States, severe complications such as corneal perforation requiring early transplant can still occur.",
"affiliations": "Department of Ophthalmology, Manhattan Eye, Ear & Throat Hospital, New York, NY, USA.;Department of Ophthalmology, New York Eye & Ear Infirmary of Mount Sinai, New York, NY, USA.;Department of Ophthalmology, New York Eye & Ear Infirmary of Mount Sinai, New York, NY, USA.;Department of Ophthalmology, Donald and Barbara Zucker School of Medicine at Hofstra Northwell, Great Neck, NY, USA.;Department of Ophthalmology, Donald and Barbara Zucker School of Medicine at Hofstra Northwell, Great Neck, NY, USA.",
"authors": "Schear|Matthew|M|;Ragam|Ashwinee|A|;Seedor|John|J|;Udell|Ira|I|;Shih|Carolyn|C|",
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"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(19)30099-4\n10.1016/j.ajoc.2020.100658\n100658\nCase Report\nRapid keratitis and perforation after corneal collagen cross-linking\nSchear Matthew a Ragam Ashwinee b Seedor John b Udell Ira c Shih Carolyn cshih@northwell.educ∗ a Department of Ophthalmology, Manhattan Eye, Ear & Throat Hospital, New York, NY, USA\nb Department of Ophthalmology, New York Eye & Ear Infirmary of Mount Sinai, New York, NY, USA\nc Department of Ophthalmology, Donald and Barbara Zucker School of Medicine at Hofstra Northwell, Great Neck, NY, USA\n∗ Corresponding author. Department of Ophthalmology, Donald and Barbara Zucker School of Medicine at Hofstra Northwell, 600 Northern Blvd, Suite 214, Great Neck, NY, 11021, USA. cshih@northwell.edu\n13 3 2020 \n6 2020 \n13 3 2020 \n18 1006584 4 2019 9 3 2020 © 2020 Published by Elsevier Inc.2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo describe a case of rapid keratitis and corneal perforation after epithelium off collagen cross-linking.\n\nObservations\nWe report a case of a 17-year-old male who underwent collagen cross-linking with the protocol and device approved by the United States Food and Drug Administration (FDA) that developed a corneal infiltrate 3 days after the procedure. He later developed corneal thinning and perforation on day 5 requiring the use of cyanoacrylate glue and a Kontur lens. Despite initial improvement in the infiltrate with fortified antibiotics he later had leakage of aqueous around the glue and a flat chamber requiring an emergent penetrating keratoplasty on postoperative day 16.\n\nConclusion and importance\nWhile collagen cross-linking has been very effective for treating keratoconus and is being recommended more frequently since FDA approval in the United States, severe complications such as corneal perforation requiring early transplant can still occur.\n\nKeywords\nCross-linkingCorneaKeratoconusPerforationInfectious keratitis\n==== Body\n1 Introduction\nCorneal ectasia is a disorder characterized by abnormal thinning and steepening of the cornea resulting in a decrease in vision due to irregular astigmatism and higher order aberrations. This disorder may be unilateral or bilateral – and occur spontaneously (i.e. keratoconus, pellucid marginal degeneration) or after having had refractive procedures.1,2 Generally this is seen in patients from late teenage years, up to the age of 30. The etiology for progression is unclear but may be linked to mechanical stress such as eye-rubbing, genetic factors, and chromosomal or enzymatic abnormalities.3\n\nWhile there is no cure for corneal ectasia, in 1997 researchers at the University of Dresden introduced the concept of corneal collagen cross-linking (CXL) using ultraviolet (UV) light to induce collagen cross-linking in riboflavin soaked porcine and rabbit corneas.4 These corneas were found to be stiffer and more resistant to enzymatic digestions. By 2003 Dresden investigators began human protocols which were found to be promising, leading to the use of cross-linking outside the United States to treat progressive corneal ectasia.5\n\nThe United States Food and Drug Administration (FDA) approved Avedro's (Avedro, Inc, Waltham, MA) CXL system for treatment of patients with progressive keratoconus and post-refractive surgery ectasia in April 2016 using Photrexa Viscous (0.1% riboflavin ophthalmic solution/20% dextran) and Photrexa (0.1% riboflavin ophthalmic solution). The Phase III trials leading to this approval noted that adverse side effects included corneal opacity (haze), punctate keratitis, corneal striae, corneal epithelium defect, eye pain, reduced visual acuity, and blurred vision.6,7 We report a patient who underwent CXL using the FDA approved Avedro protocol that experienced rapidly progressive infiltration and necrosis of his cornea followed by perforation.\n\n2 Case report\nThe patient was a 17-year-old male with a past medical history significant for childhood asthma and Scheuermann's disease that was referred for a rapid decline in vision in his right eye over the past year. His ophthalmologist noted that he was developing an increasing amount of irregular astigmatism and could not correct his vision with glasses. He denied being on any medications or eye drops but did have a prior history of using Accutane (isotretinoin) “months” before for acne. He could not elaborate on duration of use. Pentacam (Oculus GmbH, Wetzlar, Germany) scans were done which revealed significant posterior elevation of his right cornea consistent with keratoconus (Fig. 1). His right refraction was −4.50 + 3.00 × 139 with k's of 46.75 × 50.50 at 142 while his left cornea was −2.50 + 0.75 × 94 with k's of 46.25/47.25 at 94. His right cornea's thinnest point by ultrasound pachymetry was 502 μm.Fig. 1 Initial pentacam prior to cross-linking.\n\nFig. 1\n\nAfter informed consent with his family the patient elected to undergo corneal collagen cross-linking using the FDA approved epithelium off Avedro (Dresden protocol) given his progressive keratoconus of the right eye. After a 9 mm epithelial defect was created by an Amoils brush, 1 drop of Photrexa Viscous (0.1% riboflavin ophthalmic solution/20% dextran) was then applied every 2 minutes for 30 minutes topically to the cornea. The corneal thickness at this point was found to be greater than 400 μm so no additional administering of Photrexa Viscous (0.1% riboflavin ophthalmic solution/20% dextran) was needed. Following this, the patient underwent UVA irradiation at 365 mW at an intensity of 3 mW/cm2. Throughout UVA exposure, administration of the riboflavin/dextran solution was continued every 2 minutes. At the end of the case, 1 drop of Ofloxacin 0.3% and Predforte (prednisolone acetate 1%) was applied to the cornea. One drop of Diclofenac 0.1% was given over a bandage contact lens which was placed after the antibiotic and steroid drop was given. The patient was sent home on Ofloxacin 0.3% and Predforte four times a day.\n\nPostoperative day one, the patient was noted to have uncorrected visual acuity of 20/60, pinholing to 20/50. Slit lamp examination revealed a 8 mm epithelial defect, mild haze consistent with having had cross-linking, and no infiltrate. His bandage contact lens was in place. Postoperative day 3, the patient called to say that he noted a “white spot” on his cornea (which he noted seeing on day 2 but never called) was enlarging. He was asked to come in immediately. He noted that his pain which had been 8/10 postoperative day 1 was now 0/10. On examination his vision was Hand Motions and his bandage contact lens was not present. He had a central 5 × 5.5 mm stromal necrotic ulcer with associated 1 mm hypopyon (Fig. 2). Cultures were taken and the patient was started on topical fortified vancomycin 25mg/ml and tobramycin 15mg/ml every 1 hour around the clock, Doxycycline 100 mg orally bis in die (BID) and Acyclovir 800 mg orally BID. An autoimmune workup was initiated to rule out any diseases which may predispose the patient to corneal melting; these tests all came back negative. On postoperative day 5 the patient was noted to have an increasing amount of stromal thinning, approximately 2 × 3 mm in diameter temporally, with a mildly positive seidel test. He was started on oral Prednisone 30 mg once a day and cyanoacrylate glue was placed over the area of thinning along with a Kontur lens. Over the next week it was noted that his necrosis was resolving and his hypopyon was also lessening. However, on postoperative day 16 it was noted that while he was healing, the corneal glue began to loosen and his anterior chamber shallowed as a result (Fig. 3). Due to persistent leakage, he was taken to the operating room where he underwent an emergent penetrating keratoplasty (Fig. 4). The patient tolerated the procedure well without complication.Fig. 2 Initial presentation of infiltrate, corneal thinning and hypopyon.\n\nFig. 2Fig. 3 Photograph taken before penetrating keratoplasty with glue and kontur lens.\n\nFig. 3Fig. 4 Postoperative appearance after penetrating keratoplasty.\n\nFig. 4\n\nPostoperatively the patient's course has been uneventful and his vision was 20/20-2 postoperative month 3. Of note, on pathology there were no organisms noted within the corneal button with special stains – just extensive keratolysis (Fig. 5). The cultures taken on day 3 after CXL were negative however the broth revealed “unidentifiable gram-negative rods.” This was further sent to the New York State department of health who noted “gram-positive spore-forming bacillus – unable to identify further, Streptococcus parasanguinis, Streptococcus cristatus, and Neisseria species.” These organisms were sensitive to fluoroquinolones. Cultures taken at the time of surgery were all negative.Fig. 5 Corneal button with extensive keratolysis, no organisms.\n\nFig. 5\n\n3 Discussion\nCorneal collagen cross-linking was approved by the FDA in 2016. Results of the phase III clinical trials in both keratoconus patients and post-refractive surgery ectasia patients demonstrated few significant complications.5,6 For the past year and half since FDA approval many corneal providers across the United States have been performing CXL. The goal of CXL is to stabilize the cornea and maintain good vision to prevent the need for potential keratoplasty in the future. However, in this report we demonstrate that despite following the approved protocol visually debilitating complications can occur. To our knowledge this is the first case of corneal perforation following FDA-approved CXL in the United States.\n\nCXL has been performed outside the United States and off-label since 2003. There have been some reported cases of infectious keratitis and corneal perforation. A recent report from the Cornea society suggest the estimated incidence of infection was 0.0017%.8 A prior literature review noted 17 cases of post-CXL keratitis with 11 isolated case reports and 1 case series.9 In our patient the time to corneal infiltrate was 3 days versus 5 days in the literature review. The most common pathogen was bacterial, specifically Staph aureus with some cases of polymicrobial infection. There was an association with vernal kerato-conjunctivitis in 57% of cases.\n\nRapid keratolysis causing melt and perforation after CXL is extremely rare. Upon literature review there were 5 prior reported cases. 80% were done with the epi-off protocol, 1 case was done trans epithelial. The first case perforated on day 8 and was positive for Alternaria spp. and required a therapeutic penetrating keratoplasty.9 Rana et al. reported 2 cases of post-CXL microbial keratitis that ultimately perforated despite optimal therapy requiring corneal gluing. These cases perforated on postoperative day 2 and 7 and were associated with Staph aureus and methicillin-resistant Staph aureus respectively.10 Additionally, a case of post-CXL Acanthamoeba keratitis was reported that underwent penetrating keratoplasty for corneal perforation on postoperative day 11.11 There was also an isolated case of corneal melt requiring a penetrating keratoplasty with no known pathogen occurring postoperative month 2.12\n\nOur patient had no underlying inflammatory or atopic condition. Laboratory workup remained negative and cultures were inconclusive. He did have a remote history of isotretinoin use, but use was several months prior to the procedure. The etiology as to the cause of the rapid keratolysis and perforation in our case is unclear. The etiology is likely multifactorial secondary to a large epithelial defect and concomitant use of a BCL with topical steroids and nonsteroidal anti-inflammatory drugs (NSAIDs) in the immediate postoperative period. However, the NSAID was unlikely to precipitate given only one drop was given after CXL over the bandage lens. The patient was not prescribed any postoperative NSAID drops. It is also possible that patient hygiene plays a role, with more difficult to manage hygiene in younger aged patients. Those with underlying inflammatory conditions, atopy or those on certain medications that may affect corneal wound healing may play a role which tends to be more common in those with keratoconus. To our knowledge in reviewing the literature we have found nothing to implicate isotretinoin or Scheuermann's disease as a contributing factor to corneal infection, melting or perforation after CXL.\n\n4 Conclusion\nThis case report highlights a severe complication that may occur after CXL. Patients must be carefully counseled about the risk of corneal melt and perforation.\n\nPatient consent\nConsent to publish the case report was not obtained. This report does not contain any personal information that could lead to the identification of the patient.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nDeclaration of competing interests\nAuthors have no financial disclosures or conflicts of interest.\n\nAppendix A Supplementary data\nThe following is the supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgement\nNone.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajoc.2020.100658.\n==== Refs\nReferences\n1 Rabinowitz Y.S. Keratoconus Surv Ophthalmol 42 4 1998 297 319 9493273 \n2 Krachmer J.H. Feder R.S. Belin M.W. Keratoconus and related noninflammatory corneal thinning disorders Surv Ophthalmol 28 4 1984 293 322 6230745 \n3 Gordon-Shaag A. Millodot M. Shneor E. The epidemiology and etiology of keratoconus Int J Keratoconus Ectatic Corneal Dis 70 1 2012 \n4 Spörl E. Huhle M. Kasper M. Seiler T. Increased rigidity of the cornea caused by intrastromal cross-linking Ophthalmologe 94 12 1997 902 906 9487761 \n5 Wollensak G. Spoerl E. Seiler T. Riboflavin/ultraviolet-A–induced collagen crosslinking for the treatment of keratoconus Am J Ophthalmol 135 5 2003 620 627 12719068 \n6 Hersh P.S. Stulting R.D. Muller D. US multicenter clinical trial of corneal collagen crosslinking for treatment of corneal ectasia after refractive surgery Ophthalmology 124 10 2017 Oct 1 1475 1484 28655538 \n7 Hersh P.S. Stulting R.D. Muller D. United States multicenter clinical trial of corneal collagen crosslinking for keratoconus treatment Ophthalmology 124 9 2017 Sep 1 1259 1270 28495149 \n8 Belin M.W. Lim L. Rajpal R.K. Hafezi F. Gomes J.A. Cochener B. Corneal cross-linking: current USA status report from the Cornea society Cornea 37 10 2018 Oct 1 1218 1225 30067537 \n9 Maharana P.K. Sahay P. Sujeeth M. Microbial keratitis after accelerated corneal collagen cross-linking in keratoconus Cornea 37 2 2018 Feb 1 162 167 29111996 \n10 Rana M. Lau A. Aralikatti A. Shah S. Severe microbial keratitis and associated perforation after corneal crosslinking for keratoconus Contact Lens Anterior Eye 38 2 2015 134 137 25435381 \n11 Rama P. Di Matteo F. Matuska S. Paganoni G. Spinelli A. Acanthamoeba keratitis with perforation after corneal crosslinking and bandage contact lens use J Cataract Refract Surg 35 4 2009 788 791 19304108 \n12 Labiris G. Kaloghianni E. Koukoula S. Zissimopoulos A. Kozobolis V.P. Corneal melting after collagen cross-linking for keratoconus: a case report J Med Case Rep 5 1 2011 152 21496288\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "18()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Cornea; Cross-linking; Infectious keratitis; Keratoconus; Perforation",
"medline_ta": "Am J Ophthalmol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101679941",
"other_id": null,
"pages": "100658",
"pmc": null,
"pmid": "32274444",
"pubdate": "2020-06",
"publication_types": "D002363:Case Reports",
"references": "9487761;29111996;12719068;28495149;28655538;21496288;6230745;19304108;9493273;25435381;30067537",
"title": "Rapid keratitis and perforation after corneal collagen cross-linking.",
"title_normalized": "rapid keratitis and perforation after corneal collagen cross linking"
} | [
{
"companynumb": "US-AVEDRO-AVE-2018-0219-AE",
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"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "OFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHydroxychloroquine (HCQ, Plaquenil) is often prescribed in lieu of other sulfate antimalarials to treat rheumatologic diseases because of its pharmacologic efficacy and few reported side effects. However, a known potential side effect of HCQ is retinal toxicity.\n\n\nMETHODS\nA 61-year-old black female presented for screening of ophthalmic disease 2 months after initiation of HCQ for the treatment of polyarthralgia with a positive rheumatoid factor. At the time of the examination, she had taken a cumulative total of 19.8 g of HCQ and was found to have bilateral bull's-eye retinopathy. The patient had no known risk factors for HCQ toxicity. HCQ was discontinued, and the patient was prescribed ibuprofen for her polyarthralgia symptoms. The ophthalmic effects of HCQ toxicity were permanent.\n\n\nCONCLUSIONS\nKnown major risk factors for HCQ retinal toxicity include drug loads >300 mg/day (5 mg/kg/day), use for >5 years, a cumulative dose >1,000 g, underlying retinal disease or retinopathy, tamoxifen use, and renal disease. Despite not having any of these risk factors and having a reduced drug load during the treatment period, our patient developed the signs and symptoms of HCQ toxicity. This case suggests underlying mechanisms for HCQ toxicity other than those previously reported and a need for additional screening tests to prevent HCQ toxicity.",
"affiliations": "Tulane University School of Medicine, New Orleans, LA.;Department of Ophthalmology, Ochsner Clinic Foundation, New Orleans, LA.;Department of Ophthalmology, Ochsner Clinic Foundation, New Orleans, LA.",
"authors": "Stern|Ethan M|EM|;Johnson|Jordan S|JS|;Mazzulla|Donald A|DA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1524-5012",
"issue": "17(3)",
"journal": "The Ochsner journal",
"keywords": "Hydroxychloroquine; retinal diseases; scotoma",
"medline_ta": "Ochsner J",
"mesh_terms": null,
"nlm_unique_id": "101125795",
"other_id": null,
"pages": "280-283",
"pmc": null,
"pmid": "29026363",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "26992838;12193209;24922444;16912357;25408748;25372212;12093666;18215798;25275721",
"title": "Highly Accelerated Onset of Hydroxychloroquine Macular Retinopathy.",
"title_normalized": "highly accelerated onset of hydroxychloroquine macular retinopathy"
} | [
{
"companynumb": "US-CONCORDIA PHARMACEUTICALS INC.-GSH201710-005790",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
... |
{
"abstract": "A 61-year-old patient with alcohol use disorder (AUD) was referred for suspicion of sleep apnea syndrome (SAS). He had incurred three road accidents attributed to sleepiness over the previous year, shortly after initiation of high-dose (100 mg b.i.d.) treatment with baclofen, a molecule increasingly used in the management of AUD. Polysomnography revealed a severe central SAS (CSAS) with an apnea-hypopnea index (AHI) of 81.6/h. Baclofen was suggested as a possible cause of the CSAS, and after its withdrawal, a second polysomnography was done, showing the disappearance of the central apneas and a shift to severe obstructive SAS (AHI 43.9/h), for which a positive airway pressure (CPAP) treatment was initiated. A third polysomnography was performed under CPAP after reintroduction of baclofen (50 mg b.i.d.) by the patient, showing reappearance of the CSAS (AHI 42.1/h). This case report illustrates the deleterious effect of baclofen on breathing physiology during sleep. Since it is typically prescribed off label at high doses to a population of patients potentially using other substances that inhibit the ventilatory drive, this possible adverse effect is a major concern. When considering the use of baclofen in patients with AUD, the potential for sleep-disordered breathing should be weighed and carefully monitored.",
"affiliations": "Sleep Laboratory, Geneva University Hospitals, Geneva, Switzerland.",
"authors": "Perogamvros|Lampros|L|;Pépin|Jean Louis|JL|;Thorens|Gabriel|G|;Mégevand|Pierre|P|;Claudel|Elisabeth|E|;Espa|Fabrice|F|;Besson|Marie|M|;Cervena|Katerina|K|;Janssens|Jean-Paul|JP|;Lador|Frédéric|F|",
"chemical_list": "D058786:GABA-B Receptor Agonists; D001418:Baclofen",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000439542",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7931",
"issue": "90(6)",
"journal": "Respiration; international review of thoracic diseases",
"keywords": null,
"medline_ta": "Respiration",
"mesh_terms": "D000437:Alcoholism; D001418:Baclofen; D045422:Continuous Positive Airway Pressure; D058786:GABA-B Receptor Agonists; D006801:Humans; D008297:Male; D008875:Middle Aged; D017286:Polysomnography; D020182:Sleep Apnea, Central",
"nlm_unique_id": "0137356",
"other_id": null,
"pages": "507-11",
"pmc": null,
"pmid": "26390141",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Baclofen-Associated Onset of Central Sleep Apnea in Alcohol Use Disorder: A Case Report.",
"title_normalized": "baclofen associated onset of central sleep apnea in alcohol use disorder a case report"
} | [
{
"companynumb": "CH-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-104117",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BACLOFEN"
},
"drugad... |
{
"abstract": "BACKGROUND\nMethamphetamine has been recognized as a common cause of acute toxic hepatitis in adults with clinical and histologic features indistinguishable from acute viral hepatitis. Clinical presentation of methamphetamine hepatotoxicity ranges from mild acute hepatitis with prompt recovery to fulminant hepatic failure. The pathophysiology of this hepatotoxicity is not well elucidated. Prenatal exposure to methamphetamine has been linked to intrauterine growth retardation and variety of withdrawal symptoms. Neonatal cholestasis is rare but serious problem that indicates hepatobiliary dysfunction and has several categories of etiologies. These include infectious, metabolic, endocrine, toxic, structural, familial, and autoimmune disorders. Cholestatic hepatitis is a recognized complication of exposure to some drugs including carbamazepine and trimethoprim-sulfamethoxazole.\n\n\nMETHODS\nA 35-week preterm, appropriate for gestational age, white girl was born to a 39-year-old mother who had no prenatal care. The mother's urine drug screen revealed methamphetamine. The baby passed pale meconium and her subsequent stools were hypo-pigmented. A detailed work up was done and was unremarkable except for hepatobiliary scintigraphy, with no activity noted in the small bowel on delayed imaging. An operative cholangiogram and liver biopsy were performed. The cholangiogram revealed patent bile ducts. Liver biopsy was consistent with acute viral or toxic hepatitis. Gradual drop of bilirubin was noted. With negative extensive work up for other etiology, known hepatotoxicity of methamphetamine, early onset of cholestasis that improved without specific therapy, it is strongly suspected that prenatal exposure to methamphetamine is the most likely culprit in this patient.\n\n\nCONCLUSIONS\nThis is the first recorded case of neonatal cholestasis related to prenatal exposure to methamphetamine. Methamphetamine is considered the fastest-growing illicit drug in United States. Hence, prenatal exposure to methamphetamine is expected to rise. Healthcare providers should become aware of the possibility of methamphetamine effect on the fetal liver. Raising awareness of the expectant mothers through the healthcare profession may reduce the risk of this condition.",
"affiliations": "Department of Pediatrics, Division of Pediatric Gastroenterology, Oklahoma University Health Sciences Center-Tulsa, Tulsa, OK 74135, USA. adahshan@pol.net",
"authors": "Dahshan|Ahmed|A|",
"chemical_list": "D008694:Methamphetamine",
"country": "United States",
"delete": false,
"doi": "10.1097/MCG.0b013e31812f4f0f",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0192-0790",
"issue": "43(1)",
"journal": "Journal of clinical gastroenterology",
"keywords": null,
"medline_ta": "J Clin Gastroenterol",
"mesh_terms": "D019969:Amphetamine-Related Disorders; D002779:Cholestasis; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008694:Methamphetamine; D011247:Pregnancy; D011256:Pregnancy Outcome; D049188:Prenatal Injuries",
"nlm_unique_id": "7910017",
"other_id": null,
"pages": "88-90",
"pmc": null,
"pmid": "18633333",
"pubdate": "2009-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Prenatal exposure to methamphetamine presenting as neonatal cholestasis.",
"title_normalized": "prenatal exposure to methamphetamine presenting as neonatal cholestasis"
} | [
{
"companynumb": "US-RECORDATI RARE DISEASES-US-R13005-16-00124",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHAMPHETAMINE"
},
"dru... |
{
"abstract": "Low-dose radiation therapy (LD-RT) has been shown to have an anti-inflammatory effect, and preliminary results suggest it is feasible to treat patients with coronavirus disease 2019 (COVID-19) pneumonia.\n\n\n\nWe conducted a prospective, single-arm, phase 1/2 clinical trial enrolling patients aged ≥50 years, who were coronavirus disease 2019 (COVID-19) positive, at phase 2 or 3 with lung involvement at imaging study and oxygen requirement. Patients received 100 cGy to total lungs in a single fraction. Primary outcome was radiologic response using severity and extension score on baseline computed tomography (CT), at days 3 and 7 after LD-RT. Secondary outcomes were toxicity using Common Terminology Criteria for Adverse Events v.5.0, duration of hospitalization, blood work evolution, and oxygen requirements using SatO2/FiO2 index (SAFI), at days 3 and 7 after LD-RT.\n\n\n\nNine patients were included. Median age was 66 (interquartile range, 57-77). Severity score was stable or decreased in the third CT but was not statistically significant (P = .28); however, there were statistically significant changes in the extension score (P = .03). SAFI index significantly improved 72 hours and 1 week after LD-RT (P = .01). Inflammatory blood parameters decreased 1 week after RT compared with baseline; only lactate dehydrogenase decreased significantly (P = .04). Two patients presented grade 2 lymphopenia after RT and another (with baseline grade 3) worsened to grade 4. Overall, the median number of days of hospitalization was 59 (range, 26-151). After RT the median number of days in the hospital was 13 (range, 4-77). With a median follow-up after RT of 112 days (range, 105-150), 7 patients were discharged and 2 patients died, 1 due to sepsis and the other with severe baseline chronic obstructive pulmonary disease from COVID-19 pneumonia.\n\n\n\nOur preliminary results show that LD-RT was a feasible and well-tolerated treatment, with potential clinical improvement. Randomized trials are needed to establish whether LD-RT improves severe pneumonia.",
"affiliations": "Radiation Oncology Department, Clinico San Carlos Hospital, Madrid, Spain. Electronic address: Noelia_ss@hotmail.com.;Radiation Oncology Department, Clinico San Carlos Hospital, Madrid, Spain; Faculty of Medicine, Complutense University of Madrid, Madrid, Spain.;Radiation Oncology Department, Clinico San Carlos Hospital, Madrid, Spain.;Radiation Oncology Department, Clinico San Carlos Hospital, Madrid, Spain.;Internal Medicine Department, Clinico San Carlos Hospital, Madrid, Spain.;Radiology Department, Clinico San Carlos Hospital, Madrid, Spain.;Radiology Department, Clinico San Carlos Hospital, Madrid, Spain.;Radiation Oncology Department, Clinico San Carlos Hospital, Madrid, Spain.;Radiation Oncology Department, Clinico San Carlos Hospital, Madrid, Spain; Faculty of Medicine, Complutense University of Madrid, Madrid, Spain.;Medical Physics Department, Clinico San Carlos Hospital, Madrid, Spain.;Internal Medicine Department, Infanta Leonor Hospital, Madrid, Spain.;Intensive Care Unit, Clinico San Carlos Hospital, Madrid, Spain.;Intensive Care Unit, Clinico San Carlos Hospital, Madrid, Spain.;Preventive Department, Clinico San Carlos Hospital, Madrid, Spain; Investigation Institute, Clinico San Carlos Hospital, Madrid, Spain.;Medical Oncology Department, Rio Hortega Hospital, Valladolid, Spain.;Investigation Institute, Clinico San Carlos Hospital, Madrid, Spain.;Radiation Oncology Department, Clinico San Carlos Hospital, Madrid, Spain; Faculty of Medicine, Complutense University of Madrid, Madrid, Spain.",
"authors": "Sanmamed|Noelia|N|;Alcantara|Pino|P|;Cerezo|Elena|E|;Gaztañaga|Miren|M|;Cabello|Noemi|N|;Gómez|Sara|S|;Bustos|Ana|A|;Doval|Anxela|A|;Corona|Juan|J|;Rodriguez|Gabriel|G|;Duffort|Mercedes|M|;Ortuño|Francisco|F|;de Castro|Javier|J|;Fuentes|Manuel Enrique|ME|;Sanz|Alvaro|A|;López|Amanda|A|;Vazquez|Manuel|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ijrobp.2020.11.049",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0360-3016",
"issue": "109(4)",
"journal": "International journal of radiation oncology, biology, physics",
"keywords": null,
"medline_ta": "Int J Radiat Oncol Biol Phys",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000086382:COVID-19; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058873:Pandemics; D011829:Radiation Dosage; D011879:Radiotherapy Dosage; D016896:Treatment Outcome",
"nlm_unique_id": "7603616",
"other_id": null,
"pages": "880-885",
"pmc": null,
"pmid": "33249142",
"pubdate": "2021-03-15",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "32707264;32140081;32526193;32986274;17487675;24348219;2117766;16896588;32362390;16368644;32017661;32338559;25859313;32413531;26462717;28189418;18031855;19242333;23484825",
"title": "Low-Dose Radiation Therapy in the Management of Coronavirus Disease 2019 (COVID-19) Pneumonia (LOWRAD-Cov19): Preliminary Report.",
"title_normalized": "low dose radiation therapy in the management of coronavirus disease 2019 covid 19 pneumonia lowrad cov19 preliminary report"
} | [
{
"companynumb": "ES-GILEAD-2021-0522542",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "REMDESIVIR"
},
"drugadditional": "3",
... |
{
"abstract": "Alzheimer's Dementia (AD) is a devastating neurodegenerative disease that affects approximately 17% of people aged 75-84. Neuropsychiatric symptoms (NPS) such as delusions, agitation, anxiety, and hallucinations are present in up to 95% of patients in all stages of dementia. To date, any approved and effective pharmacological interventions for the treatment of NPS are still not available. We describe a clinical case of a female patient diagnosed with AD with continuous cognitive decline and dementia-related behavioral symptoms. Between 2008 and 2019, the patient was examined half-yearly at the memory clinic of the Medical University of Innsbruck. At each visit, cognitive state and pharmacological treatment were evaluated. In addition, NPs were assessed by using the neuropsychiatric inventory (NPI). In 2018, the patient progressed to severe AD stage and presented with progressive NPs (anxiety, suspected delusions, agitation, aggressive behavior, and suspected pain due to long immobility). Consequently, off-label treatment with low-dose dronabinol was initiated, which facilitated a reduction of psychopharmacological treatment from six to three psychotropics. At the same time, the patient's emotional state improved, while disruptive behavior, aggression, and sedation decreased significantly. This case report underpins the need for randomized, controlled trials to explore the effect of cannabinoid receptor agonists on behavioral and psychological symptoms in patients with severe AD.",
"affiliations": "Department of Psychiatry, Psychotherapy and Psychosomatics, Division of Psychiatry I, Medical University of Innsbruck, Innsbruck, Austria.;Department of Psychiatry, Psychotherapy and Psychosomatics, Division of Psychiatry I, Medical University of Innsbruck, Innsbruck, Austria.",
"authors": "Defrancesco|Michaela|M|;Hofer|Alex|A|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fpsyt.2020.00413",
"fulltext": "\n==== Front\nFront Psychiatry\nFront Psychiatry\nFront. Psychiatry\nFrontiers in Psychiatry\n1664-0640 Frontiers Media S.A. \n\n10.3389/fpsyt.2020.00413\nPsychiatry\nCase Report\nCannabinoid as Beneficial Replacement Therapy for Psychotropics to Treat Neuropsychiatric Symptoms in Severe Alzheimer’s Dementia: A Clinical Case Report\nDefrancesco Michaela * Hofer Alex Department of Psychiatry, Psychotherapy and Psychosomatics, Division of Psychiatry I, Medical University of Innsbruck, Innsbruck, Austria\nEdited by: Federica Piras, Santa Lucia Foundation (IRCCS), Italy\n\nReviewed by: Maria Donata Orfei, IMT School for Advanced Studies Lucca, Italy; Deana Davalos, Colorado State University, United States\n\n*Correspondence: Michaela Defrancesco, Michaela.Defrancesco@i-med.ac.atThis article was submitted to Aging Psychiatry, a section of the journal Frontiers in Psychiatry\n\n\n13 5 2020 \n2020 \n11 41308 2 2020 22 4 2020 Copyright © 2020 Defrancesco and Hofer2020Defrancesco and HoferThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.Alzheimer’s Dementia (AD) is a devastating neurodegenerative disease that affects approximately 17% of people aged 75–84. Neuropsychiatric symptoms (NPS) such as delusions, agitation, anxiety, and hallucinations are present in up to 95% of patients in all stages of dementia. To date, any approved and effective pharmacological interventions for the treatment of NPS are still not available. We describe a clinical case of a female patient diagnosed with AD with continuous cognitive decline and dementia-related behavioral symptoms. Between 2008 and 2019, the patient was examined half-yearly at the memory clinic of the Medical University of Innsbruck. At each visit, cognitive state and pharmacological treatment were evaluated. In addition, NPs were assessed by using the neuropsychiatric inventory (NPI). In 2018, the patient progressed to severe AD stage and presented with progressive NPs (anxiety, suspected delusions, agitation, aggressive behavior, and suspected pain due to long immobility). Consequently, off-label treatment with low-dose dronabinol was initiated, which facilitated a reduction of psychopharmacological treatment from six to three psychotropics. At the same time, the patient’s emotional state improved, while disruptive behavior, aggression, and sedation decreased significantly. This case report underpins the need for randomized, controlled trials to explore the effect of cannabinoid receptor agonists on behavioral and psychological symptoms in patients with severe AD.\n\nAlzheimer’s diseasedronabinolneuropsychiatric symptomspsychotropicsdementia\n==== Body\nIntroduction\nIn 2015, dementia of all aetiologies affected 47 million people worldwide and was predicted to increase to 75 million people until 2030 (1). Alzheimer’s Dementia (AD) is a devastating neurodegenerative disease and the most common form of dementia. AD contributes to 60%–70% of cases and affects approximately 17% of people aged 75–84 and 32% of people aged 85 or older (1, 2). Progressive impairment of memory and cognition is a key clinical feature of Alzheimer’s disease. It is characterized by extracellular beta-amyloid (Abeta 42) deposits in the brain (plaques), intraneuronal tau pathology, neuronal cell death, vascular dysfunction, and inflammatory processes (3, 4). Neuropsychiatric symptoms (NPS) such as delusions, agitation, anxiety, and hallucinations are common across all stages of dementia (5). NPS are associates with a more rapid disease progression (6) and poor caregiver outcome (7). Especially in severe stages of dementia the differentiation and assessment of underlying causes of NPS is challenging. Symptoms like anxiety, aggression, or agitation due to somatic reasons such as pain are frequently misinterpreted as dementia-related and are consequently consistently treated with psychotropics, although nonpharmacological medical care is recommended as first-line treatment. It has been suggested that NPS rather than cognitive or functional impairment lead to the greatest caregiver burden and predict an early institutionalisation of patients with dementia.\n\nThere is no FDA-approved pharmacotherapy for NPS, however, psychotropics such as antipsychotics or benzodiazepines are frequently used to control these symptoms. Results from randomized controlled trials on the efficacy and safety of pharmacological treatment of NPS are conflicting (8). Cholinesterase inhibitors and new-generation antipsychotics improve NPS, but high rates of adverse events have been reported. Similarly, the use of first-generation antipsychotics is associated with a significant risk for adverse events and increased mortality rates (9). As a consequence, regulatory agencies and most guidelines have advised against the use of antipsychotic drugs in patients with AD (10). Alternative pharmacological treatment options are therefore urgently needed. A small number of clinical trials and several case reports have shown that cannabinoids such as oral dronabinol (Δ9-tetrahydrocannabinol, THC) may be promising in this regard (11–14). Some in vitro studies in AD transgenic mice even reported on the neuroprotective and antiinflammatory properties of these drugs (15). To date, cannabinoid receptor agonists are commonly used to treat nausea, anorexia, pain, and anxiety in oncological patients and in those with severe spasticity. Serious side effects such as marked orthostatic hypotension or psychotic symptoms are rare, however, metabolization of THC by liver cytochromes P450 can cause considerable drug-interactions. Therefore, further investigations addressing the therapeutic potential of THC in patients with AD in clinical studies and pharmacological models are urgently needed. In this case report we describe a female patient in a severe stage of AD who presented with symptoms of anxiety, agitation, and disruptive behavior and whose condition improved significantly after implementing dronabinol as replacement therapy of prior psychotropic medication.\n\nMaterials and Methods\nThis case report describes continuous cognitive decline, behavioral symptoms, and the course of pharmacological treatment in a female patient diagnosed with AD according to the original NINCDS-ADRDA criteria (1984) in 2008. At first admission at the Department of Psychiatry, Psychotherapy and Psychosomatics of the Medical University of Innsbruck in June 2008 the patient was 69 years of age and presented with mild depressive symptoms and subjective deficits in memory and spatial orientation. Her daughter also reported on progressive deficits in activities of daily living (housekeeping, budget management, cooking), and on episodes of paranoid perception starting within the year before admission. In addition, the patient had lost 10 kg of weight within the past three years despite a good appetite.\n\nNeuropsychological testing with the Mini Mental State Examination (MMSE) and “The Consortium on the Establishment of a Registry in Alzheimer’s Disease (CERAD)-Plus Neuropsychological Battery,” revealed an MMSE score of 18 and deficits in verbal and figural memory, psychomotor speed, executive functions, and verbal fluency. These results corresponded to a moderate stage of dementia. The Neuropsychiatric Inventory (NPI) (16) indicated mild symptoms of depression, anxiety, and delusion. Caregiver distress was low. To monitor frequency, severity and caregiver distress, the NPS total score and the caregiver distress subscore were calculated (see Figure 1). Magnetic resonance imaging (1.5 tesla) revealed gray matter atrophy in the mesial temporal lobe including the hippocampus, in the insula, and in the parietal cortex. Laboratory results (blood cell count, kidney and liver function, lipid profile, thyroid function, electrolytes, and levels of folic acid and vitamin B12) were unremarkable. The Apo E4 genotype was 4/3. Prediagnosed mild hypertension and type II diabetes mellitus were treated with metformin 1,000 mg/day and enalapril 5 mg/day. In addition, the patients received oral supplement of Vitamin D3 (15 drops/week) for the prophylaxis of osteoporosis. Family history was free of dementia and cerebro- and cardiovascular events. The patient had two children (one son and one daughter), 12 years of education, and she had been employed as a secretary until 1999. Based on the results of neuropsychological assessment, neuroimaging and clinical examination AD and mild to moderate depression (ICD-10) were diagnosed and treatment with donepezil 5 mg/day (10 mg/day from week 4 on), risperidone 3 mg/day, and sertraline 50 mg/day was started in August 2008. Due to rapid cognitive decline, persisting behavioral symptoms (agitation, disruptive behavior), and progressive deficits in activities of daily living, additional treatment with memantine (titrated to 20 mg/day within 4 weeks) was implemented in February 2010. Subsequently, behavioral symptoms improved and the dose of risperidone could be reduced to 0.5 mg/day. Treatment with donepezil 10 mg/day was continued. In June 2015, the patient progressed to severe dementia stage and behavioral symptoms (agitation, disruptive behavior, anxiety) worsened again. This led to substantial difficulties in nursing care and consequently, the treating general practitioner augmented psychopharmacological treatment with quetiapine 25 mg/day and diazepam 1mg/day in January 2016. Concurrently, the dose of risperidone was increased to 2 mg/day.\n\nFigure 1 Course of psychotropic medication, cognitive decline and neuropsychiatric symptoms between time of Alzheimer’s Dementia (AD) diagnosis and August 2019.\n\nWithin the following year, a number of adverse events due to psychotropic polypharmacy occurred. The patient lost mobility, suffered from sedation, spontaneous speech stopped, and emotional reactions suspended. In consequence of frequently occurring disruptive behavior and physical aggression during nursing care, treating the patient at home became more and more difficult. Moreover, a first epileptic seizure most likely caused by AD pathology occurred in March 2017. Following three further epileptic seizures in June 2017, treatment with levetiracetam up to 1,000 mg/day was started. Concurrently, the dose of memantine was reduced to 5 mg/day in order to reduce the risk of epileptic seizures Extensive polypharmacy including seven psychotropic agents, immobility and severe impairments on a cognitive, a psychopathological and an emotional level made an immediate reevaluation of drug therapy indispensable. The patient’s low quality of life and a presumed high degree of psychological and physical burden (anxiety, suspected delusions, suspected pain due to long immobility) led to a consequent tapering of psychotropic medication and to the implementation of dronabinol (magistral prescription, Δ9-tetrahydrocannabinol, 0.833 mg dronabinol/drop) as off-label therapy in February 2018. Benefits and risks of dronabinol as off-label treatment were fully explained to both the patient and her family members, and verbal consent was obtained from the family members. Caregivers were informed on potential side effects such as hypotension, psychotic symptoms, and sedation and possible drug-interactions with other drugs metabolized by the liver e.g., anticoagulants and a number of antibiotics. Furthermore, the expected benefit of low-dose dronabinol, i.e., a reduction of disruptive behavior, agitation, and anxiety symptoms without sedation and without an increased risk of cerebrovascular adverse events were discussed. Following a comprehensive risk-benefit assessment, dronabinol was initiated. The off label use of dronabinol was carried out in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines.\n\nThe medical rationale behind this decision lay in the known positive anxiolytic, pain-relieving and calming effect of cannabinoids. As presented in Figure 1, during the following year pharmacological treatment could be reduced from six to three psychotropics including a low dose of dronabinol (6–8 drops dronabinol/day equivalent to 4.9–6.7 mg dronabinol). At the same time, the patient’s emotional state improved, while disruptive behavior, aggression, and sedation decreased significantly. So far, the patient is still in nursing care at her son’s home. She has never regained mobility and fluent speech. However, she shows little positive emotional response and allows nursing care without anxious or aggressive behavior. In the course of treatment with dronabinol, no side effects or adverse events occurred.\n\nDiscussion and Conclusion\nSummarizing, the reported case allows for the following conclusions: AD-associated NPs are common and burdensome for patients, their caregivers, and nursing care. Although there are no FDA-approved drugs for NPS (with the exception of short-term treatment with risperidone for severe aggression), it is common clinical practice to prescribe psychotropic medication such as antipsychotic drugs or sedatives to control symptoms in the long term. Some new-generation antipsychotics show modest efficacy in improving NPS, however, significant adverse effects and an increased mortality have been reported (8). Importantly, clinically significant and insufficiently treated NPS are associated with a more rapid disease progression, an increase of caregiver burden, and higher mortality.\n\nTherefore, continuous nonpharmacological medical care as well as safe and effective alternative pharmacological treatments may have the potential to modify the course of the disease, lower costs, and improve quality of life of patients and their caregivers. In this case report, oral dronabinol turned out as promising candidate for treating behavioral symptoms such as agitation, aggression and anxiety even in a severe stage of AD (11–14). We are aware that our data have several limitations. The main limitation is that we report a single case and that our findings can therefore not be generalized. Further, our data allow no clear statement whether the introduction of dronabinol and/or the change of other psychopharmacological treatment improved the patient’s NPS and reduced the caregivers’ burden. However, a strength of this case report is the very long follow-up period of 11 years with a close and detailed recording of clinical data, medication history and NPs.\n\nWe assume that the observed positive effect of dronabinol on aggression and anxiety was mediated by the activation of the cannabinoid receptors 1 (CB1) and the activation of endocannabinoids. Prior studies reported that especially lower doses of THC may have anxiolytic effects (17, 18). Further, our findings corroborate those of Herrmann et al. who reported on a positive effect of the cannabinoid nabilone—a synthetic oral THC analog—on agitation in patients with AD (19). Our report underpins the need for randomized, controlled trials to explore the effect of cannabinoid receptor agonists on behavioral and psychological symptoms in patients in different stages of AD. Cannabinoids have a distinct pharmacologic profile that may offer an alternative pharmacologic approach to antipsychotics and sedatives for treating NPs in patients with AD. In addition, the beneficial effect on appetite and pain may significantly improve quality of life of AD-patients and their caregivers. Further research is needed to investigate the effects of different doses and types of cannabinoids in more detail. Especially in patients with severe AD, controlled clinical trials comparing cannabinoids with atypical antipsychotics are urgently needed.\n\nData Availability Statement\nAll datasets generated for this study are included in the article.\n\nEthics Statement\nThe study involving human participants was approved by the local ethical committee of Innsbruck Medical University, Austria. Written informed consent was obtained from the patient’s next of kin for the publication of any identifiable data.\n\nAuthor Contributions\nMD reviewed and revised the manuscript and collected clinical data and obtained patient and caregiver consent. AH reviewed and revised the manuscript.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgments\nThe authors thank the case for supporting our report.\n==== Refs\nReferences\n1 \nWHO \nGlobal action plan on the public health response to dementia 2017–2025. \nGeneva : World Health Organization (2017 ).\n\n2 \nPrince MJ \nWorld Alzheimer Report 2015: the global impact of dementia: an analysis of prevalence, incidence, cost and trends. \nLondon : Alzheimer’s Disease International (ADI) (2015 ).\n\n3 \nBraak E Griffing K Arai K Bohl J Bratzke H Braak H \nNeuropathology of Alzheimer’s disease: what is new since A. Alzheimer\n? Eur Arch Psychiatry Clin Neurosci (1999 ) 249 (Suppl 3 ):14 –22\n. 10.1007/PL00014168 \n\n4 \nAltman R Rutledge JC \nThe vascular contribution to Alzheimer’s disease\n. Clin Sci (Lond) (2010 ) 119 :407–21. 10.1042/CS20100094 \n\n5 \nScaricamazza E Colonna I Sancesario GM Assogna F Orfei MD Franchini F \nNeuropsychiatric symptoms differently affect mild cognitive impairment and Alzheimer’s disease patients: a retrospective observational study\n. Neurol Sci (2019 ) 40 :1377–82. 10.1007/s10072-019-03840-4 \n\n6 \nDefrancesco M Marksteiner J Kemmler G Dal-Bianco P Ransmayr G Benke T \nSpecific Neuropsychiatric Symptoms Are Associated with Faster Progression in Alzheimer’s Disease: Results of the Prospective Dementia Registry (PRODEM-Austria)\n. J Alzheimers Dis (2020 ) 73 (1 ):125–33. 10.3233/JAD-190662 \n\n7 \nSousa L Sequeira C Ferre-Grau C Neves P Lleixa-Fortuno M \nTraining programmes for family caregivers of people with dementia living at home: integrative review\n. J Clin Nurs (2016 ) 25 :2757–67. 10.1111/jocn.13266 \n\n8 \nWang J Yu JT Wang HF Meng XF Wang C Tan CC \nPharmacological treatment of neuropsychiatric symptoms in Alzheimer’s disease: a systematic review and meta-analysis\n. J Neurol Neurosurg Psychiatry (2015 ) 86 :101–9. 10.1136/jnnp-2014-308112 \n\n9 \nMaust DT Kim HM Seyfried LS Chiang C Kavanagh J Schneider LS \nAntipsychotics, other psychotropics, and the risk of death in patients with dementia: number needed to harm\n. JAMA Psychiatry (2015 ) 72 :438–45. 10.1001/jamapsychiatry.2014.3018 \n\n10 \nVan Leeuwen E Petrovic M van Driel ML De Sutter AI Vander Stichele R Declercq T \nWithdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia\n. Cochrane Database Syst Rev (2018 ) 3 :CD007726. 10.1002/14651858.CD007726.pub3 \n29605970 \n11 \nWoodward MR Harper DG Stolyar A Forester BP Ellison JM \nDronabinol for the treatment of agitation and aggressive behavior in acutely hospitalized severely demented patients with noncognitive behavioral symptoms\n. Am J Geriatr Psychiatry (2014 ) 22 :415–9. 10.1016/j.jagp.2012.11.022 \n\n12 \nVolicer L Stelly M Morris J McLaughlin J Volicer BJ \nEffects of dronabinol on anorexia and disturbed behavior in patients with Alzheimer’s disease\n. Int J Geriatr Psychiatry (1997 ) 12 :913–9. 10.1002/(SICI)1099-1166(199709)12:9<913::AID-GPS663>3.0.CO;2-D \n\n13 \nWalther S Mahlberg R Eichmann U Kunz D \nDelta-9-tetrahydrocannabinol for nighttime agitation in severe dementia\n. Psychopharmacol (Berl) (2006 ) 185 :524–8. 10.1007/s00213-006-0343-1 \n\n14 \nvan den Elsen GA Ahmed AI Verkes RJ Kramers C Feuth T Rosenberg PB \nTetrahydrocannabinol for neuropsychiatric symptoms in dementia: A randomized controlled trial\n. Neurology (2015 ) 84 :2338–46. 10.1212/WNL.0000000000001675 \n\n15 \nAso E Andres-Benito P Ferrer I \nDelineating the Efficacy of a Cannabis-Based Medicine at Advanced Stages of Dementia in a Murine Model\n. J Alzheimers Dis (2016 ) 54 :903–12. 10.3233/JAD-160533 \n\n16 \nCummings JL \nThe Neuropsychiatric Inventory: assessing psychopathology in dementia patients\n. Neurology (1997 ) 48 :S10–6. 10.1212/WNL.48.5_Suppl_6.10S \n\n17 \nAndrade AK Renda B Murray JE \nCannabinoids, interoception, and anxiety\n. Pharmacol Biochem Behav (2019 ) 180 :60 –73\n. 10.1016/j.pbb.2019.03.006 \n30922834 \n18 \nMoreira FA Wotjak CT \nCannabinoids and anxiety\n. Curr Top Behav Neurosci (2010 ) 2 :429–50. 10.1007/7854_2009_16 \n\n19 \nHerrmann N Ruthirakuhan M Gallagher D Verhoeff N Kiss A Black SE \nRandomized Placebo-Controlled Trial of Nabilone for Agitation in Alzheimer’s Disease\n. Am J Geriatr Psychiatry (2019 ) 27 :1161–73. 10.1016/j.jagp.2019.05.002\n\n",
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"keywords": "Alzheimer’s disease; dementia; dronabinol; neuropsychiatric symptoms; psychotropics",
"medline_ta": "Front Psychiatry",
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"title": "Cannabinoid as Beneficial Replacement Therapy for Psychotropics to Treat Neuropsychiatric Symptoms in Severe Alzheimer's Dementia: A Clinical Case Report.",
"title_normalized": "cannabinoid as beneficial replacement therapy for psychotropics to treat neuropsychiatric symptoms in severe alzheimer s dementia a clinical case report"
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"abstract": "BACKGROUND\nSitagliptin is a new oral glucose-lowering medication that acts via the incretin hormone system. The most common side-effects are headache and pharyngitis, and few serious adverse events were observed during clinical trials. Dose adjustment is recommended in renal insufficiency, but long-term safety experience is limited.\n\n\nMETHODS\nWe present a patient with chronic renal insufficiency who developed leg pain, weakness and tenderness after starting treatment with high-dose sitagliptin while on simvastatin. The patient had acute renal failure and rhabdomyolysis that resolved with cessation of sitagliptin, simvastatin, ezetimibe, diuretics and olmesartan. All drugs except sitagliptin, ezetimibe and simvastatin were resumed, and the patient was subsequently started on lovastatin without recurrence of rhabdomyolysis.\n\n\nCONCLUSIONS\nHigh doses of sitagliptin may have worsened this patient's renal failure and precipitated rhabdomyolysis by increasing circulating levels of simvastatin. Given the high likelihood that sitagliptin will be co-administered with statins and renally active medications, further study of long-term safety of sitagliptin in renal sufficiency may be warranted.",
"affiliations": "Stanford University School of Medicine, Department of Medicine, Stanford, CA, USA. dkao42@yahoo.com",
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"journal": "Diabetic medicine : a journal of the British Diabetic Association",
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"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D054873:Dipeptidyl-Peptidase IV Inhibitors; D004359:Drug Therapy, Combination; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D011719:Pyrazines; D012206:Rhabdomyolysis; D019821:Simvastatin; D000068900:Sitagliptin Phosphate; D014230:Triazoles",
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"title": "Renal failure and rhabdomyolysis associated with sitagliptin and simvastatin use.",
"title_normalized": "renal failure and rhabdomyolysis associated with sitagliptin and simvastatin use"
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"abstract": "To report a case of severe hypercalcemia, exacerbated by vitamin A supplementation and hydrochlorothiazide, in a patient with primary hyperparathyroidism.\n\n\n\nClinical and laboratory findings are presented along with response to therapy.\n\n\n\nA 68-year-old white female presented to the emergency department complaining of nausea, vomiting, and altered mental status. Laboratory findings revealed calcium 15.8 mg/dL (8.4-10.2), albumin 4.1 g/dL (3.8-4.8), and parathyroid hormone 62 pg/mL (14-64). Serum calcium improved after intravenous hydration with normal saline. Prior to this hospitalization, over-the-counter medications were significant for calcium (600 mg daily), vitamin A (11 000 IU daily), and vitamin D (800 IU daily).The patient's prescription medications were significant for hydrochlorothiazide (12.5 mg daily). Twenty-four-hour urine calcium was subsequently found to be 146 mg (35-250). Myeloma, lymphoma, and sarcoidosis were ruled out as the etiology for hypercalcemia. The diagnosis of primary hyperparathyroidism was confirmed. She was treated surgically for primary hyperparathyroidism. The right and left superior parathyroid showed hypercellular parathyroid on pathology. The patient was normocalcemic after surgery.\n\n\n\nPrevious reports suggest that very high doses of vitamin A is required to cause hypercalcemia. This case suggests that in a setting of primary hyperparathyroidism and hydrochlorothiazide therapy, vitamin A may contribute to the development of severe hypercalcemia in patients who are on calcium and vitamin D supplements. Given their biologic effects, public awareness needs to be created regarding the injudicious use of vitamins.",
"affiliations": "1 White River Medical Center, Batesville, AR, USA.;1 White River Medical Center, Batesville, AR, USA.;1 White River Medical Center, Batesville, AR, USA.;1 White River Medical Center, Batesville, AR, USA.;1 White River Medical Center, Batesville, AR, USA.;2 CHI Little Rock Diagnostic Clinic, Little Rock, AR, USA.",
"authors": "Varghese|Ron T|RT|0000-0002-6198-4352;Khasawneh|Khaled|K|;Desikan|Raman K|RK|;Subramaniam|Anandaraj|A|;Weaver|Todd|T|;Nair|Ganesh K V|GKV|",
"chemical_list": "D010281:Parathyroid Hormone; D006852:Hydrochlorothiazide; D014801:Vitamin A; D014807:Vitamin D; D002118:Calcium",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961882380510.1177_2324709618823805Case ReportVitamin A and Hydrochlorothiazide Causing Severe Hypercalcemia in a\nPatient With Primary Hyperparathyroidism https://orcid.org/0000-0002-6198-4352Varghese Ron T. MBBS1Khasawneh Khaled MD1Desikan Raman K. MD1Subramaniam Anandaraj MBBS1Weaver Todd PharmD1Nair Ganesh K. V. MD21 White River Medical Center, Batesville,\nAR, USA2 CHI Little Rock Diagnostic Clinic,\nLittle Rock, AR, USARon T. Varghese, MBBS, White River Medical\nCenter, 1710 Harrison Street, Batesville, AR 72501, USA. Email:\nronthomasv@gmail.com11 1 2019 Jan-Dec 2019 7 232470961882380528 9 2018 11 12 2018 15 12 2018 © 2019 American Federation for Medical\nResearch2019American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which\npermits any use, reproduction and distribution of the work without further\npermission provided the original work is attributed as specified on the SAGE\nand Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Objective. To report a case of severe hypercalcemia, exacerbated\nby vitamin A supplementation and hydrochlorothiazide, in a patient with primary\nhyperparathyroidism. Methods. Clinical and laboratory findings\nare presented along with response to therapy. Results. A\n68-year-old white female presented to the emergency department complaining of\nnausea, vomiting, and altered mental status. Laboratory findings revealed\ncalcium 15.8 mg/dL (8.4-10.2), albumin 4.1 g/dL (3.8-4.8), and parathyroid\nhormone 62 pg/mL (14-64). Serum calcium improved after intravenous hydration\nwith normal saline. Prior to this hospitalization, over-the-counter medications\nwere significant for calcium (600 mg daily), vitamin A (11 000 IU daily), and\nvitamin D (800 IU daily).The patient’s prescription medications were significant\nfor hydrochlorothiazide (12.5 mg daily). Twenty-four-hour urine calcium was\nsubsequently found to be 146 mg (35-250). Myeloma, lymphoma, and sarcoidosis\nwere ruled out as the etiology for hypercalcemia. The diagnosis of primary\nhyperparathyroidism was confirmed. She was treated surgically for primary\nhyperparathyroidism. The right and left superior parathyroid showed\nhypercellular parathyroid on pathology. The patient was normocalcemic after\nsurgery. Conclusion. Previous reports suggest that very high\ndoses of vitamin A is required to cause hypercalcemia. This case suggests that\nin a setting of primary hyperparathyroidism and hydrochlorothiazide therapy,\nvitamin A may contribute to the development of severe hypercalcemia in patients\nwho are on calcium and vitamin D supplements. Given their biologic effects,\npublic awareness needs to be created regarding the injudicious use of\nvitamins.\n\nnutritionvitamin Aprimary hyperparathyroidismcover-dateJanuary-December 2019\n==== Body\nIntroduction\nVitamin supplementation is commonly used, and most of these supplements are available\nover-the-counter. We present a case of severe hypercalcemia, exacerbated by vitamin\nA supplementation and hydrochlorothiazide (HCTZ), in a patient with primary\nhyperparathyroidism (HPT).\n\nCase Report\nA 68-year-old white female presented to emergency department with complaints of\nnausea, vomiting, and altered mental status.\n\nOne day prior, she presented to an outpatient clinic with left lower quadrant pain\nand diagnosed with clinical diverticulosis. She was started on oral ciprofloxacin\nand metronidazole from the clinic. She started taking these medications that\nafternoon, both on an empty stomach. She began to have dizziness and vomiting since\n4 am on the morning of presentation. She was brought by Emergency Medical\nService to the emergency department that afternoon.\n\nThe patient was afebrile (97.3°F) but had elevated blood pressure at presentation\n(176/107 mm Hg). Physical examination revealed that she had dry oral mucosa, her\nabdomen was soft, with no organomegaly, and she did not have any neurological\ndeficits. Laboratory findings on admission are shown in Table 1. Having nausea and vomiting,\nphysical examination with findings of dry mucus membranes and laboratory tests with\nelevated blood urea nitrogen and creatinine suggested dehydration. She was also\nnoted to have hypercalcemia (Table 1). Hypercalcemia by itself could likely cause volume depletion,\nsince hypercalcemia leads to diuresis and vasoconstriction and contributes to acute\nkidney injury. However, in this patient, given her recent history of vomiting, it\nwould be difficult to attribute volume depletion solely to hypercalcemia. There was\nno history of primary HPT, thyroid disease, or thyroid cancer in her family. She was\ntreated with intravenous hydration with normal saline. Serum calcium reduced from\n15.8 to 13.6 mg/dL with hydration alone. Prior to this hospitalization, she was on\nover-the-counter calcium 600 mg, vitamin D3 800 IU, vitamin A 11 000 IU\ndaily, for history of macular degeneration, and valsartan/HCTZ 320 to 12.5 mg daily\nfor her hypertension; all medications had been taken for 3 years. These medications\nwere stopped during hospitalization.\n\nTable 1. Laboratory Findings on Admission.\n\n\tValue\tReference Range\t\nCalcium\t15.8 mg/dL\t8.4-10.2\t\nAlbumin\t4.1 g/dL\t3.8-4.8\t\nPTH\t62 pg/mL\t14-64\t\n25-OH vitamin D\t46 ng/mL\t30-100\t\nWBC\t6.9 k/uL\t4.5-11\t\nHemoglobin\t12.5 g/dL\t12.0-16.0\t\nSodium\t140 mmol/L\t137-145\t\nPotassium\t3.6 mmol/L\t3.5-5.1\t\nChloride\t99 mmol/L\t98-107\t\nBicarbonate\t29 mmol/L\t21-32\t\nBUN\t35 mg/dL\t7-18\t\nCreatinine\t2.6 mg/dL\t0.55-1.02\t\nTotal bilirubin\t0.40 mg/dL\t0.2-1.0\t\nAST\t18 U/L\t15-37\t\nALT\t23 U/L\t12-78\t\nAlkaline phosphatase\t103 U/L\t46-116\t\nTotal protein\t8.7 g/dL\t6.4-8.2\t\nGlobulin\t4.6 g/dL\t2.2-4.4\t\nAbbreviations: PTH, parathyroid hormone; 25-OH, 25-hydroxy; WBC, white\nblood cells; BUN, blood urea nitrogen; AST, aspartate aminotransferase;\nALT, alanine aminotransferase.\n\nShe was subsequently referred for endocrinology evaluation. One week later,\nlaboratory findings in endocrinology clinic showed elevated serum calcium and\nparathyroid hormone (PTH; Table\n2). 25-Hydroxy (25-OH) vitamin D; 1,25-OH vitamin D; and PTH-RP were\nwithin normal limits. Serum immunofixation electrophoresis showed poorly defined\narea of monoclonal protein. She underwent oncology evaluation to rule out multiple\nmyeloma.\n\nTable 2. Laboratory Findings at Weeks of Follow-upa.\n\n\tWeek 1\tWeek 2\tWeek 4\t\nCalcium\t15.8 mg/dL (8.4-10.2)\t11.1 mg/dL (8.6-10.5)\t10.9 mg/dL (8.6-10.5)\t\nAlbumin\t4.1 g/dL (3.8-4.8)\t4.4 g/dL (3.6-4.7)\t3.9 g/dL (3.6-4.7)\t\nCreatinine\t2.6 mg/dL (0.55-1.02)\t\t0.8 mg/dL (0.8-1.4)\t\nPhosphorus\t\t3.0 mg/dL (2.5-4.8)\t3.2 mg/dL (2.5-4.8)\t\nPTH\t62 pg/mL (14-64)\t98.9 pg/mL (14-64)\t48.6 pg/mL (14-64)\t\nPTH-RP\t\t15 pg/mL (14-27)\t\t\n25-OH vitamin D\t46 ng/mL (30-100)\t55.8 ng/mL (30-100)\t\t\n1,25-OH vitamin D\t\t45 pmol/L (19-72)\t\t\nAbbreviations: PTH, parathyroid hormone; PTH-RP, parathyroid\nhormone–related protein; 25-OH, 25-hydroxy.\n\na Reference range for labs in parenthesis.\n\nLaboratory findings on oncology evaluation showed that urine Kappa light chains were\nincreased, as was the urine free Kappa/Lambda ratio, but no monoclonal spike was\ndetected in urine electrophoresis. On quantitative immunoglobulin (Ig) evaluation,\nIgG (1327 mg/dL) and IgA (258 mg/dL) were normal, and IgM minimally elevated (289\nmg/dL). Immunofixation revealed IgG Lambda monoclonal protein. She thus had\nmonoclonal gammopathy of undetermined significance but no myeloma; therefore,\nmyeloma was not contributing to hypercalcemia. Normal 1,25-dihydroxyvitamin D level\nand angiotensin converting enzyme level ruled out the possibility of granulomatous\ndiseases like sarcoidosis and lymphoma.\n\nShe came for review in endocrinology clinic, a few weeks after her initial visit. She\nhad been off HCTZ for a few weeks at the time of this visit. Laboratory findings in\nthis visit (Tables 2 and\n3) revealed elevated\ncalcium, with non-suppressed PTH, and normal 24-hour urine calcium. The diagnosis of\nprimary HPT was thus confirmed.\n\nTable 3. Laboratory Findings at Week 7.\n\nLaboratory Findings (24-Hour Urine), Volume 2700\nmL\tValue\tReference Range\t\nCalcium\t146 mg\t35-250\t\nCreatinine\t1.27 g\t0.8-2.8\t\nCreatinine clearance\t134.5 mL/min\t88-128\t\nShe was subsequently treated surgically for primary HPT. The right and left superior\nparathyroid showed hypercellular parathyroid on pathology. The patient was\nnormocalcemic after surgery. The calcium on follow-up visit about a week after\nsurgery was 9.8 mg/dL (8.5-12.1).\n\nDiscussion\nPrimary HPT is a fairly common condition (7/1000 adults); however, severe\nhypercalcemia secondary to primary HPT is uncommon. Hypercalcemia of primary HPT can\nbe exacerbated by coexisting conditions, which cause increase in bone turnover.\nThese conditions causing increased bone turnover include Paget’s disease and\nimmobilization.1,2\nHCTZ decreases urinary excretion of calcium and thus may also have contributed to\nthe hypercalcemia.3,4\nAlthough ciprofloxacin and metronidazole were started 1 day prior to the development\nof hypercalcemia, to the best of our knowledge, there is no known association\nbetween hypercalcemia and ciprofloxacin or metronidazole. It is also possible that\nvitamin A and calcium may also have affected the management of diverticulitis, since\nthey decrease the absorption of quinolones including ciprofloxacin.5 Hypervitaminosis A is a rare cause of hypercalcemia.6,7 Vitamin A is thought to act\ndirectly on bone to stimulate osteoclastic resorption and/or inhibit osteoblastic\nformation, and thus cause hypercalcemia. The recommended dietary allowance for\nvitamin A in women aged more than 14 years is 700 µg RAE (retinol activity\nequivalents) or 5000 IU daily. Reports suggest that very high doses of vitamin A is\nrequired to cause hypercalcemia. Acute toxicity has been reported to occur at doses\nof 25 000 IU/kg, while chronic toxicity can occur at 4000 IU/kg daily for 6 to 15 months.8 The case suggests that in a setting of primary HPT and HCTZ therapy, even\nsmaller doses of vitamin A can lead to severe hypercalcemia. Hammoud et al have\nreported hypercalcemia secondary to hypervitaminosis A (7000 IU daily) in patients\nwith chronic kidney disease.9 This patient was also on calcium and vitamin D replacement. This may also\nhave contributed to worsening of the hypercalcemia, as has been reported in earlier studies.10 Gallagher et al11 have reported that episodes of hypercalcemia and hypercalciuria occur\ncommonly in patients on calcium and vitamin D supplementation, and this was\nunrelated to the dose of vitamin D dose or serum 25-OH vitamin D. This case teaches\nthat a commonly used antihypertensive diuretic and vitamin supplements may sometimes\nlead to life-threatening situations given the right setting.\n\nConclusion\nThis case suggests that in the clinical setting of HPT, volume depletion, and HCTZ\ntreatment, vitamin A may contribute to the development of severe hypercalcemia in\npatients who are on calcium and vitamin D supplements. Further studies are warranted\nin this regard to elucidate the specific role of vitamin A in contributing to severe\nhypercalcemia in the backdrop of primary HPT.\n\nWe should try to improve awareness in the population that vitamins have biological\neffects, and the injudicious use of over-the-counter vitamins and supplements may\nlead to serious health issues, triggered by certain clinical conditions, especially\nin the elderly with multiple comorbidities. Physicians should also be aware that\noveruse of vitamins may also cause atypical presentation of diseases.\n\nAuthors’ Note: The authors declare that this work has not been published previously except as an\nabstract for ENDO 2018 conference, where it was accepted as a poster\npresentation. The authors also declare that this publication is approved by all\nauthors and tacitly or explicitly by the responsible authorities where the work\nwas carried out.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases\nor case series.\n\nInformed consent: Verbal informed consent was obtained from the patient for their anonymized\ninformation to be published in this article.\n\nORCID iD: Ron T. Varghese \nhttps://orcid.org/0000-0002-6198-4352\n==== Refs\nReferences\n1 \nAlbright F Reifenstein EC Jr. \nThe Parathyroid Glands and Metabolic Bone Disease .\nBaltimore, MD : Williams &\nWilkins Co ; 1948 .\n2 \nBen-Asuly S Horne T Goldschmidt Z Eyal Z Eliakim M Chowers I. \nComa due to hypercalcemia in a patient with Paget’s disease and\nmultiple parathyroid adenomata . Am J Med\nSci .\n1975 ;269 :267 -275 .1146850 \n3 \nKlimiuk PS Davies M Adams PH. \nPrimary hyperparathyroidism and thiazide\ndiuretics . Postgrad Med J .\n1981 ;57 :80 -83 .7267512 \n4 \nDesai HV Gandhi K Sharma M Jennine M Singh P Brogan M. \nThiazide-induced severe hypercalcemia: a case report and review\nof literature . Am J Ther .\n2010 ;17 :e234 -e236 .20068444 \n5 \nSulli MM Ezzo DC. \nDrug interactions with vitamins and minerals. Complementary and\nAlternative Medicine . US Pharm .\n2007 ;1 :42 -55 .\n6 \nVyas AK White NH. \nCase of hypercalcemia secondary to hypervitaminosis A in a\n6-year-old boy with autism . Case Rep\nEndocrinol .\n2011 ;2011 :424712 .22937283 \n7 \nBhalla KH Ennis DM Ennis ED \nHypercalcemia caused by iatrogenic\nhypervitaminosis A . J Am Diet Assoc .\n2005 ;105 :119 -121 .15635357 \n8 \nRosenbloom M \nVitamin toxicity . http://www.emedicine.com/emerg/topic638.htm. Accessed\nDecember 28, 2018 .\n9 \nHammoud D El Haddad B Abdallah J. \nHypercalcaemia secondary to hypervitaminosis A in a patient with\nchronic renal failure . West Indian Med J .\n2014 ;63 :105 -108 .25303202 \n10 \nMarcus JF Shalev SM Harris CA Goodin DS Josephson SA. \nSevere hypercalcemia following vitamin D supplementation in a\npatient with multiple sclerosis: a note of caution .\nArch Neurol .\n2012 ;69 :129 -132 .22232355 \n11 \nGallagher JC Smith LM Yalamanchili V. \nIncidence of hypercalciuria and hypercalcemia during vitamin D\nand calcium supplementation in older women .\nMenopause .\n2014 ;21 :1173 -1180 .24937025\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "7()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "nutrition; primary hyperparathyroidism; vitamin A",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000368:Aged; D002118:Calcium; D019587:Dietary Supplements; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide; D006934:Hypercalcemia; D049950:Hyperparathyroidism, Primary; D010281:Parathyroid Hormone; D014801:Vitamin A; D014807:Vitamin D",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709618823805",
"pmc": null,
"pmid": "30791717",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1146850;15635357;20068444;22232355;22937283;24937025;25303202;7267512",
"title": "Vitamin A and Hydrochlorothiazide Causing Severe Hypercalcemia in a Patient With Primary Hyperparathyroidism.",
"title_normalized": "vitamin a and hydrochlorothiazide causing severe hypercalcemia in a patient with primary hyperparathyroidism"
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"abstract": "Fulminant inflammatory demyelination is a possible presentation of inflammatory demyelinating disorders, thus representing a potential stroke mimic especially in younger patients.\n\n\n\nTo describe clinical and diagnostic pitfalls in a case of fulminant inflammatory demyelination presenting with stroke-like symptoms in an elderly patient.\n\n\n\nCase report and case-based review of the literature.\n\n\n\nA 67-year-old woman, who accessed the emergency room as suspect stroke for hyperacute onset of rapidly worsening speech impairment and drowsiness, was later diagnosed with a huge brain inflammatory demyelination. Clinical, laboratory, and neuroimaging tests did not allow to put a more specific diagnosis. Due to the rapidly deteriorating course, she received immunosuppression with benefit.\n\n\n\nThis report is meant to highlight the diagnostic challenges connected with fulminant inflammatory demyelination, which sometime can resemble a stroke-in evolution and appear clinically unfitting for inclusion in any specific pathological entities within the broad-spectrum of inflammatory demyelinating disorders.",
"affiliations": "Department of Clinical Surgical Diagnostic and Pediatric Sciences, Institute of Radiology, University of Pavia, Pavia, Italy.;Neuroscience Consortium, Monza Policlinico and Pavia Mondino, University of Pavia, Pavia, Italy.;Emergency Neurology Unit, IRCCS Mondino Foundation, Pavia, Italy.;Emergency Neurology Unit, IRCCS Mondino Foundation, Pavia, Italy.;Neuroradiology Unit, IRCCS Mondino Foundation, Pavia, Italy.;Emergency Neurology Unit, IRCCS Mondino Foundation, Pavia, Italy.;Diagnostic Radiology, Interventional Radiology and Neuroradiology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Neuroradiology Unit, IRCCS Mondino Foundation, Pavia, Italy.;Emergency Neurology Unit, IRCCS Mondino Foundation, Pavia, Italy.",
"authors": "Sacco|Simone|S|;Callegari|Ilaria|I|;Canavero|Isabella|I|0000-0002-0141-0437;Coloberti|Elisa|E|;Farina|Lisa Maria|LM|;Ravaglia|Sabrina|S|;Simoncelli|Anna|A|;Pichiecchio|Anna|A|;Micieli|Giuseppe|G|",
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"doi": "10.1002/brb3.1967",
"fulltext": "\n==== Front\nBrain Behav\nBrain Behav\n10.1002/(ISSN)2157-9032\nBRB3\nBrain and Behavior\n2162-3279\nJohn Wiley and Sons Inc. Hoboken\n\n33615744\n10.1002/brb3.1967\nBRB31967\nCommentaries\nCommentaries\nFulminant inflammatory demyelination presenting as stroke‐in‐evolution in an elderly subject\nSACCO et al.\nSacco Simone 1 7\nCallegari Ilaria 2 8\nCanavero Isabella https://orcid.org/0000-0002-0141-0437\n3 isabellacanavero@gmail.com\n\nColoberti Elisa 3\nFarina Lisa Maria 4\nRavaglia Sabrina 3\nSimoncelli Anna 5\nPichiecchio Anna 4 6\nMicieli Giuseppe 3\n1 Department of Clinical Surgical Diagnostic and Pediatric Sciences Institute of Radiology University of Pavia Pavia Italy\n2 Neuroscience Consortium Monza Policlinico and Pavia Mondino University of Pavia Pavia Italy\n3 Emergency Neurology Unit IRCCS Mondino Foundation Pavia Italy\n4 Neuroradiology Unit IRCCS Mondino Foundation Pavia Italy\n5 Diagnostic Radiology Interventional Radiology and Neuroradiology Unit Fondazione IRCCS Policlinico San Matteo Pavia Italy\n6 Department of Brain and Behavioral Sciences University of Pavia Pavia Italy\n7 Present address: Department of Neurology UCSF Weill Institute for Neurosciences University of California San Francisco CA USA\n8 Present address: Department of Biomedicine University Hospital Basel University of Basel Basel Switzerland\n* Correspondence\nIsabella Canavero, IRCCS Mondino Foundation, Via Mondino, 2, Pavia, Italy.\nEmail: isabellacanavero@gmail.com\n\n08 12 2020\n8 2021\n11 8 10.1002/brb3.v11.8 e0196702 11 2020\n31 5 2020\n02 11 2020\n© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nBackground\n\nFulminant inflammatory demyelination is a possible presentation of inflammatory demyelinating disorders, thus representing a potential stroke mimic especially in younger patients.\n\nAims of the study\n\nTo describe clinical and diagnostic pitfalls in a case of fulminant inflammatory demyelination presenting with stroke‐like symptoms in an elderly patient.\n\nMethods\n\nCase report and case‐based review of the literature.\n\nResults\n\nA 67‐year‐old woman, who accessed the emergency room as suspect stroke for hyperacute onset of rapidly worsening speech impairment and drowsiness, was later diagnosed with a huge brain inflammatory demyelination. Clinical, laboratory, and neuroimaging tests did not allow to put a more specific diagnosis. Due to the rapidly deteriorating course, she received immunosuppression with benefit.\n\nConclusion\n\nThis report is meant to highlight the diagnostic challenges connected with fulminant inflammatory demyelination, which sometime can resemble a stroke‐in evolution and appear clinically unfitting for inclusion in any specific pathological entities within the broad‐spectrum of inflammatory demyelinating disorders.\n\nFulminant inflammatory demyelination represents a possible presentation of inflammatory demyelinating disorders. Here we describe a case affecting a 67 year‐old woman, who accessed the emergency room for hyperacute onset of rapidly worsening speech impairment and drowsiness. This report is meant to highlight the diagnostic challenges connected with fulminant inflammatory demyelination, which sometime can resemble a stroke‐in evolution and appear clinically unfitted for inclusion in any specific pathological entities within the broad spectrum of inflammatory demyelinating disorders.\n\nADEM\nfulminant inflammatory demyelination\ninflammatory demyelinating disorders\ntumefactive demyelinating lesions\nsource-schema-version-number2.0\ncover-dateAugust 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.6 mode:remove_FC converted:03.09.2021\nSaccoS, CallegariI, CanaveroI, et al. Fulminant inflammatory demyelination presenting as stroke‐in‐evolution in an elderly subject. Brain Behav. 2021;11 :e01967. 10.1002/brb3.1967\n\nSimone Sacco and Ilaria Callegari contributed equally to this work.\n==== Body\npmc1 BACKGROUND\n\nInflammatory demyelinating disorders (IDD) represent a potential, although uncommon, stroke mimic, which should always be considered in the emergency department (ED) setting, particularly in young subjects showing acute onset of focal neurological deficits (Gibson & Whiteley, 2013).\n\nAcute‐onset IDD can indeed be associated with rapid neurological deterioration configuring a clinical entity defined as fulminant inflammatory demyelination (FID). FID, which can be expression of several pathological entities within central nervous system (CNS) IDD spectrum, is classically associated with poor outcome, but prompt recognition through MRI and early, aggressive treatment can improve the prognosis (Bevan & Cree, 2015).\n\nHere, we describe a case of FID in an elderly woman, where the hyperacute onset and the rapid worsening of symptoms resembled a stroke‐in evolution.\n\n2 CASE REPORT\n\nA 67‐year‐old woman, without remarkable medical and neurological history, accessed the ED for acute onset of speech impairment and drowsiness. Clinical assessment revealed moderate hypertension (165/85 mmHg) and mild leukocytosis (12.1 × 103/microL; r.v. 4.8–10.8) without fever. Neurological examination, at 2 hr from onset, revealed normal alertness, nonfluent aphasia and moderate motor and sensory right‐side impairment (NIHSS 9). In the suspect of a left middle cerebral artery stroke, a brain CT was performed, detecting a wide, pale hypodensity, with finger‐like borders and flattened cerebral sulci in the left hemisphere (Figure 1). Intra and extra‐cranial vessels CT angiography resulted normal excluding eligibility for reperfusion treatments and leading to hospitalization. Within 24 hr from the onset, the patient showed rapid neurological deterioration, up to comatose state and right hemiplegia‐hemianesthesia (GCS = 5, NIHSS = 25).*\n\nFIGURE 1 Brain CT performed at the ED, revealing in the left hemisphere an extensive, pale hypodensity with finger‐like borders associated to flattened cerebral sulci*\n\nAnamnestic revision detected symptoms of upper respiratory tract infection with slight fever and headache, during the preceding 3 days. Cerebrospinal fluid (CSF) examination showed mild pleocytosis (11 lymphocytes/mm3, r.v. <2), hyperproteinorrachia (albumin 63 mg/dl, r.v. 10–30), and “mirror pattern” oligoclonal bands. An extensive infective screening on blood and CSF (bacterial and mycobacterial cultures, PCRs/antibody testing for HIV, HSV1‐2, JCV, Enterovirus, VZV, West Nile virus, Panflavivirus, Mycoplasma, Legionella, and Pneumococcus) resulted negative. A broad‐spectrum, empirical therapy with ceftriaxone and acyclovir was started. No CNS‐specific autoantibodies (anti‐AQP4, anti‐MOG; onconeural panel: anti‐ Hu, Ma/Ta, GAD, amphiphysin, CV2/CRMP5; autoimmune encephalitis panel: anti‐NMDA‐R, LG1, CASPR2, GABA‐A and B, AMPA, Glu‐R1, Gly‐R1, and D2) were detected. Blood and CSF cellular immunophenotypes were normal without signs suggesting either systemic or CNS‐specific hematological disorders. Brain MRI, performed 24 hr after symptoms onset, showed, within the anterior portion of the left hemisphere white matter (WM), a diffuse T2‐hyperintense alteration, which involved the corpus callosum and spared the cortical gray matter. No restricted diffusion was detectable within the lesion. After gadolinium administration, a peripheral open‐ring pattern of contrast enhancement suggestive for IDD was detected (Figure 2a). No other brain alterations suggestive for demyelinating lesions were detected. No spinal cord involvement was detected by spine MRI and somatosensory evoked potentials. EEG excluded epileptic activity.\n\nFIGURE 2 Axial FLAIR and postcontrast T1w images at different time points: additionally, for A and B, DWI trace and ADC sequences are shown. (a) 24 hr after symptoms onset: diffuse hyperintense alteration involving the left frontal lobe and deep white matter of the right frontal lobe, associated with a peripheral ring of contrast enhancement; there is no evidence of restricted diffusion on DWI trace and ADC sequences. (b) 11 days after symptoms onset (after conclusion of intravenous methylprednisolone treatment): disappearing of peripheral ring of contrast enhancement with progression of hyperintense alteration now partially involving the left parietal lobe and, more extensively, the right frontal lobe; there is no evidence of restricted diffusion on DWI trace and ADC sequences. (c) 25 days after symptoms onset (after first cyclophosphamide administration): initial reduction in size of T2 hyperintense alteration, without contrast enhancement. (d) 50 days after symptoms onset (after second cyclophosphamide administration): further reduction in size of T2 hyperintense alteration without contrast enhancement*\n\nTreatment with methylprednisolone 1 g daily was started within 48 hr from onset and continued for 10 days, without any clinical improvement. Follow‐up MRI showed a widening of T2‐hyperintense alterations (Figure 2b), suggesting the need for a second‐line treatment. A single dose of cyclophosphamide (1 g/m2 body surface = 1.75 g, i.v.) was thus administrated. After 10 days, the patient showed a notable neurological improvement, with full recovery of consciousness, soon followed by partial improvement of verbal fluency and sensory‐motor deficits. After 35 days from the first, a second dose of cyclophosphamide (1.75 g, i.v.) was administered. A substantially complete clinical recovery was rapidly reached, and no other treatment was applied. Follow‐up neurological examinations after 1 month, 1 and 2 years revealed only residual right‐side pyramidal signs. Follow‐up MRIs revealed progressive improvement with almost complete resolution of previously described findings (Figure 2c,d). Over a 2‐year observation, no new brain or spinal cord alterations were detected and the subject did not experience neurological relapses or clinical worsening. Due to the favorable, monophasic course and the disappearance of the cerebral lesions at follow‐up MRIs, cerebral biopsy was not performed.*\n\n3 DISCUSSION\n\nThe goal of the present report is to emphasize the diagnostic challenge connected with FID, particularly when affecting elderly. Whereas the hyperacute onset of focal neurological signs and the age of our patient initially suggested a cerebrovascular disorder, the subsequent clinical course and the neuroradiological features of the lesion oriented toward a possible IDD.\n\nThe prototypical IDD is represented by multiple sclerosis (MS), which generally affects young subjects showing space‐ and time‐disseminated WM lesions (Thompson et al., 2018). Uncommonly, certain subjects might show, since from the onset, atypical WM lesions with size >2.5 cm and mass effect (Wallner‐blazek et al., 2013) sometimes associated with a monophasic course of disease. The terms referring to these conditions are heterogeneous and range from rare MS variants such as tumefactive MS (TMS), Marburg's MS (MVMS), Balo's concentric sclerosis (BCS) to other distinct pathological entities with a presumable autoimmune inflammatory origin, such as acute disseminated encephalomyelitis (ADEM) (Bevan & Cree, 2015). Other Authors (Poser et al., 1992; Rahmlow & Kantarci, 2013) introduced the encompassing concept of tumefactive demyelinating lesions (TDL), defined as solitary large signal abnormalities associated with mass effect, perilesional edema, and/or ring enhancement, which may represent atypical presentation of the abovementioned IDD and a stand‐alone diagnosis. Clinical presentation includes headache, encephalopathy signs, and focal cortical signs depending on lesion size and location.\n\nBesides the stroke‐mimic deception we faced in the ED, the diagnostic challenge of the present case is represented by the difficulty in formulating a definite diagnosis based on clinic‐ radiological data in the absence of histo‐pathological assessment. The clinical course during the 2‐year follow‐up period, coherently with the negative hematological tests performed at onset, helped to exclude cerebral lymphoma from the neuroradiological differential diagnosis (Chiavazza et al., 2018). Furthermore, no diffusion restriction was indeed evident at any time‐point within the lesion described, making less likely the possibility of lymphoma and ruling out the possibility of a stroke outside of the ED setting. It is, however, important to remember that in FID there can be association of gadolinium enhancement and restricted diffusion, with the former sometime chronologically following the latter (Hyland et al., 2013) BCS was excluded by the lack of the classical “onion‐like” MRI appearance, showing alternated iso‐ and hyperintense rings on T2‐weighted imaging, likely as expression of layers with relatively preserved or lost myelin (Bevan & Cree, 2015). MVMS could as well be excluded given the absence of progressive deterioration overtime, usually leading to death within months from onset (Bevan and Cree, 2015). TMS mostly occurs during the 2nd and 3rd decade (Lucchinetti et al., 2008), thus is atypical in the elderly. In our case, the lack of previous neurological history and pre‐existing demyelinating lesions, as well as the 2‐year follow‐up, ruled out MS.*\n\nAcute disseminated encephalomyelitis affects mainly children and young individuals, with an incidence of 0.6 per 100,000 per year. This diagnosis is rare among young adults and almost exceptional beyond the age of 65, with only few cases reported in literature (Wang et al., 1996; Kaunzner et al., 2017). No criteria, indeed, have ever been established for diagnosis among adults. ADEM usually follows infections or vaccinations (Pohl et al., 2016) and occurs within 6 days to 6 weeks from an antigenic challenge; overlapping of neurologic and infective symptoms, as here described, is unusual and may point to a parainfective, rather than postinfective process. It is well known, however, that up to 26% of ADEM lacks of clear prodromal manifestations (Tenembaum et al., 2002).\n\nTypically, ADEM patients develop neurological deficits sub‐acutely, conveying to peak within 2–5 days instead of the 24 hr here reported. Aggressive variants, such as Hurst's disease, present neurological deterioration within hours (Rahmlow & Kantarci, 2013) but are associated with hemorrhagic lesions, which were never detected in our patient.\n\nOur report highlights the difficulty in defining a clear‐cut diagnosis in FID presenting some clinical features of multiple pathological entities (TDL, TMS, ADEM, Hurst's disease, parainfective demyelination) but also some relevant atypia precluding a conclusive labeling. The outcome‐arranged agreement to overlook pathological examination, deriving from a thoughtful risk‐benefit evaluation, contributed to this diagnostic pitfall (Hardy et al., 2016).\n\nFirst‐line treatment with high‐dose intravenous steroids may show scarce efficacy, especially in IDD with atypical presentation (Jaskowiak, 2016). In these cases, progressive neurological and radiological deterioration can justify aggressive immunosuppression strategies (Berzero et al., 2016; Rahmlow and Kantarci, 2013). Plasma exchange is generally considered the second‐line therapy for FID patients not responding to corticosteroids (Hardy and Chataway, 2013), especially children and in patients with ring‐enhancing lesions and mass effect (Magaña et al., 2011), and however, given the rarity of the disease, no randomized controlled clinical studies are available and there are no evidences for effect on eventual disease reactivation. Other therapeutic options include immunosuppressors such as cyclophosphamide (Berzero et al., 2016; Rahmlow & Kantarci, 2013) that in our patient was associated with an impressive recovery. It is unclear, however, whether the recovery was associated with the treatment rather than the disease's nature itself. Clinical recovery is indeed frequent in ADEM, and follow‐up imaging demonstrates, in the majority of cases, partial or complete resolution usually conveying to a monophasic course of disease (Rahmlow and Kantarci, 2013; Tenembaum et al., 2002).\n\nFulminant inflammatory demyelination is usually not included among stroke differential diagnosis (Gibson & Whiteley, 2013). Nonetheless, a recent case series described the stroke‐mimic, fulminant course of pathologically proven ADEM affecting 5 subjects with age ranging from 57 to 85 (Tenembaum et al., 2002). The authors suggested that an exceptionally fulminant course in this population may be due to an age‐related decrease in repair efficacy and oligodendrocyte response.\n\n4 CONCLUSION\n\nAmong the broad IDD spectrum, several pathological entities can present as FID. Specific IDD such as ADEM might show a particular fulminant course among elderly subjects. When dealing with hyperacute onset and rapidly worsening focal neurologic signs, once vascular etiology has been excluded, it is therefore always advisable considering FID among differential diagnoses. The diagnostic work‐up remains difficult for the presence of many partially and potentially overlapping IDDs often hindering clinical management. In the presence of severe and progressive neurological deterioration, not responsive to first‐line treatments, early, and aggressive immunosuppressive therapy can be considered.\n\nCONFLICT OF INTEREST\n\nNone to declare.\n\nAUTHOR CONTRIBUTION\n\nAll authors participated in the study and manuscript editing and take public responsibilities for the manuscript contents. 1) Simone Sacco and Ilaria Callegari involved in analysis and interpretation of data, drafting the article and revising it critically. 2) Isabella Canavero involved in acquisition, analysis and interpretation of data, coordination of contributors, and critical revision of the article. 3) Elisa Coloberti, Sabrina Ravaglia, Anna Simoncelli, and Lisa Maria Farina: involved in acquisition of data and critical revision of the article. 4) Anna Pichiecchio and Giuseppe Micieli involved in conception and design, acquisition, analysis and interpretation of data, and critical revision of the article.\n\nETHICAL APPROVAL\n\nWritten informed consent was obtained from the patient.\n\nPEER REVIEW\n\nThe peer review history for this article is available at https://publons.com/publon/10.1002/brb3.1967.\n\nDATA AVAILABILITY STATEMENT\n\nComplete clinical data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy restrictions. Other data sharing is not applicable to this article as no datasets were generated or analyzed during the current study (case report and case‐based narrative review).\n\n* Corrections added on March 18, 2021, after first online publication: The text “the following” was removed from the first paragraph in Section 2; the text “ at the MRI” was removed from the last paragraph in Section 2; Figures 1 and 2 were updated; the citation “(Bevan and Cree, 2015)” was added near the end of the third paragraph in Section 3.\n==== Refs\nREFERENCES\n\nBerzero, G., Cortese, A., Ravaglia, S., & Marchioni, E. (2016). Diagnosis and therapy of acute disseminated encephalomyelitis and its variants. Expert Review of Neurotherapeutics, 16 (1 ), 83–101. 10.1586/14737175.2015.1126510 26620160\nBevan, C. J., & Cree, B. A. (2015). Fulminant demyelinating diseases of the central nervous system. Seminars in Neurology, 35 (6 ), 656–666.26595866\nChiavazza, C., Pellerino, A., Ferrio, F., Cistaro, A., Soffietti, R., & Rudà, R. (2018). Primary CNS lymphomas: Challenges in diagnosis and monitoring. BioMed Research International, 2018 , 3606970.30035121\nGibson, L. M., & Whiteley, W. (2013). The differential diagnosis of suspected stroke: A systematic review. The Journal of the Royal College of Physicians of Edinburg, 43 (2 ), 114–118.\nHardy, T. A., & Chataway, J. (2013). Tumefactive demyelination: An approach to diagnosis and management. Journal of Neurology, Neurosurgery and Psychiatry, 84 (9 ), 1047–1053. 10.1136/jnnp-2012-304498\nHardy, T. A., Reddel, S. W., Barnett, M. H., Palace, J., Lucchinetti, C. F., & Weinshenker, B. G. (2016). Atypical inflammatory demyelinating syndromes of the CNS. The Lancet Neurology, 15 (9 ), 967–981. 10.1016/S1474-4422(16)30043-6 27478954\nHyland, M., Bermel, R. A., & Cohen, J. A. (2013). Restricted diffusion preceding gadolinium enhancement in large or tumefactive demyelinating lesions. Neurology, Clinical Practice, 3 (1 ), 15–21.23634380\nJaskowiak, J. M. (2016). Treatment of hemorrhagic acute disseminated encephalomyelitis with cyclophosphamide. American Journal of Health System Pharmacy, 73 (4 ), 202–205. 10.2146/ajhp150079 26843496\nKaunzner, U. W., Salamon, E., Pentsova, E., Rosenblum, M., Karimi, S., Nealon, N., Lavi, E., & Jamieson, D. G. (2017). An acute disseminated encephalomyelitis‐like illness in the elderly: Neuroimaging and neuropathology findings. Journal of Neuroimaging, 27 (3 ), 306–311. 10.1111/jon.12409 27896893\nLucchinetti, C. F., Gavrilova, R. H., Metz, I., Parisi, J. E., Scheithauer, B. W., Weigand, S., Thomsen, K., Mandrekar, J., Altintas, A., Erickson, B. J., Konig, F., Gianini, C., Lassmann, H., Linbo, L., Pittock, S. J., & Bruck, W. (2008). Clinical and radiographic spectrum of pathologically confirmed tumefactive multiple sclerosis. Brain, 131 (Pt 7 ), 1759–1775.18535080\nMagaña, S. M., Keegan, B. M., Weinshenker, B. G. et al (2011). Beneficial plasma exchange response in central nervous system inflammatory demyelination. Archives of Neurology, 68 (7 ), 870–878. 10.1001/archneurol.2011.34 21403003\nPohl, D., Alper, G., Van Haren, K., Kornberg, A. J., Lucchinetti, C. F., Tenembaum, S., & Belman, A. L. (2016). Acute disseminated encephalomyelitis: Updates on an inflammatory CNS syndrome. Neurology, 87 (9 Suppl 2 ), S38–S45. 10.1212/WNL.0000000000002825 27572859\nPoser, S., Lüer, W., Bruhn, H., Frahm, J., Brück, Y., & Felgenhauer, K. (1992). Acute demyelinating disease. Classification and non‐invasive diagnosis. Acta Neurologica Scandinavica, 86 (6 ), 579–585.1481644\nRahmlow, M. R., & Kantarci, O. (2013). Fulminant demyelinating diseases. Neurohospitalist, 3 (2 ), 81–91.23983890\nTenembaum, S., Chamoles, N., & Fejerman, N. (2002). Acute disseminated encephalomyelitis: A long‐term follow‐up study of 84 pediatric patients. Neurology, 59 (8 ), 1224–1231. 10.1212/WNL.59.8.1224 12391351\nThompson, A. J., Banwell, B. L., Barkhof, F., Carroll, W. M., Coetzee, T., Comi, G., Correale, J., Fazekas, F., Filippi, M., Freedman, M. S., Fujihara, K., Galetta, S. L., Hartung, H. P., Kappos, L., Lublin, F. D., Marrie, A. E., Miller, D. H., Montalban, X., Mowry, E. M., … Cohen, J. A. (2018). Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology, 17 (2 ), 162–173.29275977\nWallner‐blazek, M., Rovira, A., Fillipp, M., Rocca, M. A., Miller, D. H., Schmierer, K., Frederickson, J., Gass, J., Gama, H., Tilbery, C. P., Rocha, A. J., Flores, J., Barkhof, F., Seewann, A., Palace, J., Yousry, T., Montalban, X., Enzingar, C., & Fazekas, F. (2013). Atypical idiopathic inflammatory demyelinating lesions: Prognostic implications and relation to multiple sclerosis. Journal of Neurology, 260 (8 ), 2016–2022.23620065\nWang, P. N., Fuh, J. L., Liu, H. C., & Wang, S. J. (1996). Acute disseminated encephalomyelitis in middle‐aged or elderly patients. European Neurology, 36 (4 ), 219–223.8814425\n\n",
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"issue": "11(8)",
"journal": "Brain and behavior",
"keywords": "ADEM; fulminant inflammatory demyelination; inflammatory demyelinating disorders; tumefactive demyelinating lesions",
"medline_ta": "Brain Behav",
"mesh_terms": "D000368:Aged; D001921:Brain; D003711:Demyelinating Diseases; D004660:Encephalitis; D005260:Female; D006801:Humans; D059906:Neuroimaging; D020521:Stroke",
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"pages": "e01967",
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"pubdate": "2021-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Fulminant inflammatory demyelination presenting as stroke-in-evolution in an elderly subject.",
"title_normalized": "fulminant inflammatory demyelination presenting as stroke in evolution in an elderly subject"
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"abstract": "Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging. Studies over the last decade have documented increasing reports of endocrine dysfunction following the initiation of immunotherapy. Our study aimed to detect the proportion of men who have low testosterone before, during, and or/after receiving immunotherapy for malignant melanoma, and to determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone. We performed retrospective chart review of patients with malignant melanoma treated with immunotherapy. Low testosterone was identified in 34 out of 49 patients at some point during their treatment with immunotherapy. Despite low testosterone levels in two-thirds of patients, only three patients were treated with testosterone replacement therapy. In addition to laboratory evidence of low testosterone, patients were also symptomatic as 43 out of 49 patients reported fatigue to their providers. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom were receiving Ipilimumab. We conclude that patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment.",
"affiliations": "Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA.;Department of Urology, University of Iowa, Iowa City, IA, 52242, USA.;Department of Pediatrics, University of Iowa, Iowa City, IA, 52242, USA.;Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA.;Department of Medicine, University of Iowa, Iowa City, IA, 52242, USA.",
"authors": "Peters|Madeline|M|;Pearlman|Amy|A|;Terry|William|W|;Mott|Sarah L|SL|;Monga|Varun|V|",
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"doi": "10.18632/oncotarget.27876",
"fulltext": "\n==== Front\nOncotarget\nOncotarget\nImpact Journals LLC\nOncotarget\n1949-2553 Impact Journals LLC \n\n27876\n10.18632/oncotarget.27876\nResearch Paper\nTestosterone deficiency in men receiving immunotherapy for malignant melanoma\nPeters Madeline 1 Pearlman Amy 2 Terry William 3 Mott Sarah L. 4 Monga Varun 5 1Carver College of Medicine, University of Iowa, Iowa City, IA, 52242, USA\n2Department of Urology, University of Iowa, Iowa City, IA, 52242, USA\n3Department of Pediatrics, University of Iowa, Iowa City, IA, 52242, USA\n4Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA\n5Department of Medicine, University of Iowa, Iowa City, IA, 52242, USA\nCorrespondence to: Madeline Peters, email: madeline-peters@uiowa.edu\n02 2 2021 \n02 2 2021 \n12 3 199 208\n23 9 2020 19 1 2021 Copyright: © 2021 Peters et al.This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging. Studies over the last decade have documented increasing reports of endocrine dysfunction following the initiation of immunotherapy. Our study aimed to detect the proportion of men who have low testosterone before, during, and or/after receiving immunotherapy for malignant melanoma, and to determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone. We performed retrospective chart review of patients with malignant melanoma treated with immunotherapy. Low testosterone was identified in 34 out of 49 patients at some point during their treatment with immunotherapy. Despite low testosterone levels in two-thirds of patients, only three patients were treated with testosterone replacement therapy. In addition to laboratory evidence of low testosterone, patients were also symptomatic as 43 out of 49 patients reported fatigue to their providers. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom were receiving Ipilimumab. We conclude that patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment.\n\ncancermelanomaimmunotherapytestosterone deficiencyandrogens\n==== Body\nINTRODUCTION\nMalignant melanoma is one of the fastest growing cancers worldwide and men account for 60% of new diagnoses [1]. Fortunately, cancer treatments have greatly improved and those impacted by cancer are now living longer. Immunotherapy has been established as a standard of care for patients with malignant melanoma, however, the long-term side-effects of immunotherapy are still emerging [2].\n\nIt has been well documented that cancer treatment-related toxicities create short and long-term side effects, which can significantly impair the quality of life of cancer survivors. Conventional chemotherapy agents have been thoroughly studied, and there are an abundance of data detailing the negative effects of chemotherapy on testosterone levels, fertility, and the quality of life of cancer patients [3–5]. As immunotherapy is a relatively new treatment for cancer, their side effects on testosterone levels have not been as extensively explored.\n\nImmune checkpoint inhibitors, which are intravenously administered therapies used to treat melanoma, include anti-programmed death-1 (anti-PD-1) antibodies (Pembrolizumab, Nivolumab) and anti-cytotoxic T-lymphocyte antigen-4 inhibition (anti-CTLA4) antibodies (Ipilimumab). There have also been recent developments of investigational therapies, including Indoximod and intratumoral SD-101. Intratumoral SD-101, a synthetic CpG oligonucleotide that stimulates Toll-like receptor 9 (TLR9) and is directly injected into the tumor site, has been shown to increase effectiveness of immune activation at the tumor site when used in combination with PD-1 inhibitors [6]. Indoximod, an inhibitor of the indoleamine 2,3-dioxygenase (IDO) pathway and is administered orally, has many effects on immune regulation allowing for the restoration of immune reactivity against cancer after there has been primary treatment with an active immunization processes (i.e., checkpoint inhibitor therapy) [7, 8]. The duration of treatment for unresectable and metastatic melanoma is currently recommended to continue until there is either disease progression or unacceptable toxicity, however, it is recommended to continue for approximately one year if used as an adjuvant therapy.\n\nWhile side effects of immunotherapy have not been as comprehensively studied as older therapies, there are known adverse effects related to the attempted modulation of the immune system, including nonspecific inflammation and autoimmunity [9]. Studies over the last decade have begun documenting increasing reports of endocrine dysfunction following the initiation of immunotherapy. Specifically, hypophysitis, or inflammation of the pituitary gland, has been reported in 9–13% of patients treated with immunotherapy [3, 10–15]. Most of the patients who developed hypophysitis received Ipilimumab and there were higher rates observed in males (16.1%) than females (8.7%) [15–17]. Hypophysitis results in dysfunction of the pituitary gland and can cause a deficiency of one or more pituitary hormones, including luteinizing hormone (LH), which may then lead to testosterone deficiency. Thus far, no studies have specifically focused on androgen levels associated with immunotherapy or the clinical significance of androgen hormone deficiency. In our literature review, there was only one study which investigated testosterone levels following immunotherapy. The study reported incidences of Ipilimumab-associated low testosterone, in the absence of hypophysitis, in nine out of 256 patients assessed [15]. However, this study did not routinely assess testosterone levels and few measurements were actually obtained. Additionally, reassessment of testosterone levels was not always performed, so it is difficult to ascertain whether the low testosterone levels were transient or permanent.\n\nSymptoms of low testosterone can be nonspecific and include fatigue, weight fluctuations, muscle loss, depression, insomnia, and sexual dysfunction [4, 18]. Sexual symptoms of androgen deficiency include decreased libido and erectile dysfunction [18, 19]. The implications of sexual dysfunction are far reaching, and may include reduction in self-esteem, impact on relationships, anxiety, and depression [4, 18]. It has been documented that male cancer survivors are likely to experience fatigue, impaired quality of life, and sexual dysfunction, regardless of type of cancer treatment received, and these effects are exacerbated by those with concurrent androgen deficiency [4, 5].\n\nWhile the impact from chemotherapy agents on patients’ reproductive potential is well known, the impact from immunotherapy still needs to be established, as melanoma is becoming more prevalent in the AYA (adolescent and young adult) population [20–22]. Preclinical studies of Ipilimumab in monkeys demonstrated a clinically significant decrease in testicular weight, with no evidence of sperm histopathology changes [20]. A small study assessing testicular histopathology after immunotherapy for metastatic melanoma found evidence that spermatogenesis may be impacted by immunotherapies, however, the mechanism remains unclear [23]. While it is difficult to calculate fertility risk based on these small studies, there is concern for some level of gonadal dysfunction that needs to be further explored [24].\n\nWhile immunotherapy has proven to be a successful treatment option for melanoma, there is concern for treatment-related dysfunction of the hypothalamic-pituitary-gonadal axis, which may impair quality of life [4, 5, 18, 20]. As immunotherapy is now widely used for a variety of cancers specifically in early stages, including non-small cell lung cancer, bladder cancer, renal cell carcinoma, and Hodgkin’s lymphoma [13], understanding the side effects associated with immunotherapy, while keeping in mind the direct impact of the treated malignancy, will allow for better recognition and earlier treatment for adverse effects in many future patients.\n\nThe aims of our study include: (1) detect the proportion of men who have low testosterone levels before, during, and or/after receiving immunotherapy for malignant melanoma; (2) identify risk factors for development of low testosterone levels during treatment with immunotherapy; (3) and determine the proportion of men who receive testosterone replacement therapy after detection of low testosterone levels.\n\nRESULTS\nForty-nine patients met inclusion criteria. Patient demographics are reported in Table 1. Median age at diagnosis was 64 (33–92) years. Fifteen patients had stage 3, 33 patients had stage 4, and one patient had a primary pineal gland melanoma that was not staged. At the time of analysis, 16 patients were deceased and 31 patients were alive, 13 of whom were tumor free. Two patients transferred care to a local cancer center and their status was unknown. Patients were treated with Pembrolizumab, Ipilimumab, Nivolumab, or investigational immunotherapy agents Indoximod and intratumoral SD-101 (Figure 1). Of the 49 patients who received immunotherapy, 45 of these patients had metastatic disease. The other four patients received immunotherapy as adjuvant therapy for melanoma.\n\nTable 1 Patient demographics at time of diagnosis\nPatient Demographics\t\nn, %\n\t\nNumber of patients, male\t49 (100%)\t\n\nStaging:\n\t\t\n Stage 3\t15 (30.6%)\t\n Stage 4\t33 (67%)\t\n Primary pineal gland melanoma\t1 (0.2%)\t\nPrevious history of melanoma\t3 (6.1%)\t\nObesity\t26 (53.1%)\t\nDiabetes\t10 (20.4%)\t\nHeart disease (CAD, HTN)\t35 (71.4%)\t\nHypothyroidism\t8 (16.3%)\t\nObstructive sleep apnea\t5 (10.2%)\t\nChronic kidney disease\t3 (6.1%)\t\nCorticosteroid use\t1 (2.0%)\t\nOpioid use\t4 (8.2%)\t\nPre-existing autoimmune disease\t2 (4.1%)\t\nPrevious cancer diagnosis\t10 (20.4%)\t\n\nType of cancer:\n\t\t\n Basal cell carcinoma\t2 (20.0%)\t\n Bladder cancer\t1 (10.0%)\t\n Colon cancer\t1 (10.0%)\t\n Diffuse large B cell lymphoma\t1 (10.0%)\t\n Hodgkin’s lymphoma\t1 (10.0%)\t\n Neuroendocrine tumor\t1 (10.0%)\t\n Prostate cancer\t3 (30.0%)\t\nReceived radiation therapy\t26 (53.1%)\t\n\nType of radiation:\n\t\t\n Local\t12 (46.2%)\t\n Brain\t14 (53.8%)\t\nEnrolled in clinical trial\t14 (28.6%)\t\nFigure 1 The different rows demonstrate each patient’s treatment paradigm across time.\nThe heterogeneity in treatment regimens made it difficult to distinguish how each individual immunotherapy agent affected testosterone levels. On covariate analysis, there was no significant association between testosterone levels and treatment modality.\n\nLow testosterone was identified in 34 out of 49 patients at some point during treatment with immunotherapy (Figure 2). Of these 34 patients with low testosterone, eight had their testosterone levels return to > 300 ng/dL within three months after detection. One patient’s testosterone level returned to normal after one year. Twenty-five patients with low testosterone did not see a complete recovery in their testosterone levels throughout the remainder of their follow-up. Four patients developed hypophysitis and subsequent hypopituitarism, all of whom received Ipilimumab. All patients who developed hypophysitis began showing evidence of hypopituitarism after 2–3 doses of Ipilimumab. Forty-three patients reported fatigue to their provider during their treatment with immunotherapy. Only three patients, all diagnosed with hypopituitarism, were treated with testosterone replacement therapy. The fourth patient diagnosed with hypopituitarism was treated with corticosteroids. Ten (29%) of the patients who developed low testosterone had normal testosterone levels prior to initiation of immunotherapy (Table 2). Eight (24%) of the patients had a low baseline testosterone prior to immunotherapy initiation, and their levels remained low throughout their treatment. Thirteen (38%) of the patients identified with low testosterone did not have a baseline testosterone level checked prior to starting immunotherapy. Three (9%) of the patients had low baseline testosterone levels, however, they also had brain radiation within two months prior to checking their baseline level.\n\nFigure 2 Testosterone levels assessed after initiation of immunotherapy.\nThe red line is a reference for 300 ng/dL. There was large intrapersonal variability in testosterone levels, as demonstrated by the oscillating values within each patient. However, it is evident many patients had testosterone levels drop below 300 ng/dL, with many of those patients dipping well below 200 ng/dL.\n\nTable 2 Additional clinical information of the patients with previously normal testosterone who subsequently developed low testosterone after treatment with immunotherapy\nClinical information of patients with normal T who developed low T after immunotherapy\t\nPt\tAge at diagnosis\tImmunotherapy Agent(s)\tBaseline T\tLowest T value\tResolution of low T\tComorbidities\tRadiation\tClinical trial\tEndocrine dysfunction during tx\t\n1\t50\tIpilimumab, Pembrolizumab\tNormal (314)\t55\tNo\tHeart disease\tLocal\t-\t-\t\n2\t72\tIpilimumab\tNormal (498)\t78\tNo\t-\t-\t-\t-\t\n3\t66\tPembrolizumab\tNormal (319)\t144\tNo\tHeart disease\tBrain\t-\tPituitary, adrenal\t\n4\t61\tIpilimumab, Pembrolizumab\tNormal (338)\t69\tNo\tObese, heart disease, diabetes, hypothyroid\tBrain\tYes\t-\t\n5\t82\tPembrolizumab\tNormal (399)\t181\tNo\tHeart disease, diabetes\t-\t-\t-\t\n6\t59\tIpilimumab, Pembrolizumab\tNormal (419)\t< 5\tNo\tObesity, heart disease\tLocal\t-\tHypophysitis\t\n7\t35\tIpilimumab, Pembrolizumab\tNormal (524)\t170\tYes\tObesity\tBrain\tYes\tPituitary, thyroid\t\n8\t85\tPembrolizumab\tNormal (351)\t206\tYes\tObesity, heart disease, previous prostate cancer\t-\t-\tPituitary, adrenal\t\n9\t46\tPembrolizumab\tNormal (369)\t22\tYes\t-\t-\t-\tAdrenal\t\n10\t52\tPembrolizumab\tNormal (456)\t133\tYes\tObesity, heart disease, OSA, previous melanoma\tLocal\t-\tPituitary, adrenal, and thyroid\t\n\nAvg:\n\t\n60.8\n\t\t\n398.7\n\t\n105.8\n\t\t\t\t\t\t\nWhile these patients had diverse treatment courses, most of these patients had multiple comorbidities prior to their development of low testosterone.\n\nCovariate analysis demonstrated no significant association between low testosterone and treatment with either Ipilimumab, Pembrolizumab, or Nivolumab. On univariate analysis, obesity and enrollment in a clinical trial were associated with lower testosterone levels (Table 3). During the treatment course with immunotherapy, 19 patients had evidence of pituitary dysfunction, 16 patients had evidence of adrenal dysfunction, and 18 patients had evidence of thyroid dysfunction. On univariate analysis, a trend was noted between testosterone and adrenal dysfunction and thyroid dysfunction. On multivariable analysis (Table 4), participation in a clinical trial and weeks since immunotherapy initiation were significant (p < 0.01), and a trend was noted for thyroid dysfunction (p = 0.08) and adrenal dysfunction (p = 0.08). More specifically, clinical trial patients had testosterone levels that were 80.38 ng/dL lower on average. There was not a clinically significant difference between clinical trial enrollment and cancer stage. Of the 15 patients with stage 3, five were enrolled in a clinical trial; while there were nine out of 33 patients with stage 4 enrolled in a clinical trial. Testosterone levels declined at a rate of 0.71 ng/dL per week, on average. Obesity, adrenal dysfunction, and thyroid dysfunction tended to be associated with lower testosterone levels.\n\nTable 3 Univariate analysis assessing for associations with low testosterone and patient demographics, co-morbidities, treatment modalities, and treatment complications\nCovariate\tUnivariate Analysis\t\nTestosterone (ng/dL)\t\nLevel\tBeta\t95% CI\t\nP-value\n\t\nObesity\tYes\t–56.71\t–110.41\t–3.01\t0.04\t\nNo\tRef\t-\t-\t\nDiabetes\tYes\t–18.77\t–89.16\t51.63\t0.60\t\nNo\tRef\t-\t-\t\nHeart Disease (CAD, HTN)\tYes\t–16.97\t–78.93\t44.99\t0.59\t\nNo\tRef\t-\t-\t\nCancer Stage\t4\t–18.05\t–81.07\t44.97\t0.57\t\n3\tRef\t-\t-\t\nOther Cancer Diagnoses\tYes\t40.46\t–27.45\t108.37\t0.24\t\nNo\tRef\t-\t-\t\nClinical trial\tYes\t–87.04\t–143.19\t–30.88\t< 0.01\t\nNo\tRef\t-\t-\t\nRadiation\tYes\t–17.80\t–65.16\t29.56\t0.46\t\nNo\tRef\t-\t-\t\nRadiation\tLocal\t–2.81\t–63.67\t58.04\t0.56\t\nBrain\t–34.24\t–97.67\t29.20\t\nPituitary\tYes\t–22.01\t–64.11\t20.08\t0.30\t\nNo\tRef\t-\t-\t\nAdrenal\tYes\t–45.52\t–96.51\t5.47\t0.08\t\nNo\tRef\t-\t-\t\nThyroid\tYes\t–40.99\t–86.22\t4.23\t0.08\t\nNo\tRef\t-\t-\t\nTestosterone Replacement\tYes\t98.91\t–11.35\t209.17\t0.08\t\nNo\tRef\t-\t-\t\nAge\tUnits = 1\t0.64\t–1.35\t2.63\t0.52\t\nBMI at diagnosis\tUnits = 1\t–4.22\t–9.80\t1.36\t0.14\t\nMonths Since Diagnosis\tUnits = 1\t–2.13\t–5.02\t0.75\t0.14\t\nTime obtained (minutes)\tUnits = 60\t0.06\t–2.81\t2.93\t0.97\t\nWeeks Since Immunotherapy Initiation\tUnits = 1\t0.44\t–0.11\t0.99\t0.12\t\nObesity and enrollment in a clinical trial were associated with low testosterone. A trend is observed between low testosterone and adrenal and thyroid dysfunction.\n\nTable 4 Multivariable model was utilized to include variables that were significant or nearly significant on univariate analysis\nMultivariable analysis\t\nCovariate\tTestosterone (ng/dL)\t\nLevel\tBeta\t95% CI\t\nP-value\n\t\nIntercept\t\t348.53\t300.37\t396.69\t\n< 0.01\n\t\nObesity\tYes\t–36.72\t–90.57\t17.13\t0.18\t\nNo\tRef\t-\t-\t\nClinical trial\tYes\t–80.35\t–139.85\t–20.86\t\n< 0.01\n\t\nNo\tRef\t-\t-\t\nAdrenal\tYes\t–50.54\t–108.60\t7.53\t0.08\t\nNo\tRef\t-\t-\t\nThyroid\tYes\t–43.84\t–94.37\t6.69\t0.08\t\nNo\tRef\t-\t-\t\nTestosterone Replacement\tYes\t135.84\t–109.79\t381.48\t0.14\t\nNo\tRef\t-\t-\t\nWeeks Since Immunotherapy Initiation\tUnits = 1\t0.71\t0.18\t1.25\t\n< 0.01\n\t\nEnrollment in a clinical trial and weeks since immunotherapy initiation were significant.\n\nDISCUSSION\nIn our cohort, roughly two-thirds of patients developed low testosterone at some point during their treatment with immunotherapy. While some patients did have a recovery in their testosterone levels after a few months, over half of the patients continued to have low testosterone levels throughout the remainder of their follow-up. Despite persistently low testosterone levels in 25 patients, only three patients were treated with testosterone replacement therapy, all of whom had hypophysitis and testosterone levels < 5 ng/dL. In addition to laboratory evidence of low testosterone, patients were also symptomatic as the vast majority of patients reported fatigue to their providers. The three patients who received testosterone replacement therapy reported improved energy levels after treatment, however, they also received steroids and thyroid replacement therapy so it cannot be determined from our study whether testosterone replacement directly improves energy in these patients. While many factors contribute to fatigue, low testosterone levels may be playing an important role in the development of fatigue in these cancer patients. There was no chart documentation of whether providers assessed for other symptoms of low testosterone, including low libido or sexual dysfunction. These findings suggest that providers may be under-diagnosing and under-treating low testosterone in melanoma patients receiving immunotherapy.\n\nOut of our patient population, 8% developed hypophysitis. All four patients showed evidence of hypopituitarism within three months of initiation of Ipilimumab, which has been documented in previous studies [15–17]. These data suggest that patients being treated with Ipilimumab need diligent monitoring of their endocrine function during the first three months of their treatment and up to 12 months after completion of their immunotherapy treatment [25].\n\nIn our study, there were clinically significant associations of low testosterone with obesity and patients that were enrolled in a clinical trial. It has been well documented that obesity is associated with low testosterone due to the high expression of aromatase in adipocytes, which converts testosterone to estradiol and lowers circulating androgens [26]. Of the 14 patients enrolled in a clinical trial, 10 of these patients developed low testosterone. The type of clinical trial each patient participated in was extremely variable, however, Indoximod and high dose (10 mg/kg) Ipilimumab were utilized most frequently. These patients may have been more likely to develop lower testosterone levels due to the higher dose of immunotherapy and the use of investigational immunotherapy agents, the side effects of which have not been completely studied. Additionally, Indoximod was used in conjunction with an anti-PD1 immunotherapy agent. The use of two immunotherapy agents has typically shown to have a synergistic effect on cancer control. This synergy may also reflect how immunotherapy affects testosterone levels, and therefore, those patients who are receiving two types of immunotherapy could be more susceptible to developing low testosterone. There may have also been a delayed effect of prior therapeutic agents used to treat melanoma on testosterone levels. On multivariable analysis, there was also an association with decreasing testosterone levels and weeks since initiation of immunotherapy. On average, the testosterone levels declined at a rate of 0.71 ng/dL per week. This change is minimal and most likely not clinically significant.\n\nTo our knowledge, this is the first study directly analyzing the effect of immunotherapy on testosterone levels in patients with melanoma. One limitation of this study is the low number of analyzed patients. While there were 143 male patients with malignant melanoma that received immunotherapy from 2009–2019, only 49 patients had at least two testosterone levels drawn. There were also inconsistencies as to when these patients had their testosterone levels checked. Only 30 of the 49 patients had a baseline testosterone level checked prior to initiation of immunotherapy. The other 19 patients had their level checked some variable amount of time after receiving immunotherapy. Additionally, further assessments of testosterone levels were not at regular intervals. Because roughly half of the patients had irregular assessment of testosterone levels, we are unable to report the causality of low testosterone.\n\nAnother limitation of this study is the heterogeneity within each patient’s treatment course, which made it difficult to analyze patients based on specific treatment received. Specifically, of the 34 patients identified with low testosterone during immunotherapy treatment, two patients were also being treated with steroids and five patients received concurrent radiation therapy (one received retroperitoneal radiation while the other four received brain radiation). It cannot be determined whether the low testosterone was due to immunotherapy and/or the concurrent treatment with steroids or radiation therapy.\n\nAs this was a retrospective study, fertility was not assessed in these patients. However, as melanoma is becoming more prevalent in the AYA population, future work needs to be completed to addresses any potential fertility risk in melanoma patients receiving immunotherapy, with particular attention to sperm count and function.\n\nIn conclusion, patients with stage 3 or 4 melanoma treated with immunotherapy appear to be at an increased risk of developing testosterone deficiency during their treatment. The majority of patients also report fatigue, which is commonly associated with low testosterone levels, yet only a minority of those with low levels received testosterone supplementation. Patients who are obese and have been enrolled in a clinical trial appear to be at increased risk of developing low testosterone during treatment with immunotherapy, and these patients would benefit from close observation and potentially testosterone replacement therapy. Encouraging weight loss in obese patients diagnosed with low testosterone should also be considered in conjunction with testosterone replacement therapy. Regardless of the reason for the development of low testosterone, our study has identified that this patient population is at risk for under-diagnosis and under-treatment of low testosterone. Further research needs to be performed to assess whether or not testosterone supplementation improves patient-reported outcomes in this patient population.\n\nMATERIALS AND METHODS\nAfter seeking Institutional Review Board and Ethics approval, we performed a retrospective chart review of patients with malignant melanoma treated with immunotherapy at Holden Comprehensive Cancer Center from 2009–2019 using the Melanoma Molecular Epidemiology Resource database. Patients were included in the analysis if they had at least two testosterone levels checked while on immunotherapy (Figure 3). Low testosterone was defined in this study as total testosterone < 300 ng/dL upon two consecutive lab draws, according to American Urological Association (AUA) guidelines on testosterone deficiency [27]. Blood was collected and total testosterone was assessed via electrochemiluminscence immunoassay.\n\nFigure 3 Systematic review of 149 patients.\nPatients were excluded in the study if they had fewer than two assessments of testosterone levels.\n\nPatients were also evaluated for pituitary, adrenal, and thyroid dysfunction, based on the reference ranges from Clinical Laboratory Improvement Amendments certified laboratory at the University of Iowa Hospitals and Clinics. Pituitary dysfunction was defined as adrenocorticotropic hormone (ACTH) < 7 pg/mL. Adrenal dysfunction was defined as cortisol < 3 μg/dL. Thyroid dysfunction was defined as TSH < 0.27 or > 4.20 μIU/mL. Patient demographics and co-morbidities were gathered from chart review. Obesity was classified as BMI > 30 at the time of initial office visit.\n\nMixed effects regression models were applied to assess for changes in serum testosterone levels over time while adjusting for potential confounders. Time-dependent covariates were incorporated to capture changes in treatment and onset of other medical conditions. Random effects were included to account for the longitudinally correlated nature of repeat assessment and unequal time spacing between visits. Beta coefficients and 95% confidence intervals are reported. All statistical testing was two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC). Power calculations were not performed, as this was a retrospective study meant to gain preliminary estimates of the true underlying population values.\n\n\nAuthor contributions\n\n\nA.P., V.M., and W.T. conceived the presented idea. M.P. collected the data for analysis. S.M. analyzed the data and performed the computations. All authors discussed the results. M.P. wrote the manuscript with support from A.P., V.M., W.T., and S.M.\n\n\nCONFLICTS OF INTEREST\n\n\nAuthors have no conflicts of interest to declare.\n\n\nFUNDING\n\n\nThis project was in part supported by the National Cancer Institute Cancer Center Support Grant 5P30CA086862-09 (P30).\n==== Refs\nREFERENCES\n1. \nMelanoma Skin Cancer Statistics\n.\nAmerican Cancer Society . 2020 \nhttps://www.cancer.org/cancer/melanoma-skin-cancer/about/key-statistics.html.\n\n2. \n\nLiu \nY \n, \nSheikh \nMS \n. Melanoma: Molecular Pathogenesis and Therapeutic Management\n.\nMol Cell Pharmacol . 2014 ; 6 :228 .\n25745537 \n3. \n\nBarroso-Sousa \nR \n, \nBarry \nWT \n, \nGarrido-Castro \nAC \n, \nHodi \nFS \n, \nMin \nL \n, \nKrop \nIE \n, \nTolaney \nSM \n. 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Ipilimumab-Induced Hypophysitis: A Detailed Longitudinal Analysis in a Large Cohort of Patients With Metastatic Melanoma\n.\nJ Clin Endocrinol Metab . 2014 ; 99 :4078 –85\n. 10.1210/jc.2014-2306 .\n25078147 \n18. \n\nKumar \nP \n, \nKumar \nN \n, \nThakur \nD \n, \nPatidar \nA \n. Male hypogonadism: Symptoms and treatment\n.\nJ Adv Pharm Technol Res . 2010 ; 1 :297 . 10.4103/0110-5558.72420 .\n22247861 \n19. \n\nTraish \nAM \n, \nGoldstein \nI \n, \nKim \nNN \n. Testosterone and Erectile Function: From Basic Research to a New Clinical Paradigm for Managing Men with Androgen Insufficiency and Erectile Dysfunction\n.\nEur Urol . 2007 ; 52 :54 –70\n. 10.1016/j.eururo.2007.02.034 .\n17329016 \n20. \n\nWalter \nJR \n, \nXu \nS \n, \nPaller \nAS \n, \nChoi \nJN \n, \nWoodruff \nTK \n. Oncofertility considerations in adolescents and young adults given a diagnosis of melanoma: Fertility risk of Food and Drug Administration–approved systemic therapies\n.\nJ Am Acad Dermatol . 2016 ; 75 :528 –34\n. 10.1016/j.jaad.2016.04.031 .\n27543212 \n21. \n\nMoke \nDJ \n, \nTsai \nK \n, \nHamilton \nAS \n, \nHwang \nA \n, \nLiu \nL \n, \nFreyer \nDR \n, \nDeapen \nD \n. Emerging Cancer Survival Trends, Disparities, and Priorities in Adolescents and Young Adults: A California Cancer Registry-Based Study\n.\nJNCI Cancer Spectr . 2019 ; 3 :pkz031 . 10.1093/jncics/pkz031 .\n31276099 \n22. \n\nBleyer \nA \n, \nO’Leary \nM \n, \nBarr \nR \n, \nRies \nLAG \n (eds). Cancer Epidemiology in Older Adolescents and Young Adults 15 to 29 Years of Age, Including SEER Incidence and Survival: 1975–2000. National Cancer Institute, NIH Pub\n. No. 06–5767. 2006 .\n\n23. \n\nBenz \nKS \n, \nMaruf \nM \n, \nDuregon \nE \n, \nHooper \nJ \n, \nMatoso \nA \n, \nHerati \nAS \n. Testicular histopathology after immunotherapy for metastatic melanoma\n.\nJ Clin Oncol . 2018 ; 36 :e15114 –e15114\n. 10.1200/JCO.2018.36.15_suppl.e15114 .\n\n24. \n\nDuma \nN \n, \nLambertini \nM \n. It Is Time to Talk About Fertility and Immunotherapy\n.\nOncologist . 2020 ; 25 :277 –8\n. 10.1634/theoncologist.2019-0837 .\n32091651 \n25. \n\nHaanen \nJBAG \n, \nCarbonnel \nF \n, \nRobert \nC \n, \nKerr \nKM \n, \nPeters \nS \n, \nLarkin \nJ \n, \nJordan \nK \n. Corrections to “Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up\n.\nAnn Oncol . 2018 ; 29 :iv264 –6\n. 10.1093/annonc/mdy162 .\n29917046 \n26. \n\nKelly \nDM \n, \nJones \nTH \n. Testosterone and obesity\n.\nObes Rev . 2015 ; 16 :581 –606\n. 10.1111/obr.12282 .\n25982085 \n27. \n\nMulhall \nJP \n, \nTrost \nLW \n, \nBrannigan \nRE \n, \nKurtz \nEG \n, \nRedmon \nJB \n, \nChiles \nKA \n, \nLightner \nDJ \n, \nMiner \nMM \n, \nMurad \nMH \n, \nNelson \nCJ \n, \nPlatz \nEA \n, \nRamanathan \nLV \n, \nLewis \nRW \n. Evaluation and Management of Testosterone Deficiency: AUA Guideline\n.\nJ Urol . 2018 ; 200 :423 –32\n. 10.1016/j.juro.2018.03.115 .\n29601923\n\n",
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"keywords": "androgens; cancer; immunotherapy; melanoma; testosterone deficiency",
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"title": "Testosterone deficiency in men receiving immunotherapy for malignant melanoma.",
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"abstract": "Down Syndrome (DS) is the most common genetic cause of mental retardation, with a reported frequency of epilepsy between 1.4-17% (1). There is a paucity of data in the literature regarding epilepsy in Down syndrome and its relation to intellectual disability.\n\n\nOBJECTIVE\nThe purpose of this article is to analyze the association of epilepsy in children with DS - frequency and type of seizures, treatment, outcome and to compare cognitive impairment of children with DS and epilepsy and DS without epilepsy from our cohort.\n\n\nMETHODS\nA four years systematic retrospective analysis of the database of the Pediatric Neurology Clinic (January 2010 - December 2013) identified a cohort of 39 pediatric cases with DS and neurological symptoms, 9 of them (23%) associating epileptic seizures. Following data were analysed: clinical and neurological examination, type/s of seizures, electroencephalography (EEG), cerebral magnetic resonance imaging (MRI), psychological examination, psychiatric evaluation in selected cases, electrocardiography (ECG), cardiac ultrasonography, ophthalmologic examination.\n\n\nRESULTS\n23% (9 patients) of the children with DS of our cohort presented epilepsy. Five patients had epileptic spasms (56%), one of these further developed astatic seizures. Focal seizures were observed in three patients (33%) and absence with eyelid myoclonias in one patient (11%). Two of the nine patients with DS and epilepsy had generalized seizures, both with very good response to levetiracetam (LEV). EEG was abnormal at seizure onset, and was improved after treatment. Of the nine children with DS and epilepsy, two (22%) presented mild mental retardation and seven (78%) had moderate to severe cognitive delay. Of the 30 children with DS and without epilepsy, 21 (70%) had mild mental retardation and 9 (30%) had moderate to severe cognitive impairment.\n\n\nCONCLUSIONS\nThe most frequent epileptic syndrome associated with DS is West syndrome, with good response to specific antiepileptics. All children with DS from our cohort have intelectual disability, more severe in those with epilepsy. Slight improvement of intelectual and language capabilities were seen after seizures control.",
"affiliations": "Clinic of Pediatric Neurology, \"Prof. Dr. Alexandru Obregia\" Clinical Psychiatric Hospital, Bucharest, Romania ; \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;Clinic of Pediatric Neurology, \"Prof. Dr. Alexandru Obregia\" Clinical Psychiatric Hospital, Bucharest, Romania ; \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;Department of Research, \"Professor Dr. Alexandru Obregia\" Clinical Psychiatric Hospital, Bucharest, Romania.;Clinic of Pediatric Neurology, \"Prof. Dr. Alexandru Obregia\" Clinical Psychiatric Hospital, Bucharest, Romania ; \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;Department of Research, \"Professor Dr. Alexandru Obregia\" Clinical Psychiatric Hospital, Bucharest, Romania ; Department of Genetics, \"Victor Babes\" National Institute of Research and Development in the Field of Pathology and Biomedical Sciences, Bucharest, Romania ; \"Titu Maiorescu\" University, Bucharest, Romania.;\"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;Clinic of Pediatric Neurology, \"Prof. Dr. Alexandru Obregia\" Clinical Psychiatric Hospital, Bucharest, Romania ; \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;Clinic of Pediatric Neurology, \"Prof. Dr. Alexandru Obregia\" Clinical Psychiatric Hospital, Bucharest, Romania ; \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.",
"authors": "Barca|Diana|D|;Tarta-Arsene|Oana|O|;Dica|Alice|A|;Iliescu|Catrinel|C|;Budisteanu|Magdalena|M|;Motoescu|Cristina|C|;Butoianu|Niculina|N|;Craiu|Dana|D|",
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"pages": "344-50",
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"pubdate": "2014-12",
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"title": "Intellectual disability and epilepsy in down syndrome.",
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"abstract": "We describe a case of inherited restrictive cardiomyopathy in a patient presenting with severe biatrial enlargement. We review the evaluation and management of restrictive cardiomyopathy with a focus on genetic etiologies. (Level of Difficulty: Intermediate.).",
"affiliations": "Division of Cardiology, Department of Medicine, Duke University Hospital, Durham, North Carolina.;Division of Cardiology, Department of Medicine, Duke University Hospital, Durham, North Carolina.;Division of Cardiothoracic Surgery, Duke University Hospital, Durham, North Carolina.;Division of Cardiology, Department of Medicine, Duke University Hospital, Durham, North Carolina.;Division of Cardiology, Department of Medicine, Duke University Hospital, Durham, North Carolina.;Division of Cardiology, Department of Medicine, Duke University Hospital, Durham, North Carolina.",
"authors": "Nafissi|Navid A|NA|;Fudim|Marat|M|;Milano|Carmelo A|CA|;Rosenberg|Paul B|PB|;DeVore|Adam D|AD|;Agarwal|Richa|R|",
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"doi": "10.1016/j.jaccas.2019.08.026",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(19)30364-X\n10.1016/j.jaccas.2019.08.026\nCase Report\nClinical Case\nA Case of Rare Inherited Restrictive Cardiomyopathy With Severe Biatrial Enlargement\nNafissi Navid A. MD navid.nafissi@duke.edu\n@NavidNafissi\na∗\nFudim Marat MD ab\nMilano Carmelo A. MD c\nRosenberg Paul B. MD a\nDeVore Adam D. MD, MHS ab\nAgarwal Richa MD a\nfor the Duke Heart Team\na Division of Cardiology, Department of Medicine, Duke University Hospital, Durham, North Carolina\nb Duke Clinical Research Institute, Durham, North Carolina\nc Division of Cardiothoracic Surgery, Duke University Hospital, Durham, North Carolina\n∗ Address for correspondence: Dr. Navid A. Nafissi, Division of Cardiology, Duke University Hospital, 2301 Erwin Road, Durham, North Carolina 27713. navid.nafissi@duke.edu@NavidNafissi\n06 11 2019\n12 2019\n06 11 2019\n1 4 588591\n10 6 2019\n14 8 2019\n29 8 2019\n© 2019 The Authors\n2019\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nWe describe a case of inherited restrictive cardiomyopathy in a patient presenting with severe biatrial enlargement. We review the evaluation and management of restrictive cardiomyopathy with a focus on genetic etiologies. (Level of Difficulty: Intermediate.)\n\nGraphical abstract\n\nWe describe a case of inherited restrictive cardiomyopathy in a patient presenting with severe biatrial enlargement. We review the evaluation and…\n\nKey Words\n\ncardiac transplant\ncardiomyopathy\nimaging\ngenetic disorders\nrestrictive\nAbbreviations and Acronyms\n\nAF, atrial fibrillation\nBVA, blood volume analysis\nHCM, hypertrophic cardiomyopathy\nLV, left ventricular\nRCM, restrictive cardiomyopathy\n==== Body\nHistory of Presentation\n\nA 69-year-old man presented with 5 months of progressive dyspnea on exertion and volume overload. He was transferred to our hospital for medically refractory heart failure.Learning Objectives\n\n• To develop a differential diagnosis and evaluation for RCM and its clinical sequelae.\n\n• To understand the genotypic and phenotypic similarities between hereditary RCM and HCM.\n\nMedical History\n\nThe patient’s medical history was notable for longstanding, persistent atrial fibrillation (AF). His earliest transthoracic echocardiogram 6 years previously showed severe biatrial enlargement, normal left ventricular (LV) function with moderate concentric LV hypertrophy, normal right ventricular function, mild mitral regurgitation, and moderate to severe tricuspid regurgitation.\n\nThe patient has the following family history: AF in his mother; AF and heart failure in his father; and AF in his younger brother. He is a remote smoker (10 pack-year history). He is retired from working in historical restorations and previously served as a rescue diver for the U.S. Coast Guard.\n\nDifferential Diagnosis\n\nThe differential diagnosis for the patient’s heart failure symptoms included tachycardia-induced cardiomyopathy secondary to AF with primary atrial remodeling, chronic obstructive pulmonary disease with cor pulmonale, heart failure with preserved ejection fraction and secondary pulmonary hypertension, valvular heart disease, ischemic cardiomyopathy, inherited cardiomyopathy, amyloid cardiomyopathy, and other forms of restrictive cardiomyopathy (RCM).\n\nInvestigations\n\nThe patient’s examination showed marked jugular venous distention, abdominal distention, and lower extremity edema. He was tachycardic in an irregularly irregular rhythm with holosystolic murmurs at the apex and right lower sternal border. His oxygen saturation was 91% on 3 L by nasal cannula, and his lung fields had bibasilar crackles. Basic laboratory test results were notable for an elevated creatinine level of 1.4 mg/dl and low hemoglobin level of 7.6 g/dl. His total bilirubin level was elevated at 1.8 mg/dl with normal transaminase levels, and his N-terminal pro–B-type natriuretic peptide level was elevated at 2,200 pg/ml.\n\nThe patient’s electrocardiogram revealed AF with frequent premature ventricular contractions and left posterior fascicular block (Figure 1). His chest radiograph showed pulmonary edema and profound cardiomegaly. His transthoracic echocardiogram revealed massively enlarged left and right atria, nondilated ventricular chambers, preserved LV systolic function with moderate LV hypertrophy and grade III diastolic dysfunction, mild right ventricular dysfunction, moderate mitral regurgitation, and torrential tricuspid regurgitation (Figure 1, Videos 1 and 2). A saline microcavitation contrast study to assess for interatrial shunting was positive at rest, concerning for a patent foramen ovale. Cardiac magnetic resonance delayed enhancement imaging showed no evidence of myocardial infarction, scar, or infiltrative disease (e.g., amyloidosis or sarcoidosis), although single-shot imaging was used due to his inability to breath hold. The patient’s intracardiac pressures on right heart catheterization were significantly elevated with a normal cardiac index of 3.3 l/min/m2 (Table 1). Unfortunately, we were unsuccessful in performing an endomyocardial biopsy due to severe right atrial enlargement and severe tricuspid regurgitation.Figure 1 Representative Clinical Data\n\n(Upper left panel) Electrocardiogram showing atrial fibrillation with frequent premature ventricular contractions. (Upper right panel) Chest radiograph showing pulmonary edema and profound cardiomegaly. (Lower left panel) Still frame from transthoracic echocardiogram apical 4-chamber view showing massively enlarged left and right atria. (Lower right panel)99mTechnetium-pyrophosphate scan showing no myocardial uptake of radiotracer. See Videos 1 and 2. LA = left atrium; LV = left ventricle; RA = right atrium; RV = right ventricle.\n\nOnline Video 1 Transthoracic echocardiogram apical 2-chamber view showing preserved left ventricular systolic function and moderate mitral regurgitation.\n\nOnline Video 2 Transthoracic echocardiogram apical 4-chamber view with right ventricular focus showing severe tricuspid regurgitation.\n\nTable 1 Right Heart Catheterization Pressures\n\n\tSystolic (mm Hg)\tDiastolic (mm Hg)\tEDP (mm Hg)\tMean (mm Hg)\t\nAorta (cuff)\t106\t62\t–\t77\t\nRight atrium\t–\t–\t–\t23\t\nRight ventricle\t44\t15\t22\t\t\nPulmonary artery\t42\t27\t–\t33\t\nPulmonary capillary wedge\t–\t–\t–\t27\t\nEDP = end-diastolic pressure.\n\nPulmonary function testing to assess for chronic obstructive pulmonary disease revealed a mixed obstructive and restrictive defect. A 99mTechnetium-pyrophosphate scan showed no evidence of transthyretin amyloidosis and no discernible myocardial uptake of radiotracer (Figure 1). Results of laboratory evaluation for hemochromatosis (i.e., ferritin, transferrin saturation) and inherited disorders of metabolism (i.e., acylcarnitine profile, plasma amino acids) were negative.\n\nAs part of an ongoing research protocol to determine intravascular volume status and the nature of anemia in patients with heart failure, we performed a blood volume analysis (BVA) using I131-radiolabeled albumin (1). The patient’s BVA revealed an extreme plasma volume excess as well as dilutional anemia based on a severe red blood cell excess (Figure 2).Figure 2 BVA Results\n\nBlood volume analysis (BVA) using I131-radiolabeled albumin showing an extreme plasma volume excess and severe red blood cell excess. BV = blood volume; PV = plasma volume; RCV = red blood cell volume.\n\nNext-generation sequencing of a comprehensive cardiac genetic panel revealed a pathogenic missense mutation in the gene MYBPC3 (coding deoxyribonucleic acid 1624: guanine to cytosine). It also revealed variants of unknown significance in the genes TTN, GAA, and DSG2.\n\nManagement\n\nThe patient underwent aggressive diuresis with furosemide infusion and metolazone, and he required low-dose inotropic support for worsening right heart failure and cardiorenal syndrome. He was anticoagulated with heparin infusion and started on amiodarone, which resulted in modest rate control of his AF. A rhythm control strategy was not pursued due to low likelihood of maintaining sinus rhythm given the patient’s severe left atrial enlargement. Due to lack of effective medical stabilization and mechanical support options, he was listed for heart transplantation, and he underwent a successful transplant with an uncomplicated post-transplant course. His oxygen requirement resolved several days after his transplantation, and his acute kidney injury resolved before discharge.\n\nDiscussion\n\nSevere biatrial enlargement can be seen in RCM as a result of high atrial filling pressures and chronic remodeling. RCM, characterized by severe diastolic dysfunction secondary to increased myocardial stiffness, has a broad differential diagnosis, including infiltrative disorders (e.g., amyloidosis, sarcoidosis), storage diseases (e.g., hemochromatosis, Fabry’s disease), endomyocardial disorders, and hereditary RCM (2). Hereditary RCM is caused by sarcomeric and cytoskeletal gene mutations with autosomal dominant inheritance and variable penetrance due to epigenetic and environmental factors (3,4).\n\nThe patient carried a missense mutation in the gene encoding myosin-binding protein-C, which is involved in sarcomere formation, organization, and function. Mutations in MYBPC3 can cause hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy, and RCM (4,5). Although the mutation this patient carried (MYBPC3:c.1624G>C) has been reported to be causative in HCM, it has not been reported to cause RCM (6). Pathological analysis of his explanted heart showed biventricular hypertrophy (LV posterior wall thickness of 1.4 cm, septal wall thickness of 1.5 cm, and right ventricular wall thickness of 0.7 cm), as well as myocyte hypertrophy and mild focal myocyte disarray on histology, which can be seen in both HCM and hereditary RCM. Taken together, the patient’s clinical presentation highlights the overlap between these 2 hereditary disorders and emphasizes the value of genetic testing in idiopathic RCM to improve genotype–phenotype correlations. Moreover, genetic testing in cases with a high index of suspicion for disease inheritance should be considered to help identify at-risk family members and avoid delays in diagnosis and treatment (7).\n\nManagement of RCM, as with other forms of diastolic heart failure, involves optimizing volume status with diuretic agents. Notably, the patient’s BVA revealed massive intravascular plasma volume expansion. AF is commonly associated with RCM and warrants systemic anticoagulation. Heart transplantation should be considered for suitable candidates with American College of Cardiology/American Heart Association Stage D heart failure from RCM (8).\n\nFollow-Up\n\nThe patient did well after cardiac transplantation, with significant improvement in symptoms and functional capacity. Results of his latest heart biopsy show no evidence of rejection. He has been referred for follow-up in our Genetics Clinic. We have recommended genetic screening for his first-degree relatives, including a 35-year-old son and 10-year-old daughter.\n\nConclusions\n\nThe authors present a case of inherited RCM caused by an MYBPC3 mutation in a patient with severe biatrial enlargement and rapid symptom progression who ultimately underwent a successful heart transplantation. The evaluation of RCM requires an understanding of its varied etiologies. Genetic testing for hereditary RCM should be considered when secondary causes have been excluded. Select patients with end-stage RCM may be referred for evaluation for heart transplantation.\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nInformed consent was obtained for this case.\n\nAppendix\n\nFor supplemental videos, please see the online version of this paper.\n==== Refs\nReferences\n\n1 Fudim M. Miller W.L. Calculated estimates of plasma volume in patients with chronic heart failure—comparison with measured volumes J Card Fail 24 2018 553 560 30098381\n2 Pereira N.L. Grogan M. Dec G.W. Spectrum of restrictive and infiltrative cardiomyopathies J Am Coll Cardiol 71 2018 1130 1148 29519355\n3 Gallego-Delgado M. Delgado J. Brossa-Loidi V. Idiopathic restrictive cardiomyopathy is primarily a genetic disease J Am Coll Cardiol 67 2016 3021 3023 27339502\n4 Burke M.A. Cook S.A. Seidman J.G. Seidman C.E. Clinical and mechanistic insights into the genetics of cardiomyopathy J Am Coll Cardiol 68 2016 2871 2886 28007147\n5 Wu W. Lu C.X. Wang Y.N. Novel phenotype-genotype correlations of restrictive cardiomyopathy with myosin-binding protein C (MYBPC3) gene mutations tested by next-generation sequencing J Am Heart Assoc 4 2015 e001879\n6 Walsh R. Thomson K.L. Ware J.S. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples Genet Med 19 2017 192 203 27532257\n7 Hershberger R.E. Lindenfeld J. Mestroni L. Seidman C.E. Taylor M.R.G. Towbin J.A. Genetic evaluation of cardiomyopathy—a Heart Failure Society of America practice guideline J Card Fail 15 2009 83 97 19254666\n8 Yancy C.W. Jessup M. Bozkurt B. 2013 ACCF/AHA guideline for the management of heart failure J Am Coll Cardiol 62 2013 e147 e239 23747642\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-0849",
"issue": "1(4)",
"journal": "JACC. Case reports",
"keywords": "AF, atrial fibrillation; BVA, blood volume analysis; HCM, hypertrophic cardiomyopathy; LV, left ventricular; RCM, restrictive cardiomyopathy; cardiac transplant; cardiomyopathy; genetic disorders; imaging; restrictive",
"medline_ta": "JACC Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101757292",
"other_id": null,
"pages": "588-591",
"pmc": null,
"pmid": "34316885",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "26163040;23747642;29519355;30098381;19254666;27532257;28007147;27339502",
"title": "A Case of Rare Inherited Restrictive Cardiomyopathy With Severe Biatrial Enlargement.",
"title_normalized": "a case of rare inherited restrictive cardiomyopathy with severe biatrial enlargement"
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"companynumb": "US-MYLANLABS-2020M1023137",
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"abstract": "The role of chemotherapy in low-/intermediate-grade neuroendocrine tumors (NETs) is still debated. We present the results of an Italian multicenter retrospective study evaluating activity and toxicity of oxaliplatin-based chemotherapy in patients with advanced NETs.\n\n\n\nClinical records from 5 referral centers were reviewed. Disease control rate (DCR) corresponding to PR + SD (partial response + stable disease) at 6 months, progression-free survival (PFS), overall survival (OS) and toxicity were calculated. Ki67 labeling index, grade of differentiation and excision- repair-cross-complementing group 1 (ERCC-1) were analyzed in tissue tumor samples.\n\n\n\nSeventy-eight patients entered the study. Primary sites were: pancreas in 46, gastrointestinal in 24, lung in 19 and unknown in 10% of patients. The vast majority were G2 (2010 WHO classification). Eighty-six percent of the patients were metastatic, and 87% were pretreated and progressive to previous therapies. Sixty-five percent of the patients received capecitabine/oxaliplatin (CAPOX), 6% gemcitabine/oxaliplatin (GEMOX), and 29% leucovorin/fluorouracil/oxaliplatin (FOLFOX-6). PR occurred in 26% of the patients, half of them with pancreatic NETs, and SD in 54%. With a median follow-up of 21 months, the median PFS and OS were 8 and 32 months with 70 and 45 events, respectively. The most frequent G3 toxicities were neurological and gastrointestinal. ERCC-1 immunohistochemical overexpression was positive in 4/28 evaluated samples, with no significant correlation with clinical outcome.\n\n\n\nThis analysis suggests that oxaliplatin-based chemotherapy can be active with a manageable safety profile in advanced NETs irrespective of the primary sites and tumor grade. The 80% DCR and 8-month PFS could justify a prospective study in NETs with intermediate biological characteristics, especially with pancreatic primary tumors.",
"affiliations": "Gastrointestinal Medical Oncology and Neuroendocrine Tumors Unit, European Institute of Oncology, Milan, Italy.",
"authors": "Spada|Francesca|F|;Antonuzzo|Lorenzo|L|;Marconcini|Riccardo|R|;Radice|Davide|D|;Antonuzzo|Andrea|A|;Ricci|Sergio|S|;Di Costanzo|Francesco|F|;Fontana|Annalisa|A|;Gelsomino|Fabio|F|;Luppi|Gabriele|G|;Nobili|Elisabetta|E|;Galdy|Salvatore|S|;Cella|Chiara Alessandra|CA|;Sonzogni|Angelica|A|;Pisa|Eleonora|E|;Barberis|Massimo|M|;Fazio|Nicola|N|",
"chemical_list": "D000970:Antineoplastic Agents; D001685:Biological Factors; D004268:DNA-Binding Proteins; D019394:Ki-67 Antigen; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; C071447:ERCC1 protein, human; D004720:Endonucleases",
"country": "Switzerland",
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"doi": "10.1159/000444087",
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"journal": "Neuroendocrinology",
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"medline_ta": "Neuroendocrinology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001685:Biological Factors; D015179:Colorectal Neoplasms; D004268:DNA-Binding Proteins; D004720:Endonucleases; D005260:Female; D006801:Humans; D019394:Ki-67 Antigen; D008297:Male; D008875:Middle Aged; D018358:Neuroendocrine Tumors; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D010190:Pancreatic Neoplasms; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "0035665",
"other_id": null,
"pages": "806-14",
"pmc": null,
"pmid": "26789262",
"pubdate": "2016",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Oxaliplatin-Based Chemotherapy in Advanced Neuroendocrine Tumors: Clinical Outcomes and Preliminary Correlation with Biological Factors.",
"title_normalized": "oxaliplatin based chemotherapy in advanced neuroendocrine tumors clinical outcomes and preliminary correlation with biological factors"
} | [
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"companynumb": "IT-CIPLA LTD.-2016IT00779",
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"activesubstancename": "OXALIPLATIN"
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"abstract": "OBJECTIVE\nStrategies for limiting the extent of bowel resection in cases of enterocutaneous or interenteric fistulas in severely active Crohn's disease are urgently necessary. Anti-inflammatory therapy with tumor necrosis factor alpha (anti-TNF alpha) inhibitors has positive impact on fistulizing Crohn's disease. We describe a case of a 32-year-old male suffering from enterocutaneous fistula in severely active Crohn's disease.\n\n\nMETHODS\nThe patient's clinical course and data of therapy monitoring before bowel resection were reviewed and compared to the pretherapeutic findings. In addition, the reports of surgery and histopathological workup were evaluated and a clinical follow-up was performed. The literature on anti-TNF alpha treatment in fistulizing Crohn's disease was surveyed.\n\n\nRESULTS\nA 32-year-old male with an 8-year history of Crohn's disease and condition after previous ileocecal and sigmoid resection at the age of 28 presented with increasing pain in the middle-right abdomen. Laboratory and radiologic assessment detected elevated C-reactive protein and presence of a conglomerate of inflammatory thickened and narrowed small intestine involving the neoterminal ileum and enteroenteric fistulas. Ileocolonoscopy showed a stenosing inflammation of the neoterminal ileum. After initial anti-infective therapy, as a result of an interdisciplinary decision, preoperative anti-TNF alpha treatment was performed to achieve limited bowel resection. After declining of inflammation, limited bowel resection was carried out successfully.\n\n\nCONCLUSIONS\nPreoperative therapy with anti-TNF alpha might potentially reduce inflammation to subsequently limit the extent of bowel resection in selected cases of enterocutaneous or interenteric fistulas in severely active Crohn's disease. We describe an impressive case in which such therapeutic approach was carried out.",
"affiliations": "Department of Surgery and Transplantation, University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany.;Department of Surgery and Transplantation, University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany.;Department of Surgery and Transplantation, University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany.;Department of Radiology, University of Tuebingen, Hoppe-Seyler-Strasse 3, Tuebingen, Germany.;Department of Internal Medicine I, University of Tuebingen, Otfried-Müller-Strasse 10, Tuebingen, Germany.;Department of Internal Medicine I, University of Tuebingen, Otfried-Müller-Strasse 10, Tuebingen, Germany.;Department of Surgery and Transplantation, University of Tuebingen, Hoppe-Seyler-Strasse 3, 72076, Tuebingen, Germany. claudius.falch@med.uni-tuebingen.de.",
"authors": "Wilhelm|Peter|P|;Kirschniak|Andreas|A|;Johannink|Jonas|J|;Kaufmann|Sascha|S|;Klag|Thomas|T|;Wehkamp|Jan|J|;Falch|Claudius|C|http://orcid.org/0000-0003-1595-7422",
"chemical_list": "D014409:Tumor Necrosis Factor-alpha",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00384-018-3206-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0179-1958",
"issue": "34(2)",
"journal": "International journal of colorectal disease",
"keywords": "Anti-TNF therapy; Enterocutaneous fistula; IBD; Inflammatory bowel disease; Surgery in Crohn’s disease",
"medline_ta": "Int J Colorectal Dis",
"mesh_terms": "D000328:Adult; D003113:Colonoscopy; D003424:Crohn Disease; D013505:Digestive System Surgical Procedures; D006801:Humans; D007412:Intestinal Fistula; D008297:Male; D011300:Preoperative Care; D014057:Tomography, X-Ray Computed; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8607899",
"other_id": null,
"pages": "369-373",
"pmc": null,
"pmid": "30498853",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10565383;14764257;14985485;16151544;19801322;23896172;24030229;25474276;26897946;27958285;28147371;28522944;29300710;8101267",
"title": "Enterocutaneous fistula in severely active Crohn's disease: preoperative anti-TNF alpha treatment to limit bowel resection-report of a case.",
"title_normalized": "enterocutaneous fistula in severely active crohn s disease preoperative anti tnf alpha treatment to limit bowel resection report of a case"
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"companynumb": "DE-BAUSCH-BL-2019-004078",
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"occurcountry": "DE",
"patient": {
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"actiondrug": "1",
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"activesubstancename": "MESALAMINE"
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"abstract": "Immune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs.\n\n\n\nWe retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors.\n\n\n\nAmong patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes.\n\n\n\nRoutine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.",
"affiliations": "Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA igor.puzanov@roswellpark.org.;CPL Associates, Buffalo, New York, USA.;Department of Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA.;CPL Associates, Buffalo, New York, USA.;Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York, USA.;Department of Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA.;Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.;CPL Associates, Buffalo, New York, USA.;CPL Associates, Buffalo, New York, USA.;Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.;Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA.;Department of Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA.;Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.;Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.;Division of Cancer Treatment and Diagnosis/Developmental Therapeutics Program, National Cancer Institute, Rockville, Maryland, USA.;Department of Medicine, Division of Hematology and Oncology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA.;Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA.;Department of Cardiovascular Medicine, The University of Texas at Houston/MD Anderson Cancer Center, Houston, Texas, USA.;Department of Internal Medicine, Memorial Hospital West, Pembroke Pines, Florida, USA.;Department of Internal Medicine, Rochester General Hospital, Rochester, New York, USA.;Department of Cardiovascular Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA.;CPL Associates, Buffalo, New York, USA.",
"authors": "Puzanov|Igor|I|;Subramanian|Poornima|P|0000-0002-6449-6549;Yatsynovich|Yan V|YV|;Jacobs|David M|DM|;Chilbert|Maya R|MR|;Sharma|Umesh C|UC|;Ito|Fumito|F|0000-0002-6866-671X;Feuerstein|Steven G|SG|;Stefanovic|Filip|F|;Switzer|Benjamin|B|0000-0001-8150-1963;Hicar|Mark D|MD|;Curtis|Anne B|AB|;Spangenthal|Edward J|EJ|;Dy|Grace K|GK|;Ernstoff|Marc S|MS|0000-0002-8132-7069;Vachhani|Pankit|P|;Page|Brian J|BJ|;Agrawal|Nikhil|N|;Khunger|Arjun|A|;Kapoor|Ankita|A|;Hattoum|Alexander|A|;Jerome|Schentag J|SJ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/jitc-2021-002553",
"fulltext": "\n==== Front\nJ Immunother Cancer\nJ Immunother Cancer\njitc\njitc\nJournal for Immunotherapy of Cancer\n2051-1426\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34162715\njitc-2021-002553\n10.1136/jitc-2021-002553\nClinical/Translational Cancer Immunotherapy\n1506\n2435\nOriginal researchClinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis\nPuzanov Igor 1\nhttp://orcid.org/0000-0002-6449-6549\nSubramanian Poornima 2\nYatsynovich Yan V 3\nJacobs David M 24\nChilbert Maya R 4\nSharma Umesh C 3\nhttp://orcid.org/0000-0002-6866-671X\nIto Fumito 567\nFeuerstein Steven G 24\nStefanovic Filip 28\nhttp://orcid.org/0000-0001-8150-1963\nSwitzer Benjamin 1\nHicar Mark D 9\nCurtis Anne B 3\nSpangenthal Edward J 1\nDy Grace K 1\nhttp://orcid.org/0000-0002-8132-7069\nErnstoff Marc S 10\nVachhani Pankit 11\nPage Brian J 1\nAgrawal Nikhil 12\nKhunger Arjun 13\nKapoor Ankita 14\nHattoum Alexander 15\nJerome Schentag J 24\n1 Department of Medicine, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA\n2 CPL Associates, Buffalo, New York, USA\n3 Department of Medicine, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA\n4 Department of Pharmacy Practice, University at Buffalo School of Pharmacy and Pharmaceutical Sciences, Buffalo, New York, USA\n5 Center for Immunotherapy, Roswell Park Comprehensive Cancer Center, Buffalo, New York, USA\n6 Department of Surgical Oncology, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA\n7 Department of Surgery, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, NY, USA\n8 Department of Biomedical Engineering, University at Buffalo School of Engineering and Applied Sciences, Buffalo, New York, USA\n9 Department of Pediatrics, University at Buffalo Jacobs School of Medicine and Biomedical Sciences, Buffalo, New York, USA\n10 Division of Cancer Treatment and Diagnosis/Developmental Therapeutics Program, National Cancer Institute, Rockville, Maryland, USA\n11 Department of Medicine, Division of Hematology and Oncology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USA\n12 Department of Cardiovascular Medicine, The University of Texas at Houston/MD Anderson Cancer Center, Houston, Texas, USA\n13 Department of Internal Medicine, Memorial Hospital West, Pembroke Pines, Florida, USA\n14 Department of Internal Medicine, Rochester General Hospital, Rochester, New York, USA\n15 Department of Cardiovascular Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA\nCorrespondence to Igor Puzanov; igor.puzanov@roswellpark.org\n2021\n23 6 2021\n9 6 e00255327 5 2021\n© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.\n\nBackground\n\nImmune checkpoint inhibitors (ICI) have emerged as a front-line therapy for a variety of solid tumors. With the widespread use of these agents, immune-associated toxicities are increasingly being recognized, including fatal myocarditis. There are limited data on the outcomes and prognostic utility of biomarkers associated with ICI-associated myocarditis. Our objective was to examine the associations between clinical biomarkers of cardiomyocyte damage and mortality in patients with cancer treated with ICIs.\n\nMethods\n\nWe retrospectively studied 23 patients who developed symptomatic and asymptomatic troponin elevations while receiving ICI therapy at a National Cancer Institute-designated comprehensive cancer center. We obtained serial ECGs, troponin I, and creatine kinase-MD (CK-MB), in addition to other conventional clinical biomarkers, and compared covariates between survivors and non-survivors.\n\nResults\n\nAmong patients with myocarditis, higher troponin I (p=0.037) and CK-MB (p=0.034) levels on presentation correlated with progression to severe myocarditis. Higher troponin I (p=0.016), CK (p=0.013), and CK-MB (p=0.034) levels were associated with increased mortality, while the presence of advanced atrioventricular block on presentation (p=0.088) trended toward increased mortality. Weekly troponin monitoring lead to earlier hospitalization for potential myocarditis (p=0.022) and was associated with decreased time to steroid initiation (p=0.053) and improved outcomes.\n\nConclusions\n\nRoutine troponin surveillance may be helpful in predicting mortality in ICI-treated patients with cancer in the early phase of ICI therapy initiation. Early detection of troponin elevation is associated with earlier intervention and improved outcomes in ICI-associated myocarditis. The recommended assessment and diagnostic studies guiding treatment decisions are presented.\n\nimmunotherapy\nNHLBI K08HL131987 NIH/NCI K08CA197966 http://dx.doi.org/10.13039/100007038 Lung Cancer Research Foundation LC180245 University of Buffalo Roswell Park Alliance Foundation LC180245 http://dx.doi.org/10.13039/100005190 Melanoma Research Alliance Department of Defense National Cancer Institute (NCI) P30CA016056 http://dx.doi.org/10.13039/100006398 Roswell Park Alliance Foundation, Roswell Park Cancer Institute National Center for Advancing Translational Sciences of the NIH UL1TR001412 special-featureunlocked\n==== Body\nIntroduction\n\nThe emergence of immune checkpoint inhibitor (ICI) therapy has dramatically altered cancer treatment over the last decade. The ICI class of current Food and Drug Administration-approved drugs includes anti-programmed cell death 1 (anti-PD-1) antibodies (nivolumab, pembrolizumab, and cemiplimab), anti-programmed cell death ligand-1 (anti-PD-L1) antibodies (atezolizumab, durvalumab, and avelumab), and anti-cytotoxic T lymphocyte-associated antigen (CTLA-4) agents (ipilimumab). The PD-1/PD-L1 and CTLA-4 pathways provide negative feedback to immune activation; however, their blockade may lead to development of autoimmune toxicities.\n\nImmune-related adverse events (irAEs) associated with ICI therapy can develop in virtually any organ and can limit their clinical utility.1 Cardiotoxicities, including myocarditis2 3 can result from ICI therapy. Myocarditis remains relatively rare, with a reported incidence of 0.06%–1%, although the precise incidence is unknown.2 ICI-associated myocarditis results in high case fatality, estimated to be around 50%.3 The prevalence of fatal myocarditis is increased for patients on anti-PD-1 and anti-CTLA4 combination immunotherapy.4 There exists uncertainty regarding the optimal treatment strategy for ICI-induced myocarditis, with a variety of immunosuppressants currently utilized in clinical practice, including high dose steroids, anti-thymocyte globulin (ATG), and abatacept.5\n\nPreviously, a single center study estimated the prevalence of ICI-associated myocarditis at 1.14%, with a variety of ICIs utilized.6 In that study, steroid treatment was initiated in 89% of ICI-associated myocarditis cases and lower doses of steroids were associated with higher residual troponin and higher major adverse cardiac event rates.6 Most reported cases of fulminant myocarditis appeared to be severe, requiring hospitalization and often intensive care unit (ICU) admission. We recently reported a case series of patients with severe myocarditis associated with ICI therapy,7 and we found a similar mortality but variable steroid treatment response.\n\nTreatment of patients with ICI-associated myocarditis has been largely based on expert consensus encompassing grade ≥3 toxicity.5 Cases of ICI-associated severe myocarditis have been successfully treated with systemic corticosteroid therapy.2 8–13 Although some steroid-refractory cases responded to second-line immunosuppressive agents,14 most were clinically advanced with a fulminant course before steroid initiation.15–18 Recently, cases of a milder or ‘subclinical’ ICI-associated myocarditis have been reported.17 19 The incidence, treatment, and outcomes of mild ‘subclinical’ cases of myocarditis (grade 1–2), often managed without hospitalization, remain an area of further investigation.\n\nWe report a retrospective study of 15 patients with probable ICI-associated myocarditis, including 11 patients with severe, acute myocarditis and 4 patients with subclinical myocarditis. Our objective was to examine clinical characteristics, outcomes, and response to steroid therapy in these patients. Additionally, a subcohort analysis comparing clinical outcomes of patients with subclinical myocarditis with severe cases was performed. In these patients, we studied the association between troponin monitoring and clinical outcomes.\n\nMethods\n\nThis is a retrospective single center study from an National Cancer Institute-designated comprehensive cancer center.\n\nPatients\n\nCases were identified from the Roswell Park Comprehensive Cancer Center (RPCCC) electronic medical health record from January 2016 to January 2020. Patients included in this study had an elevated cardiac troponin I defined as ≥0.06 ng/mL during ICI therapy. Troponin levels were obtained either in the context of routine troponin monitoring or otherwise when prompted by the patient’s presentation. Patients who were determined by clinical assessment without an alternative cause for elevated troponin (eg, ischemic heart disease) and had a Naranjo Score20 of ‘possible’ to ‘definite’ elevated troponin as a result of ICI therapy were included in this study.\n\nTroponin and ECG monitoring\n\nThe RPCCC Melanoma Program clinicians (IP and MSE) implemented a practice of weekly troponin monitoring in patients who are initiating ICI treatment, with the intention of facilitating early detection and treatment of cardiotoxicity. Patients were selected based on physicians’ choice. Under this monitoring protocol, patients were monitored every week for the first 4–6 weeks following the initiation of ICI treatment. Cases with elevated troponin were referred to a cardio-oncology team for subsequent evaluation. All patients in the study group were assessed by ECGs before ICI treatment initiation and after their presentation with signs of cardiotoxicity.\n\nMyocarditis subgroups\n\nPatients were considered to have myocarditis if they met the criteria proposed in the position statement of the European Society of Cardiology Working group,21 displaying either symptomatic troponin elevation or troponin elevation with newly abnormal ECG or functional or structural abnormalities on cardiac imaging (cardiac echocardiogram and cardiac MRI), in the absence of angiographically-detected coronary artery disease or contributing cardiovascular history. Patients were categorized as ‘severe’ acute myocarditis if they displayed a grade 3–4 toxicity according to criteria adapted from the Common Terminology Criteria for Adverse Events V.5.022 (specific criteria are presented in the online supplemental table 1). Patients were categorized as exhibiting ‘subclinical’ myocarditis if they displayed a persistent low-grade troponin elevation not requiring hospitalization (grade 2 or less toxicity), in the absence of ischemic supply/demand mismatch etiologies, angiographically-detected coronary artery disease, contributing cardiovascular history or alternative causes. For more details on patient severity scoring and data abstraction, please see the Supplementonline supplemental file 1.\n\n10.1136/jitc-2021-002553.supp1 Supplementary data\n\nEvaluation and treatment of suspected ICI-associated myocarditis were driven by the degree of troponin elevation and ECG changes. All patients were referred to cardio-oncology for consultation, and were assessed by repeat ECG, cardiac biomarkers including troponin, creatine kinase (CK), CK-MB, B-type natriuretic peptide (BNP), echocardiogram. Decision was made to follow as outpatient with repeat evaluation in 24 hours or for inpatient management. Patients with high probability of severe myocarditis (troponin >5–10×upper limit of normal, low suspicion for acute coronary syndrome, ECG changes including atrioventricular (AV) block), received 1 g of methylprednisolone intravenously in the clinic, prior to transfer. Inpatient management included evaluation for acute coronary syndrome, cardiac MRI (CMR), and further steroid therapy. Once myocarditis was confirmed, intravenous steroids (typically 1 g of methylprednisolone daily) were continued for 3–5 days followed by conversion to a long-term oral steroid taper.\n\nStatistical analysis\n\nSummary statistics were computed, including medians and IQRs for continuous variables and percentages for categorical variables. All analyses included only patients with documented myocarditis (n=15). Cardiac parameters at presentation were compared using Wilcoxon rank-sum tests for continuous variables and χ2 or Fisher’s exact test, as appropriate, for categorical variables. Latency to steroid initiation was compared with mortality using a Wilcoxon rank-sum test. The prognostic significance of specific biomarkers (troponin, BNP, CK, and CK-MB) at symptom onset and their relationship with myocarditis-associated mortality were first explored using logistic regression models. Cox proportional hazard regression models were then used to calculate the HRs and 95% CIs associated with the risk of 90-day myocarditis-associated mortality. Patients were entered into the survival analysis at the time of symptom onset for myocarditis and were followed for 90 days to determine the survival status. We explored the discriminatory ability of each biomarker for predicting mortality using area under the curve of receiver operating characteristic (ROC) plots. The optimal cut point for the ROC plots was identified using the Youden’s Index. Kaplan-Meier survival curves and log-rank tests were used to assess the association between the identified cut points and 90-day myocarditis-associated mortality. All statistical tests were two-tailed with a p<0.05 level of significance and were performed using Microsoft Excel 2019 (Microsoft Corporation) and SAS V.9.4 (SAS Institute).\n\nResults\n\nWe identified a total of 1001 patients who received one or more ICIs from January 2016 to January 2020. Among all patients treated with ICIs, abnormal troponin elevation (≥0.06 ng/mL) was identified in 34 patients in the context of immunotherapy administration. Of the 34 patients initially screened, 4 patients were excluded based on a lack of temporal relationship between checkpoint administration and troponin elevation (greater than 2 months from the last dose of checkpoint inhibitor to first troponin elevation), and 7 patients were excluded due to underlying sepsis. Following exclusion, we found evidence of probable checkpoint-associated toxicity in 23 patients, out of which, 15 patients were determined to have ICI-associated myocarditis. Eight patients were determined to have other causes for troponin rise, such as acute coronary syndromes and exacerbations of heart failure. Those cases are presented in the Supplement under online supplemental results. Of the entire cohort of ICI-treated patients, 339 (34%) underwent serial troponin measurements with at least two sequential tests.\n\nPatient characteristics\n\nIndividual characteristics and case summaries of patients with severe myocarditis and subclinical myocarditis are presented in online supplemental tables 2–5. Summary characteristics of the two cohorts are presented in table 1. The most common indications for ICI therapy were melanoma (n=9), non-small cell lung cancer (n=3) and squamous cell carcinoma (n=2). The most common comorbidities were hypertension (93.3%), hyperlipidemia (40%), coronary artery disease (33.3%), atrial fibrillation (26.6%), history of myocardial infarction (26.6%), peripheral vascular disease (20%), history of pulmonary embolism (13.3%), chronic kidney disease (13.3%), hypothyroidism (13.3%), and diabetes (6.6%).\n\nTable 1 Clinical characteristics of patients with immune checkpoint inhibitor-associated severe and subclinical myocarditis\n\n\tSevere myocarditis (n=11)\tSubclinical myocarditis (n=4)\tP value\t\nMedian age (IQR)\t73 (66–79)\t73.5 (62.8–80)\t0.448\t\n% female\t3/11 (27.3)\t1/4 (25)\t1\t\n% pembrolizumab\t5/11 (45.5)\t2/4 (50)\t1\t\n% nivolumab\t5/11 (45.5)\t2/4 (50)\t1\t\n% atezolizumab\t1/11 (9.1)\t0/4 (0)\t1\t\nMedian days to onset (IQR)\t31 (18.5–116)\t51.5 (37.8–88)\t0.180\t\nMedian days from previous dose (IQR)\t16 (13.5–20.5)\t18.5 (4–26.25)\t0.397\t\nMortality from myocarditis\t4/11 (36.4%)\t0/4 (0%)\t0.516\t\nUnderlying conditions\t\t\t\t\n Hypertension\t11/11 (100%)\t3/4 (75%)\t0.267\t\n Heart failure with reduced ejection fraction\t2/11 (18.2%)\t1/4 (20%)\t1\t\n Coronary artery disease\t3/11 (27.3%)\t2/4 (50%)\t0.560\t\n History of myocardial infarction\t2/11 (18.2%)\t2/4 (50%)\t0.275\t\n Hyperlipidemia\t4/11 (36.4%)\t2/4 (50%)\t1\t\nConcurrent symptoms\t\t\t\t\n Dyspnea\t5/11 (45.5%)\t3/4 (75%)\t0.569\t\n Chest pain\t3/11 (27.3%)\t0/4 (0%)\t0.516\t\n Colitis\t1/11 (9%)\t2/4 (50%)\t0.154\t\n Myalgia\t2/11 (18.2%)\t0/4 (0%)\t1\t\n Edema\t2/11 (18.2%)\t1/4 (25%)\t1\t\nConcurrent side effects\t\t\t\t\n Myasthenia gravis\t2/11 (18.2%)\t0/4 (0%)\t1\t\n Pneumonitis\t0/11 (0%)\t1/4 (25%)\t0.267\t\nLaboratory studies on presentation\t\t\t\t\n Troponin\t1.52 (0.33–5.78)\t0.15 (0.10–0.28)\t0.037\t\n B-type natriuretic peptide\t423 (108–664)\t93 (39–659)\t0.288\t\n Creatine kinase (CK)\t465 (76–1445)\t54 (35–375)\t0.229\t\n CK-MB\t68 (6.9–138)\t1.80 (1.15–3.05)\t0.034\t\nLaboratory studies presented as median (IQR) and analyzed using the Wilcoxon rank-sum test.\n\nNo statistically significant differences were observed in the rates of cardiovascular comorbidities between severe and subclinical myocarditis cohorts (table 1). There were no statistically significant differences in the rate of use of specific ICI agents between the two cohorts (table 1).\n\nMyocarditis presentation\n\nThe median time from the initiation of checkpoint therapy to presentation of clinical myocarditis was 31 days (IQR 18.5–116) for patients with severe myocarditis and 51.5 days (IQR 37.75–88) in the subclinical myocarditis cohorts, a difference that was not statistically significant. Dyspnea was the most common symptom in patients in both the severe myocarditis (45.5%) and subclinical myocarditis (75%) groups (table 1). Chest pain was a less common presentation, reported in three patients (27.3%) with severe myocarditis (table 1). Other reported signs and symptoms included chills, pruritus, bradycardia, myalgia, and peripheral edema (online supplemental tables 2 and 4).\n\nConcomitant irAEs occurred in 73% (8/11) of patients with severe myocarditis and 75% (3/4) of patients with subclinical myocarditis, a difference that was not statistically significant. Common irAEs included colitis (20%), thyroiditis (20%), myasthenia gravis (13.3%), pneumonitis (6.7%), hepatitis (6.7%), pancreatitis (6.7%), and optic neuritis (6.7%). There were no statistically significant differences in the rates of specific irAEs between the severe and subclinical myocarditis cohorts (table 1). There is no distinct pattern regarding whether these concomitant irAEs occurred before or after the development of myocarditis, with 5 out of 11 patients experiencing other irAEs before myocarditis, while the other 6 patients experienced these irAEs either after or contemporaneously.\n\nDespite similar baseline characteristics in those with severe myocarditis versus those with subclinical myocarditis (table 1), there were notable differences in their cardiac diagnostics (table 1). Troponin on presentation was significantly higher in patients who progressed to severe myocarditis (n=11, median 1.52 ng/mL, IQR 0.33–5.78) than patients with subclinical myocarditis (n=4, median 0.15 ng/mL, IQR, 0.10–0.28, p=0.037). CK-MB on presentation was also significantly higher in patients who progressed to severe myocarditis (n=7, median 68 ng/mL, IQR 6.9–138) than in patients with subclinical myocarditis (n=4, median 1.8 ng/mL, IQR 1.15–3.05, p=0.034). BNP tended to be higher on presentation in patients with severe myocarditis (n=11, median 423 pg/mL, IQR 108–66) than patients with subclinical myocarditis (n=4, median 93 pg/mL, IQR 39–659) but this difference was not statistically significant (p=0.288) (table 1). CK at presentation was also higher in patients with severe myocarditis (n=10, median 465 IU/L, IQR 76–1445) than in patients with subclinical myocarditis (n=4, median 54 IU/L, IQR 35–375) but this difference was also not statistically significant (p=0.229).\n\nAll patients with severe myocarditis were treated with steroids. Patients #1 and #3 were additionally treated with ATG while patient #5 was additionally treated with infliximab (figure 1). Patients with subclinical myocarditis were treated either by halting immunotherapy and supportive care alone, or by halting immunotherapy and initiating steroids (figure 1, online supplemental table 4).\n\nFigure 1 Event timelines for patients with ICI-associated severe and subclinical myocarditis. Patient level timelines showing the time from symptom onset to death/myocarditis resolution, including all immunosuppressants used in treatment of ICI-associated myocarditis. Death in this figure includes death by all causes and exact cause of death is noted. ATG, anti-thymocyte globulin; ICI, immune checkpoint inhibitor; INF, infliximab; IV, intravenous steroids; PO, oral steroids.\n\nComparison of electrocardiographic, echocardiographic, and CMR assessment\n\nAll patients in both the severe and subclinical myocarditis groups had ECGs available before ICI initiation and after their presentation with signs of cardiotoxicity. Eight out of 11 patients with severe myocarditis (72.7%) had ECG abnormalities on presentation, while no significant ECG findings were seen in any of the patients with the subclinical form (p=0.021). The most common ECG abnormalities noted in the severe myocarditis group consisted of new AV block (55%) and right bundle branch block (36%) (online supplemental table 3). Presentation with advanced AV block trended toward an association with myocarditis-associated mortality (p=0.088) (table 2). No other ECG findings were associated with myocarditis-associated mortality (table 2).\n\nTable 2 Cardiac parameters among survivors and deceased patients\n\n\tSurvived (n=11)\tDeceased (n=4)*\tP value\t\nLaboratory studies on presentation\t\t\t\t\n Troponin\t0.33 (0.11–1.37)\t4.8 (3.3–8.9)\t0.016\t\n B-type natriuretic peptide\t230 (82–750)\t339 (134–564)\t1\t\n CK\t74 (32–144)\t2541 (876–5676)\t0.013\t\n CK-MB\t2.5 (1.5–7.5)\t90 (68–242)\t0.034\t\nElectrocardiographic\t\t\t\t\n First-degree AV block\t2/11 (18%)\t0/4 (0%)\t0.491\t\n Advanced AV block†\t1/11 (9%)\t3/4 (75%)\t0.088\t\n New Right Bundle Branch Block\t1/11 (9%)\t2/4 (50%)\t0.491\t\n Non-specific ST/T wave changes\t3/11 (27%)\t1/4 (25%)\t1\t\nLaboratory studies presented as median (IQR) and analyzed using the Wilcoxon rank-sum test.\n\n*Deceased includes patients who died due to myocarditis-related complications within a 90-day window.\n\n†Defined as: second-degree AV block Mobitz type I or II, high-grade AV block and third-degree AV block.\n\nAV, atrioventricular; CK, creatine kinase.\n\nIschemic evaluation with coronary angiography was performed in three patients with severe myocarditis, with no significant lesions found. No patients with subclinical myocarditis underwent ischemic evaluation. Gadolinium-enhanced CMR was performed in three patients with severe myocarditis with 66% (2/3 patients) demonstrating diagnostic Lake Louise criteria.23 The equivocal MRI of the third case was performed early in the patient’s clinical course, which has been associated with non-diagnostic findings previously.24 CMR protocol details are provided in the online supplemental file 1.\n\nTen patients in the severe myocarditis and three patients in the subclinical myocarditis cohorts had echocardiograms with estimated ejection fractions available for comparison. Left ventricular ejection fraction (LVEF) was estimated from echocardiograms by modified Simpson’s method. Left ventricular systolic dysfunction (LVEF ≤50%) was seen in 6 out of 10 patients in the severe myocarditis group where echocardiograms were available and in none of the patients in the subclinical myocarditis group (online supplemental tables 3 and 5). There was no statistically significant association between reduced LVEF and progression to severe myocarditis. There was also no statistically significant association between reduced LVEF and mortality, with death due to myocarditis occurring in 2 out of 4 patients (50%) with normal LVEF, while 5 out of 6 patients (83%) with reduced LVEF survived.\n\nTroponin monitoring and referral\n\nThree patients with severe myocarditis and one patient with subclinical myocarditis were among the 334 patients on a weekly troponin monitoring protocol at the time of their identified cardiotoxicity. The remaining 11 myocarditis presented with symptoms which prompted troponin measurement for cause. Serial troponin monitoring led to early initiation of steroids within 6 days of symptom onset in two severe myocarditis patients. Patients on a weekly troponin monitoring protocol (n=4) had significantly lower troponins on presentation (median 0.1 ng/mL, IQR 0.083–0.248 ng/mL) than patients who were not (n=11, median 1.52 ng/mL, IQR 0.405–4.8 ng/mL, p=0.022). There were no statistically significant differences in BNP, CK or CK-MB between patients who had troponin monitored weekly and those who were not. Patients identified on a weekly troponin monitoring protocol also had a shorter time to steroid initiation (n=4, median 4.5 days, IQR 2.25–6), than patients who were not (n=9, median 8 days, IQR 8–20 days, p=0.053). There were no deaths among patients who were on a weekly troponin monitoring protocol, while there were four deaths due to myocarditis among patients who were not monitored weekly. However, our analysis did not show a statistically significant difference in the rates of mortality between patients on troponin monitoring and those who were not.\n\nPrognostic significance of biomarkers\n\nIn total, 6 out of 15 (40%) patients with severe myocarditis died, 4 of whom died as a direct consequence of myocarditis (figure 1). Patient #1 was recovering from myocarditis when she succumbed to a hemorrhagic stroke, likely due to brain metastasis, which were found on autopsy. Patient #8 died of respiratory failure from concomitant ICI-associated axonal neuropathy. Troponin at onset was significantly higher in patients who died of myocarditis, (median 4.8 ng/mL, IQR 3.3–8.9) than survivors (median 0.33 ng/mL, IQR 0.11–1.37, p=0.016) (table 2). CK at onset was significantly higher in patients who died of myocarditis (median 2541 U/L, IQR 876–5676, p=0.013) than survivors (median 74 U/L, IQR 32–144) (table 2). CK-MB at onset was also significantly higher in patients who died of myocarditis (median 90 ng/mL, IQR 68–242) than in patients who survived (median 2.5 ng/mL, IQR 1.5–7.5, p=0.034) (table 2). BNP at onset did not differ significantly between patients who died of myocarditis (median 339 pg/mL, IQR 134–564) and survivors (median 230 pg/mL, IQR 82–750) (table 2).\n\nUnivariate logistic regression analysis for predictors of myocarditis-associated mortality is shown in table 3. Each one unit increase in troponin levels at onset was associated with a higher odds of death (OR 1.72, 95% CI 0.96 to 3.06, p=0.067). Higher levels of CK (OR 1.30, 95% CI 0.91 to 1.85) and CK-MB (OR 1.21, 95% CI 0.93 to 1.56) at onset were also associated with significantly higher odds of death, but these associations were not statistically significant.\n\nTable 3 Relationship between clinical characteristics at onset and 90-day myocarditis-associated mortality\n\n\tSurvived\n(n=11)\tDeceased*\n(n=4)\tOR\n(95% CI)\tP value\tUnivariate HR\n(95% CI)\tP value\tMultivariable HR\n(95% CI)\tP value\t\nTroponin (each 1-unit increase)\t0.33 (0.11 to 1.37)\t4.8 (3.3 to 8.9)\t1.72 (0.96 to 3.06)\t0.067\t1.47 (1.08 to 2)\t0.014\t2.55 (0.78 to 8.31)\t0.120\t\nB-type natriuretic peptide (each 100-unit increase)\t230 (82 to 750)\t339 (134 to 564)\t0.93 (0.73 to 1.18)\t0.553\t0.93 (0.76 to 1.16)\t0.555\t\t\t\nCreatine kinase (CK) (each 100-unit increase)\t74 (32 to 144)\t2541 (876 to 5676)\t1.30 (0.91 to 1.85)\t0.145\t1.05 (1.01 to 1.09)\t0.025\t1.11 (0.98 to 1.26)\t0.107\t\nCK-MB (each 10-unit increase)\t2.5 (1.5 to 7.5)\t90 (68 to 242)\t1.21 (0.93 to 1.56)\t0.156\t1.08 (0.99 to 1.17)\t0.051\t\t\t\n*Deceased includes patients who died due to myocarditis-related complications within a 90-day window.\n\nUnivariate Cox proportional hazard analysis for predictors of 90-day myocarditis-associated mortality are shown in table 3. Each one unit increase in troponin (HR 1.47, 95% CI 1.08 to 2, p=0.014) at onset was significantly associated with a higher risk of 90-day myocarditis-associated mortality. Higher CK levels (HR 1.05, 95% CI 1.01 to 1.09, p=0.025) were also associated with a higher risk of mortality. The significant variables were then included in multivariable Cox proportional hazard analysis for predictors of mortality. Higher troponin at onset was associated with a higher risk of 90-day myocarditis-associated mortality (HR 2.55, 95% CI 0.78 to 8.31) and trended toward significance (p=0.120). Likewise, although higher CK at onset appeared to be associated with mortality (HR 1.11, 95% CI 0.98 to 1.26) this was not statistically significant (p=0.107).\n\nKaplan-Meier survival curves at 90-day follow-up for troponin are shown in figure 2A, with a discriminating troponin defined as 3.73 ng/mL (sensitivity: 100%, specificity: 91%). For CK (figure 2B), a discriminating value of 1153 U/L (sensitivity: 75%, specificity: 90%) was selected. For CK-MB (figure 2C), a discriminating value of 99 ng/mL (sensitivity: 100%, specificity: 88%) was selected. Each discriminating value above was based on the maximized Youden’s Index obtained by ROC curves.\n\nFigure 2 Kaplan-Meier for cardiac biomarkers at onset and 90-day mortality. Each breakpoint was determined based on the maximized Youden’s Index obtained by receiver operating characteristic curves. (A) Kaplan-Meier of the relationship between troponin ≥3.73 ng/mL and 90-day myocarditis-associated mortality. Troponin elevation ≥3.73 ng/mL was associated with a statistically significantly increased risk of mortality (HR 10.34, 95% CI 1.07 to 100, p=0.044). (B) Kaplan-Meier of the relationship between creatine kinase (CK) at onset of ≥1153 IU/L and 90-day myocarditis-associated mortality. CK elevation of ≥1153 IU/L was associated with an increased risk of mortality (HR 4.26, 95% CI 0.60 to 30, p=0.115) but this relationship was not statistically significant. (C) Kaplan-Meier of the relationship between CK-MB at onset of ≥99 ng/mL and 90-day myocarditis-associated mortality. CK-MB elevation of ≥99 ng/mL was associated with an increased risk of mortality (HR 5.18, 95% CI 0.70 to 38, p=0.106), but this relationship was not statistically significant.\n\nPatients with troponin values of ≥3.73 ng/mL exhibited significantly increased risk of myocarditis-associated death at 90-day follow-up (HR 10.34, 95% CI 1.07 to 100, p=0.044). A trend toward higher likelihood of death at 90-day follow-up occurred with CK values ≥1153 U/L (HR 4.26, 95% CI 0.60 to 30 p=0.115) and CK-MB values ≥99 ng/mL (HR 5.18, 95% CI 0.70 to 38.2, p=0.106), however these associations were not statistically significant.\n\nOverall 90-day survival and all-cause mortality between severe ICI-associated myocarditis, ICI-associated subclinical myocarditis, and other ICI-associated cardiotoxicity groups were obtained through Kaplan-Meier and log-rank testing. The median survival for severe myocarditis patients was 75 days, with no statistically significant association between the three groups and 90-day overall survival (p=0.180) (figure 3).\n\nFigure 3 Ninety-day survival of patients with severe myocarditis (1), subclinical myocarditis (2), and other cardiotoxicities (3). Ninety-day survival did not significantly differ between the three groups of immune checkpoint inhibitor-associated toxicities.\n\nDiscussion\n\nOur study supports the role of proactive outpatient surveillance for early detection of ICI-associated myocarditis. Since no strongly predictive risk factors for ICI-associated myocarditis have yet been identified in the literature, we implemented serial troponin measurements for the first 6 weeks in patients treated with ICI. The results from this practice suggest reduced severity of disease and earlier treatment in patients so monitored. We found that patients who were monitored using serial weekly troponins had lower troponins on presentation and received steroid therapy more quickly compared with patients who were not monitored. Serial monitoring with weekly troponin allowed for earlier detection of myocarditis in three of our cases, all of which exhibited halted disease progression, normalization of cardiac biomarkers and improvement of left ventricular (LV) function on steroid treatment.\n\nAmong the biomarkers available, troponin I was the most reliable and early predictor of both progression to severe myocarditis and mortality. CK-MB on presentation was also found to be a reliable predictor of progression to severe myocarditis and mortality. CK on presentation was significantly correlated with myocarditis-associated death. BNP was not found to correlate significantly with adverse outcomes of progression to severe myocarditis or myocarditis-associated death, although these values tended to be higher in patients with more severe presentations. Our findings also corroborate the observation of ICI-associated subclinical myocarditis, which presents with lower cardiac biomarkers and a milder, shorter course.19\n\nIn addition, our study supports the role of prompt troponin and ECG evaluation of patients presenting with cardiac symptoms. Our experience also suggests consideration for cardiac evaluation in patients with myasthenia gravis, myositis, and other systemic irAEs, as these conditions were closely associated with myocarditis in our patient population. If severe myocarditis from ICI therapy is suspected, a multidisciplinary approach should be promptly implemented, and ICI therapy should be suspended until the cause of the troponin elevation is determined by the multidisciplinary team. Our recommended initial diagnostics for these patients include an expedited 12-lead ECG and echocardiographic assessment of LV function, followed by consideration for angiography or myocardial perfusion to exclude coronary artery disease. CMR should be pursued when available, as this is the best means of detecting myocardial inflammation associated with myocarditis.23 In our study, the diagnosis of clinically suspected myocarditis was defined as per Caforio et al,21 which takes into consideration the clinical as well as biochemical and ECG changes and relies less on invasive or imaging studies.23 CMR may be equivocal and in one of our cases, the patient had a negative CMR despite a clinical syndrome consistent with myocarditis early in his course. In cases of a non-diagnostic CMR but strong clinical suspicion for ICI myocarditis, endomyocardial biopsy or traditional positron emission tomography fluorodeoxyglucose may have a role.25 It is also important to note that patients with fulminant myocarditis often require ICU care and may not be suitable candidates for these imaging protocols.\n\nOnce ICI-associated myocarditis is confirmed, high dose steroids should be implemented without delay. Early use of high dose steroid therapy is crucial in all cases of ICI-associated myocarditis, and their use should be continued until troponin normalizes, ECG abnormalities subside, and LV systolic function improves. Serial surveillance imaging (echocardiography and CMR) is useful to determine the extent of myocardial damage and potential reversibility. Clinical deterioration and progression despite high dose corticosteroid therapy should prompt consideration and use of additional immunosuppressants.\n\nThe decision to restart ICIs in patients with ICI-associated myocarditis is a difficult question that has not been well studied. At present, the American Society of Clinical Oncology guideline recommends permanent cessation with grade 1 toxicity (abnormal cardiac biomarker testing including ECG),26 while some centers have proposed a cautious reinitiation of ICI therapy with or without low dose steroids.27 In our study, two patients with subclinical myocarditis (grade 1 toxicity) were re-introduced to immunotherapy following normalization of their cardiac parameters. In one case the troponin elevation returned, and ICI therapy was discontinued permanently. In the other case, reinitiation did not result in recurrence of cardiotoxicity. No patients in the severe myocarditis cohort were restarted on ICI therapy, as reinitiation was deemed to carry too high a risk of cardiac re-injury. A clinical algorithm for the assessment and management of ICI-treated patients with troponin elevations is presented in figure 4 based on our clinical experience but requires further validation.\n\nFigure 4 Algorithm for assessment and management of troponin elevation in patients receiving ICI therapy. Recommendations for the assessment and treatment of ICI-associated myocarditis presented include initial assessment for likelihood of ICI-associated toxicity, and further assessment and treatment guided by the grade of the toxicity. ATG, anti-thymocyte globulin; AV, atrioventricular; ICI, immune checkpoint inhibitor; IV, intravenous; IG, immunoglobulin; LV, left ventricular; RBBB, right bundle branch block.\n\nThe relationship between irAEs and ICI efficacy remains controversial.22 28–30 A large re-analysis of one ICI clinical trial involving over 1000 patients with melanoma reported that patients with a robust immune activation and many irAEs had longer progression-free survival times than comparable patients without irAEs.31 Additionally, a previous case report of two patients with melanoma who developed fulminant myocarditis revealed that T-cell clones infiltrating the myocardium were identical to those present in tumors,32 providing insights into the overlapping mechanisms of irAEs and the therapeutic effects of ICI treatment. Future studies, including a comprehensive analysis of immune signatures in the heart, tumors and circulating immune cells are required to better understand the mechanism of cardiac irAEs, cancer progression and its association with activation of the immune system.\n\nLimitations\n\nDue to the relative rarity of ICI-associated myocarditis, our data are limited by the small sample size and lack of power to demonstrate significance in secondary analyses. Although we recommend baseline followed by weekly troponin monitoring at ICI initiation, we did not establish this recommendation with a randomized study, hence the significance of its association with myocarditis outcomes may be questioned. Although our study lacked these advantages, the data we report shows that earlier detection for ICI-associated myocarditis results in less ICI-associated myocarditis mortality. In the future, detailed investigations of early intervention should use larger, multicenter data to better establish the role of steroid timing and dose on patient outcomes.\n\nConclusions\n\nTreatment with ICIs is associated with a spectrum of cardiotoxicities, including myocarditis, that range from subclinical to a severe form. In our study cohort, higher values of troponin and evidence of advanced conduction disease on ECG at presentation were associated with greater disease severity and mortality from ICI-associated myocarditis. Accordingly, a focus in ICI-treated patients that includes early detection of myocarditis, prompt cardio-oncology evaluation to rule out other etiologies, and expedited steroid treatment appears to provide a reduction in the risk of progression to fulminant and potentially lethal outcomes. Baseline and serial troponin measurements may contribute to the crucial step of early detection.\n\nData availability statement\n\nData are available upon reasonable request. Case level information is provided in the online supplement. All other relevant data are available from the corresponding author upon reasonable request.\n\nEthics statements\n\nPatient consent for publication\n\nNot required.\n\nEthics approval\n\nAll clinical procedures and protocols conformed to institutional guidelines and were approved by the institutional review board at the Roswell Park Comprehensive Cancer Center and at University at Buffalo.\n\nTwitter: @BenSwitzerDO, @Ankitakap\n\nContributors: Each author contributed significantly to this research article. IP helped organize this project, developed the main objectives of the article, collected and analyzed data and wrote sections of the manuscript. SJJ oversaw the project, contributed to its organization, developed research questions and wrote sections of the manuscript. PS collected data, analyzed data, developed research questions, and wrote sections of the manuscript. YVY collected data, developed research questions and wrote the cardiology sections of this manuscript. DMJ developed research questions, conducted data analysis and wrote sections of this manuscript. MRC collected data and provided critical revision to the manuscript. UCS also collected data, developed research questions and provided critical revision to the manuscript. FI collected immune biomarker data, analyzed immune biomarker data, and edited this manuscript. SGF extracted and formatted the data for analysis. BS, ABC, MDH, EJS, GKD, MSE, PV, BJP, NA, AKh, AKa, and AH provided intellectual content and critical revision to the manuscript.\n\nFunding: This work was supported by National Cancer Institute (NCI) grant P30CA016056 involving the use of Roswell Park Comprehensive Cancer Center’s Flow Cytometry Core, and by the National Center for Advancing Translational Sciences of the NIH (UL1TR001412) to the University of Buffalo. This work was also supported by grants from the Roswell Park Alliance Foundation, the Melanoma Research Alliance, Department of Defense Lung Cancer Research Program (LC180245), NIH/NHLBI K08HL131987 (U. Sharma), and the NIH/NCI (K08CA197966) (F. Ito).\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n\nSupplemental material: This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.\n==== Refs\nReferences\n\n1 Puzanov I, Diab A, Abdallah K, et al . Managing toxicities associated with immune checkpoint inhibitors: consensus recommendations from the Society for immunotherapy of cancer (SITC) toxicity management Working group. J Immunother Cancer 2017;5 :95. 10.1186/s40425-017-0300-z 29162153\n2 Ganatra S, Neilan TG. Immune checkpoint inhibitor-associated myocarditis. Oncologist 2018;23 :879–86. 10.1634/theoncologist.2018-0130 29802219\n3 Moslehi JJ, Salem J-E, Sosman JA, et al . Increased reporting of fatal immune checkpoint inhibitor-associated myocarditis. Lancet 2018;391 :933. 10.1016/S0140-6736(18)30533-6\n4 Upadhrasta S, Elias H, Patel K, et al . Managing cardiotoxicity associated with immune checkpoint inhibitors. Chronic Dis Transl Med 2019;5 :6–14. 10.1016/j.cdtm.2019.02.004 30993259\n5 Neilan TG, Rothenberg ML, Amiri-Kordestani L, et al . Myocarditis associated with immune checkpoint inhibitors: an expert consensus on data gaps and a call to action. Oncologist 2018;23 :874–8. 10.1634/theoncologist.2018-0157 29802220\n6 Mahmood SS, Fradley MG, Cohen JV, et al . Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol 2018;71 :1755–64. 10.1016/j.jacc.2018.02.037 29567210\n7 Agrawal N, Khunger A, Vachhani P, et al . Cardiac toxicity associated with immune checkpoint inhibitors: case series and review of the literature. Case Rep Oncol 2019;12 :260–76. 10.1159/000498985 31011325\n8 Matsuo K, Ishiguro T, Najama T, et al . Nivolumab-induced myocarditis successfully treated with corticosteroid therapy: a case report and review of the literature. Intern Med 2019;58 :2367–72. 10.2169/internalmedicine.2596-18 31118387\n9 Wang Q, Hu B. Successful therapy for autoimmune myocarditis with pembrolizumab treatment for nasopharyngeal carcinoma. Ann Transl Med 2019;7 :247. 10.21037/atm.2019.04.73 31317017\n10 Touat M, Maisonobe T, Knauss S, et al . Immune checkpoint inhibitor-related myositis and myocarditis in patients with cancer. Neurology 2018;91 :e985–94. 10.1212/WNL.0000000000006124 30089619\n11 Mahmood SS, Chen CL, Shapnik N, et al . Myocarditis with tremelimumab plus durvalumab combination therapy for endometrial cancer: a case report. Gynecol Oncol Rep 2018;25 :74–7. 10.1016/j.gore.2018.05.014 29922709\n12 Inayat F, Masab M, Gupta S, et al . New drugs and new toxicities: pembrolizumab-induced myocarditis. BMJ Case Rep 2018;2018 . 10.1136/bcr-2017-223252. [Epub ahead of print: 23 Jan 2018].\n13 Läubli H, Balmelli C, Bossard M, et al . Acute heart failure due to autoimmune myocarditis under pembrolizumab treatment for metastatic melanoma. J Immunother Cancer 2015;3 :11. 10.1186/s40425-015-0057-1 25901283\n14 Tay RY, Blackley E, McLean C, et al . Successful use of equine anti-thymocyte globulin (ATGAM) for fulminant myocarditis secondary to nivolumab therapy. Br J Cancer 2017;117 :921–4. 10.1038/bjc.2017.253 28797029\n15 Saibil SD, Bonilla L, Majeed H, et al . Fatal myocarditis and rhabdomyositis in a patient with stage IV melanoma treated with combined ipilimumab and nivolumab. Curr Oncol 2019;26 :418–21. 10.3747/co.26.4381\n16 Reuben A, Petaccia de Macedo M, McQuade J, et al . Comparative immunologic characterization of autoimmune giant cell myocarditis with ipilimumab. Oncoimmunology 2017;6 :e1361097. 10.1080/2162402X.2017.1361097 29209563\n17 Norwood TG, Westbrook BC, Johnson DB, et al . Smoldering myocarditis following immune checkpoint blockade. J Immunother Cancer 2017;5 :91. 10.1186/s40425-017-0296-4 29157297\n18 Kwon OH, Kim M-N, Kim S-A, et al . Fulminant lymphocytic myocarditis associated with orbital myositis and diaphragmatic paralysis. Cardiovasc Pathol 2016;25 :55–8. 10.1016/j.carpath.2015.08.004 26481055\n19 Sarocchi M, Grossi F, Arboscello E, et al . Serial troponin for early detection of nivolumab cardiotoxicity in advanced non-small cell lung cancer patients. Oncologist 2018;23 :936–42. 10.1634/theoncologist.2017-0452 29567824\n20 Naranjo CA, Busto U, Sellers EM, et al . A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30 :239–45. 10.1038/clpt.1981.154 7249508\n21 Caforio ALP, Adler Y, Agostini C, et al . Diagnosis and management of myocardial involvement in systemic immune-mediated diseases: a position statement of the European Society of cardiology Working group on myocardial and pericardial disease. Eur Heart J 2017;38 :2649–62. 10.1093/eurheartj/ehx321 28655210\n22 Haratani K, Hayashi H, Chiba Y, et al . Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer. JAMA Oncol 2018;4 :374–8. 10.1001/jamaoncol.2017.2925 28975219\n23 Bonaca MP, Olenchock BA, Salem J-E, et al . Myocarditis in the setting of cancer therapeutics: proposed case definitions for emerging clinical syndromes in Cardio-Oncology. Circulation 2019;140 :80–91. 10.1161/CIRCULATIONAHA.118.034497 31390169\n24 Escudier M, Cautela J, Malissen N, et al . Clinical features, management, and outcomes of immune checkpoint Inhibitor-Related cardiotoxicity. Circulation 2017;136 :2085–7. 10.1161/CIRCULATIONAHA.117.030571 29158217\n25 Hu J-R, Florido R, Lipson EJ, et al . Cardiovascular toxicities associated with immune checkpoint inhibitors. Cardiovasc Res 2019;115 :854–68. 10.1093/cvr/cvz026 30715219\n26 Brahmer JR, Lacchetti C, Schneider BJ, et al . Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of clinical oncology clinical practice guideline. J Clin Oncol 2018;36 :1714–68. 10.1200/JCO.2017.77.6385 29442540\n27 Peleg Hasson S, Salwen B, Sivan A, et al . Re-introducing immunotherapy in patients surviving immune checkpoint inhibitors-mediated myocarditis. Clin Res Cardiol 2021;110 :50-60. 10.1007/s00392-020-01648-3 32296970\n28 Das S, Johnson DB. Immune-Related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer 2019;7 :306. 10.1186/s40425-019-0805-8 31730012\n29 Freeman-Keller M, Kim Y, Cronin H, et al . Nivolumab in resected and unresectable metastatic melanoma: characteristics of immune-related adverse events and association with outcomes. Clin Cancer Res 2016;22 :886–94. 10.1158/1078-0432.CCR-15-1136 26446948\n30 Teulings H-E, Limpens J, Jansen SN, et al . Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis. J Clin Oncol 2015;33 :773–81. 10.1200/JCO.2014.57.4756 25605840\n31 Eggermont AMM, Kicinski M, Blank CU, et al . Association between immune-related adverse events and recurrence-free survival among patients with stage III melanoma randomized to receive pembrolizumab or placebo. JAMA Oncol 2020;6 :519. 10.1001/jamaoncol.2019.5570 31895407\n32 Johnson DB, Balko JM, Compton ML, et al . Fulminant myocarditis with combination immune checkpoint blockade. N Engl J Med 2016;375 :1749–55. 10.1056/NEJMoa1609214 27806233\n\n",
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"issn_linking": "2051-1426",
"issue": "9(6)",
"journal": "Journal for immunotherapy of cancer",
"keywords": "immunotherapy",
"medline_ta": "J Immunother Cancer",
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"pmid": "34162715",
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"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
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"title": "Clinical characteristics, time course, treatment and outcomes of patients with immune checkpoint inhibitor-associated myocarditis.",
"title_normalized": "clinical characteristics time course treatment and outcomes of patients with immune checkpoint inhibitor associated myocarditis"
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"abstract": "Background: Stepwise approach to therapy and increasing use of immunosuppressive agents have led to increasingly good prognosis and survival in myasthenia gravis (MG). However, there is a small subset of patients with treatment-refractory disease who experience a higher disease burden and increased rates of myasthenic crises and exacerbations, including respiratory failure. A 54-year-old man with treatment-refractory MG on chronic plasma exchange therapy had rapidly fluctuating weakness, poor sleep quality, and worsening respiratory symptoms in between treatments. He was started on home nocturnal noninvasive ventilation with volume-assured pressure support mode and experienced marked improvement in sleep quality, dyspnea, fatigue, and daytime sleepiness.",
"affiliations": "Dr. Diaz-Abad and Dr. Todd are with the Department of Medicine, University of Maryland School of Medicine in Baltimore, Maryland.;Dr. Diaz-Abad and Dr. Todd are with the Department of Medicine, University of Maryland School of Medicine in Baltimore, Maryland.;Dr. Diaz-Abad and Dr. Todd are with the Department of Medicine, University of Maryland School of Medicine in Baltimore, Maryland.;Dr. Diaz-Abad and Dr. Todd are with the Department of Medicine, University of Maryland School of Medicine in Baltimore, Maryland.;Dr. Diaz-Abad and Dr. Todd are with the Department of Medicine, University of Maryland School of Medicine in Baltimore, Maryland.",
"authors": "Diaz-Abad|Montserrat|M|;Todd|Nevins|N|;Zilliox|Lindsay|L|;Sanchez|Ana|A|;Hafer-Macho|Charlene|C|",
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"issue": "16(11-12)",
"journal": "Innovations in clinical neuroscience",
"keywords": "myasthenia gravis; noninvasive ventilation; respiratory failure; sleep hypoventilation; treatment-refractory; volume-assured pressure support",
"medline_ta": "Innov Clin Neurosci",
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"nlm_unique_id": "101549695",
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"pages": "11-13",
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"references": "26688194;28029925;26872323;25210968;16631799;24872217;29486521;18795255;27358333",
"title": "Use of Noninvasive Ventilation with Volume-assured Pressure Support for Treatment-refractory Myasthenia Gravis.",
"title_normalized": "use of noninvasive ventilation with volume assured pressure support for treatment refractory myasthenia gravis"
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"abstract": "Many homemade tamper processes of medical codeine formulations are available on selected \"forums\" on the Internet, where recreational codeine users claim to be able to purify codeine by removing additives, such as acetaminophen, to avoid or limit adverse effects. In this work, it is reported and discussed a fatal case of codeine intoxication. The findings of objects such as jars, filters, and tablets, and amounts of unknown liquid material at the death scene investigation suggested a fatal codeine intoxication after the tampering procedure called \"cold water extraction.\" Toxicological results obtained from the analysis of both the nonbiological material and the body fluids of the decedent integrated with the information collected at the death scene investigation confirmed the above-mentioned hypothesis. This report underlines the importance of a tight interconnection between criminalistics and legal medicine to strengthen the identification of the cause of death and the reconstruction of the event.",
"affiliations": "Department of Medical and Surgical Sciences - Unit of Legal Medicine, University of Bologna, Via Irnerio 49, 40126, Bologna, Italy.;Department of Diagnostics and Public Health - Unit of Forensic Medicine, University of Verona, P.le L.A. Scuro 10, Verona, Italy.;Legal Medicine and Toxicology, University-Hospital of Padova, Via Falloppio 50, 35121, Padova, Italy.;Legal Medicine and Toxicology, University-Hospital of Padova, Via Falloppio 50, 35121, Padova, Italy.;Department of Diagnostics and Public Health - Unit of Forensic Medicine, University of Verona, P.le L.A. Scuro 10, Verona, Italy.;Legal Medicine and Toxicology, University-Hospital of Padova, Via Falloppio 50, 35121, Padova, Italy.;Forensic Toxicology Division, Department of Health Science, University of Florence, Italy.;Department of Diagnostics and Public Health - Unit of Forensic Medicine, University of Verona, P.le L.A. Scuro 10, Verona, Italy.",
"authors": "Fais|Paolo|P|;Pigaiani|Nicola|N|;Cecchetto|Giovanni|G|;Montisci|Massimo|M|;Gottardo|Rossella|R|;Viel|Guido|G|;Pascali|Jennifer Paola|JP|;Tagliaro|Franco|F|",
"chemical_list": "D000701:Analgesics, Opioid; D013607:Tablets; D003061:Codeine",
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"issue": "62(6)",
"journal": "Journal of forensic sciences",
"keywords": "codeine-related death; death scene investigation; drug abuse; drug tampering; forensic pathology; forensic science; opiate abuse; toxicology",
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D002626:Chemistry, Pharmaceutical; D003061:Codeine; D004339:Drug Compounding; D062787:Drug Overdose; D006801:Humans; D008297:Male; D009293:Opioid-Related Disorders; D013607:Tablets",
"nlm_unique_id": "0375370",
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"pubdate": "2017-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "\"Tampering to Death\": A Fatal Codeine Intoxication Due to a Homemade Purification of a Medical Formulation.",
"title_normalized": "tampering to death a fatal codeine intoxication due to a homemade purification of a medical formulation"
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"companynumb": "IT-VERNALIS THERAPEUTICS, INC.-2018VRN00016",
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"abstract": "We describe a young patient who ingested 18 g (240 times the daily therapeutic dose) of venlafaxine in a suicide attempt. She developed severe cardiomyopathy in a takotsubo distribution causing cardiogenic shock and multi-organ dysfunction syndrome (MODS). She was successfully treated with intravenous lipid emulsion (ILE), extracorporeal life support (ECLS) and CytoSorb®. This is remarkable as, to the best of the authors' knowledge, this is the highest amount of venlafaxine intake seen in the literature with a nonfatal outcome.",
"affiliations": "Department of Anesthesiology, University Hospital Ludwig-Maximilians (LMU) University of Munich, Munich - Germany.;Department of Anesthesiology, University Hospital Ludwig-Maximilians (LMU) University of Munich, Munich - Germany.;Department of Internal Medicine I, University Hospital Ludwig-Maximilians (LMU) University of Munich, Munich - Germany.;Clinic of Cardiac Surgery, University Hospital Ludwig-Maximilians-University (LMU) University of Munich, Munich - Germany.;Department of Anesthesiology, University Hospital Ludwig-Maximilians (LMU) University of Munich, Munich - Germany.",
"authors": "Schroeder|Ines|I|;Zoller|Michael|M|;Angstwurm|Matthias|M|;Kur|Felix|F|;Frey|Lorenz|L|",
"chemical_list": "D005217:Fat Emulsions, Intravenous; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D000069470:Venlafaxine Hydrochloride",
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"issue": "40(7)",
"journal": "The International journal of artificial organs",
"keywords": null,
"medline_ta": "Int J Artif Organs",
"mesh_terms": "D015199:Extracorporeal Membrane Oxygenation; D005217:Fat Emulsions, Intravenous; D005260:Female; D006440:Hemofiltration; D006801:Humans; D009102:Multiple Organ Failure; D000068760:Serotonin and Noradrenaline Reuptake Inhibitors; D012770:Shock, Cardiogenic; D013406:Suicide, Attempted; D054549:Takotsubo Cardiomyopathy; D000069470:Venlafaxine Hydrochloride; D055815:Young Adult",
"nlm_unique_id": "7802649",
"other_id": null,
"pages": "358-360",
"pmc": null,
"pmid": "28574114",
"pubdate": "2017-07-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Venlafaxine intoxication with development of takotsubo cardiomyopathy: successful use of extracorporeal life support, intravenous lipid emulsion and CytoSorb®.",
"title_normalized": "venlafaxine intoxication with development of takotsubo cardiomyopathy successful use of extracorporeal life support intravenous lipid emulsion and cytosorb"
} | [
{
"companynumb": "DE-PRINSTON PHARMACEUTICAL INC.-2017PRN00413",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VENLAFAXINE HYDROCHLORIDE"
},
... |
{
"abstract": "Sarcoid-like granulomatosis is a known but rare adverse reaction to immune checkpoint inhibitors and chemotherapy in the treatment of advanced solid tumors. We present a case of a 29-year-old female with a pathologically confirmed poorly differentiated invasive ductal carcinoma of the breast with presumed metastases to the lungs, hilar lymph nodes, liver, and spleen. Despite appropriate chemotherapy, the patient developed pulmonary lesions that were interpreted on imaging studies as progression of malignancy. Autopsy revealed disseminated sarcoid-like granulomatosis with multiple noncaseating granulomata with associated fibrosis in the lungs, liver, and spleen. No residual invasive carcinoma or metastatic disease was identified. This case illustrates the difficulty in differentiating this nonneoplastic process from progressive disease in the clinical setting.",
"affiliations": "NewYork-Presbyterian Weill Cornell Medical Center, New York, NY, USA.;NewYork-Presbyterian Weill Cornell Medical Center, New York, NY, USA.;NewYork-Presbyterian Weill Cornell Medical Center, New York, NY, USA.",
"authors": "Mostyka|Maria|M|https://orcid.org/0000-0002-9215-3236;Jessurun|Jose|J|;Matrai|Cathleen|C|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1066896920905887",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1066-8969",
"issue": "28(6)",
"journal": "International journal of surgical pathology",
"keywords": "autopsy; breast carcinoma; granuloma; metastasis; mimic; sarcoid",
"medline_ta": "Int J Surg Pathol",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D005260:Female; D015769:Granuloma, Respiratory Tract; D006801:Humans; D008168:Lung; D011658:Pulmonary Fibrosis",
"nlm_unique_id": "9314927",
"other_id": null,
"pages": "668-671",
"pmc": null,
"pmid": "32050826",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Sarcoid-Like Granulomatosis in a Patient With Breast Cancer Mimicking Refractory Metastatic Disease.",
"title_normalized": "sarcoid like granulomatosis in a patient with breast cancer mimicking refractory metastatic disease"
} | [
{
"companynumb": "US-CIPLA LTD.-2020US05759",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "The Stevens-Johnson syndrome (SJS) and the toxic epidermal necrolysis (TEN) are clinical conditions manifesting as adverse cutaneous reaction to drugs in majority of cases, constituting the same clinical spectrum, differing only in the severity of epidermolysis; both conditions are distinguished by their severity and extensiveness of skin lesions; it can also involve mucous membranes of eyes, respiratory, digestive and urogenital tracts. Two per 1,000,000 are affected annually, among them approximately 20% are children and both of them are considered as potentially fatal medical emergency conditions. Even though the condition was described 89 years ago, until now the exact pathophysiology has not been completely explained. An immune-mediated mechanism has been implicated in its origin, which involves cytotoxic lymphocytes, cytokines, Fas-ligand in keratinocyte apoptosis; genetic makers also has been identified in some racial groups (HLA-B*1520, HLA-B*5801) in relationship with specific susceptibility to certain drugs such as carbamazepine, allopurinol. In children there are no uniform criteria for classification of the skin lesions, neither for the treatment, however recently the authors describe better response of the patients with use intravenous immunoglobulin (IGIV).",
"affiliations": "Departamento de Medicina y Ciencias de la Salud Universidad de Sonora, Hospital Infantil del Estado de Sonora, México. nsotelo@guaymas.uson.mx",
"authors": "Sotelo-Cruz|Norberto|N|",
"chemical_list": null,
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-3813",
"issue": "148(3)",
"journal": "Gaceta medica de Mexico",
"keywords": null,
"medline_ta": "Gac Med Mex",
"mesh_terms": "D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D017410:Practice Guidelines as Topic; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "0010333",
"other_id": null,
"pages": "265-75",
"pmc": null,
"pmid": "22820360",
"pubdate": "2012",
"publication_types": "D004740:English Abstract; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Stevens-Johnson syndrome and toxic epidermal necrolysis in children.",
"title_normalized": "stevens johnson syndrome and toxic epidermal necrolysis in children"
} | [
{
"companynumb": "RS-LUPIN PHARMACEUTICALS INC.-2014-01547",
"fulfillexpeditecriteria": "2",
"occurcountry": "RS",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PENICILLIN G PROCAINE"
},
"dr... |
{
"abstract": "The study included 309 HIV-infected pregnant women receiving a lamivudine-containing antiretroviral regimen from week 25 of gestational age until 6 months postpartum, during breastfeeding. Twenty-seven of them (8.7%) were hepatitis B virus surface antigen (HBsAg) positive; at baseline, hepatitis B virus (HBV) DNA levels >3 log(10) IU/mL (with a median level of 6.2 log(10) IU/mL) were found in 10 women, who at one, three and six months postpartum had median levels of 5.2 log(10) IU/mL, 4.5 log(10) IU/mL and 2.8 log(10) IU/mL, respectively. Twenty-four of the 30 breast milk samples evaluated had undetectable HBV DNA and the other six had values between 15 and 155 IU/mL. Median lamivudine concentrations were 1070 ng/mL in serum and 684 ng/mL in breast milk. Among the 24 HBV-exposed children with available samples, 16 always tested negative, four had a transient infection, one had an undetermined status and three (12.5%) first tested positive at Month 12 or Month 24. Among the children born to the HBV-uninfected mothers of the same cohort, the rate of HBsAg positivity at 12-24 months was 2% (4/196). Our finding of the absence of significative levels of HBV DNA in the breast milk of co-infected mothers supports the present recommendations for breastfeeding in HBV-infected women. Horizontal transmission can be hypothesized for the infections detected in children at 12-24 months. Children born to HBV-positive mothers remained at higher risk of postnatal HBV acquisition compared to those born to HBV-negative women.",
"affiliations": "Department of Therapeutic Research and Medicines Evaluation, Istituto Superiore di Sanità, Rome, Italy.",
"authors": "Pirillo|M F|MF|;Scarcella|P|P|;Andreotti|M|M|;Jere|H|H|;Buonomo|E|E|;Sagno|J-B|JB|;Amici|R|R|;Mancini|M G|MG|;Leone|P|P|;Ceffa|S|S|;Mancinelli|S|S|;Marazzi|M C|MC|;Vella|S|S|;Palombi|L|L|;Giuliano|M|M|",
"chemical_list": "D019380:Anti-HIV Agents; D019259:Lamivudine",
"country": "England",
"delete": false,
"doi": "10.1111/jvh.12301",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-0504",
"issue": "22(3)",
"journal": "Journal of viral hepatitis",
"keywords": "Africa; HIV; breastfeeding; hepatitis B virus; lamivudine; perinatal transmission",
"medline_ta": "J Viral Hepat",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D001942:Breast Feeding; D002648:Child; D060085:Coinfection; D005260:Female; D015658:HIV Infections; D006509:Hepatitis B; D006515:Hepatitis B virus; D006801:Humans; D018445:Infectious Disease Transmission, Vertical; D019259:Lamivudine; D008297:Male; D011247:Pregnancy; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "9435672",
"other_id": null,
"pages": "289-96",
"pmc": null,
"pmid": "25174900",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Hepatitis B virus mother-to-child transmission among HIV-infected women receiving lamivudine-containing antiretroviral regimens during pregnancy and breastfeeding.",
"title_normalized": "hepatitis b virus mother to child transmission among hiv infected women receiving lamivudine containing antiretroviral regimens during pregnancy and breastfeeding"
} | [
{
"companynumb": "IT-GLAXOSMITHKLINE INC.-IT2015GSK031972",
"fulfillexpeditecriteria": "1",
"occurcountry": "MW",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional... |
{
"abstract": "Chronic obstructive pulmonary disease (COPD) treatment guidelines do not currently include recommendations for escalation directly from monotherapy to triple therapy. This 12-week, double-blind, double-dummy study randomized 800 symptomatic moderate-to-very-severe COPD patients receiving tiotropium (TIO) for ≥3 months to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg via ELLIPTA (n = 400) or TIO 18 mcg via HandiHaler (n = 400) plus matched placebo. Study endpoints included change from baseline in trough forced expiratory volume in 1 s (FEV1) at Days 85 (primary), 28 and 84 (secondary), health status (St George's Respiratory Questionnaire [SGRQ] and COPD Assessment Test [CAT]) and safety. FF/UMEC/VI significantly improved trough FEV1 at all timepoints (Day 85 treatment difference [95% CI] 95 mL [62-128]; P < 0.001), and significantly improved SGRQ and CAT versus TIO. Treatment safety profiles were similar. Once-daily single-inhaler FF/UMEC/VI significantly improved lung function and health status versus once-daily TIO in symptomatic moderate-to-very-severe COPD patients, with a similar safety profile.",
"affiliations": "The Lung Center, Penn Highlands Healthcare, Du Bois, PA, USA.;Karolinska Institutet, Stockholm, Sweden.;Division of Pulmonary Diseases and Critical Care Medicine, School of Medicine, The University of Texas Health Science Center, San Antonio, TX, USA.;GSK, Stockley Park West, Iron Bridge Road North, West Drayton, Uxbridge, Middlesex, UK.;GSK, Brentford, Middlesex, UK.;GSK, Research Triangle Park, NC, USA.;VitaLink Research Gaffney, Gaffney, SC, USA.;GSK, Stockley Park West, Iron Bridge Road North, West Drayton, Uxbridge, Middlesex, UK.;GSK, Collegeville, PA, USA.;Minnesota Lung Center, Minneapolis, MN, USA.;GSK, Collegeville, PA, USA.;GSK, Brentford, Middlesex, UK.;GSK, Stockley Park West, Iron Bridge Road North, West Drayton, Uxbridge, Middlesex, UK.;Respiratory Unit, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, FE, Italy. ppa@unife.it.",
"authors": "Bansal|Sandeep|S|;Anderson|Martin|M|;Anzueto|Antonio|A|;Brown|Nicola|N|;Compton|Chris|C|;Corbridge|Thomas C|TC|;Erb|David|D|;Harvey|Catherine|C|;Kaisermann|Morrys C|MC|;Kaye|Mitchell|M|;Lipson|David A|DA|0000-0001-6732-4593;Martin|Neil|N|;Zhu|Chang-Qing|CQ|;Papi|Alberto|A|0000-0002-6924-4500",
"chemical_list": "D000730:Androstadienes; D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D002722:Chlorobenzenes; C573971:GSK573719; D011812:Quinuclidines; C550468:vilanterol; C523187:fluticasone furoate; D000069447:Tiotropium Bromide",
"country": "England",
"delete": false,
"doi": "10.1038/s41533-021-00241-z",
"fulltext": "\n==== Front\nNPJ Prim Care Respir Med\nNPJ Prim Care Respir Med\nNPJ Primary Care Respiratory Medicine\n2055-1010\nNature Publishing Group UK London\n\n241\n10.1038/s41533-021-00241-z\nArticle\nSingle-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus tiotropium monotherapy in patients with COPD\nBansal Sandeep 1\nAnderson Martin 2\nAnzueto Antonio 34\nBrown Nicola 5\nCompton Chris 6\nCorbridge Thomas C. 78\nErb David 9\nHarvey Catherine 5\nKaisermann Morrys C. 10\nKaye Mitchell 11\nhttp://orcid.org/0000-0001-6732-4593\nLipson David A. 1012\nMartin Neil 613\nZhu Chang-Qing 5\nhttp://orcid.org/0000-0002-6924-4500\nPapi Alberto ppa@unife.it\n\n14\n1 grid.428754.8 0000 0004 4659 5935 The Lung Center, Penn Highlands Healthcare, Du Bois, PA USA\n2 grid.4714.6 0000 0004 1937 0626 Karolinska Institutet, Stockholm, Sweden\n3 grid.468222.8 Division of Pulmonary Diseases and Critical Care Medicine, School of Medicine, The University of Texas Health Science Center, San Antonio, TX USA\n4 grid.280682.6 0000 0004 0420 5695 Audie L. Murphy Memorial VA Hospital, South Texas Veterans Health Care System, San Antonio, TX USA\n5 grid.418236.a 0000 0001 2162 0389 GSK, Stockley Park West, Iron Bridge Road North, West Drayton, Uxbridge, Middlesex UK\n6 grid.418236.a 0000 0001 2162 0389 GSK, Brentford, Middlesex UK\n7 grid.418019.5 0000 0004 0393 4335 GSK, Research Triangle Park, NC USA\n8 grid.16753.36 0000 0001 2299 3507 Feinberg School of Medicine, Northwestern University, Chicago, IL USA\n9 VitaLink Research Gaffney, Gaffney, SC USA\n10 grid.418019.5 0000 0004 0393 4335 GSK, Collegeville, PA USA\n11 Minnesota Lung Center, Minneapolis, MN USA\n12 grid.25879.31 0000 0004 1936 8972 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA USA\n13 grid.9918.9 0000 0004 1936 8411 University of Leicester, Leicester, Leicestershire UK\n14 grid.8484.0 0000 0004 1757 2064 Respiratory Unit, Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, Ferrara, FE Italy\n25 5 2021\n25 5 2021\n2021\n31 2910 9 2020\n19 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.\nChronic obstructive pulmonary disease (COPD) treatment guidelines do not currently include recommendations for escalation directly from monotherapy to triple therapy. This 12-week, double-blind, double-dummy study randomized 800 symptomatic moderate-to-very-severe COPD patients receiving tiotropium (TIO) for ≥3 months to once-daily fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) 100/62.5/25 mcg via ELLIPTA (n = 400) or TIO 18 mcg via HandiHaler (n = 400) plus matched placebo. Study endpoints included change from baseline in trough forced expiratory volume in 1 s (FEV1) at Days 85 (primary), 28 and 84 (secondary), health status (St George’s Respiratory Questionnaire [SGRQ] and COPD Assessment Test [CAT]) and safety. FF/UMEC/VI significantly improved trough FEV1 at all timepoints (Day 85 treatment difference [95% CI] 95 mL [62–128]; P < 0.001), and significantly improved SGRQ and CAT versus TIO. Treatment safety profiles were similar. Once-daily single-inhaler FF/UMEC/VI significantly improved lung function and health status versus once-daily TIO in symptomatic moderate-to-very-severe COPD patients, with a similar safety profile.\n\nSubject terms\n\nChronic obstructive pulmonary disease\nTherapeutics\nMedical research\nhttps://doi.org/10.13039/100004330 GlaxoSmithKline (GlaxoSmithKline plc.) issue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nChronic obstructive pulmonary disease (COPD) is a major cause of chronic morbidity and mortality worldwide1. It is a preventable and treatable disease, characterized by persistent respiratory symptoms and airflow limitation1. Determining the appropriate treatment requires a thorough understanding of the disease at an individual level, and assessments should cover symptomatology, exacerbation risk, and the degree of airflow limitation1. Treatment should then be tailored based on these disease characteristics and escalated, as needed, should the patient experience clinically significant symptoms and/or exacerbations1.\n\nThe Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2020 strategy document recommends escalating from monotherapy (long-acting muscarinic antagonist [LAMA] or long-acting β2-agonist [LABA]) to dual therapy (LAMA/LABA or inhaled corticosteroid [ICS]/LABA) or from dual therapy to triple therapy (ICS/LAMA/LABA) for patients who continue to experience clinically significant symptoms and/or exacerbations on their current maintenance therapy1. In real-life management of COPD, patients are often escalated to triple therapy by adding ICS/LABA to LAMA monotherapy, with one study showing that over a quarter of patients with newly diagnosed COPD progress to triple therapy within 24 months of diagnosis2,3. However, despite its occurrence in clinical practice, recommendations for escalation from monotherapy directly to triple therapy are currently not included in treatment guidelines. The reasons for this are varied but include heterogeneous endpoints in the clinical studies performed to date and a lack of updated recommendations based on the current body of evidence.\n\nIn a number of clinical studies, stepping up from LAMA monotherapy to ICS/LAMA/LABA triple therapy improved lung function compared with LAMA monotherapy in patients with symptomatic COPD4–10. Triple therapy versus LAMA monotherapy also led to statistically significant decreases (improvements) in St George’s Respiratory Questionnaire (SGRQ) score5–9, which measures health-related quality of life11, while a study with moderate/severe exacerbation rate as the primary endpoint showed that single-inhaler triple therapy led to a significant reduction in moderate/severe exacerbation rate versus LAMA monotherapy5. In most of these studies, triple therapy was administered using multiple inhalers, therefore evidence comparing single-inhaler triple therapy to LAMA monotherapy would be of clinical relevance. It has previously been demonstrated in Phase III trials that single-inhaler triple therapy with fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) significantly reduces moderate/severe exacerbations and improves lung function and health status compared with dual therapy with FF/VI or UMEC/VI (IMPACT trial) or budesonide/formoterol (FULFIL trial) in patients with symptomatic COPD who are at risk of exacerbations, while the safety profile of triple therapy reflected the known profiles of its components12,13. The current Phase IV study (study 207626) evaluated the efficacy and safety of once-daily single-inhaler FF/UMEC/VI therapy versus once-daily LAMA monotherapy with tiotropium (TIO) in patients with symptomatic COPD with moderate-to-very-severe airflow limitation.\n\nResults\n\nTrial population\n\nThe ITT population included 800 patients who underwent randomization (FF/UMEC/VI, N = 400; TIO, N = 400; Fig. 1). Nearly all patients (96%) completed all protocol-defined study visits, with similar discontinuation and withdrawal rates between treatment groups (Fig. 1). Baseline characteristics and demographics were similar between the two treatment groups (Table 1).Fig. 1 Study design.\n\nFF fluticasone furoate, ITT intent-to-treat, TIO tiotropium, UMEC umeclidinium, VI vilanterol.\n\nTable 1 Patient demographics and baseline characteristics (ITT population).\n\n\tFF/UMEC/VI N = 400\tTIO N = 400\tTotal N = 800\t\nAge, years, mean (SD)\t66.2 (8.08)\t66.1 (7.78)\t66.2 (7.93)\t\nMale, n (%)\t274 (69)\t269 (67)\t543 (68)\t\nBMI, kg/m2, mean (SD)\t27.5 (6.1)\t27.2 (5.3)\t27.4 (5.7)\t\nCurrent smoker at screening, n (%)\t189 (47)\t192 (48)\t381 (48)\t\nLung function at screening, mean (SD)\t\t\t\t\n Post-bronchodilator FEV1, mLa\t1434 (493)\t1443 (504)\t1439 (498)\t\n Post-bronchodilator percent predicted FEV1, %a\t49.8 (14.0)\t50.2 (14.2)\t50.0 (14.1)\t\n Post-bronchodilator FEV1/FVC ratioa\t0.493 (0.109)\t0.502 (0.106)\t0.498 (0.107)\t\n Percent reversibility to salbutamol, %b\t8.7 (13.4)\t8.6 (11.6)\t8.6 (12.5)\t\nCOPD exacerbations in the previous 12 months, n (%)\t\t\t\t\nModerate COPD exacerbations\t\t\t\t\n 0\t145 (36)\t151 (38)\t296 (37)\t\n 1\t44 (11)\t40 (10)\t84 (11)\t\n ≥2\t211 (53)\t209 (52)\t420 (53)\t\nSevere COPD exacerbations\t\t\t\t\n 0\t318 (80)\t312 (78)\t630 (79)\t\n 1\t72 (18)\t77 (19)\t149 (19)\t\n ≥2\t10 (3)\t11 (3)\t21 (3)\t\nCAT score at screening, mean (SD)c\t20.7 (5.32)\t20.5 (5.16)\t20.6 (5.24)\t\nGOLD grade, n (%)a\t\t\t\t\n Grade 1 (mild)\t1 (<1)\t0\t1 (<1)\t\n Grade 2 (moderate)\t184 (46)\t195 (49)\t379 (48)\t\n Grade 3 (severe)\t180 (45)\t173 (43)\t353 (44)\t\n Grade 4 (very severe)\t32 (8)\t30 (8)\t62 (8)\t\nBMI body mass index, CAT COPD Assessment Test, COPD chronic obstructive pulmonary disease, FEV1 forced expiratory volume in 1 s, FF fluticasone furoate, FVC forced vital capacity, GOLD Global Initiative for Chronic Obstructive Lung Disease, ITT intent-to-treat, SD standard deviation, TIO tiotropium, UMEC umeclidinium, VI vilanterol.\n\naFF/UMEC/VI: n = 397, TIO: n = 398, total: n = 795.\n\nbFF/UMEC/VI: n = 392, TIO: n = 391, total: n = 783.\n\ncTIO: n = 399, total: n = 799.\n\nEfficacy\n\nThe mean change from baseline in trough FEV1 at Day 85 was significantly greater with FF/UMEC/VI versus TIO, with a treatment difference of 95 mL (95% confidence interval [CI]: 62, 128; P < 0.001; Fig. 2a).Fig. 2 Trough FEV1 (ITT population).\n\nLeast squares mean (95% CI) change from baseline in trough FEV1 at a Day 85 and b Days 28 and 84. CFB change from baseline, CI confidence interval, FEV1 forced expiratory volume in 1 s, FF fluticasone furoate, ITT intent-to-treat, LS least squares, TIO tiotropium, UMEC umeclidinium, VI vilanterol.\n\nThe mean change from baseline in trough FEV1 was significantly greater with FF/UMEC/VI versus TIO at both Day 28 and Day 84, with treatment differences (95% CI) of 122 mL (94, 150; P < 0.001) and 87 mL (56, 118; P < 0.001), respectively (Fig. 2b).\n\nA significantly greater mean decrease from baseline in SGRQ total score was observed with FF/UMEC/VI versus TIO at both Day 28 and Day 84. The between treatment differences (95% CI) were −3.0 (−4.7, −1.3; P < 0.001) and −3.2 (−5.0, −1.4; P < 0.001), respectively (Fig. 3a). The odds of being a SGRQ total score responder were significantly greater with FF/UMEC/VI versus TIO at Day 28 (odds ratio [OR] [95% CI]: 1.61 [1.20, 2.15]; P = 0.001) and Day 84 (OR [95% CI]: 1.62 [1.22, 2.17]; P = 0.001; Fig. 3b).Fig. 3 SGRQ total score (ITT population).\n\na Least squares mean (95% CI) change from baseline in SGRQ total score and b proportion of SGRQ responders (≥4-point decrease in SGRQ total score) at Day 28 and Day 84. CFB change from baseline, CI confidence interval, FF fluticasone furoate, ITT intent-to-treat, LS least squares, SGRQ St George’s Respiratory Questionnaire, TIO tiotropium, UMEC umeclidinium, VI vilanterol.\n\nCAT score decreased significantly from baseline with FF/UMEC/VI versus TIO at Days 28 and 84. Between treatment differences (95% CI) were −0.9 (−1.5, −0.2; P = 0.006) and −1.2 (−1.9, −0.5; P = 0.001), respectively (Fig. 4a). For CAT responder analyses, ORs were in favor of FF/UMEC/VI at both Day 28 and 84. Statistical significance in favor of FF/UMEC/VI was achieved at Day 28 (OR [95% CI]: 1.49 [1.12, 1.99]; P = 0.006) but not Day 84 (OR [95% CI]: 1.15 [0.86, 1.53]; P = 0.354; Fig. 4b).Fig. 4 CAT Score (ITT population).\n\na Least squares mean (95% CI) change from baseline in CAT score and b proportion of CAT responders (≥2-point decrease in CAT score) at Day 28 and Day 84. CAT COPD Assessment Test, CFB change from baseline, CI confidence interval, FF fluticasone furoate, ITT intent-to-treat, LS least squares, TIO tiotropium, UMEC umeclidinium, VI vilanterol.\n\nIn total, 27 (7%) and 43 (11%) patients receiving FF/UMEC/VI and TIO, respectively, experienced a moderate/severe exacerbation during the 12-week study period. Severe exacerbations were seen in 5 (1%) and 3 (<1%) patients receiving FF/UMEC/VI and TIO, respectively.\n\nThe FEV1 < 50% predicted subgroup comprised 212 patients receiving FF/UMEC/VI and 203 patients receiving TIO; the FEV1 ≥ 50% predicted subgroup comprised 185 patients receiving FF/UMEC/VI and 195 patients receiving TIO (Table 2). Demographics at screening were similar across FEV1 subgroups, although lung function parameters differed substantially. Patients in the ≥50% subgroup experienced substantially more moderate COPD exacerbations in the 12 months prior to the study (Table 2), as the study inclusion criteria required a documented history of ≥2 moderate exacerbations or 1 severe exacerbation in the last 12 months for this subgroup.Table 2 Screening demographics and characteristics for FEV1 percent predicted subgroups (ITT population).\n\n\tPredicted FEV1 at screening <50% N = 415\tPredicted FEV1 at screening ≥50% N = 380\t\n\tFF/UMEC/VI\tTIO\tFF/UMEC/VI\tTIO\t\n\tn = 212\tn = 203\tn = 185\tn = 195\t\nAge, years, mean (SD)\t65.9 (8.02)\t65.2 (7.44)\t66.7 (8.16)\t67.0 (8.05)\t\nMale, n (%)\t149 (70)\t129 (64)\t123 (66)\t139 (71)\t\nBMI, kg/m2, mean (SD)\t27.4 (6.4)\t27.0 (5.8)\t27.6 (5.7)\t27.4 (4.8)\t\nCurrent smoker at screening, n (%)\t104 (49)\t100 (49)\t82 (44)\t91 (47)\t\nLung function at screening, mean (SD)\t\n Post-bronchodilator FEV1, mL\t1137 (314)\t1097 (290)\t1775 (437)\t1803 (420)\t\n Post-bronchodilator percent predicted FEV1, %\t39.2 (7.8)\t38.6 (7.6)\t62.1 (8.2)\t62.4 (7.8)\t\n Post-bronchodilator FEV1/FVC ratio\t0.437 (0.099)\t0.445 (0.097)\t0.557 (0.081)\t0.561 (0.079)\t\n Percent reversibility to salbutamol, %a\t10.9 (14.9)\t9.8 (12.1)\t6.3 (11.0)\t7.4 (10.9)\t\nCOPD exacerbations in the previous 12 months, n (%)\t\nModerate COPD exacerbations\t\n 0\t117 (55)\t115 (57)\t27 (15)\t36 (18)\t\n 1\t39 (18)\t32 (16)\t4 (2)\t8 (4)\t\n ≥2\t56 (26)\t56 (28)\t154 (83)\t151 (77)\t\nSevere COPD exacerbations\t\n 0\t168 (79)\t163 (80)\t148 (80)\t147 (75)\t\n 1\t41 (19)\t37 (18)\t31 (17)\t40 (21)\t\n ≥2\t3 (1)\t3 (1)\t6 (3)\t8 (4)\t\nCAT score at screening, mean (SD)b\t21.6 (5.58)\t21.2 (5.41)\t19.7 (4.68)\t19.8 (4.76)\t\nSGRQ total score at baseline, mean (SD)c\t53.3 (15.39)\t50.0 (15.62)\t46.4 (15.55)\t45.5 (14.24)\t\nBMI body mass index, CAT COPD Assessment Test, COPD chronic obstructive pulmonary disease, FEV1 forced expiratory volume in 1 s, FF fluticasone furoate, FVC forced vital capacity, ITT intent-to-treat, SD standard deviation, SGRQ St George’s Respiratory Questionnaire, TIO tiotropium, UMEC umeclidinium, VI vilanterol.\n\naPercent predicted FEV1 < 50%: FF/UMEC/VI, n = 207, TIO, n = 197; percent predicted FEV1 ≥ 50%: TIO, n = 194.\n\nbPercent predicted FEV1 < 50%: TIO, n = 202.\n\ncPercent predicted FEV1 < 50%: FF/UMEC/VI, n = 210; percent predicted FEV1 ≥ 50%: FF/UMEC/VI, n = 184, TIO, n = 194.\n\nMean change from baseline in trough FEV1 was significantly greater with FF/UMEC/VI versus TIO at Days 28, 84, and 85 in both subgroups (Fig. 5). Significantly greater decreases from baseline in SGRQ total score with FF/UMEC/VI versus TIO were observed at Days 28 and 84 for the FEV1 < 50% subgroup. For the FEV1 ≥ 50% subgroup, a numerical decrease in favor of FF/UMEC/VI was observed at Day 28, and the decrease with FF/UMEC/VI versus TIO was statistically significant at Day 84 (Supplementary Fig. 1). Greater decreases from baseline in CAT scores with FF/UMEC/VI versus TIO were observed at Days 28 and 84 for both subgroups, but treatment differences were statistically significant for the FEV1 < 50% subgroup only (Supplementary Fig. 2).Fig. 5 Trough FEV1 for percent predicted FEV1 at screening subgroups (ITT population).\n\nLeast squares mean (95% CI) change from baseline in trough FEV1 at a Day 28, b Day 84, and c Day 85. CFB change from baseline, CI confidence interval, FEV1 forced expiratory volume in 1 s, FF fluticasone furoate, ITT intent-to-treat, LS least squares, TIO tiotropium, UMEC umeclidinium, VI vilanterol.\n\nSafety profile\n\nThe incidence of AEs, SAEs, and AESIs was similar between treatment groups, including cardiovascular effects, and there was no between-group difference in pneumonia rates (Table 3). There were no new safety findings associated with the use of an ICS, a LAMA, and a LABA in combination. Two patients died in the FF/UMEC/VI arm and one patient died in the TIO arm; these deaths were not considered to be related to study treatment.Table 3 Incidence of on-treatment AEs (ITT population).\n\n\tFF/UMEC/VI\tTIO\t\nN = 400\tN = 400\t\nn (%)\tRate [#]\tn (%)\tRate [#]\t\nTotal treatment exposure, patient-years\t90.5\t\t92.0\t\t\nAEs\t\t\t\t\t\n Any\t127 (32)\t2609.2 [236]\t115 (29)\t2695.2 [248]\t\n Drug related\t11 (3)\t199.0 [18]\t4 (1)\t228.2 [21]\t\n Leading to permanent discontinuation or study withdrawala\t7 (2)\t110.6 [10]\t3 (<1)\t32.6 [3]\t\nSAEs\t\t\t\t\t\n Any\t13 (3)\t187.9 [17]\t10 (3)\t130.4 [12]\t\n Drug related\t0\t–\t0\t–\t\n Leading to permanent discontinuation or study withdrawal\t4 (1)\t44.2 [4]\t3 (<1)\t32.6 [3]\t\n Fatal\t2 (<1)\t22.1 [2]\t1 (<1)\t10.9 [1]\t\nAESIs\t\t\t\t\t\n Cardiovascular effects\t11 (3)\t143.7 [13]\t11 (3)\t195.6 [18]\t\n Decreased BMD and associated fractures\t2 (<1)\t22.1 [2]\t0\t–\t\n LRTI excluding pneumonia\t0\t–\t1 (<1)\t10.9 [1]\t\n Pneumonia\t3 (<1)\t33.2 [3]\t3 (<1)\t32.6 [3]\t\nRate is the number of events per 1000 patient-years, calculated as the number of events × 1000 divided by the total treatment exposure.\n\n# number of events, AE adverse event, AESI adverse event of special interest, BMD bone mineral density, COPD chronic obstructive pulmonary disease, FF fluticasone furoate, ITT intent-to-treat, LRTI lower respiratory tract infection, SAE serious adverse event, TIO tiotropium, UMEC umeclidinium, VI vilanterol.\n\naAEs leading to permanent discontinuation or study withdrawal included pneumonia (FF/UMEC/VI n = 1 [<1%]; TIO n = 1 [<1%]), oral fungal infection (FF/UMEC/VI n = 1 [<1%]; TIO n = 0), postoperative wound infection (FF/UMEC/VI n = 1 [<1%]; TIO n = 0), hemorrhagic stroke (FF/UMEC/VI n = 0; TIO n = 1 [<1%]), ischemic stroke (FF/UMEC/VI n = 0; TIO n = 1 [<1%]), tremor (FF/UMEC/VI n = 1 [<1%]; TIO n = 0), cardiac arrest (FF/UMEC/VI n = 1 [<1%]; TIO n = 0), palpitations (FF/UMEC/VI n = 1 [<1%]; TIO n = 0), asthenia (FF/UMEC/VI n = 1 [<1%]; TIO n = 0), insomnia (FF/UMEC/VI n = 1 [<1%]; TIO n = 0), COPD (FF/UMEC/VI n = 1 [<1%]; TIO n = 0), and hyperhidrosis (FF/UMEC/VI n = 1 [<1%]; TIO n = 0).\n\nDiscussion\n\nThis study examined the effect of single-inhaler FF/UMEC/VI triple therapy versus TIO monotherapy in patients with symptomatic COPD with moderate-to-very-severe airflow limitation, as in clinical practice patients are often escalated directly from LAMA monotherapy to triple therapy with the addition of ICS/LABA. The superiority of FF/UMEC/VI versus TIO was demonstrated for the primary endpoint of change from baseline in trough FEV1 at Day 85. Furthermore, significant improvements were seen in trough FEV1 at Days 28 and 84, with the greatest improvement at Day 28 (exceeding the MCID value of 100 mL), indicating that FF/UMEC/VI leads to early and sustained benefits in lung function in this population. These findings are in line with previous studies comparing TIO monotherapy to multiple-inhaler ICS/LAMA/LABA triple therapy in patients with COPD, all of which demonstrated statistically significant improvements in pre-dose FEV1 in favor of triple therapy14. These data are also consistent with a recent study demonstrating significant improvements in pre-dose FEV1 from 4 to 52 weeks following initiation of single-inhaler triple therapy (beclometasone dipropionate, formoterol fumarate, glycopyrronium bromide) compared with TIO monotherapy in patients with symptomatic COPD with FEV1 < 50% and a history of exacerbations5. However, while sustained and significant improvements with triple therapy versus LAMA monotherapy were observed in this study, the whole clinical picture and general symptom burden must be taken into account in clinical practice. For example, while this study showed greater improvements in lung function in patients with FEV1 ≥ 50%, these results cannot necessarily be extrapolated to improving dyspnea in patients with symptomatic COPD and a history of exacerbation but preserved lung function.\n\nEarly and sustained improvements in health status, as assessed by SGRQ total score and CAT score, were also seen in the current study, with significant decreases in both scores with FF/UMEC/VI versus TIO at Days 28 and 84. Moreover, significantly more patients achieved a ≥ 4-point decrease in SGRQ total score with FF/UMEC/VI versus TIO at both Day 28 and 84. The CAT responder analysis showed a similar trend, with an OR favoring FF/UMEC/VI at both time points, although statistical significance in favor of FF/UMEC/VI was only achieved at Day 28. This was likely due to small decreases in CAT score in the TIO group at Day 84 which tipped patients over the response threshold despite a minimal change versus Day 28, resulting in the loss of statistical significance for the odds of response between the treatment groups at Day 84. These results indicate that addition of ICS and LABA therapy to LAMA monotherapy improves not only lung function but also health status in patients with symptomatic COPD with moderate-to-very-severe airflow limitation. These findings are consistent with previous studies showing that multiple-inhaler triple therapy significantly improved health status, as measured by SGRQ score, versus TIO monotherapy5–9. The early decreases in CAT and SGRQ total scores, seen within 28 days in the current study, are notable given that in most previous studies changes in SGRQ score were only assessed after ≥12 weeks of treatment5–7,9. Together, these data suggest that single-inhaler FF/UMEC/VI triple therapy leads to relatively rapid improvements in patient symptoms and quality of life in patients with symptomatic COPD with moderate-to-very-severe airflow limitation.\n\nThe post hoc subgroup analysis, conducted according to airflow limitation at screening, demonstrated significant improvements in lung function with FF/UMEC/VI versus TIO both in patients with FEV1 < 50% predicted and ≥50% predicted at baseline. These findings are consistent with a previous study, which showed that lung function benefits in patients with COPD treated with fluticasone/salmeterol plus TIO versus TIO monotherapy were more pronounced for those with severe airflow limitation (FEV1 < 50% predicted)4. Additionally, patients with FEV1 < 50% predicted at baseline experienced significant decreases in SGRQ total score and CAT score at Days 28 and 84, while those with FEV1 ≥ 50% predicted experienced numerical decreases in both scores at each time point that only reached significance at Day 84 for SGRQ total score. These data suggest that a step-up from TIO monotherapy to single-inhaler FF/UMEC/VI triple therapy improves clinical outcomes for patients with symptomatic COPD regardless of airflow limitation, with particular benefit for patients with severe airflow limitation (FEV1 < 50% predicted).\n\nFew patients experienced a moderate/severe exacerbation in either treatment group, despite the population being at risk for exacerbation based on the inclusion criterion of FEV1 < 50% predicted or <80% predicted with a documented history of ≥2 moderate or 1 severe exacerbation in the 12 months prior to screening. The low overall number of exacerbations is likely due to the short length of the study, which along with the size of the population leaves the study underpowered to detect a between-group difference in the rate of exacerbations. Nonetheless, the proportion of patients experiencing a moderate/severe COPD exacerbation during the study was numerically higher in TIO-treated patients compared with those receiving FF/UMEC/VI. These data are consistent with a real-world observational study that showed a lower risk of COPD exacerbations in patients receiving triple therapy with fluticasone-salmeterol plus TIO compared with TIO alone15.\n\nThe safety profile of FF/UMEC/VI was similar to that of TIO, with no unexpected safety findings. Rates of SAEs and AESIs, including pneumonia and cardiovascular effects, were low and consistent with previous studies comparing multiple-inhaler triple therapy with TIO monotherapy4–10. The low pneumonia rates are reassuring given the association seen between pneumonia and ICS use in previous studies16.\n\nOverall, these data show that direct escalation from TIO monotherapy to single-inhaler FF/UMEC/VI triple therapy led to rapid improvements in lung function, symptoms, and health status without an increased risk of pneumonia or other AEs in patients with symptomatic COPD with moderate-to-very-severe airflow limitation. Study limitations include the short study length, which may limit data interpretation. As such, a 1-year study focusing on other outcomes, including the rate of COPD exacerbations, is required. Nonetheless, these data provide valuable clinical information to inform treatment decisions for patients on LAMA monotherapy who continue to experience symptoms and/or exacerbations.\n\nThis study demonstrated superiority of once-daily single-inhaler FF/UMEC/VI versus TIO for lung function and patient health status, with a similar safety profile and no difference in pneumonia rates, in patients with symptomatic COPD with moderate-to-very-severe airflow limitation. These results suggest that FF/UMEC/VI is a viable treatment step-up option for optimizing outcomes in patients who continue to experience symptoms and/or exacerbations while receiving LAMA monotherapy.\n\nMethods\n\nTrial design\n\nStudy 207626 (NCT03474081) was a 12-week, Phase IV, parallel-group, active-controlled, double-blind, double-dummy, randomized, multicenter study comparing once-daily single-inhaler FF/UMEC/VI with TIO monotherapy in patients with symptomatic COPD and moderate-to-very-severe airflow limitation. The study was conducted in 72 centers in three countries (Poland, Russian Federation, and the USA) from March 2018 to July 2019.\n\nEligible patients were instructed on the proper use of the ELLIPTA and HandiHaler devices at a screening visit (Visit 1) before entering a 4-week run-in period during which they received open-label TIO 18 mcg once daily via HandiHaler and placebo once daily via ELLIPTA. Eligible patients were then randomized 1:1 (using an Interactive Web Response System) to receive either FF/UMEC/VI 100/62.5/25 mcg via ELLIPTA and placebo via HandiHaler or TIO 18 mcg via HandiHaler and placebo via ELLIPTA, all taken once daily in the morning (Visit 2). A double-dummy design was used to ensure blinding, with each patient given two inhalers (ELLIPTA and HandiHaler) to administer the active medication and placebo, and patients self-administered treatment each day. All site personnel involved in efficacy and safety assessments were also blinded to assigned treatment during the study. Rescue albuterol/salbutamol was available as needed throughout the study but withheld for ≥4 hours prior to spirometry assessments. Patients attended two on-treatment study visits (Day 28 [Visit 3] and Day 84 [Visit 4]). Final clinical assessments were conducted on Day 85 (Visit 5). A safety follow-up telephone call or on-site visit (Visit 6) was conducted ~7 days after Visit 5, at the study treatment discontinuation visit, or at the end of the study, whichever was first.\n\nAll study patients provided written informed consent. The study was approved by a national, regional, or investigational center ethics committee or institutional review board, in accordance with the International Council on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Good Clinical Practice and applicable country-specific requirements. Further details are provided in Table 4.Table 4 Institutional Review Board approval numbers by country.\n\nCountry\tName, city\tInitial approval number\tAmendment approval number\t\nPoland\tBIOETHICS COMMITTEE at the Regional Medical Chamber in Białystok, Białystok\t5/2018/VII\tN/A\t\nRussian Federation\tEthics Committee of GBOU VPO Saratov State Medical University named after V.I., Saratov\t4063977-20-1\t4081983-20-1/IIII\t\nBest Clinical Practice, Saint Petersburg\t\nCity Clinical Hospital of Emergency #2, Novosibirsk, Russian Federation\t\nBudgetary Healthcare Institution of the Voronezh region “Voronezh Regional Clinical Hospital # 1”, Voronezh\t\nNovosibirsk State Regional Clinical Hospital, Novosibirsk\t\nLimited Liability Company Medical Association New Hospital, Ekaterinburg\t\nCity Clinical Hospital #4, Ivanovo\t\nMedical Research Institute, St Petersburg\t\nUlyanovsk Regional Clinical Hospital, Ulyanovsk\t\nCity Clinical Hospital Number 13, Moscow\t\nMoscow City Ethical Committee, Moscow\t\nSaint-Petersburg SBHI “City Pokrovskaya hospital”, Saint Petersburg\t\nGOU VPO Saint Petersburg State Medical University “I.P.Pavlova”, Saint Petersburg\t\nFSBI Scientific Research Institute of Pulmonology of FMBA, Moscow\t\nUSA\tWestern Institutional Review Board, Puyallup, Washington\t201800018\tMOD00288865\t\nAdvarra Institutional Review Board, Columbia, Maryland\t\n\nTrial population\n\nAt screening, eligible patients were ≥40 years of age, current or former smokers with a history of ≥10 pack-years, had an established clinical history of COPD, had been receiving daily COPD maintenance treatment with TIO alone for ≥3 months, had a post-bronchodilator forced expiratory volume in 1 s (FEV1) of <50% predicted (or a post-bronchodilator FEV1 < 80% predicted and a documented history of ≥2 moderate exacerbations [worsening COPD symptoms requiring treatment with oral/systemic corticosteroids and/or antibiotics] or ≥1 severe exacerbation [worsening COPD symptoms requiring in-patient hospitalization] in the last 12 months), and had a COPD Assessment Test (CAT) score ≥10.\n\nPatients with a current diagnosis of asthma, other respiratory disorders, or other clinically significant diseases were excluded, although participants with a prior history of asthma were eligible if they had a current diagnosis of COPD. Also excluded were those with α1-antitrypsin deficiency as the underlying cause of COPD, a lung resection in the last 12 months, risk factors for pneumonia or recent pneumonia and/or a moderate or severe COPD exacerbation that had not resolved ≥14 days prior to screening and ≥30 days following the last dose of oral/systemic corticosteroids, a respiratory tract infection that had not resolved ≥7 days prior to screening, or an abnormal chest x-ray at or 3 months prior to screening.\n\nPatients were not eligible to be randomized to study treatment if they had a CAT score <10 at Visit 2, demonstrated lack of compliance to run-in treatment (<80% or >120% compliant with either ELLIPTA or HandiHaler), experienced pneumonia, had a moderate or severe COPD exacerbation, or required a change in COPD medication during the run-in period. Assessment of compliance with study treatment between visits was conducted through patient conversations and recording the number of doses left in the ELLIPTA device and the number of capsules dispensed through the HandiHaler. Full inclusion, exclusion, and randomization criteria are provided in Supplementary Note 1.\n\nEfficacy endpoints\n\nThe primary endpoint was change from baseline in trough FEV1 at Day 85. To provide a reliable measurement of on-treatment trough FEV1 on Day 85, the final dose of study treatment was administered in clinic on Day 84, to ensure high adherence to dosing. Secondary endpoints were change from baseline in trough FEV1 at Days 28 and 84. Other endpoints included: change from baseline in SGRQ total score at Days 28 and 84; proportion of SGRQ total score responders at Days 28 and 84 (defined as ≥4-unit decrease in SGRQ total score from baseline); change from baseline in CAT score at Days 28 and 84; proportion of CAT score responders at Days 28 and 84 (defined as ≥2-unit decrease in CAT score from baseline); and moderate or severe exacerbation events. Subgroup analyses by percent predicted FEV1 at screening (FEV1 < 50% or ≥50%) were performed post hoc.\n\nSafety assessments\n\nOn-treatment AEs were defined as those occurring from the day of starting randomized study treatment until 1 day after stopping randomized study treatment. Incidences of on-treatment adverse events (AEs), including AEs of special interest (AESIs), and serious AEs (SAEs) were recorded. AESIs included cardiovascular effects, decreased bone mineral density and associated fractures, pneumonia, and lower respiratory tract infection (excluding pneumonia). All pneumonias we confirmed clinically and by x-ray, as detailed in Supplementary Note 1.\n\nStatistical analysis\n\nSample size was based on the primary endpoint of trough FEV1 at Day 85 and assumed 90% power, a two-sided 1% significance level, an estimate of residual standard deviation of 240 mL (based on mixed model repeated measures [MMRM] analyses of the Phase III IMPACT study)13 and a treatment difference of 70 mL. Under these assumptions, a total of 702 evaluable patients (351 per treatment group) were required. Assuming an 8% withdrawal rate during the run-in period and 10% withdrawal rate during the study period, it was aimed to enroll ~848 patients into the 4-week run-in period in order to randomize 780 patients.\n\nThe intent-to-treat (ITT) population included all randomized patients, excluding those randomized in error, and was used for the analyses of study population, efficacy, and safety. A participant who was recorded as a screen or run-in failure and also randomized but who did not receive any dose of study treatment was considered to be randomized in error. Any participant who received a randomization number was considered to have been randomized.\n\nBoth primary and secondary lung function endpoints were analyzed using MMRM, with covariates of baseline FEV1, visit, geographical region, and treatment; interaction terms included visit-by-baseline FEV1. A visit-by-treatment interaction term was also included to allow treatment effects to be estimated at each visit separately. The variance-covariance matrix was assumed to be unstructured. The primary treatment effect was estimated using a hypothetical strategy that only data up to the time of treatment discontinuation was used in the analysis and data following treatment discontinuation was assumed to follow the same pattern as if the patients had remained on treatment, ie. missing at random.\n\nCAT score and SGRQ total score were analyzed using MMRM, including covariates of baseline value, visit, geographical region, and treatment; interaction terms included visit-by-baseline value and visit-by-treatment. The proportions of CAT or SGRQ responders were analyzed using a generalized linear mixed model with a logit link function and covariates of baseline score, geographical region, treatment group, visit, and visit-by-baseline and visit-by-treatment interactions. TIO was used as the reference level for treatment.\n\nSafety endpoints were analyzed in the ITT population using descriptive statistics. AESIs were defined as AEs that have specified areas of interest for FF, UMEC, and VI, or the overall COPD population.\n\nReporting summary\n\nFurther information on research design is available in the Nature Research Reporting Summary linked to this article.\n\nSupplementary information\n\nReporting Summary\n\nSupplementary Information\n\nSupplementary information\n\nThe online version contains supplementary material available at 10.1038/s41533-021-00241-z.\n\nAcknowledgements\n\nThis study was funded by GlaxoSmithKline (GSK study 207626; NCT03474081). The funders of the study had a role in the study design, data analysis, data interpretation, and writing of the report. Editorial support (in the form of writing assistance, assembling figures, collating author comments, grammatical editing, and referencing) was provided by Anne Errichelli, DPhil, at Fishawack Indicia Ltd, UK, and was funded by GSK. ELLIPTA is owned by or licensed to the GSK Group of Companies. HandiHaler is a trademark of Boehringer Ingelheim International GmbH.\n\nAuthor contributions\n\nThe authors meet criteria for authorship as recommended by the International Committee of Medical Journal Editors, take responsibility for the integrity of the work as a whole, contributed to the writing and reviewing of the manuscript, and have given final approval for the version to be published. All authors had full access to the data in this study and take complete responsibility for the integrity of the data and accuracy of the data analysis. S.B., D.E., and M.K. were involved in acquisition of data and analysis/interpretation of data. N.B., M.C.K., D.A.L., and C.-Q.Z. were involved in the conception/design of the study and analysis/interpretation of data. C.C., T.C.C., C.H., N.M., A.P., M.A., and A.A. were involved in the analysis/interpretation of data.\n\nData availability\n\nAnonymized individual participant data and study documents can be requested for further research from www.clinicalstudydatarequest.com by submitting an enquiry citing GSK study number 207626.\n\nCompeting interests\n\nS.B. has received speaker fees from GSK, Boehringer Ingelheim, Auris Health, Veran, Veracyte, Biodesix, Pinnacle Biologics, and Circulogene. He has also previously participated in speaker’s bureau for Sunovion Pharmaceuticals and holds stocks/shares in Veracyte. M.A. has received speaker fees from AstraZeneca, Boehringer Ingelheim, GSK, MEDA, Orion Pharma, and TEVA. A.A. has received consultancy fees from Boehringer Ingelheim, Novartis, AstraZeneca, and Theravance Mylan. N.B., C.C., T.C.C., C.H., M.C.K., D.A.L., N.M., and C.-Q.Z. are employees of GSK and own stocks/shares. D.E. has received compensation for being a trial investigator for Vitalink Research. M.K. has nothing to disclose. A.P. has received consultancy fees and board membership from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Mundipharma, and TEVA, and consultancy fees and payment for lectures from Sanofi. He has also received reimbursement of travel expenses from Avillion, reimbursement of travel expenses and payment for lectures from AstraZeneca, Boehringer Ingelheim, Chiesi, ELPEN Pharmaceutical, GSK, Menarini, MSD, Mundipharma, Novartis, TEVA, and Zambon, and research grants from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Pfizer, Sanofi, and TEVA.\n\nPublisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Global Initiative for Chronic Obstructive Lung Disease. 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Vestbo J Single inhaler extrafine triple therapy versus long-acting muscarinic antagonist therapy for chronic obstructive pulmonary disease (TRINITY): a double-blind, parallel group, randomised controlled trial Lancet 2017 389 1919 1929 10.1016/S0140-6736(17)30188-5 28385353\n6. Jung KS Comparison of tiotropium plus fluticasone propionate/salmeterol with tiotropium in COPD: a randomized controlled study Respir. Med. 2012 106 382 389 10.1016/j.rmed.2011.09.004 21975275\n7. Welte T Efficacy and tolerability of budesonide/formoterol added to tiotropium in patients with chronic obstructive pulmonary disease Am. J. Respir. Crit. Care. Med. 2009 180 741 750 10.1164/rccm.200904-0492OC 19644045\n8. Aaron SD Tiotropium in combination with placebo, salmeterol, or fluticasone-salmeterol for treatment of chronic obstructive pulmonary disease: a randomized trial Ann. Intern. Med. 2007 146 545 555 10.7326/0003-4819-146-8-200704170-00152 17310045\n9. Hoshino M Ohtawa J Effects of adding salmeterol/fluticasone propionate to tiotropium on airway dimensions in patients with chronic obstructive pulmonary disease Respirology 2011 16 95 101 10.1111/j.1440-1843.2010.01869.x 20920142\n10. Cazzola M A pilot study to assess the effects of combining fluticasone propionate/salmeterol and tiotropium on the airflow obstruction of patients with severe-to-very severe COPD Pulm. Pharmacol. Ther. 2007 20 556 561 10.1016/j.pupt.2006.06.001 16914336\n11. Meguro M Barley EA Spencer S Jones PW Development and validation of an improved, COPD-specific version of the St. George respiratory questionnaire Chest 2007 132 456 463 10.1378/chest.06-0702 17646240\n12. Lipson DA FULFIL trial: once-daily triple therapy for patients with chronic obstructive pulmonary disease Am. J. Respir. Crit. Care Med. 2017 196 438 446 10.1164/rccm.201703-0449OC 28375647\n13. Lipson DA Once-daily single-inhaler triple versus dual therapy in patients with COPD N. Engl. J. Med 2018 378 1671 1680 10.1056/NEJMoa1713901 29668352\n14. Rojas-Reyes M. X., Garcia Morales O. M., Dennis R. J. & Karner C. Combination inhaled steroid and long-acting beta(2)-agonist in addition to tiotropium versus tiotropium or combination alone for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. CD008532 (2016).\n15. Chatterjee A Shah M D’Souza AO Bechtel B Crater G Dalal AA Observational study on the impact of initiating tiotropium alone versus tiotropium with fluticasone propionate/salmeterol combination therapy on outcomes and costs in chronic obstructive pulmonary disease Respir. Res. 2012 13 15 10.1186/1465-9921-13-15 22340019\n16. Kew K. M. & Seniukovich A. Inhaled steroids and risk of pneumonia for chronic obstructive pulmonary disease. Cochrane Database Syst. Rev. CD010115 (2014).\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2055-1010",
"issue": "31(1)",
"journal": "NPJ primary care respiratory medicine",
"keywords": null,
"medline_ta": "NPJ Prim Care Respir Med",
"mesh_terms": "D000280:Administration, Inhalation; D000730:Androstadienes; D001592:Benzyl Alcohols; D001993:Bronchodilator Agents; D002722:Chlorobenzenes; D004311:Double-Blind Method; D005541:Forced Expiratory Volume; D006801:Humans; D009330:Nebulizers and Vaporizers; D029424:Pulmonary Disease, Chronic Obstructive; D011812:Quinuclidines; D000069447:Tiotropium Bromide; D016896:Treatment Outcome",
"nlm_unique_id": "101631999",
"other_id": null,
"pages": "29",
"pmc": null,
"pmid": "34035312",
"pubdate": "2021-05-25",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "27271056;22340019;29668352;19644045;28385353;20920142;16914336;17310045;28375647;21975275;30362922;17646240;24615270;22040533",
"title": "Single-inhaler fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI) triple therapy versus tiotropium monotherapy in patients with COPD.",
"title_normalized": "single inhaler fluticasone furoate umeclidinium vilanterol ff umec vi triple therapy versus tiotropium monotherapy in patients with copd"
} | [
{
"companynumb": "IT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2021-BI-106587",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TIOTROPIUM BROMIDE MONOHYDRATE"
... |
{
"abstract": "Hepatitis B virus (HBV) reactivation in patients with prior exposure to HBV and protective levels of hepatitis B surface antibody (HBsAb) is a rare phenomenon and is termed reverse seroconversion. We describe a case of reactivation of HBV infection following reverse seroconversion in a patient who underwent umbilical cord allogeneic hematopoietic cell transplantation (UHCT). The patient developed acute hepatitis with positive hepatitis B surface antigen (HBsAg) and HBV DNA in the context of prior strongly positive HBsAb. The patient was treated with oral tenofovir and liver function tests returned to normal 3 months later. Long-term monitoring for HBV reactivation should be considered in patients with prior exposure to HBV undergoing UHCT regardless of HBsAb status.",
"affiliations": "Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA. Electronic address: dsingh@umn.edu.;Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA.;Division of Gastroenterology, Hepatology and Nutrition, University of Minnesota, Minneapolis, MN, USA.",
"authors": "Singh|D|D|;Hassan|M|M|;Lim|N|N|",
"chemical_list": "D000998:Antiviral Agents; D006510:Hepatitis B Antibodies; D000068698:Tenofovir",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.12.022",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "51(2)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D036101:Cord Blood Stem Cell Transplantation; D006509:Hepatitis B; D006510:Hepatitis B Antibodies; D006515:Hepatitis B virus; D006801:Humans; D008297:Male; D000069078:Seroconversion; D000068698:Tenofovir; D014775:Virus Activation",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "602-604",
"pmc": null,
"pmid": "30879599",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reactivation of Hepatitis B Virus Infection With Reverse Seroconversion Following Umbilical Cord Allogeneic Hematopoietic Cell Transplantation in a Hepatitis-B-Immune Patient: A Case Report.",
"title_normalized": "reactivation of hepatitis b virus infection with reverse seroconversion following umbilical cord allogeneic hematopoietic cell transplantation in a hepatitis b immune patient a case report"
} | [
{
"companynumb": "US-SA-2019SA093901",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"d... |
{
"abstract": "The highest number of COVID-19 cases in Italy have been reported in Lombardy, a region in northern Italy. We aimed to analyse the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in patients with rheumatic and musculoskeletal diseases living in a district of Lombardy with a high prevalence of COVID-19.\nWe did a single-centre observational study at the Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili of Brescia, Italy. We collected data from patients with rheumatic and musculoskeletal diseases enrolled in our outpatient clinic to identify confirmed or possible cases of SARS-CoV-2 infection. Data were collected through a survey that was administered via telephone or in the outpatient clinic by rheumatologists. We also did a case-control study of all patients with confirmed COVID-19 pneumonia and rheumatic and musculoskeletal diseases who were admitted to the ASST Spedali Civili of Brescia during the study period. Cases were matched by age, sex, and month of hospital admission to at least two controls admitted to the same hospital for COVID-19 pneumonia during the study period.\nBetween Feb 24 and May 1, 2020, we collected data from 1525 patients with rheumatic and musculoskeletal diseases: 117 (8%) presented with symptoms that were compatible with COVID-19. 65 patients had a swab confirmation of SARS-CoV-2 infection, whereas 52 presented with a spectrum of symptoms indicative of COVID-19 but were not swab tested. Patients with confirmed COVID-19 were older than those with suspected COVID-19 (median age 68 [IQR 55-76] years vs 57 [49-67] years; p=0·0010) and more likely to have arterial hypertension (33 [51%] vs 14 [27%] patients; odds ratio [OR] 2·8 [95% CI 1·3-6·1]; p=0·031) and obesity (11 [17%] vs 1 [2%]; OR 11·0 [1·3-83·4]; p=0·0059). We found no differences in rheumatological disease or background therapy between confirmed and suspected COVID-19 cases. 47 (72%) of the 65 patients with confirmed COVID-19 developed pneumonia that required admission to hospital. 12 (10%) deaths occurred among the 117 patients with confirmed or suspected COVID-19 (ten in those with confirmed COVID-19 and two in those with suspected COVID-19). Deceased patients with confirmed COVID-19 were older than survivors (median age 78·8 years [IQR 75·3-81·3] vs 65·5 years [53·3-74·0]; p=0·0002). We observed no differences in sex, comorbidities, or therapies between the deceased patients and survivors. The case-control study comprised 26 patients with rheumatic and musculoskeletal diseases and COVID-19 pneumonia and 62 matched controls. We found no significant differences between cases and controls in duration of COVID-19 symptoms before admission, duration of stay in hospital, or the local chest X-ray scoring system. Glucocorticoids were used for severe respiratory manifestations related to lung involvement in 17 (65%) of 26 cases and tocilizumab in six (23%) of 26; thrombotic events occurred in four (15%) of 26 cases. Four (15%) of 26 cases and six (10%) of 62 controls died during the study period.\nIn this cohort of patients with rheumatic and musculoskeletal diseases in a geographical region with a high prevalence of COVID-19, a poor outcome from COVID-19 seems to be associated with older age and the presence of comorbidities rather than the type of rheumatic disease or the degree of pharmacological immunosuppression.\nNone.",
"affiliations": "Rheumatology and Clinical Immunology Unit, ASST Spedali Civili of Brescia, Brescia, Italy.;Rheumatology and Clinical Immunology Unit, ASST Spedali Civili of Brescia, Brescia, Italy.;Rheumatology and Clinical Immunology Unit, ASST Spedali Civili of Brescia, Brescia, Italy.;Rheumatology and Clinical Immunology Unit, ASST Spedali Civili of Brescia, Brescia, Italy.;Rheumatology and Clinical Immunology Unit, ASST Spedali Civili of Brescia, Brescia, Italy.",
"authors": "Fredi|Micaela|M|;Cavazzana|Ilaria|I|;Moschetti|Liala|L|;Andreoli|Laura|L|;Franceschini|Franco|F|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/S2665-9913(20)30169-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2665-9913",
"issue": "2(9)",
"journal": "The Lancet. Rheumatology",
"keywords": null,
"medline_ta": "Lancet Rheumatol",
"mesh_terms": null,
"nlm_unique_id": "101765308",
"other_id": null,
"pages": "e549-e556",
"pmc": null,
"pmid": "32838307",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": "32091533;32376395;32376398;32293098;32358689;18064739;32309814;32356577;32241793;32007143;32321723;32332072;32330817;32471903;32349183;32348641;32304772;32835249",
"title": "COVID-19 in patients with rheumatic diseases in northern Italy: a single-centre observational and case-control study.",
"title_normalized": "covid 19 in patients with rheumatic diseases in northern italy a single centre observational and case control study"
} | [
{
"companynumb": "IT-AMGEN-ITASP2020149477",
"fulfillexpeditecriteria": "2",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APREMILAST"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nA significant number of patients undergoing Mohs micrographic surgery (MMS) for skin cancer are treated with oral anticoagulants. The incidence of postoperative complications associated with new classes of oral anticoagulants remains largely unknown.\n\n\nOBJECTIVE\nTo determine the incidence of postoperative complications in patients undergoing MMS on both traditional oral anticoagulants and new novel oral anticoagulants.\n\n\nMETHODS\nA single-center retrospective chart review was performed for all patients treated with oral anticoagulants who underwent MMS between July 1, 2012 and June 30, 2015 at University of California, San Diego.\n\n\nRESULTS\nThe data from this study demonstrated that patients treated with a novel oral anticoagulant at the time of MMS had a statistically significant greater risk for developing postoperative hemorrhagic complications compared to patients treated with traditional oral anticoagulants.\n\n\nCONCLUSIONS\nDermatologic surgeons should manage both traditional oral anticoagulants and novel oral anticoagulants in a similar manner. Future studies are warranted.",
"affiliations": "*All authors are affiliated with the San Diego Medical Center, University of California, San Diego, California.;All authors are affiliated with the San Diego Medical Center, University of California, San Diego, California.",
"authors": "Eilers|Robert E|RE|;Goldenberg|Alina|A|;Cowan|Natasha L|NL|;Basu|Pallavi|P|;Brian Jiang|Shang I|SI|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.1097/DSS.0000000000001394",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-0512",
"issue": "44(4)",
"journal": "Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]",
"keywords": null,
"medline_ta": "Dermatol Surg",
"mesh_terms": "D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015580:Mohs Surgery; D019106:Postoperative Hemorrhage; D012189:Retrospective Studies; D012878:Skin Neoplasms",
"nlm_unique_id": "9504371",
"other_id": null,
"pages": "504-511",
"pmc": null,
"pmid": "29140870",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Retrospective Assessment of Postoperative Bleeding Complications in Anticoagulated Patients Following Mohs Micrographic Surgery.",
"title_normalized": "a retrospective assessment of postoperative bleeding complications in anticoagulated patients following mohs micrographic surgery"
} | [
{
"companynumb": "US-BAYER-2018-193889",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nTriple-negative breast cancer (TNBC) is an aggressive disease with limited therapeutic options. Antibodies targeting programmed cell death protein 1 (PD-1)/PD-1 ligand 1 (PD-L1) have entered the therapeutic landscape in TNBC, but only a minority of patients benefit. A way to reliably enhance immunogenicity, T-cell infiltration, and predict responsiveness is critically needed.\n\n\nMETHODS\nUsing mouse models of TNBC, we evaluate immune activation and tumor targeting of intratumoral IL12 plasmid followed by electroporation (tavokinogene telseplasmid; Tavo). We further present a single-arm, prospective clinical trial of Tavo monotherapy in patients with treatment refractory, advanced TNBC (OMS-I140). Finally, we expand these findings using publicly available breast cancer and melanoma datasets.\n\n\nRESULTS\nSingle-cell RNA sequencing of murine tumors identified a CXCR3 gene signature (CXCR3-GS) following Tavo treatment associated with enhanced antigen presentation, T-cell infiltration and expansion, and PD-1/PD-L1 expression. Assessment of pretreatment and posttreatment tissue from patients confirms enrichment of this CXCR3-GS in tumors from patients that exhibited an enhancement of CD8+ T-cell infiltration following treatment. One patient, previously unresponsive to anti-PD-L1 therapy, but who exhibited an increased CXCR3-GS after Tavo treatment, went on to receive additional anti-PD-1 therapy as their immediate next treatment after OMS-I140, and demonstrated a significant clinical response.\n\n\nCONCLUSIONS\nThese data show a safe, effective intratumoral therapy that can enhance antigen presentation and recruit CD8 T cells, which are required for the antitumor efficacy. We identify a Tavo treatment-related gene signature associated with improved outcomes and conversion of nonresponsive tumors, potentially even beyond TNBC.",
"affiliations": "Department of Medicine, Stanford University School of Medicine, Stanford, California. erika.crosby@duke.edu mtelli@stanford.edu.;Department of Surgery, Duke University, Durham, North Carolina.;Department of Surgery, Stanford University School of Medicine, Stanford, California.;Department of Surgery, Duke University, Durham, North Carolina.;Department of Medicine, Stanford University School of Medicine, Stanford, California.;Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.;Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.;Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.;Earle A. Chiles Research Institute, Providence Portland Medical Center, Portland, Oregon.;OncoSec Medical Incorporated, San Diego, California.;OncoSec Medical Incorporated, San Diego, California.;OncoSec Medical Incorporated, San Diego, California.;OncoSec Medical Incorporated, San Diego, California.;OncoSec Medical Incorporated, San Diego, California.;OncoSec Medical Incorporated, San Diego, California.;OncoSec Medical Incorporated, San Diego, California.;OncoSec Medical Incorporated, San Diego, California.;OncoSec Medical Incorporated, San Diego, California.;OncoSec Medical Incorporated, San Diego, California.;OncoSec Medical Incorporated, San Diego, California.;Department of Surgery, Duke University, Durham, North Carolina.;Department of Surgery, Duke University, Durham, North Carolina.;Department of Surgery, Duke University, Durham, North Carolina. erika.crosby@duke.edu mtelli@stanford.edu.",
"authors": "Telli|Melinda L|ML|;Nagata|Hiroshi|H|;Wapnir|Irene|I|;Acharya|Chaitanya R|CR|https://orcid.org/0000-0001-7149-1749;Zablotsky|Kaitlin|K|;Fox|Bernard A|BA|;Bifulco|Carlo B|CB|;Jensen|Shawn M|SM|;Ballesteros-Merino|Carmen|C|https://orcid.org/0000-0002-5073-7188;Le|Mai Hope|MH|;Pierce|Robert H|RH|;Browning|Erica|E|;Hermiz|Reneta|R|;Svenson|Lauren|L|;Bannavong|Donna|D|;Jaffe|Kim|K|;Sell|Jendy|J|;Foerter|Kellie Malloy|KM|;Canton|David A|DA|;Twitty|Christopher G|CG|;Osada|Takuya|T|https://orcid.org/0000-0003-1424-5001;Lyerly|H Kim|HK|https://orcid.org/0000-0002-0063-4770;Crosby|Erika J|EJ|https://orcid.org/0000-0002-4872-6711",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1158/1078-0432.CCR-20-3944",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-0432",
"issue": "27(9)",
"journal": "Clinical cancer research : an official journal of the American Association for Cancer Research",
"keywords": null,
"medline_ta": "Clin Cancer Res",
"mesh_terms": null,
"nlm_unique_id": "9502500",
"other_id": null,
"pages": "2481-2493",
"pmc": null,
"pmid": "33593880",
"pubdate": "2021-05-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intratumoral Plasmid IL12 Expands CD8+ T Cells and Induces a CXCR3 Gene Signature in Triple-negative Breast Tumors that Sensitizes Patients to Anti-PD-1 Therapy.",
"title_normalized": "intratumoral plasmid il12 expands cd8 t cells and induces a cxcr3 gene signature in triple negative breast tumors that sensitizes patients to anti pd 1 therapy"
} | [
{
"companynumb": "US-MYLANLABS-2022M1024428",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "Abdominal compartment syndrome (ACS) is an infrequently encountered life-threatening disorder characterised by elevated abdominal pressure with evidence of new organ dysfunction. It is rarely reported in paediatrics. We describe an extremely unusual presentation of a 13-year-old boy with long-standing constipation who developed ACS complicated by refractory septic shock and multiorgan failure. He was treated with emergent decompressive laparotomy and supportive critical care. This case highlights the need for early diagnosis and timely management of ACS to improve its outcome.",
"affiliations": "Department of Pediatric Critical Care Medicine, Children's Hospital, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada alalali.uae@gmail.com.;Department of Pediatric Critical Care Medicine, Children's Hospital, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada.;Paediatrics, Univ Western Ontario, London, Ontario, Canada.;Pediatric Critical Care, Shaikh Khalifa Medical City, Abu Dhabi, UAE.",
"authors": "Al Ali|Alyaa|A|;Singh|Ram|R|;Filler|Guido|G|http://orcid.org/0000-0003-1891-6765;Ramsi|Musaab|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-242104",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(6)",
"journal": "BMJ case reports",
"keywords": "gastrointestinal surgery; paediatrics",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000293:Adolescent; D002648:Child; D003161:Compartment Syndromes; D003248:Constipation; D019299:Decompression, Surgical; D006801:Humans; D059325:Intra-Abdominal Hypertension; D007813:Laparotomy; D008297:Male; D038901:Mental Retardation, X-Linked; D009102:Multiple Organ Failure",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34083193",
"pubdate": "2021-06-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Abdominal compartment syndrome secondary to chronic constipation in MECP2 duplication syndrome.",
"title_normalized": "abdominal compartment syndrome secondary to chronic constipation in mecp2 duplication syndrome"
} | [
{
"companynumb": "CA-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-334332",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NOREPINEPHRINE"
},
"... |
{
"abstract": "Secondary hemophagocytic syndrome (HPS) has been described after autologous hematopoietic cell transplant (AutoHCT). We report two cases of secondary HPS after novel consolidation therapy for high-risk neuroblastoma as part of an institutional phase 2 trial incorporating immunotherapy into a \"standard\" AutoHCT regimen. Both patients developed liver dysfunction beyond expected course of hepatic veno-occlusive disease, coagulopathy, hyperferritinemia, and when evaluated, elevated soluble interleukin-2 receptor and hemophagocytosis. These cases highlight the need for clinicians to have a high index of suspicion for immune-related complications in patients receiving immune therapies.",
"affiliations": "Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Pediatric Medicine, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.",
"authors": "Epperly|Rebecca|R|0000-0002-8998-0732;Furman|Wayne|W|;Hines|Melissa|M|;Santiago|Teresa|T|0000-0002-2838-3619;Li|Ying|Y|;Madden|Renee|R|;Mamcarz|Ewelina|E|;Cervi|David|D|0000-0003-0595-4834;Federico|Sara|S|;Triplett|Brandon|B|0000-0001-8220-9980;Talleur|Aimee|A|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D005293:Ferritins; D002066:Busulfan; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27964",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "66(11)",
"journal": "Pediatric blood & cancer",
"keywords": "autologous hematopoietic cell transplant; hemophagocytic syndrome; immunotherapy; neuroblastoma",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000074322:Antineoplastic Agents, Immunological; D000971:Antineoplastic Combined Chemotherapy Protocols; D002066:Busulfan; D002675:Child, Preschool; D005293:Ferritins; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D007167:Immunotherapy; D016219:Immunotherapy, Adoptive; D007223:Infant; D007694:Killer Cells, Natural; D017093:Liver Failure; D051359:Lymphohistiocytosis, Hemophagocytic; D008297:Male; D008558:Melphalan; D009447:Neuroblastoma; D036102:Peripheral Blood Stem Cell Transplantation; D018746:Systemic Inflammatory Response Syndrome; D019172:Transplantation Conditioning",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27964",
"pmc": null,
"pmid": "31407508",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Secondary hemophagocytic syndrome after autologous hematopoietic cell transplant and immune therapy for neuroblastoma.",
"title_normalized": "secondary hemophagocytic syndrome after autologous hematopoietic cell transplant and immune therapy for neuroblastoma"
} | [
{
"companynumb": "US-OTSUKA-2019_016466",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nCOVID19 is a viral disease with pneumonia as its most common presentation. Many presentations and complications have been reported, but gastro-intestinal perforation has not received much attention.\n\n\nMETHODS\nthree cases from our hospital are presented, and the current literature was reviewed.\nAll three patients were admitted to the ICU with respiratory failure due to COVID19 pneumonia and intubated. Our first patient was treated with steroids, and subsequently diagnosed with rectal perforation on day 34 of his hospital admission. The second patient was treated with steroids and tocilizumab, and diagnosed with colonic perforation 1 day after neostigmine administration, on day 14 of his hospital admission. Our third patient was treated with steroids and tocilizumab, and diagnosed colonic perforation 4 days after neostigmine administration, on day 14 of his hospital admission.\n25 more cases were found in current literature, both upper GI and lower GI perforations, either as a presenting symptom or during the course of hospitalization. These were often associated with treatment with steroids, interleukin 6 inhibitors, or both.\n\n\nCONCLUSIONS\nGastro-intestinal perforation is a rare but dangerous complication of COVID19. Treatment with tocilizumab and steroids may both increase the risk of this complication, and hamper diagnosis.",
"affiliations": "Queen Beatrix Regional Hospital: Streekziekenhuis Koningin Beatrix, General Surgery, the Netherlands. Electronic address: jorisbulte@gmail.com.;Queen Beatrix Regional Hospital: Streekziekenhuis Koningin Beatrix, Anesthesiology, the Netherlands; Queen Beatrix Regional Hospital: Streekziekenhuis Koningin Beatrix, Intensive Care, the Netherlands.;Queen Beatrix Regional Hospital: Streekziekenhuis Koningin Beatrix, Intensive Care, the Netherlands; Queen Beatrix Regional Hospital: Streekziekenhuis Koningin Beatrix, Internal Medicine, the Netherlands.;Queen Beatrix Regional Hospital: Streekziekenhuis Koningin Beatrix, General Surgery, the Netherlands.;Queen Beatrix Regional Hospital: Streekziekenhuis Koningin Beatrix, Anesthesiology, the Netherlands; Queen Beatrix Regional Hospital: Streekziekenhuis Koningin Beatrix, Intensive Care, the Netherlands.;Radboudumc, Intensive Care, the Netherlands.",
"authors": "Bulte|Joris Paul|JP|;Postma|Nynke|N|;Beukema|Menno|M|;Inberg|Bas|B|;Stegeman|Abe Gerrit|AG|;van der Hoeven|Hans|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jcrc.2021.10.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0883-9441",
"issue": "67()",
"journal": "Journal of critical care",
"keywords": "COVID19; Complication; Gastro-intestinal perforation; IL-6 inhibition",
"medline_ta": "J Crit Care",
"mesh_terms": null,
"nlm_unique_id": "8610642",
"other_id": null,
"pages": "100-103",
"pmc": null,
"pmid": "34741961",
"pubdate": "2021-11-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "COVID 19 and the risk of gastro-intestinal perforation: A case series and literature review.",
"title_normalized": "covid 19 and the risk of gastro intestinal perforation a case series and literature review"
} | [
{
"companynumb": "NL-TEVA-2022-NL-1998982",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nPatients with a renal transplant are an ever-increasing demographic. Their life expectancy is also on the rise and thus malignancies or tumors in these cases are more frequent. These patients are often on immunosuppressive drugs that are known to cause changes in the microvasculature, especially of the deep white matter. However, benign dural-based lesions are a rarity in these cases with very few (<5) ever being reported. Imaging findings in such cases are altered, which leads to an altered set of differential diagnosis.\n\n\nMETHODS\nWe present a case of a right parasagittal lesion in case of postrenal transplant with imaging findings suggestive of an inflammatory lesion. The lesion was excised and histopathology was that of a fibrous meningioma. Pathological basis of altered imaging is discussed and potential causes elaborated along with a thorough review of similar cases and their findings.\n\n\nCONCLUSIONS\nRenal transplants and long-term survival are now a reality; calcineurin inhibitors are a staple for these cases. The drugs alter imaging findings and hence cases need to be carefully evaluated with a host of differential diagnosis. Knowledge of these changes is now necessary for these new spectra of cases.",
"affiliations": "Department of Neurosurgery, National Institute of Mental Health and Neurosciences (NIMHANS), Bangalore, India.;Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India. Electronic address: kkdas@sgpgi.ac.in.;Department of Pathology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.;Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.;Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India.",
"authors": "Deora|Harsh|H|;Das|Kuntal Kanti|KK|;Jaiswal|Sushila|S|;Jaiswal|Awadesh K|AK|;Behari|Sanjay|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2019.07.056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "130()",
"journal": "World neurosurgery",
"keywords": "Calcineurin inhibitors; Dural lesion; MRI; Meningioma; Renal transplant",
"medline_ta": "World Neurosurg",
"mesh_terms": "D001932:Brain Neoplasms; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008577:Meningeal Neoplasms; D008579:Meningioma; D008875:Middle Aged; D019737:Transplants",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "211-215",
"pmc": null,
"pmid": "31302277",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Meningioma in a Postrenal Transplant Case: More than Meets the Eye.",
"title_normalized": "meningioma in a postrenal transplant case more than meets the eye"
} | [
{
"companynumb": "PHHY2019IN194614",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "Oseltamivir is a neuraminidase inhibitor that is labeled for prophylaxis and treatment of influenza. We describe a previously healthy 4-month-old infant who tested positive for influenza A and was started on oseltamivir. One hour after receiving his first dose of oseltamivir, the infant had a diaphoretic episode and appeared grey and clammy. The infant was subsequently seen by the primary care physician and referred for admission to the hospital. Approximately 40 minutes after the second dose of oseltamivir in the hospital, the infant's heart rate rose to greater than 300 bpm. An electrocardiogram was suggestive of supraventricular tachycardia. At the time of the event, the infant received 2 doses of adenosine, and oseltamivir was discontinued prior to transfer to a tertiary facility for a higher level of care.",
"affiliations": null,
"authors": "Bodo|Emily C|EC|;Boucher|Elizabeth A|EA|;Shultz|Kelley H|KH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-25.7.654",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "25(7)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "adverse drug effect; influenza; oseltamivir; pediatrics; supraventricular tachycardia",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "654-657",
"pmc": null,
"pmid": "33041722",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "25369576;7249508;10628898;20615742;19281331;21248682;23474244;23999962;19743581",
"title": "Oseltamivir-Associated Supraventricular Tachycardia in an Infant.",
"title_normalized": "oseltamivir associated supraventricular tachycardia in an infant"
} | [
{
"companynumb": "US-TEVA-2020-US-1846307",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
... |
{
"abstract": "Genitourinary (GU) tract infection with Mycobacterium avium intracellulare complex (MAI) is very rare and, to our knowledge, has never been reported in the solid organ transplant literature. CASE DESCRIPTION: A 61-year-old Somali-born woman had a history of liver cirrhosis due to chronic hepatitis C infection. She was diagnosed as having and treated for latent tuberculosis infection and GU tract infection due to MAI. She received a total of 17 months antimycobacterial therapy consisting of azithromycin, ethambutol, and moxifloxacin. Within 5 months of the initiation of antimicrobial therapy, there was documented sterilization of urine mycobacterial cultures. Liver and kidney transplant was performed 3 months after finishing the treatment course. One year following transplant, GU tract infection due to MAI recurred. She declined further diagnostic testing as well as mycobacterial therapy. She died 15 months following transplant for reasons not related to infections. CONCLUSION: The treatment of MAI infection in solid organ transplant candidates and recipients is challenging, and the duration of therapy in this population is not known. The recurrence of infection following transplant in this case may argue in favor of a duration that extends beyond the date of transplant. The combination of a fluoroquinolone and ethambutol may successfully prevent reactivation of tuberculosis in patients with history of latent tuberculosis infection and deserves further evaluation.",
"affiliations": "Program in Adult Transplant Infectious Disease, Division of Infectious Disease and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota. Electronic address: kmobeid@umn.edu.;Division of Gastroenterology, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.;Division of Transplantation, Department of Surgery, University of Minnesota, Minneapolis, Minnesota.;Program in Adult Transplant Infectious Disease, Division of Infectious Disease and International Medicine, Department of Medicine, University of Minnesota, Minneapolis, Minnesota.",
"authors": "Obeid|K M|KM|;Hassan|M A|MA|;Chinnakotla|S|S|;Young|J H|JH|",
"chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D004977:Ethambutol",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2018.09.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "50(10)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000900:Anti-Bacterial Agents; D004977:Ethambutol; D005260:Female; D024841:Fluoroquinolones; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D055985:Latent Tuberculosis; D016031:Liver Transplantation; D008875:Middle Aged; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D012008:Recurrence; D014552:Urinary Tract Infections",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "3937-3939",
"pmc": null,
"pmid": "30577290",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Genitourinary Tract Infection Due to Mycobacterium avium intracellulare Complex Infection in Pretransplant Setting With Recurrence Following Transplant: A Case Report.",
"title_normalized": "genitourinary tract infection due to mycobacterium avium intracellulare complex infection in pretransplant setting with recurrence following transplant a case report"
} | [
{
"companynumb": "US-ASTELLAS-2019US001263",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS\\TACROLIMUS ANHYDROUS"
},
"drugaddi... |
{
"abstract": "A 70-year-old man with history of heart transplant performed in 1986, presented with altered mental status. CT scan of brain showed ring-enhancing lesions, raising suspicion for metastatic malignancy. Work-up revealed bilateral adrenal masses, biopsy showed granulomatous changes consistent with histoplasmosis. The possibility of histoplasmosis was less likely as the patient had no prior history of symptomatic disease and had lived in the endemic area 30 years prior to presentation. Brain biopsy confirmed central nervous system involvement. Amphotericin B was initiated for disseminated disease but his hospital course was complicated by renal failure and new liver hypodensities on follow-up imaging. Acute progressive disseminated histoplasmosis can manifest after decades of initial exposure and should always be in differential diagnosis even in non-endemic areas for prompt diagnosis and better clinical outcome.",
"affiliations": "Department of Infectious diseases, University of Arizona Arizona Health Sciences Center, Tucson, Arizona, USA.;Division of Hematology-Oncology, University of Arizona Arizona Health Sciences Center, Tucson, Arizona, USA.;Division of Hematology-Oncology, University of Arizona Arizona Health Sciences Center, Tucson, Arizona, USA.;Department of Infectious Diseases, The University of Arizona College of Medicine, Tucson, Arizona, USA.",
"authors": "Majeed|Aneela|A|;Kapoor|Vikas|V|;Latif|Azka|A|;Zangeneh|Tirdad|T|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "infection (neurology); infectious diseases",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000307:Adrenal Gland Diseases; D000368:Aged; D000666:Amphotericin B; D000935:Antifungal Agents; D001921:Brain; D057210:Delayed Diagnosis; D003937:Diagnosis, Differential; D016027:Heart Transplantation; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D014057:Tomography, X-Ray Computed; D066027:Transplant Recipients; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29122900",
"pubdate": "2017-11-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16784440;18594296;11036122;1562697;23387927;27169478;19911965;8664511;24861869;24046304;18194370;19635026;9195082;7756497;26251798;13317782;12679679;10404698;26485441;17806045;23465018;12421460;11486286;21888792",
"title": "A 30-year delayed presentation of disseminated histoplasmosis in a heart transplant recipient: diagnostic challenges in a non-endemic area.",
"title_normalized": "a 30 year delayed presentation of disseminated histoplasmosis in a heart transplant recipient diagnostic challenges in a non endemic area"
} | [
{
"companynumb": "PHHY2017US185050",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Coronavirus-19 disease is still a pandemic health problem and uncertainty in the management of severe or critically ill pregnant women confuses continually the obstetricians. The nationwide maternal mortality rate due to covid-19 still has not been presented in any study in Turkey. The study includes four maternal mortality cases in a referral single pandemic center in our country. Case 1, a 34-year-old, 34 weeks of gestation with moderate disease. The cesarean section was performed due to nonreassuring nonstress tests. She died on the postpartum seventh day. Case 2, a 37-year-old, at 36 weeks of gestation. The symptoms consisted of dry cough, shortness of breath and labor pain, and 3 cm cervical opening. Her second cesarean section was performed and she died at postpartum ninth day. Case 3, 33 years old, 33 weeks of gestation with moderate/severe stage of the disease. A few days after the treatment, CS was performed due to her severe condition and she died at postpartum 15th day. Case 4, 39 years old, 35 weeks of gestation, she was at a severe stage of the disease. On the second day after the treatment, CS was performed due to her severe condition and she died at postpartum seventh day. The postpartum period after cesarean section should be followed cautiously under the appropriate treatment of the COVID-19 disease. Unfortunately, the reason for this rapid deterioration which we observed in our cases is not well known and appropriate medications and algorithms should be established as soon as possible.",
"affiliations": "Department of Obstetrics and Gynecology, University of Health Sciences Diyarbakir Gazi Yasargil Research and Training Hospital, Diyarbakır, Turkey.;Department of Obstetrics and Gynecology, University of Health Sciences Diyarbakir Gazi Yasargil Research and Training Hospital, Diyarbakır, Turkey.;Department of Obstetrics and Gynecology, University of Health Sciences Diyarbakir Gazi Yasargil Research and Training Hospital, Diyarbakır, Turkey.;Department of Anesthesiology and Reanimation, University of Health Sciences Diyarbakir Gazi Yasargil Research and Training Hospital, Diyarbakır, Turkey.;Department of Infectious Diseases, University of Health Sciences Diyarbakir Gazi Yasargil Research and Training Hospital, Diyarbakır, Turkey.",
"authors": "Bağlı|İhsan|İ|;Öcal|Ece|E|;Yavuz|Mustafa|M|;Uzundere|Osman|O|;Bozkurt|Fatma|F|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14928",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "47(11)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "COVID-19 disease; maternal mortality; pregnancy",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D002585:Cesarean Section; D005260:Female; D006761:Hospitals; D006801:Humans; D063130:Maternal Death; D058873:Pandemics; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D000086402:SARS-CoV-2; D014421:Turkey",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "4067-4076",
"pmc": null,
"pmid": "34254718",
"pubdate": "2021-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Maternal deaths due to COVID-19 disease: The cases in a single center pandemic hospital in the south east of Turkey.",
"title_normalized": "maternal deaths due to covid 19 disease the cases in a single center pandemic hospital in the south east of turkey"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-335972",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LOPINAVIR\\RITONAVIR"
},
... |
{
"abstract": "Thymoma is a rare mediastinal tumour that can be accompanied by different paraneoplastic syndromes. Here we report a case of Type A thymoma associated with relapsing minimal change disease (MCD). This case highlights: (1) The need to balance rapid prednisolone weaning against risk for relapse in an elderly patient at risk for steroid-induced complications. (2) The addition of calcineurin inhibitor in relapsed thymoma-related MCD, to achieve steroid sparing effects. Resection of the offending tumour and prompt immunosuppressive therapy are critical in getting best renal and overall outcomes in this rare entity.",
"affiliations": "National University Health System, Department of Medicine, Singapore. wkwong100@yahoo.com.;National University Health System, Department of Pathology, Singapore.;National University Health System, Department of Medicine, Singapore.",
"authors": "Ngoh|C L Y|CLY|;Goh|G H S|GHS|;Wong|W K|WK|",
"chemical_list": null,
"country": "Malaysia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-5283",
"issue": "74(1)",
"journal": "The Medical journal of Malaysia",
"keywords": null,
"medline_ta": "Med J Malaysia",
"mesh_terms": "D000368:Aged; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D009402:Nephrosis, Lipoid; D010257:Paraneoplastic Syndromes; D013945:Thymoma; D013953:Thymus Neoplasms",
"nlm_unique_id": "0361547",
"other_id": null,
"pages": "97-98",
"pmc": null,
"pmid": "30846674",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Paraneoplastic relapsing minimal change disease associated with type A thymoma in an elderly patient: A case report and literature review.",
"title_normalized": "paraneoplastic relapsing minimal change disease associated with type a thymoma in an elderly patient a case report and literature review"
} | [
{
"companynumb": "SG-EDENBRIDGE PHARMACEUTICALS, LLC-SG-2019EDE000049",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE SODIUM PHOSPHATE"
... |
{
"abstract": "Chemotherapy-related death can occur, but is rarely experienced in the case of head and neck cancer. In this report, we present the case of a 55-year-old male who died of a severe febrile neutropenia during adjuvant chemotherapy. He was initially diagnosed as having nasopharyngeal carcinoma (cT2N0M0), and concurrent chemoradiotherapy was used as a primary treatment. He did not show any critical side effects during that therapy. After residual disease was proven by biopsy, docetaxel, cisplatin and 5-fluorouracil (TPF) therapy was introduced as adjuvant chemotherapy. The patient developed a high fever with a decreased neutrophil count on day 8, and went into a state of shock on day 9. He underwent immediate systemic management, but methicillin-resistant Staphylococcus aureus (MRSA) pneumonia and enteritis were uncontrolled, resulting in death on day 43. The autopsy findings suggested that the main cause of death was acute respiratory distress syndrome (ARDS), but cytomegalovirus (CMV) infection was also noted in multiple organs. . Since it is assumed from literature that the mortality rate in TPF therapy is about 2-4%, it was considered that prior sufficient explanations and informed consent should be required before this therapy.",
"affiliations": null,
"authors": "Nakahara|Susumu|S|;Kitamura|Koji|K|;Honma|Keiichiro|K|;Yamamoto|Yoshifumi|Y|;Takenaka|Yukinori|Y|;Yasui|Toshimichi|T|;Hanamoto|Atsushi|A|;Morii|Eiichi|E|;Inohara|Hidenori|H|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.3950/jibiinkoka.118.763",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-6622",
"issue": "118(6)",
"journal": "Nihon Jibiinkoka Gakkai kaiho",
"keywords": null,
"medline_ta": "Nihon Jibiinkoka Gakkai Kaiho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001344:Autopsy; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D003092:Colitis; D000077143:Docetaxel; D017809:Fatal Outcome; D064147:Febrile Neutropenia; D005472:Fluorouracil; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D009303:Nasopharyngeal Neoplasms; D000077195:Squamous Cell Carcinoma of Head and Neck; D013203:Staphylococcal Infections; D043823:Taxoids",
"nlm_unique_id": "7505728",
"other_id": null,
"pages": "763-9",
"pmc": null,
"pmid": "26336750",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Case of Nasopharyngeal Cancer with Febrile Neutropenia Followed by Death during Adjuvant Chemotherapy.",
"title_normalized": "a case of nasopharyngeal cancer with febrile neutropenia followed by death during adjuvant chemotherapy"
} | [
{
"companynumb": "JP-TEVA-581592ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"drug... |
{
"abstract": "Nephropathic cystinosis is a lysosomal storage disorder, which, if untreated, results in renal failure by age 10 years. Oral cysteamine has been shown to preserve renal function in these patients. In this study, a 2-year-old girl with nephropathic cystinosis and severe gastrointestinal dysmotility was treated with intravenous (i.v.) administration of cysteamine hydrochloride (HCl). This is only the second report of long-term i.v. cysteamine therapy for nephropathic cystinosis. Unlike the treatment in the previous case, however, treatment in our patient was limited by liver toxicity.",
"affiliations": "Division of Pediatric Nephrology, MMC 491, University of Minnesota Children's Hospital, 420 Delaware St SE, Minneapolis, MN, 55455, USA. bende014@umn.edu",
"authors": "Bendel-Stenzel|Michael R|MR|;Steinke|Julia|J|;Dohil|Ranjan|R|;Kim|Youngki|Y|",
"chemical_list": "D011837:Radiation-Protective Agents; D003543:Cysteamine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-007-0529-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0931-041X",
"issue": "23(2)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": null,
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D056486:Chemical and Drug Induced Liver Injury; D003131:Combined Modality Therapy; D003543:Cysteamine; D003554:Cystinosis; D004359:Drug Therapy, Combination; D005260:Female; D005767:Gastrointestinal Diseases; D005769:Gastrointestinal Motility; D006801:Humans; D007037:Hypothyroidism; D007223:Infant; D007275:Injections, Intravenous; D016030:Kidney Transplantation; D011837:Radiation-Protective Agents; D051437:Renal Insufficiency",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "311-5",
"pmc": null,
"pmid": "17668247",
"pubdate": "2008-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"abstract": "Acute promyelocytic leukemia (APL) constitutes 5-10% of all cases of newly diagnosed acute myeloid leukemia. However, data on the epidemiology and risk factors for acute kidney injury (AKI) in patients with newly diagnosed APL are lacking. This study determined the incidence rate of AKI during induction chemotherapy for patients with newly diagnosed APL and the risk factors for AKI.\nWe conducted a retrospective observational study of patients with newly diagnosed APL in the Shonan Kamakura General Hospital between April 2004 and April 2020. Data of 27 patients with newly diagnosed APL were analyzed. The patients were classified as no AKI and AKI stages 1, 2 or 3.\nThe incidence rate of AKI during induction chemotherapy was 40% (11/27). Among patients who developed AKI, four patients experienced AKI stage 3, and two patients required renal replacement therapy. No significant differences were found in the white blood cell count and baseline renal function between the groups; however, D-dimer and C-reactive protein levels upon admission were significantly higher in patients with AKI than in patients without AKI. Among patients who developed AKI, in hospital mortality at 90 days was 36% (4/11), which was significantly higher than among patients without AKI (p = 0.02). Patients who developed AKI were administered vancomycin more frequently, while almost all blood culture results were negative.\nIncidence of AKI development in patients with newly diagnosed APL during induction chemotherapy was approximately 40%. Moreover, patients who developed AKI tended to be administered vancomycin more frequently. Unnecessary use of vancomycin should be avoided in patients with newly diagnosed APL, and using alternative non-nephrotoxic drugs should be considered for patients at risk of AKI.",
"affiliations": "Division of Critical Care, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan.;Division of Critical Care, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan.;Division of Critical Care, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan.;Department of Hematology, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan.;Department of Hematology, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan.;Department of Hematology, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan.;Department of Hematology, Shonan Kamakura General Hospital, Kamakura, Kanagawa 247-8533, Japan.",
"authors": "Kamio|Tadashi|T|;Koyama|Hiroshi|H|;Fukaguchi|Kiyomitsu|K|0000-0003-2262-1898;Sato|Shuku|S|;Kamata|Wataru|W|0000-0001-5887-6097;Okada|Satomi|S|;Tamai|Yotaro|Y|",
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"doi": "10.2147/JBM.S278270",
"fulltext": "\n==== Front\nJ Blood Med\nJ Blood Med\njbm\njbm\nJournal of Blood Medicine\n1179-2736 Dove \n\n278270\n10.2147/JBM.S278270\nOriginal Research\nRetrospective Study of Acute Kidney Injury Incidence in Patients with Newly Diagnosed Acute Promyelocytic Leukemia\nKamio et alKamio et alKamio Tadashi 1 Koyama Hiroshi 1 http://orcid.org/0000-0003-2262-1898Fukaguchi Kiyomitsu 1 Sato Shuku 2 http://orcid.org/0000-0001-5887-6097Kamata Wataru 2 Okada Satomi 2 Tamai Yotaro 2 1 Division of Critical Care, Shonan Kamakura General Hospital, Kamakura, Kanagawa\n247-8533, Japan\n2 Department of Hematology, Shonan Kamakura General Hospital, Kamakura, Kanagawa\n247-8533, Japan\nCorrespondence: Tadashi Kamio Division of Critical Care, Shonan Kamakura General Hospital, 1370-1 Okamoto, Kamakura, Kanagawa247-8533, JapanTel +81-467-46-1717Fax +81-467-47-8243 Email tadashi-kamio@mail.goo.ne.jp\n15 10 2020 \n2020 \n11 363 369\n21 8 2020 27 9 2020 © 2020 Kamio et al.2020Kamio et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Purpose\nAcute promyelocytic leukemia (APL) constitutes 5–10% of all cases of newly diagnosed acute myeloid leukemia. However, data on the epidemiology and risk factors for acute kidney injury (AKI) in patients with newly diagnosed APL are lacking. This study determined the incidence rate of AKI during induction chemotherapy for patients with newly diagnosed APL and the risk factors for AKI.\n\nPatients and Methods\nWe conducted a retrospective observational study of patients with newly diagnosed APL in the Shonan Kamakura General Hospital between April 2004 and April 2020. Data of 27 patients with newly diagnosed APL were analyzed. The patients were classified as no AKI and AKI stages 1, 2 or 3.\n\nResults\nThe incidence rate of AKI during induction chemotherapy was 40% (11/27). Among patients who developed AKI, four patients experienced AKI stage 3, and two patients required renal replacement therapy. No significant differences were found in the white blood cell count and baseline renal function between the groups; however, D-dimer and C-reactive protein levels upon admission were significantly higher in patients with AKI than in patients without AKI. Among patients who developed AKI, in hospital mortality at 90 days was 36% (4/11), which was significantly higher than among patients without AKI (p = 0.02). Patients who developed AKI were administered vancomycin more frequently, while almost all blood culture results were negative.\n\nConclusion\nIncidence of AKI development in patients with newly diagnosed APL during induction chemotherapy was approximately 40%. Moreover, patients who developed AKI tended to be administered vancomycin more frequently. Unnecessary use of vancomycin should be avoided in patients with newly diagnosed APL, and using alternative non-nephrotoxic drugs should be considered for patients at risk of AKI.\n\nKeywords\nacute promyelocytic leukemiaacute kidney injuryincidence rateinduction chemotherapy\n==== Body\nIntroduction\nAcute promyelocytic leukemia (APL) accounts for approximately 5–10% of all cases of newly diagnosed acute myeloid leukemia (AML) and frequently presents in combination with coagulation disorders, including a high risk of life-threatening intracerebral hemorrhages.1 Treatment for APL has dramatically changed the management and outcome of the disease over the two decades after the introduction of highly active drugs, including all-trans retinoic acid (ATRA) and arsenic trioxide (ATO).2\n\nHowever, differentiation syndrome is a potentially fatal complication of the treatment for APL and epidemiology studies have revealed that the incidence of early death in patients with APL remains high.3,4 Differentiation syndrome is characterized by unexplained fever, acute respiratory distress with interstitial pulmonary infiltrates, and/or acute kidney injury (AKI) due to capillary leakage.5 The pathogenesis of the syndrome is considered as microvascular damage, since similar histologic findings are found in a variety of diseases (including trauma, sepsis, and adult respiratory distress syndrome).6\n\nIn addition, a number of situations, such as tumor lysis syndrome, sepsis, decreased cardiac output, or drug toxicity, may lead to AKI. Even small changes in the serum creatinine levels are associated with increased mortality; thus, early identification of patients at risk and application of preventive strategies and treatment are fundamental for reducing its incidence.7\n\nPatients with hematological malignancies, more often experience AKI associated with sepsis, hypovolemia, and nephrotoxic drugs, given their differential characteristics. A previous study has revealed that AKI occurred in 36% of patients with AML and high-risk myelodysplastic syndrome undergoing induction chemotherapy.8 Moreover, AKI is common in patients with newly diagnosed high-grade malignancies and is associated with lower complete remission and higher mortality rates.8,9\n\nHowever, there are limited epidemiological data, and risk factors for AKI in patients with newly diagnosed APL is lacking. Prevention is the best method for avoiding AKI, with early identification of patients at risk and controlling the potentially modifiable risk factors, including the non-prescription or discontinuation of nephrotoxic drugs.10 This study aimed to investigate the incidence of AKI during induction chemotherapy for patients with newly diagnosed APL and determine the risk factors for AKI.\n\nPatients and Methods\nWe conducted a retrospective observational study of all patients with newly diagnosed APL in the Shonan Kamakura General Hospital between April 2004 and April 2020; APL diagnosis was confirmed according to clinical presentations, morphological criteria of the French-American-British classification, cytogenetic assay for t (15; 17) (q22; q21), and reverse transcription polymerase chain reaction assay for promyelocytic leukemia-retinoic acid receptor α transcripts. The study institution is a 629-bed tertiary care hospital that provides advanced medical care (including stem cell transplant) and admits more than 200 patients with hematological malignancies annually.\n\nClinical data for patients with APL who underwent induction chemotherapy were retrospectively collected and reviewed. Among these patients, we examined the incidence of AKI within 28 days of admission; AKI was confirmed according to the Kidney Disease Improving Global Outcomes Clinical Practice Guideline (KDIGO) criteria. The patients were classified as no AKI (KDIGO 0) and AKI stages 1, 2 or 3, according to the changes in serum creatinine (sCr) levels;11 severity of AKI was categorized as stage 1 (increase in sCr levels 1.5–1.9 times the baseline value or ≥0.3 mg/dL); stage 2 (increase in sCr levels 2.0–2.9 times the baseline value); or stage 3 (increase in sCr levels ≥3.0 times the baseline value, or ≥4.0 mg/dL, or initiation of renal replacement therapy).\n\nThe following information was also collected: demographic data; laboratory data; sequential organ failure assessment score on admission;12 induction regimen; presence of differentiation syndrome (presence of any of the following signs and symptoms: unexplained fever, weight gain, peripheral edema, dyspnea with interstitial pulmonary infiltrates, pleural and pericardial effusions, hypotension, and acute renal failure);13 use of antibiotics, including cefepime, vancomycin (VCM), meropenem, piperacillin-tazobactam, amikacin, and amphotericin B, within 28 days of admission; blood culture results; intensive care unit (ICU) admission; renal replacement therapy for renal indications; use of mechanical ventilation; and mortality within 90 days following induction chemotherapy. The following criteria were used to exclude patients from this analysis: age under 18 years, patients undergoing chronic dialysis, lack of accurate medical records, and patients who underwent induction chemotherapy in other hospitals.\n\nThe study was conducted in agreement with the tenets of the Declaration of Helsinki. This retrospective observational study was approved by the Ethics committee from the institutional review board of the Shonan Kamakura General Hospital in Japan. Because this was a retrospective study using patients’ data obtained from the electronic health records, the institutional review board and medical ethics committee waived the need for written informed consent from the participants.\n\nStatistical Analyses\nData are presented as median (25th–75th percentile) for continuous variables, and frequency (percentage) for qualitative variables. Nonparametric data were analyzed using the Mann–Whitney U (two independent samples) or the Kruskal–Wallis tests (more than two groups) with Dunn’s post hoc test. Categorical data were analyzed using the Fisher’s exact test for two variables. All tests were two-tailed, with results considered significant if p <0.05. All statistical analyses were performed using SPSS statistics, version 23.0 (IBM Japan, Ltd., Tokyo, Japan).\n\nResults\nThe search strategy initially identified 29 patients; however, two patients were excluded, based on the exclusion criteria. Finally, data of 27 patients with newly diagnosed APL were analyzed in this study. Baseline characteristics of the patients are summarized in Table 1. Patients’ median age at initiation of induction chemotherapy was 61 (35–73) years; 63% (17/27) were men. Baseline renal function parameters were sCr level of 0.81 (0.70–0.99) mg/dl and estimated glomerular filtration rate level of 68.6 (59.7–87.5) mL/min/1.73 m2. Of the 27 patients, all were administered ATRA, and 16 patients were administered a combination of ATRA and idarubicin and/or cytarabine; 59% (16/27) of patients developed differentiation syndrome, and 15% (4/27) underwent mechanical ventilation.Table 1 Patient Characteristics in All Patients\n\nVariables n (%) or Median [IQR]\tAll Patients (n=27)\tNon-AKI (n=16)\tAKI (n=11)\tP-value\t\nDemographics\t\t\t\t\t\n Age (years), [IQR]\t61 [35–73]\t60 [38–74]\t63 [32–74]\t0.92\t\n Male Gender, n (%)\t17 (63%)\t12 (75%)\t5 (45%)\t0.22\t\nLaboratory data before chemotherapy, [IQR]\t\t\t\t\t\n WBC count (/μL)\t2500 [900–15,900]\t1300 [800–10,500]\t4200 [1000–29,650]\t0.92\t\n Platelet count (103/μL)\t43 [18–67]\t45 [21–75]\t43 [12–61]\t0.49\t\n Fibrinogen (mg/dL)\t166 [79–227]\t151 [78–213]\t166 [66–235]\t0.86\t\n D-dimer (μg/mL)\t24.1 [14.9–48.4]\t19.7 [13.3–32.2]\t49.7 [17.8–103.6]\t0.03\t\n Serum creatinine (mg/dL)\t0.81 [0.70–0.99]\t0.85 [0.72–0.99]\t0.80 [0.64–0.99]\t0.57\t\n eGFR (mL/min/1.73m2)\t68.6 [59.7–87.5]\t72.2 [62.2–84.0]\t68.6 [53.6–97.1]\t0.92\t\n LDH (U/L)\t315 [205–741]\t419 [203–701]\t315 [148–994]\t0.96\t\n C-reactive protein (mg/dL)\t1.2 [0.3–9.9]\t0.7 [0.1–4.9]\t7.3 [1.0–19.2]\t0.02\t\n SOFA score at admission, [IQR]\t3 [2–5]\t3 [2–3]\t5 [2–6]\t0.14\t\nInduction Regimen, n (%)\t\t\t\t\t\n ATRA\t11 (41%)\t9 (56%)\t2 (18%)\t0.11\t\n ATRA+Anthracycline (IDA or DNR)\t3 (3%)\t0\t3 (27%)\t0.06\t\n ATRA+Ara-C\t1 (4%)\t1 (6%)\t0\t0.99\t\n ATRA+Anthracycline+Ara-C\t12 (44%)\t6 (38%)\t6 (55%)\t0.45\t\n ICU admission, n (%)\t5 (19%)\t0\t5 (45%)\t0.01\t\n Differentiation syndrome, n (%)\t16 (59%)\t9 (56%)\t7 (64%)\t0.99\t\n Mechanical ventilation, n (%)\t4 (15%)\t0\t4 (36%)\t0.02\t\n Renal replacement therapy, n (%)\t2 (7%)\t0\t2 (18%)\t0.16\t\nAntibiotics within 28 days of admission, n (%)\t\t\t\t\t\n Cefepime\t17 (63%)\t9 (56%)\t8 (73%)\t0.45\t\n Vancomycin\t13 (48%)\t4 (25%)\t9 (82%)\t0.01\t\n Meropenem\t12 (44%)\t8 (50%)\t4 (36%)\t0.70\t\n Tazobactam/Piperacillin\t6 (22%)\t3 (19%)\t3 (27%)\t0.99\t\n Amikacin\t1 (4%)\t1 (6%)\t0\t0.99\t\n Amphotericin B\t1 (4%)\t0\t1 (9%)\t0.41\t\n Patients with highest trough>20mg/L\t5 (19%)\t0\t5 (45%)\t0.01\t\nBlood culture result within 28 days of admission, n (%)\t\t\t\t\t\n Positive\t2 (7%)\t1 (6%)\t1 (9%)\t0.99\t\n Negative\t24 (89%)\t14 (88%)\t10 (91%)\t\n Not taken\t1 (4%)\t1 (6%)\t0\t0.99\t\n In hospital death at 90 days, n (%)\t4 (15%)\t0\t4 (36%)\t0.02\t\nAbbreviations: eGFR, estimated glomerular filtration rate; SOFA, sequential organ failure assessment; ATRA, all-trans retinoic acid; IDR, idarubicin; DNR, daunorubicin; AraC, cytarabine.\n\n\n\n\nAccording to the KDIGO classification, AKI was observed in 11 (40.7%) patients. Neither age at diagnosis, white blood cell (WBC) count, platelet count, and fibrinogen level, nor baseline renal function parameters significantly differed between patients with and without AKI. However, D-dimer and C-reactive protein levels were significantly higher in patients with AKI at admission than in patients without AKI. A total of four (15%) patients died during induction chemotherapy. Among patients with AKI, 45% (5/11) required ICU admission, and 36% (4/11) required mechanical ventilation. Moreover, 82% (9/11) had previous exposure to vancomycin, a percentage that was significantly higher than that among patients without AKI (p = 0.01). Among patients who developed AKI, in hospital mortality at 90 days was 36% (4/11), which was significantly higher than patients without AKI (p = 0.02).\n\nOf all patients, 19% (5/27) had AKI stage 1, 7% (2/27) had AKI stage 2, and 15% (4/27) had AKI stage 3 (two patients required renal replacement therapy). (Figure 1) The median time from the initiation of induction chemotherapy to the peak in sCr level for AKI was 10 (5–15) days (Figure 2); Table 2 summarizes the demographic data and clinical characteristics of the patients who developed stage 3 AKI. All four patients were administered vancomycin during induction chemotherapy; however, all blood culture results were negative despite multiple separate blood cultures from one patient. Of the four patients who developed stage 3 AKI, three patients had the highest through >20 mg/L. Mortality curves of the outcomes after induction chemotherapy are shown in Figure 3. The overall mortality rate was 15% (4/27) at 90 days.Table 2 Characteristics of Patients Who Developed Stage 3 AKI\n\nNo\tGender\tAge\tBaseline\tTime of the Peak sCr After Induction Chemotherapy (Day)\tRRT\tAntibiotics Within 28 Days of Admission\tBlood Culture Result/Number of Blood Culture Sets\t\nsCr\teGFR\tCFPM\tVCM\tHighest VCM Trough (mg/L)\tMEPM\tAMK\tPIPC/TAZ\t\n1\tFemale\t52\t0.81\t57.8\t15\t(-)\t(-)\t(+)\t24.3\t(+)\t(-)\t(-)\tNegative/2\t\n2\tMale\t35\t1.01\t68.6\t10\t(+)\t(+)\t(+)\t33.1\t(+)\t(-)\t(-)\tNegative/5\t\n3\tFemale\t72\t0.8\t53.6\t16\t(-)\t(+)\t(+)\t9.9\t(-)\t(-)\t(-)\tNegative/4\t\n4\tMale\t29\t0.59\t97.1\t15\t(+)\t(+)\t(+)\t21.7\t(+)\t(-)\t(-)\tNegative/3\t\nAbbreviations: sCr, serum creatinine; RRT, renal replacement therapy; CFPM, Cefepime; VCM, Vancomycin; MEPM, Meropenem; PIPC/TAZ, Piperacillin-Tazobactam; AMK, Amikacin.\n\n\nFigure 1 Number of patients with AKI defined by the KDIGO criteria.\n\nFigure 2 Number of patients who developed AKI and time from the initiation of induction chemotherapy to peak creatinine level in AKI.\n\nFigure 3 Kaplan–Meier survival curves of 90-day survival for AKI compared with non-AKI in newly diagnosed APL patients. Survival at 90 days was significantly lower in patients with an AKI (p=0.01).\n\n\n\nDiscussion\nThe incidence rate of AKI during induction chemotherapy for patients with newly diagnosed APL was 40.7% in this study. Among patients who developed AKI, four patients experienced AKI stage 3, and two patients required renal replacement therapy. No significant differences were found between the groups, with respect to WBC count and baseline renal function; however, D-dimer and C-reactive protein levels at admission in patients with AKI were significantly higher than those in patients without AKI because patients with AKI were administered vancomycin significantly more frequently.\n\nOur findings support previous research regarding the risk of AKI among patients with newly diagnosed high-grade hematological malignancies.8,9,14 Reported independent risk factors for AKI among patients with hematologic malignancies include age ≥55 years, mechanical ventilation, use of vancomycin, diuretics, amphotericin B lipid formulations, vasopressors, leukopenia, hypoalbuminemia, and non‐fludarabine-based chemotherapy.8 Although differentiation syndrome is the main life-threatening complication of differentiating agents in patients with APL, epidemiology of AKI in newly diagnosed patients with APL is still lacking.15 Therefore, we provide evidence from demographic data regarding the prevalence and risk factors of AKI among patients with newly diagnosed APL. Because the etiology of AKI is significantly associated with the 6-month complete response rate and 28-day mortality,9,16 Identifying patients who are at risk of developing AKI during induction chemotherapy is essential.\n\nChamoun et al have revealed that that old age, high creatinine levels, low hemoglobin counts, hypoalbuminemia at the time of diagnosis, and an elevated total volume of blood product transfusions were significant predictors of early death in patients with APL who were treated with ATRA and ATO (with or without gemtuzumab ozogamicin).17 Consistent with the study, we found that patients with AKI had higher hospital mortality at 90 days than patients without AKI. Although discussing the general prevention of AKI in patients with hematological malignancies is difficult, management of acute kidney injury involves fluid resuscitation, avoidance of nephrotoxic medications, and contrast media exposure. Diuretics do not have a proven role in reducing the incidence of tumor lysis syndrome and their routine use is not recommended, unless there are clinical signs or symptoms of volume overload.18 Conversely, fluid overload was found to be the most significant clinical factor associated with ICU transfers and endotracheal intubation in patients with APL;17 thus, early intervention with aggressive diuresis and early renal replacement therapy should be considered.\n\nAdditionally, we found that patients who developed AKI were more frequently administered vancomycin than patients without AKI. Vancomycin is a commonly used tricyclic glycopeptide antibiotic, which is considered the antibiotic-of-choice, primarily for infections involving methicillin-resistant Staphylococcus aureus.19 Because vancomycin has been plagued with concerns about nephrotoxicity, there is a vancomycin-associated measurable risk of AKI.19,20 Lahoti et al have identified that use of vancomycin was the significant independent risk factor (odds ratio: 2.3) for AKI in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome.8 In a previous study that has investigated the factors associated with VCM-induced AKI in 150 patients with hematologic malignancies, multivariate analysis revealed that the risk factors of VCM-induced AKI were an initial VCM trough concentration of >15 mg/L.21 Our finding that three-fourths patients who developed stage 3 AKI had the highest through >20 mg/L is consistent with this result. A retrospective study has shown that the target through vancomycin concentration of approximately 11.5 μg/mL is favorable for febrile neutropenia in patients with hematological malignancies.22 Therefore, we need to monitor more closely vancomycin serum levels to allow dose adjustment.\n\nIn this study, 82% patients with AKI were administered vancomycin within 28 days of admission; however, almost all blood culture results were negative despite multiple separate blood cultures. While patients with hematological malignancies are often neutropenic due to the disease or during chemotherapy for it, our result suggested that unnecessary use of vancomycin might lead to an increased risk of AKI. A study that evaluated the use of empirical vancomycin for patients with febrile neutropenia (with regard to adherence to treatment guidelines) has revealed that inappropriate use of empirical vancomycin was observed in >30% of patients.23 Vancomycin is still widely used to treat febrile neutropenia in patients with hematological malignancies, by potentially increasing toxicity. A recent analysis of a large cohort of critically ill adults being administered empirical vancomycin found that gram-positive cocci were identified within 48 h, during almost all episodes of methicillin-resistant Staphylococcus aureus bacteremia.24 These findings may inform the timing of discontinuation of empirical vancomycin among patients with hematological malignancies. Moreover, intravenous vancomycin treatment is associated with a higher risk for kidney injury; thus, using an alternative non-nephrotoxic drug (such as linezolid) should be considered for patients at risk of AKI.25\n\nOur study had some limitations. First, this is a retrospective study; multiple unmeasured variables may have affected the outcomes, and conclusions should be validated by certain prospective studies in the future. Secondly, this study was performed in a single center; hence, population size was comparatively small. Thus, we thought it would be impractical to conduct a multivariate analysis on such a small number of cases. Therefore, causal association between AKI and administration of vancomycin is not entirely clear. A larger study group could have revealed other risk factors for AKI. However, the findings of this study offer new, potentially useful information for this patient population; APL has become the most curable subtype of adult AML. However, early death rate in APL remains high.26 Several studies have already shown that the risk of AKI among patients with newly diagnosed high-grade hematological malignancies and patients with AKI had significantly higher mortality rates than patients without AKI.8,9 Further studies, specifically designed to investigate the incidence rate of AKI during induction chemotherapy between APL and other subtypes of acute myeloid leukemia are needed.\n\nConclusion\nWe found that the incidence of AKI development in patients with newly diagnosed APL during induction chemotherapy was approximately 40%. Patients who developed AKI tended to be administered vancomycin more frequently, while almost all blood culture results were negative. Therefore, unnecessary use of vancomycin should be avoided in patients with newly diagnosed APL, and using alternative non-nephrotoxic drugs should be considered for patients at risk of AKI. Preventing the development of AKI during APL induction chemotherapy is essential.\n\nAcknowledgments\nThe authors thank all of the physicians and staff at the hospital for their help in this study.\n\nAbbreviations\nAKI, acute kidney injury; AMK, Amikacin; APL, acute promyelocytic leukemia; AraC, cytarabine; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; CFPM, Cefepime; CR, complete response; DNR, daunorubicin; eGFR, estimated glomerular filtration rate; IDR, idarubicin; KDIGO, Kidney Disease Improving Global Outcomes Clinical Practice Guideline; MEPM, Meropenem; PIPC/TAZ, Piperacillin-Tazobactam; RRT, renal replacement therapy; sCr, serum creatinine; SOFA, sequential organ failure assessment; VCM, Vancomycin.\n\nData Sharing Statement\nThe data used to support the findings of this study are available and may be released upon application to the corresponding author.\n\nDisclosure\nThe authors report that they have no conflict of interest.\n==== Refs\nReferences\n1. 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Siddall \nE , Khatri \nM , Radhakrishnan \nJ . Capillary leak syndrome: etiologies, pathophysiology, and management\n. Kidney Int . 2017 ;92 (1 ):37 –46\n. doi:10.1016/j.kint.2016.11.029 28318633 \n6. Tallman \nMS , Andersen \nJW , Schiffer \nCA , et al. Clinical description of 44 patients with acute promyelocytic leukemia who developed the retinoic acid syndrome\n. Blood . 2000 ;95 :90 –95\n.10607690 \n7. Chertow \nGM , Burdick \nE , Honour \nM , Bonventre \nJV , Bates \nDW . Acute kidney injury, mortality, length of stay, and costs in hospitalized patients\n. J Am Soc Nephrol . 2005 ;16 (11 ):3365 –3370\n. doi:10.1681/ASN.2004090740 16177006 \n8. Lahoti \nA , Kantarjian \nH , Salahudeen \nAK , et al. Predictors and outcome of acute kidney injury in patients with acute myelogenous leukemia or high-risk myelodysplastic syndrome\n. Cancer . 2010 ;116 (17 ):4063 –4068\n. doi:10.1002/cncr.25306 20564156 \n9. Canet \nE , Zafrani \nL , Lambert \nJ , et al. Acute kidney injury in patients with newly diagnosed high-grade hematological malignancies: impact on remission and survival\n. PLoS One . 2013 ;8 (2 ):e55870 . doi:10.1371/journal.pone.0055870 23457485 \n10. Meersch \nM , Schmidt \nC , Hoffmeier \nA , et al. Prevention of cardiac surgery-associated AKI by implementing the KDIGO guidelines in high risk patients identified by biomarkers: the prevAKI randomized controlled trial\n. Intensive Care Med . 2017 ;43 (11 ):1551 –1561\n. doi:10.1007/s00134-016-4670-3 28110412 \n11. Summary of recommendation statements\n. Kidney Int Suppl . 2012 ;2 (1 ):8 –12\n. doi:10.1038/kisup.2012.7 \n12. Vincent \nJL , de Mendonça \nA , Cantraine \nF , et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Working group on “sepsis-related problems” of the European Society of Intensive Care Medicine\n. Crit Care Med . 1998 ;26 (11 ):1793 –1800\n. doi:10.1097/00003246-199811000-00016 9824069 \n13. Sanz \nMA , Montesinos \nP . How we prevent and treat differentiation syndrome in patients with acute promyelocytic leukemia\n. Blood . 2014 ;123 (18 ):2777 –2782\n. doi:10.1182/blood-2013-10-512640 24627526 \n14. Luciano \nRL , Brewster \nUC . Kidney involvement in leukemia and lymphoma\n. Adv Chronic Kidney Dis . 2014 ;21 (1 ):27 –35\n. doi:10.1053/j.ackd.2013.07.004 24359984 \n15. Di Micco \nL , Mirenghi \nF , Morelli \nE , De Simone \nE . Acute kidney failure in differentiation syndrome: a possible complication during therapy with differentiating agents for acute promyelocytic leukemia. A case report\n. G Ital Nefrol . 2019 ;36 (4 ).\n16. Seylanova \nN , Crichton \nS , Zhang \nJ , Fisher \nR , Ostermann \nM . Acute kidney injury in critically ill cancer patients is associated with mortality: a retrospective analysis\n. PLoS One . 2020 ;15 (5 ):e0232370 . doi:10.1371/journal.pone.0232370 32437362 \n17. Chamoun \nK , Kantarjian \nHM , Wang \nX , et al. Unrecognized fluid overload during induction therapy increases morbidity in patients with acute promyelocytic leukemia\n. Cancer . 2019 ;125 (18 ):3219 –3224\n. doi:10.1002/cncr.32196 31150121 \n18. Liu \nC , Bayer \nA , Cosgrove \nSE , et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant staphylococcus aureus infections in adults and children: executive summary\n. Clin Infect Dis . 2011 ;52 (3 ):285 –292\n. doi:10.1093/cid/cir034 21217178 \n19. Wilson \nFP , Berns \nJS . Tumor lysis syndrome: new challenges and recent advances\n. Adv Chronic Kidney Dis . 2014 ;21 (1 ):18 –26\n. doi:10.1053/j.ackd.2013.07.001 24359983 \n20. Filippone \nEJ , Kraft \nWK , Farber \nJL . The nephrotoxicity of vancomycin\n. Clin Pharmacol Ther . 2017 ;102 (3 ):459 –469\n. doi:10.1002/cpt.726 28474732 \n21. Okada \nN , Chuma \nM , Azuma \nM , et al. Effect of serum concentration and concomitant drugs on vancomycin-induced acute kidney injury in haematologic patients: a single-centre retrospective study\n. Eur J Clin Pharmacol . 2019 ;75 (12 ):1695 –1704\n. doi:10.1007/s00228-019-02756-4 31511938 \n22. Suzuki \nY , Tokimatsu \nI , Morinaga \nY , et al. A retrospective analysis to estimate target trough concentration of vancomycin for febrile neutropenia in patients with hematological malignancy\n. Clin Chim Acta . 2015 ;440 :183 –187\n. doi:10.1016/j.cca.2014.11.027 25476135 \n23. Chastain \nDB , Wheeler \nS , Franco-Paredes \nC , Olubajo \nB , Hawkins \nWA . Evaluating guideline adherence regarding empirical vancomycin use in patients with neutropenic fever\n. Clin Infect Dis . 2018 ;69 :88 –93\n.\n24. Melling \nPA , Noto \nMJ , Rice \nTW , Semler \nMW , Stollings \nJL . Time to first culture positivity among critically ill adults with methicillin-resistant staphylococcus aureus growth in respiratory or blood cultures\n. Ann Pharmacother . 2020 ;54 (2 ):131 –137\n. doi:10.1177/1060028019877937 31544471 \n25. Sinha Ray \nA , Haikal \nA , Hammoud \nKA , Yu \nAS . Vancomycin and the risk of AKI: a systematic review and meta-analysis\n. Clin J Am Soc Nephrol . 2016 ;11 (12 ):2132 –2140\n. doi:10.2215/CJN.05920616 27895134 \n26. Park \nJH , Qiao \nB , Panageas \nKS , et al. Early death rate in acute promyelocytic leukemia remains high despite all-trans retinoic acid\n. Blood . 2011 ;118 (5 ):1248 –1254\n. doi:10.1182/blood-2011-04-346437 21653939\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-2736",
"issue": "11()",
"journal": "Journal of blood medicine",
"keywords": "acute kidney injury; acute promyelocytic leukemia; incidence rate; induction chemotherapy",
"medline_ta": "J Blood Med",
"mesh_terms": null,
"nlm_unique_id": "101550884",
"other_id": null,
"pages": "363-369",
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"title": "Retrospective Study of Acute Kidney Injury Incidence in Patients with Newly Diagnosed Acute Promyelocytic Leukemia.",
"title_normalized": "retrospective study of acute kidney injury incidence in patients with newly diagnosed acute promyelocytic leukemia"
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"abstract": "We report a case of a 37-year-old woman who presented to our hospital with retrosternal chest pain following intramuscular administration of epinephrine due to presumed anaphylaxis. On arrival, she was found to have ST segment depression in the anterolateral leads on ECG and elevated cardiac troponins. She was diagnosed with stress cardiomyopathy based on left ventricle dysfunction and angiographically normal coronary arteries on cardiac catheterisation. To the best of our knowledge, this is the third reported case of takotsubo cardiomyopathy following appropriately dosed intramuscular administration of epinephrine for anaphylaxis. This case highlights the importance of considering stress cardiomyopathy in patients presenting with chest pain syndrome following systemic administration of epinephrine.",
"affiliations": "Reading Hospital and Medical Center, Reading, Pennsylvania, USA.;Reading Hospital and Medical Center, Reading, Pennsylvania, USA.;Reading Hospital and Medical Center, Reading, Pennsylvania, USA.;Reading Hospital and Medical Center, Reading, Pennsylvania, USA.",
"authors": "Nazir|Salik|S|;Melnick|Stephen|S|;Lohani|Saroj|S|;Lloyd|Benjamin|B|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001241:Aspirin; D004837:Epinephrine",
"country": "England",
"delete": false,
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"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000281:Administration, Intranasal; D000319:Adrenergic beta-Antagonists; D000328:Adult; D000707:Anaphylaxis; D000806:Angiotensin-Converting Enzyme Inhibitors; D001241:Aspirin; D004452:Echocardiography; D004837:Epinephrine; D005260:Female; D006801:Humans; D035583:Rare Diseases; D054549:Takotsubo Cardiomyopathy",
"nlm_unique_id": "101526291",
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"pages": null,
"pmc": null,
"pmid": "27268785",
"pubdate": "2016-06-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15687136;18242481;25598903;20215125;11868050;1841907;14557691;17395683;26332547;17403953;22083008;26800126;19120537;17651841;17324313;15703419",
"title": "Rare case of stress cardiomyopathy due to intramuscular epinephrine administration.",
"title_normalized": "rare case of stress cardiomyopathy due to intramuscular epinephrine administration"
} | [
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"companynumb": "DE-IMPAX LABORATORIES, INC-2016-IPXL-00743",
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"abstract": "Among the increasing number of new psychoactive substances, 3',4'-methylenedioxy-α-pyrrolidinohexanophenone (MDPHP) belongs to the group of synthetic cathinones, which are the derivatives of the naturally occurring compound cathinone, the main psychoactive ingredient in the khat plant. Currently, only limited data are available for MDPHP, and no information is available on its human metabolism. We describe the toxicological investigation of nine cases associated with the use of MDPHP during the period February-June 2019. Serum MDPHP concentrations showed a high variability ranging from 3.3 to 140 ng/mL (mean 30.3 ng/mL and median 16 ng/mL). Intoxication symptoms of the described cases could not be explained by the abuse of MDPHP alone because in all cases the co-consumption of other psychotropic drugs with frequent occurrence of opiates and benzodiazepines could be verified. Therefore, the patients showed different clinical symptoms, including aggressive behaviour, delayed physical response, loss of consciousness and coma. Liquid chromatography-high-resolution mass spectrometry was successfully used to investigate the human in vivo metabolism of MDPHP using authentic human urine samples. The metabolism data for MDPHP were further substantiated by the analysis of human urine using gas chromatography-mass spectrometry (GC-MS, a widely used systematic toxicological analysis method appropriate for the toxicological detection of MDPHP intake), which revealed the presence of seven phase I metabolites and three phase II metabolites as glucuronides. GC-MS spectral data for MDPHP and metabolites are provided. The identified metabolite pattern corroborates the principal metabolic pathways of α-pyrrolidinophenones in humans.",
"affiliations": "Forensic Toxicological Laboratory, University Medical Center Göttingen, Georg-August-University, Göttingen, Germany.;Forensic Toxicological Laboratory, University Medical Center Göttingen, Georg-August-University, Göttingen, Germany.;Institute of Forensic Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.;Institute of Forensic Medicine, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Germany.;Interdisciplinary Emergency Care Department, University Medical Center Göttingen, Georg-August-University, Göttingen, Germany.;Institute for Clinical Chemistry/UMG-Laboratories, University Medical Center Göttingen, Georg-August-University, Göttingen, Germany.",
"authors": "Grapp|Marcel|M|https://orcid.org/0000-0001-9728-5767;Kaufmann|Christoph|C|;Schwelm|Hannes M|HM|;Neukamm|Merja A|MA|https://orcid.org/0000-0002-3826-2327;Blaschke|Sabine|S|;Eidizadeh|Abass|A|",
"chemical_list": "D015198:Designer Drugs; D011619:Psychotropic Drugs",
"country": "England",
"delete": false,
"doi": "10.1002/dta.2869",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1942-7603",
"issue": "12(9)",
"journal": "Drug testing and analysis",
"keywords": "LC-QTOF-MS; MDPHP; gas chromatography-mass spectrometry; new psychoactive substances; nones; synthetic cathi",
"medline_ta": "Drug Test Anal",
"mesh_terms": "D000328:Adult; D002853:Chromatography, Liquid; D015198:Designer Drugs; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D011619:Psychotropic Drugs; D015813:Substance Abuse Detection",
"nlm_unique_id": "101483449",
"other_id": null,
"pages": "1320-1335",
"pmc": null,
"pmid": "32476242",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article; D023361:Validation Study",
"references": null,
"title": "Intoxication cases associated with the novel designer drug 3',4'-methylenedioxy-α-pyrrolidinohexanophenone and studies on its human metabolism using high-resolution mass spectrometry.",
"title_normalized": "intoxication cases associated with the novel designer drug 3 4 methylenedioxy pyrrolidinohexanophenone and studies on its human metabolism using high resolution mass spectrometry"
} | [
{
"companynumb": "DE-PFIZER INC-2020446759",
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"activesubstance": {
"activesubstancename": "BENZOYLECGONINE"
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"drugadditional": "3",
... |
{
"abstract": "Five days following the 3rd cycle of nivolumab, a monoclonal antibody, which acts as immune checkpoint inhibitor against the programmed cell death protein-1, for metastatic lung adenocarcinoma, a 56-year-old woman presented at the hospital critically ill. On admission, she had severe diabetic ketoacidosis (DKA), as evidenced by venous glucose of 47 mmol/L, blood ketones of 7.5 mmol/L, pH of 6.95 and bicarbonate of 6.6 mmol/L. She has had no personal or family history of diabetes mellitus (DM), while random venous glucose, measured 1 week prior to hospitalisation, was 6.1 mmol/L. On admission, her HbA1c was 8.2% and anti-GAD antibodies were 12 kIU/L (0-5 kU/L), while islet cell antibodies and serum C-peptide were undetectable. Nivolumab was recommenced without the development of other immune-mediated phenomena until 6 months later, when she developed hypothyroidism with TSH 18 U/L and low free T4. She remains insulin dependent and has required levothyroxine replacement, while she has maintained good radiological and clinical response to immunotherapy. This case is notable for the rapidity of onset and profound nature of DKA at presentation, which occurred two months following commencement of immunotherapy. Despite the association of nivolumab with immune-mediated endocrinopathies, only a very small number of patients developing type 1 DM has been reported to date. Patients should be closely monitored for hyperglycaemia and thyroid dysfunction prior to and periodically during immunotherapy.\nNivolumab can induce fulminant type 1 diabetes, resulting in DKA.Nivolumab is frequently associated with thyroid dysfunction, mostly hypothyroidism.Nivolumab-treated patients should be monitored regularly for hyperglycaemia and thyroid dysfunction.Clinicians should be aware and warn patients of potential signs and symptoms of severe hyperglycaemia.",
"affiliations": "Department of Diabetes, The Whittington Hospital, Whittington Health NHS Trust, London, UK.;Department of Medicine, Imperial College London, London, UK.;Department of Diabetes, The Whittington Hospital, Whittington Health NHS Trust, London, UK.;Department of Diabetes, The Whittington Hospital, Whittington Health NHS Trust, London, UK.;Department of Diabetes, The Whittington Hospital, Whittington Health NHS Trust, London, UK.;Medical School, University of Athens, Athens, Greece.;Department of Surgery and Cancer, Imperial College London, London, UK.",
"authors": "Tzoulis|Ploutarchos|P|;Corbett|Richard W|RW|;Ponnampalam|Swarupini|S|;Baker|Elly|E|;Heaton|Daniel|D|;Doulgeraki|Triada|T|;Stebbing|Justin|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1530/EDM-18-0111",
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 2953586610.1530/EDM-18-0111EDM180111Unusual Effects of Medical TreatmentNivolumab-induced fulminant diabetic ketoacidosis followed by thyroiditis P Tzoulis, R W Corbett and othersNivolumab-induced DKA and thyroiditisTzoulis Ploutarchos 1*Corbett Richard W 2*Ponnampalam Swarupini 1Baker Elly 1Heaton Daniel 1Doulgeraki Triada 3Stebbing Justin 41 Department of Diabetes, The Whittington Hospital, Whittington Health NHS Trust, London, UK2 Department of Medicine, Imperial College London, London, UK3 Medical School, University of Athens, Athens, Greece4 Department of Surgery and Cancer, Imperial College London, London, UKCorrespondence should be addressed to P Tzoulis Email: ptzoulis@yahoo.co.uk*(P Tzoulis and R W Corbett contributed equally to this work)\n\n21 3 2018 2018 2018 18-011123 1 2018 02 3 2018 © 2018 The authors2018The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License.Summary\nFive days following the 3rd cycle of nivolumab, a monoclonal antibody, which acts as immune checkpoint inhibitor against the programmed cell death protein-1, for metastatic lung adenocarcinoma, a 56-year-old woman presented at the hospital critically ill. On admission, she had severe diabetic ketoacidosis (DKA), as evidenced by venous glucose of 47 mmol/L, blood ketones of 7.5 mmol/L, pH of 6.95 and bicarbonate of 6.6 mmol/L. She has had no personal or family history of diabetes mellitus (DM), while random venous glucose, measured 1 week prior to hospitalisation, was 6.1 mmol/L. On admission, her HbA1c was 8.2% and anti-GAD antibodies were 12 kIU/L (0–5 kU/L), while islet cell antibodies and serum C-peptide were undetectable. Nivolumab was recommenced without the development of other immune-mediated phenomena until 6 months later, when she developed hypothyroidism with TSH 18 U/L and low free T4. She remains insulin dependent and has required levothyroxine replacement, while she has maintained good radiological and clinical response to immunotherapy. This case is notable for the rapidity of onset and profound nature of DKA at presentation, which occurred two months following commencement of immunotherapy. Despite the association of nivolumab with immune-mediated endocrinopathies, only a very small number of patients developing type 1 DM has been reported to date. Patients should be closely monitored for hyperglycaemia and thyroid dysfunction prior to and periodically during immunotherapy.\n\nLearning points:\nNivolumab can induce fulminant type 1 diabetes, resulting in DKA.\n\nNivolumab is frequently associated with thyroid dysfunction, mostly hypothyroidism.\n\nNivolumab-treated patients should be monitored regularly for hyperglycaemia and thyroid dysfunction.\n\nClinicians should be aware and warn patients of potential signs and symptoms of severe hyperglycaemia.\n==== Body\nBackground\nThe programmed cell death-1 protein (PD-1) is an immune checkpoint, a cell surface protein found on activated T cells, which, through interaction with its ligands, PD-L1 and PD-L2, inhibits kinase signalling pathways that normally lead to T-cell activation (1). Several tumour types can evade host immune surveillance by downregulating cytotoxic T-cell signalling through the upregulation of PD-L1 expression (2). This pathway is targeted by anti-PD-1 agents (3). Nivolumab is an anti-PD-1 monoclonal antibody that selectively blocks the interaction of the cancer cell PD-L1 and the PD-1 receptor of the activated T cells; as a result, T cells, instead of undergoing apoptosis, are capable of surviving and help to eliminate cancer cells (3). Therefore, nivolumab acts as an immunomodulatory antibody that ultimately augments the anticancer immune response through downregulation of T-cell inhibition.\n\nNivolumab was introduced and firstly approved for the treatment of melanoma, but has an increasing role in other tumours such as non-small-cell lung cancer (NSCLC) (4), renal cell carcinoma, head and neck squamous cell carcinoma (HNSCC), Hodgkin’s lymphoma and urothelial carcinoma. An improvement in the overall survival in a multicentre, randomised, open-label trial comparing nivolumab to docetaxel formed the basis for approval by the regulatory authorities in 2015 for the use of this drug in previously treated metastatic NSCLC (4).\n\nAs immune checkpoint inhibitors enhance T-cell immunity by disrupting the inhibitory signalling for the purpose of an increased anti-tumour response, they also reduce immune tolerance and, thereby cause autoimmune toxicities. These immune-related adverse events affect dermatological, gastrointestinal, hepatic, endocrine and other systems, with the commonest adverse effects being immune-related hepatitis, colitis and pneumonitis. Several immune-mediated endocrinopathies, such as autoimmune thyroid disorders, hypophysitis and adrenal insufficiency, are well recognised. However, only very few cases of type 1 diabetes mellitus (DM) have been reported so far.\n\nThe case presented here is notable because of the rapidity of development of type 1 DM in combination with the severity of diabetic ketoacidosis (DKA). In addition, this is the second case ever reported in the literature of autoimmune diabetes and hypothyroidism complicating nivolumab therapy.\n\nCase presentation\nFive days following the 3rd cycle of nivolumab as second-line treatment for metastatic lung adenocarcinoma, a 56-year-old Caucasian woman presented at the hospital critically ill. She was initially diagnosed with non-small-cell lung cancer three years ago and treated with pemetrexed and cisplatin. Subsequently, she received pemetrexed as maintenance chemotherapy until it was discontinued due to side effects two months prior to her emergency presentation. At that stage, therapy with nivolumab every 2 weeks was initiated with the patient showing good radiological and clinical response to it.\n\nOn admission, she was disorientated, agitated and combative without evidence of haemodynamic compromise and required sedation and intubation to permit assessment and initial resuscitation. She had severe metabolic acidosis predominantly due to diabetic ketoacidosis (DKA), as evidenced by glucose of 47 mmol/L (846 mg/dL), blood ketones of 7.5 mmol/L, pH of 6.95 and bicarbonate of 6.6 mmol/L.\n\nIn retrospect, she reported severe polyuria and polydipsia for the preceding 48 h, while one week prior to presentation, she was clinically well and normoglycaemic with random venous glucose of 6.1 mmol/L (110 mg/dL). Apart from metastatic lung adenocarcinoma, she had no personal/family history of DM or other organ-specific autoimmune conditions. Venous glucose had been normal at numerous measurements, while there was no evidence of pancreatic involvement, as evidenced by unremarkable appearances in CT abdomen, which was performed 2 days prior to emergency presentation.\n\nInvestigation\nThe patient had evidence of acute kidney injury with serum creatinine elevated at 300 µmol/L, compared to a baseline of 120 µmol/L. Her HbA1c on admission was 8.2%, as seen in Table 1. She was biochemically euthyroid and had appropriately elevated serum cortisol >1000 nmol/L. Her adrenal, thyroid peroxidase and islet cell antibodies were undetectable, while anti-GAD antibodies were present at 12 kU/L (0–5 kU/L). Serum C-peptide was also inappropriately undetectable. She has not been HLA genotyped.\nTable 1 Blood biochemical parameters one month and one week prior to, at the time of presentation and one week after discharge.\n\n\t1 month before\t1 week before\tAt the time of presentation\t1 week after\t\nGlucose (mmol/L)\t5.1\t6.1\t47.0\t14.2\t\nSodium (mmol/L)\t136\t141\t131\t140\t\nPotassium (mmol/L)\t4.4\t4.4\t5.3\t4.4\t\nUrea (mmol/L)\t\t\t22.4\t4.8\t\nCreatinine (µmol/L)\t122\t119\t300\t128\t\nHaemoglobin (g/L)\t134\t131\t137\t118\t\nWCC (×109/L)\t6.1\t5.7\t19.1\t7.9\t\nCRP (mg/L)\t1\t1\t28\t5\t\nHbA1c\t\t\t8.2 (66)\t\t\npH\t\t\t6.95\t\t\npCO2 (kPa)\t\t\t3.2\t\t\npO2 (kPa)\t\t\t18.4\t\t\nBicarbonate (mmol/L)\t\t\t6.6\t\t\nLactate (mmol/L)\t\t\t2.3\t\t\nChloride (mmol/L)\t\t\t105\t\t\nKetones (mmol/L)\t\t\t7.5\t\t\n\n\n\nBiochemical values, prior to, at the time of presentation, and after, are illustrated in Table 1.\n\nTreatment\nShe responded well to standard treatment for DKA. In specific, she required infusion of large volumes (11 L) of isotonic saline over the first 48 h and continuous intravenous insulin infusion with daily requirements of 72 units in the first 24 h and 59 units in the subsequent 24 h. She was extubated 24 h following admission, and her cognitive state normalised. However, at the initial stages of recovery, she was susceptible to unpredictable ketosis. Shortly after conversion to subcutaneous insulin administration on day 3 of hospitalisation, she rapidly developed hyperglycaemia and ketosis with blood glucose of about 20 mmol/L and ketones of 2.0 mmol/L, requiring reinstatement of intravenous insulin infusion for a few hours. In the following 2 days, blood glucose readings ranged between 2.5 and 21.5 mmol/L. Another episode of short-lived hyperglycaemic ketosis occurred 24 h later, which rapidly resolved with subcutaneous administration of an additional dose of rapid-acting insulin.\n\nOutcome and follow-up\nAfter developing fulminant type 1 DM leading to severe DKA, this patient remains insulin dependent. She exhibits significant glycaemic variability and her insulin requirements have gradually increased. One year after her diagnosis with nivolumab-induced type 1 DM, she is treated with basal bolus insulin regimen in the form of 24 units of insulin glargine and 1 unit of insulin aspart per 10 g of carbohydrate with an overall 24-h insulin requirement of approximately 54 units. Her most recent HbA1c was 9.1% (76 mmol/L).\n\nHer oncologist recommenced nivolumab therapy 1 month after development of DM, and she has maintained good radiological and clinical response to immunotherapy.\n\nNo other immune-mediated phenomena were reported until 6 months following her presentation with DKA when she developed subclinical hypothyroidism with TSH: 11.1 U/L and normal fT4 of 12.6 pmol/L (normal range: 12–22 pmol/L). Three weeks later, thyroid dysfunction progressed with TSH rising to 18.9 U/L and fT4 below the lower end of normal range at 11.2 pmol/L. She also developed symptoms, such as fatigue, cold intolerance and weight gain of 3 kg, necessitating initiation of levothyroxine replacement at a dose of 50 µg/day. Since then, she remains clinically and biochemically euthyroid on the current 50 µg daily dose of levothyroxine.\n\nWith respect to the possibility of other autoimmune endocrinopathies, she undergoes periodical testing, which has not shown deficiency of any other anterior pituitary hormones. In specific, most recent serum 09:00 h cortisol was 420 mmol/L, IGF-1: 14.4 (normal range: 5.6–22.9 nmol/L) and prolactin 226 U/L (normal range: 102–496 U/L), while FSH and LH remain appropriately elevated at 101.9 IU/L and 62.9 IU/L in keeping with her postmenopausal status.\n\nDiscussion\nA few case reports have been published of rapid onset type 1 DM after initiation with anti-PD-1 monoclonal antibody treatment. The largest case series of five patients with an onset of diabetes occurring between 1 and 5 months following the commencement of anti-PD-1 drugs (5) cannot attribute DM to immunotherapy with certainty because of the presence of other risk factors like co-administration of other immunomodulators, the presence of pancreatic metastases and pre-existing type 2 diabetes. The first Asian patient to develop type 1 diabetes with nivolumab therapy was described by Okamoto et al. (6). Our case report as well as other reported cases are characterised by the rapid onset of insulin-dependent DM in close proximity with the initiation of nivolumab. Further cases (7) have been reported primarily in patients in Japan, where fulminant type 1 DM is recognised to occur spontaneously within the population, though these patients had been receiving nivolumab for between 4 and 12 months.\n\nAs many MHC-linked and non-MHC-linked genes and genetic regions in humans and mice, determining the susceptibility to autoimmune diseases, have been identified, further work in mice suggests that immunotherapy may precipitate diabetes development in those with these susceptible HLA alleles (8). In humans, there is a preponderance of high risk HLA alleles in individuals who have developed type 1 DM in the context of PD-1 immunotherapy (9), supporting a genetic predisposition to this complication of therapy. The biological plausibility of these drugs inducing diabetes is supported by experimental work where inhibition of the PD-1/PD-L1 interaction rapidly precipitated diabetes in prediabetic non-obese diabetic (NOD) mice, especially in older mice (10). Thus, PD-1 appears to be critical for progression of autoimmune diabetes in susceptible individuals (10).\n\nPD-1 inhibitors, nivolumab and pembrolizumab, have been associated with a high incidence of thyroid dysfunction (11, 12, 13). Phase 3 studies of nivolumab therapy for malignant melanoma and non-squamous non-small cell lung cancer (4) have reported a frequency for hypothyroidism of 5.6–6.6% and for thyrotoxicosis of 1.4–1.9% respectively. Noteworthy, the risk of thyroid abnormalities increases substantially when patients are treated with a combination of PD-1 and CTLA-4 (cytotoxic T-lymphocyte antigen-4) inhibitors (14, 15) or when PD-1 inhibitor follows CTLA-4 therapy, such as ipilimumab, especially when the wash-out period is <4 weeks (15). The most commonly described types of nivolumab-related thyroid dysfunction are either a transient thyrotoxic phase, which tends to resolve spontaneously and is often followed by hypothyroidism (11) or development of isolated hypothyroidism, both caused by painless thyroiditis (12). Thyrotoxicosis tends to occur within 6 weeks after the first administration of nivolumab. However, the time to onset of hypothyroidism ranges from 4 days to months following initiation of immunotherapy, making it very difficult to predict the occurrence time (11, 12, 14, 15). Finally, it has been suggested that new occurrence of thyroid and extra-thyroid autoimmune disorders may be associated with a better treatment response to PD-1 inhibitors (13, 15), but this finding needs to be studied further.\n\nA high incidence of positive thyroid peroxidase antibodies (anti-TPO antibodies) and thyroglobulin antibodies (anti-TG antibodies) has been reported in patients with nivolumab-induced thyroid dysfunction (11, 12, 13, 16), while Maekura and coworkers recently suggested that positive anti-TPO and anti-TG antibodies at baseline may predict nivolumab-induced hypothyroidism (16). These data provide evidence for a possible link of immunologic pathways with nivolumab-induced thyroid dysfunction. It is also known that PD-L1 and PD-L2 are expressed in normal thyroid tissue. Consequently, inhibiting the PD-1 pathway could be correlated with reduced immune tolerance and development of thyroiditis (12). In addition, polymorphic variants of the PD-1 receptor gene may be related to the occurrence of painless thyroiditis (11).\n\nThe rapidity of onset and profound nature of the diabetic ketoacidosis at presentation in our non-Asian patient, which occurred two months following the commencement of immunotherapy and was followed by the development of hypothyroidism 6 months later, highlight the need for regular patient monitoring in order to promptly identify immune-related endocrinopathies. In addition, clinicians should be aware and warn patients of potential signs and symptoms indicative of hyperglycaemia. In our practice, we monitor glucose levels every 2 weeks during the period of nivolumab therapy. We also educate patients on symptoms of hyperglycaemia and provide them with blood glucose monitor to check glucose levels in case of hyperglycaemic symptoms. Serum concentration of TSH and free T4 is measured prior to and 2-weekly after nivolumab therapy. Moreover, all patients who have already developed a nivolumab-related endocrine adverse event undergo periodical monitoring for other possible endocrinopathies. For example, in our case, we regularly measure early morning serum cortisol in view of the risk for hypophysitis or adrenalitis.\n\nDespite a recent systematic review and meta-analysis of 7551 patients in 38 randomised trials reporting an overall incidence of about 10% for immunotherapy-related clinically significant endocrinopathies (17), immunotherapy is usually not discontinued since its favourable outcomes seem to outweigh these adverse events (3). Studies are warranted to identify the risk factors for development of immunotherapy-induced type 1 diabetes (3), but also the frequency and natural history of this adverse event. The same need for prospective studies applies to examining the utility of baseline evaluation of thyroid TPO or/and TG antibodies as a predictor for development of thyroid dysfunction (16). Most importantly, patients and healthcare professionals should be well educated on symptom recognition and management of these endocrinopathies while on immunotherapy.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nA written informed consent has been obtained from the patient for publication of the submitted article and accompanying images.\n\nAuthor contribution statement\nP T was in charge of patient’s management, coordinated with the other authors and prepared the final manuscript. R W C was involved in the initial management of the patient, wrote the initial draft of the article and contributed substantially to writing the case report. S P and T D undertook literature review and contributed substantially to writing the case report. E B, D H and J S were actively involved in the immediate and long-term management of the patient.\n==== Refs\nReferences\n1 Godwin JL Jaggi S Sirisena I Sharda P Rao AD Mehra R Veloski C \nNivolumab-induced autoimmune diabetes mellitus presenting as diabetic ketoacidosis in a patient with metastatic lung cancer . Journal for ImmunoTherapy of Cancer \n2017 \n5 \n40 (10.1186/s40425-017-0245-2 )28515940 \n2 Li L Masood A Bari S Yavuz S Grosbach AB \nAutoimmune diabetes and thyroiditis complicating treatment with nivolumab . Case Reports in Oncology \n2017 \n10 \n230 –234 . (10.1159/000456540 )28611636 \n3 Araújo M Ligeiro D Costa L Marques F Trindade H Correia JM Fonseca C \nA case of fulminant Type 1 diabetes following anti-PD1 immunotherapy in a genetically susceptible patient . Immunotherapy \n2017 \n9 \n531 –535 . (10.2217/imt-2017-0020 )28595520 \n4 Borghaei H Paz-Ares L Horn L Spigel DR Steins M Ready NE Chow LQ Vokes EE Felip E Holgado E , \nNivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer . New England Journal of Medicine \n2015 \n373 \n1627 –1639 . (10.1056/NEJMoa1507643 )26412456 \n5 Hughes J Vudattu N Sznol M Gettinger S Kluger H Lupsa B Herold KC. \nPrecipitation of autoimmune diabetes with anti-PD-1 immunotherapy . Diabetes Care \n2015 \n38 \ne55 –e57 . (10.2337/dc14-2349 )25805871 \n6 Okamoto M Okamoto M Gotoh K Masaki T Ozeki Y Ando H Anai M Sato A Yoshida Y Ueda S , \nFulminant type 1 diabetes mellitus with anti-programmed cell death-1 therapy . Journal of Diabetes Investigation \n2016 \n7 \n915 –918 . (10.1111/jdi.12531 )27181090 \n7 Mellati M Eaton KD Brooks-Worrell BM Hagopian WA Martins R Palmer JP Hirsch IB \nAnti-PD-1 and anti-PDL-1 monoclonal antibodies causing type 1 diabetes . Diabetes Care \n2015 \n38 \ne137 –e138 . (10.2337/dc15-0889 )26116720 \n8 Kochupurakkal NM Kruger AJ Tripathi S Zhu B Adams LT Rainbow DB Rossini A Greiner DL Sayegh MH Wicker LS , et al\nBlockade of the programmed death-1 (PD1) pathway undermines potent genetic protection from type 1 diabetes . PLoS ONE \n2014 \n9 \n1 –11 . (10.1371/journal.pone.0089561 )\n9 Chae YK Chiec L Mohindra N Gentzler R Patel J Giles F. \nA case of pembrolizumab-induced type-1 diabetes mellitus and discussion of immune checkpoint inhibitor-induced type 1 diabetes . Cancer Immunology, Immunotherapy \n2016 \n66 \n1 –8 . (10.1007/s00262-016-1913-7 )27714433 \n10 Ansari MJ Salama AD Chitnis T Smith RN Yagita H Akiba H Yamazaki T Azuma M Iwai H Khoury SJ , \nThe programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice . Journal of Experimental Medicine \n2003 \n198 \n63 –69 . (10.1084/jem.20022125 )12847137 \n11 Orlov S Salari F Kashat L Walfish PG. \nInduction of painless thyroiditis in patients receiving programmed death 1 receptor immunotherapy for metastatic malignancies . Journal of Clinical Endocrinology and Metabolism \n2015 \n100 \n1738 –1741 . (10.1210/jc.2014-4560 )25751110 \n12 Yamauchi I Sakane Y Fukuda Y Fujii T Taura D Hirata M Hirota K Ueda Y Kanai Y Yamashita Y , et al\nClinical features of nivolumab-induced thyroiditis: a case series study . Thyroid \n2017 \n27 \n894 –901 . (10.1089/thy.2016.0562 )28537531 \n13 Alhusseini M Samantray J. \nHypothyroidism in cancer patients on immune checkpoint inhibitors with anti-PD1 agents: insights on underlying mechanisms . Experimental and Clinical Endocrinology and Diabetes \n2017 \n125 \n267 –269 . (10.1055/s-0042-119528 )28073132 \n14 Morganstein DL Lai Z Spain L Diem S Levine D Mace C Gore M Larkin J \nThyroid abnormalities following the use of cytotoxic T‐lymphocyte antigen‐4 and programmed death receptor protein‐1 inhibitors in the treatment of melanoma . Clinical Endocrinology \n2017 \n86 \n614 –620 . (10.1111/cen.13297 )28028828 \n15 Guaraldi F La Selva R Samà MT D’Angelo V Gori D Fava P Fierro MT Savoia P Arvat E. \nCharacterization and implications of thyroid dysfunction induced by immune checkpoint inhibitors in real-life clinical practice: a long-term prospective study from a referral institution . Journal of Endocrinological Investigation \n2017 Epub. (doi:10.1007/s40618-017-0772-1)\n16 Maekura T Naito M Tahara M Ikegami N Kimura Y Sonobe S Kobayashi T Tsuji T Minomo S Tamiya A , et al\nPredictive factors of nivolumab-induced hypothyroidism in patients with non-small cell lung cancer . In Vivo \n2017 \n31 \n1035 –1039 . (10.21873/invivo.11166 )28882978 \n17 Barroso-Sousa R Barry WT Garrido-Castro AC Hodi FS Min L Krop IE Tolaney SM \nIncidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: a systematic review and meta-analysis . JAMA Oncology \n2018 4 \n173 –182 . (10.1001/jamaoncol.2017.3064 )28973656\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-0573",
"issue": "2018()",
"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": "29576870",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "26412456;28882978;28028828;28537531;28515940;28073132;24586872;28595520;27761609;26116720;25805871;29043574;28973656;25751110;12847137;27181090;28611636",
"title": "Nivolumab-induced fulminant diabetic ketoacidosis followed by thyroiditis.",
"title_normalized": "nivolumab induced fulminant diabetic ketoacidosis followed by thyroiditis"
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"abstract": "The optimal management of elderly patients (pts) with Hodgkin's lymphoma is not yet defined. The aims of the present study were: 1) to evaluate clinical and laboratory characteristics of elderly pts; 2) to indentify risk factors for unfavorable outcome.\n\n\n\nThe outcome of 182 pts ≥ 60 years (y) was retrospectively analyzed (median age, 67y). Mixed cellularity histology was diagnosed in 49.5 %, advanced stage of disease was in 68.7 % pts, CIRS > 3 in 35.7 %, ECOG PS ≥ 2 in 22.9 % (60-69y) of pts. Chemotherapy (CMT) alone was used in 69.2 % and combination of CMT and radiotherapy in 26.9 % of pts. Anthracycline-based CMT received 83.5 % of pts. The median follow-up was 4.5y.\n\n\n\nThe overall response/complete remission rate was 85.6/70.7 %. The median progression free survival (PFS) and overall survival (OS) were 10y and 11.3y, respectively. Estimated 5-y PFS and 5-y OS were 65.7 % (in contrast to 98.2 % in pts < 60y; p < 0.001) and 70.5 % (99.4 % in pts < 60y; p < 0.001). Overall 70 (38.5 %) elderly pts died. The independent risk factors for a shorter OS included CIRS > 3, lymphopenia < 8 % and anthracycline-free CMT, for a shorter PFS anthracycline-free CMT and lymphopenia < 8 %.\n\n\n\nCIRS > 3, lymphopenia < 8 % and anthracycline-free chemotherapy appear to be significant for unfavorable outcome.",
"affiliations": "4th Department of Internal Medicine - Hematology, University Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic. Electronic address: ali.sykorova@seznam.cz.;Department of Clinical Hematology, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic.;Department of Haemato-Oncology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.;1st Department of Medicine, Department of Hematology, Charles University, General Hospital, Prague, Czech Republic.;4th Department of Internal Medicine - Hematology, University Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic.;Department of Haemato-Oncology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.;4th Department of Internal Medicine - Hematology, University Hospital and Faculty of Medicine, Hradec Kralove, Czech Republic.;Department of Clinical Hematology, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic.;Department of Clinical Hematology, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic.;DSC Services, Tišnov, Czech Republic.;DSC Services, Tišnov, Czech Republic.;Department of Clinical Hematology, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University, Prague, Czech Republic.",
"authors": "Sykorova|A|A|;Mocikova|H|H|;Lukasova|M|M|;Koren|J|J|;Stepankova|P|P|;Prochazka|V|V|;Belada|D|D|;Klaskova|K|K|;Gaherova|L|L|;Chroust|K|K|;Buresova|L|L|;Markova|J|J|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.leukres.2020.106311",
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"issn_linking": "0145-2126",
"issue": "90()",
"journal": "Leukemia research",
"keywords": "Chemotherapy; Elderly population; Hodgkin’s lymphoma; Outcome; Radiotherapy; Risk factors",
"medline_ta": "Leuk Res",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D018153:Czech Republic; D019468:Disease Management; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D017063:Outcome Assessment, Health Care; D011379:Prognosis; D062486:Public Health Surveillance; D012042:Registries; D016896:Treatment Outcome",
"nlm_unique_id": "7706787",
"other_id": null,
"pages": "106311",
"pmc": null,
"pmid": "32050133",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Outcome of elderly patients with classical Hodgkin's lymphoma.",
"title_normalized": "outcome of elderly patients with classical hodgkin s lymphoma"
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"companynumb": "CZ-MYLANLABS-2020M1031333",
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"abstract": "Myasthenia gravis is an autoimmune disorder affecting the neuromuscular junction, resulting in muscle fatiguability and weakness. The pathological characteristics of the disorder include ocular weakness resulting in diplopia and/or ptosis. More generally, the disease can result in fluctuant weakness of skeletal muscle, predominantly affecting ocular, bulbar and respiratory muscles. Autoimmunity in this instance is mediated by IgG anti-acetylcholine receptor antibodies that results in an impaired structure of postsynaptic neurotransmission. Approximately 15% of patients with myasthenia gravis present with bulbar symptoms, of which isolated bulbar symptoms are seen only on occasion. As with our patient, this presentation is most commonly seen in men with late-onset myasthenia gravis. We present a case of an 83-year-old male who presented with a 1 year history of dysphagia for solids and fatigable dysarthria. Following a diagnosis of myasthenia gravis, he was initiated on corticosteroid treatment. He later descended into myasthenic crisis, requiring invasive ventilation measures due to a failure of both non-invasive ventilation and intravenous immunoglobulin G (IVIG) to achieve therapeutic goals.\nIsolated bulbar symptoms in an elderly man warrants consideration of myasthenia gravis to be included in the differential diagnosis.There is possibly an increased risk of myasthenic crisis in late-onset isolated bulbar myasthenia gravis.Empirical treatment for myasthenia gravis must be administered within a hospital setting, paying attention to respiratory tract infection and corticosteroid treatment as triggers for myasthenic crisis.",
"affiliations": "Internal Medicine Department, St. Luke General Hospital, Kilkenny, Ireland.;Internal Medicine Department, St. Luke General Hospital, Kilkenny, Ireland.;Internal Medicine Department, St. Luke General Hospital, Kilkenny, Ireland.;Internal Medicine Department, St. Luke General Hospital, Kilkenny, Ireland.",
"authors": "Mustafa|Moneeb Sefeldawla|MS|;Marshal|Megan|M|;Ahern|Emer|E|;Crowley|Paul|P|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2017_000785",
"fulltext": "\n==== Front\nEur J Case Rep Intern MedEur J Case Rep Intern MedEuropean Journal of Case Reports in Internal Medicine2284-2594SMC Media Srl 10.12890/2017_000785785-1-4588-1-10-20171219ArticlesDelayed Diagnosis of Atypical Presentation of Myasthenia Gravis Mustafa Moneeb Sefeldawla Marshal Megan Ahern Emer Crowley Paul Internal Medicine Department, St. Luke General Hospital, Kilkenny, Ireland2018 22 2 2018 5 2 00078514 11 2017 20 11 2017 © EFIM 20172017This article is licensed under a Commons Attribution Non-Commercial 4.0 LicenseMyasthenia gravis is an autoimmune disorder affecting the neuromuscular junction, resulting in muscle fatiguability and weakness.\n\nThe pathological characteristics of the disorder include ocular weakness resulting in diplopia and/or ptosis. More generally, the disease can result in fluctuant weakness of skeletal muscle, predominantly affecting ocular, bulbar and respiratory muscles. Autoimmunity in this instance is mediated by IgG anti-acetylcholine receptor antibodies that results in an impaired structure of postsynaptic neurotransmission. Approximately 15% of patients with myasthenia gravis present with bulbar symptoms, of which isolated bulbar symptoms are seen only on occasion. As with our patient, this presentation is most commonly seen in men with late-onset myasthenia gravis.\n\nWe present a case of an 83-year-old male who presented with a 1 year history of dysphagia for solids and fatigable dysarthria. Following a diagnosis of myasthenia gravis, he was initiated on corticosteroid treatment. He later descended into myasthenic crisis, requiring invasive ventilation measures due to a failure of both non-invasive ventilation and intravenous immunoglobulin G (IVIG) to achieve therapeutic goals.\n\nLEARNING POINTS\nIsolated bulbar symptoms in an elderly man warrants consideration of myasthenia gravis to be included in the differential diagnosis.\n\nThere is possibly an increased risk of myasthenic crisis in late-onset isolated bulbar myasthenia gravis.\n\nEmpirical treatment for myasthenia gravis must be administered within a hospital setting, paying attention to respiratory tract infection and corticosteroid treatment as triggers for myasthenic crisis.\n\nGlanzmann thrombastheniableedingrFVIIa\n==== Body\nCASE DESCRIPTION\nAn 83-year-old male presented with a 1 year history of dysphagia for solids that intensified over a 2 week period. The patient also complained of fatigable dysarthria that worsened throughout the day, and on presentation he had slurred speech.\n\nOn examination, no ptosis or diplopia was elicited and patient denied history of same. Past medical history included hypertension, hypercholesterolaemia, and benign prostatic hyperplasia. Differential diagnoses at this point included amyotrophic lateral sclerosis, cerebrovascular accident, paraneoplastic disease, and oesophageal motility disorder. CT brain, neck and thorax were performed and determined to be normal. Barium swallow revealed an incoordination of swallow of the pharynx with some leakage of contrast into the oesophagus. Following neurology review, a diagnosis of myasthenia gravis was made and treatment was initiated, consisting of pyridostigmine, prednisone 500 mg per day for 3 days, with an ongoing dose of 25 mg.\n\nOne day post treatment, the patient reported that his speech and swallow had improved. However, 4 days post treatment, the patient developed type II respiratory failure with hypoxia, hypercapnia and decreased air entry in basal segments, bilaterally, along with left bundle branch block on ECG and chest X-ray showing right-sided infiltrate.\n\nThe patient was treated with tazobactam/piperacillin and clarithromycin for aspiration pneumonia. This treatment elicited minimal improvement overnight. Following this, the patient was assessed by the neurology team who suggested a diagnosis of myasthenic crisis secondary to pneumonia and prednisone treatment. The patient was treated for myasthenic crisis with neostigmine and glycopyrronium bromide and was initiated on non-invasive ventilation.\n\nFailure of this treatment led to the patient commencing intravenous immunoglobulin G (IVIG) therapy and was continued on this for 1 day. Failure of these measures to achieve adequate respiratory function prompted a case management review with the senior consultant in intensive care and elective invasive ventilation was initiated, while continuing IVIG therapy for a total of 5 days.\n\nFollowing 4 days in the intensive care setting, the patient was extubated and discharged to the ward.\n\nHis medical treatment continued with pyridostigmine and he was subsequently recommenced on prednisone 25 mg following control of myasthenia symptoms. The patient was discharged from hospital to be reviewed in the outpatient department in 4 weeks.\n\nMethods and Procedures\nStrongly positive acetylcholine receptor antibody levels\n\nSenior neurologist opinion\n\nImprovement following myasthenia gravis treatment and minimal symptoms on discharge\n\nDISCUSSION\nMyasthenia gravis is the most common disorder of the neuromuscular junction, with an annual incidence of 0.21–2 patients per 100,000[1].\n\nIt is known that the peak incidence of myasthenia gravis in men occurs at 65 years of age, whereas the peak incidence for women is at 30 years. Late-onset myasthenia gravis often presents with bulbar symptoms, including dysphagia, dysphonia, tongue weakness, slurred speech, and chewing problems[2]. This represents a total of 30% of all myasthenia gravis cases. It is also known that elevated anti-acetylcholine receptor antibody serum titres are the definitive diagnostic test. However, these may also be absent in an older patient set, known as seronegative myasthenia gravis, who have neither antibodies to acetylcholine receptors nor muscle-specific tyrosine kinase[3].\n\nThe mainstay of treatment for myasthenia gravis is pyridostigmine, with adjunctive corticosteroids for all patients with myasthenia gravis who have not reached treatment goals following a trial of pyridostigmine. If steroids are not tolerated by the patient, a non-steroidal immunosuppressant can be used, such as cyclosporine, azathioprine or methotrexate. If refractory to these measures, chronic IVIG should be initiated in a speciality centre for myasthenia gravis[4]. Some 15–20% of patients with myasthenia gravis will be affected by myasthenic crisis at least once in their lives and, in one-fifth of patients, this may be their initial presentation[1]. The mortality rate in myasthenia crisis has decreased from 42% in the early 1960s to 4% currently[1]. Of utmost importance in the treatment of myasthenic crisis is adequate management of respiratory function. Some 66–90% of patients will require intubation and mechanical ventilation. Non-invasive ventilation can be successfully used to support patients with myasthenic crisis. However, an independent indication of failed non-invasive ventilation is a PCO2 level of >45 mmHg, thus requiring invasive ventilation to be initiated.\n\nIt is clear that elective intubation is favourable over an emergent procedure, and this should be anticipated in the ongoing care for a patient in myasthenic crisis. Furthermore, prolonged intubation should be avoided as this can result in further complications, such as increased hospital stay. The most clearly established precipitant of myasthenia crisis is infection. Other precipitating factors are surgery, aspiration pneumonia, pregnancy, and a reduction in immune-modulating medications. Furthermore, certain medications have a clearly established link in precipitating myasthenic crisis, especially corticosteroids. The incidence of corticosteroid-induced myasthenic crisis is understood to be in the range of 9–18%[3].\n\nFurthermore, this is likely to be increased in older patients with isolated bulbar symptoms. The increased risk of myasthenic crisis following corticosteroid treatment of myasthenia gravis should prompt the initial treatment to be delivered solely in the hospital setting where respiratory function can be monitored and managed appropriately to decrease the risk of increased mortality in these patients.\n\nThe initial decline following corticosteroid treatment is not however an indicator of overall response to corticosteroids. As previously mentioned, vigilance should be exercised when dealing with late-onset, isolated bulbar myasthenia gravis and the possibility of progression to myasthenic crisis following initiation of corticosteroids.\n\nConflicts of Interests: The Authors declare that there are no competing interests.\n==== Refs\nREFERENCES\n1 Wendell L Levine J Myasthenic crisis Neurohospitalist 2011 1 16 22 23983833 \n2 Basiri K Ansari B Okhovat A Life-threatening misdiagnosis of bulbar onset myasthenia gravis as a motor neuron disease: how much can one rely on exaggerated deep tendon reflexes Adv Biomed Res 2015 4 58 25802827 \n3 Montero-Odasso M Dysphonia as first symptom of late-onset myasthenia gravis J Gen Intern Med 2006 21 C4 C6 \n4 Sanders D Wolfe G Narayanaswami P Author response: International consensus guidance for management of myasthenia gravis: executive summary Neurology 2017 88 505 506\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2284-2594",
"issue": "5(2)",
"journal": "European journal of case reports in internal medicine",
"keywords": "Glanzmann thrombasthenia; bleeding; rFVIIa",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "000785",
"pmc": null,
"pmid": "30756011",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "16808732;23983833;25802827;28138082",
"title": "Delayed Diagnosis of Atypical Presentation of Myasthenia Gravis.",
"title_normalized": "delayed diagnosis of atypical presentation of myasthenia gravis"
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{
"companynumb": "IE-MYLANLABS-2018M1018983",
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"occurcountry": "IE",
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"activesubstancename": "PREDNISONE"
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{
"abstract": "BACKGROUND\nAntiretroviral therapy (ART) is known to save lives. Among HIV-infected infants living in resource constrained settings, the short and long term benefits of ART are only partially known. This study was designed to determine the virologic, immunologic and clinical outcomes of antiretroviral therapy in a cohort of HIV-infected infants receiving care from an outpatient clinic in Kampala, Uganda.\n\n\nMETHODS\nA prospective cohort of HIV-infected infants receiving treatment at the Baylor-Uganda clinic was analyzed. Patients were diagnosed, enrolled and followed up at the clinic. HIV viral load, CD4 cell counts and clinical progress were assessed during follow-up. Descriptive statistical analysis and logistic regression modeling to determine predictors of treatment success were conducted.\n\n\nRESULTS\nOf 91 HIV-infected infants enrolled into the cohort, 53 (58.2%) infants were female; 43 (47.3%) were 6 months of age or younger, and 50 (55.6%) had advanced HIV/AIDS disease (Clinical stage 3 or 4). Eighty four infants started ART and 78 (92.9%) completed 6 months of treatments. Fifty six (71.8%) infants attained virologic suppression by month-6 of ART, and at month-12 of ART, the cumulative probability of attaining viral suppression was 83.1%. None of the baseline infant factors (age, sex, WHO stage, CD4 cell percent, weight for age, or height for age z-score) predicted treatment success. There was an increase in CD4 cells from a baseline mean of 23% to 30% at month-6 of treatment (p<0.001) and by month-24 of ART, the mean CD4 percent was 36%. A total of 7 patients died while on ART and another 7 experienced adverse events that were related to treatment.\n\n\nCONCLUSIONS\nOur results show that, even among very young patients from resource constrained settings, ART dramatically suppresses HIV replication, allows immune recovery and clinical improvement, and is safe. However, baseline characteristics do not predict recovery in this age group.",
"affiliations": "Baylor College of Medicine-Bristol Myers Squibb Children's Clinical Center of Excellence at Mulago Hospital, Kampala, Uganda. vtukei@baylor-uganda.org",
"authors": "Tukei|Vincent J|VJ|;Murungi|Miriam|M|;Asiimwe|Alice R|AR|;Migisha|Daniella|D|;Maganda|Albert|A|;Bakeera-Kitaka|Sabrina|S|;Kalyesubula|Israel|I|;Musoke|Philippa|P|;Kekitiinwa|Adeodata|A|",
"chemical_list": "D019380:Anti-HIV Agents",
"country": "England",
"delete": false,
"doi": "10.1186/1471-2431-13-42",
"fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central 1471-2431-13-422353697610.1186/1471-2431-13-42Research ArticleVirologic, immunologic and clinical response of infants to antiretroviral therapy in Kampala, Uganda Tukei Vincent J 1vtukei@baylor-uganda.orgMurungi Miriam 1mrmurungi@yahoo.comAsiimwe Alice R 1aasiimwe@baylor-uganda.orgMigisha Daniella 1migishad@yahoo.comMaganda Albert 1amaganda@baylor-uganda.orgBakeera-Kitaka Sabrina 3sabrinakitaka@yahoo.co.ukKalyesubula Israel 1ikalyesubula@baylor-uganda.orgMusoke Philippa 23pmusoke@mujhu.orgKekitiinwa Adeodata 1akekitiinwa@baylor-uganda.org1 Baylor College of Medicine-Bristol Myers Squibb Children’s Clinical Center of Excellence at Mulago Hospital, Kampala, Uganda2 Makerere University-Johns Hopkins University Research Collaboration Clinic, Kampala, Uganda3 Department of Pediatrics and Child Health, Makerere University College of Health Sciences, Kampala, Uganda2013 27 3 2013 13 42 42 14 12 2012 22 3 2013 Copyright © 2013 Tukei et al.; licensee BioMed Central Ltd.2013Tukei et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nAntiretroviral therapy (ART) is known to save lives. Among HIV-infected infants living in resource constrained settings, the short and long term benefits of ART are only partially known. This study was designed to determine the virologic, immunologic and clinical outcomes of antiretroviral therapy in a cohort of HIV-infected infants receiving care from an outpatient clinic in Kampala, Uganda.\n\nMethods\nA prospective cohort of HIV-infected infants receiving treatment at the Baylor-Uganda clinic was analyzed. Patients were diagnosed, enrolled and followed up at the clinic. HIV viral load, CD4 cell counts and clinical progress were assessed during follow-up. Descriptive statistical analysis and logistic regression modeling to determine predictors of treatment success were conducted.\n\nResults\nOf 91 HIV-infected infants enrolled into the cohort, 53 (58.2%) infants were female; 43 (47.3%) were 6 months of age or younger, and 50 (55.6%) had advanced HIV/AIDS disease (Clinical stage 3 or 4). Eighty four infants started ART and 78 (92.9%) completed 6 months of treatments. Fifty six (71.8%) infants attained virologic suppression by month-6 of ART, and at month-12 of ART, the cumulative probability of attaining viral suppression was 83.1%. None of the baseline infant factors (age, sex, WHO stage, CD4 cell percent, weight for age, or height for age z-score) predicted treatment success. There was an increase in CD4 cells from a baseline mean of 23% to 30% at month-6 of treatment (p<0.001) and by month-24 of ART, the mean CD4 percent was 36%. A total of 7 patients died while on ART and another 7 experienced adverse events that were related to treatment.\n\nConclusion\nOur results show that, even among very young patients from resource constrained settings, ART dramatically suppresses HIV replication, allows immune recovery and clinical improvement, and is safe. However, baseline characteristics do not predict recovery in this age group.\n\nInfantHIVAntiretroviral therapyMortalityMalnutrition\n==== Body\nBackground\nOver the last decade, the beneficial effects of antiretroviral therapy (ART) have been reported among HIV-infected adults and children in both resource rich and resource poor countries [1-4]. Antiretroviral therapy markedly reduces morbidity and mortality by suppressing viral replication which ultimately leads to immune recovery and a reduction in opportunistic infections. Among infants and children, early introduction of ART is known to save lives [5-7]. However, the effects of early initiation of life-long treatment among infants receiving care in HIV treatment programs in the resource constrained settings of Africa are not fully known.\n\nThe World Health Organization (WHO) in its 2010 revision of HIV treatment guidelines recommends early initiation of ART among infants and young children [8]. As these recommendations are being implemented across Africa, a sizable number of HIV-infected infants, some as young as 6 weeks, are being started on these daily medications. The short and long term effects of early ART initiation among these very young patients are yet to be fully known. The frequency of adverse events among these infants, and the level of immunologic and clinical recovery that occurs when these drugs are administered to infants outside of the controlled environment of clinical trials are yet to be determined.\n\nThe objective of this study was to determine the virologic response to ART in a cohort of HIV-infected Ugandan infants (children less than 12 months of age) as measured by HIV viral suppression after 6 months of therapy; determine the level of immunologic recovery as measured by increase in CD4 cell counts; and determine the proportion of infants developing ART-related adverse events.\n\nMethods\nStudy design and setting\nFor this observational cohort study, we recruited and followed HIV-infected infants who were enrolling for care and treatment at the Baylor College of Medicine Bristol Myers Squibb Children’s clinical centre of excellence at Mulago Hospital (Baylor-Uganda) in Kampala, Uganda. Baylor-Uganda is a Non Governmental Organization (NGO) involved in the prevention, care and treatment of HIV-infected children and their families in Uganda. The Foundation is donor funded and runs a clinic that offers free clinical care to all its patients. The clinic is an out-patient treatment center that operates five days a week with an average daily attendance of 170 patients. Over 90% of patients seen at the clinic are children from the age of 6 weeks to 18 years. Parents or adult caretakers constitute the remainder of the patients.\n\nAt the clinic, patient care involves HIV diagnosis and treatment, nutritional rehabilitation, diagnosis and treatment of opportunistic infections, counseling and social support. Infants enrolled for care at the clinic are referred from the nearby Mulago National Referral hospital wards and from other centers involved in Prevention of Mother to Child HIV Transmission (PMTCT). Some infants are referred from HIV treatment centers within the country, and others are self referrals.\n\nStudy participants\nStudy participants were identified and recruited into the cohort from the Baylor-Uganda clinic patient population. Study participants were selected based on a criteria that required them to be clinic patients, confirmed to be HIV positive (by 2 positive blood tests showing the presence of viral nucleic acids in the patient’s blood samples); between 6-weeks and 12 months of age; ART naïve, but willing to start ART as soon as deemed necessary by the clinician; reside within 20 kilometer radius from the clinic; willing to be visited at home; and agree to be regularly followed-up at the clinic. Children without parents or guardians were excluded. Patients less than 6 weeks of age were not included since they were not routinely registered for care at the clinic. Based on WHO guidelines for infant diagnosis [9], and recommendations from the Ugandan Ministry of Health, routine diagnosis of HIV at Baylor-Uganda is carried out from the age of 6 weeks when infants are brought back to hospital for immunization.\n\nFrom April 2009 to March 2012, all clinic patients that fulfilled the selection criteria were consecutively recruited into the cohort and were subsequently followed up.\n\nFollow-up procedures and variables measured\nBefore starting ART, we confirmed HIV infection in the infants by carrying out an HIV DNA Polymerase Chain Reaction (PCR) test followed 2 weeks later by a viral RNA PCR test to quantify the HIV virus in the blood. To be considered HIV infected, both tests had to confirm presence of the virus in blood.\n\nAll laboratory- confirmed HIV infected infants were started on ART. Infants enrolled before July 2010 were started on ART based on the 2006 WHO guidelines for ART initiation. Based on these guidelines, all infants with CD4 cell counts below 25% or in advanced WHO clinical stages (stages 3 and 4) were considered eligible for ART and were started on treatment. Following the 2010 revision of WHO treatment guidelines, all HIV-infected infants were started on ART irrespective of their clinical stage or CD4 cell counts. A combination of 2 Nucleoside Reverse transcriptase inhibitor (NRTI) drugs and 1 Non-Nucleoside Reverse Transcriptase (NNRTI) or Protease Inhibitor was the ART combination of choice. Zidovudine (ZDV) or stavudine (D4T) combined with lamivudine (3TC) together with either nevirapine (NVP) or Lopinavir/ritonavir were the main ART drug combinations as recommended by WHO. Stavudine was preferred in patients with anemia (hemoglobin <7.5 g/dl) and Lopinavir/ritonavir was preferred in patients exposed to single dose NVP for PMTCT. Patients on rifampicin for treatment of tuberculosis were put on 3 NRTIs (ZDV or D4T + 3TC + Abacavir).\n\nBaseline measurements and tests were carried out on the date when ART was started and subsequent follow-up visits were scheduled 2, 4, and 8 weeks after starting treatment. Thereafter, patients returned to the clinic monthly, and if an appointment was missed, a home visit was carried out by trained home health workers. In addition, parents were encouraged to bring the children for medical care whenever they fell sick. At baseline and every 6 months thereafter, blood samples were drawn for complete blood count (CBC), CD4 cell count; liver function test [serum alanine amino transferase (ALT)], and HIV viral load.\n\nAt every visit, physicians reviewed the infant, documented and managed any adverse events or opportunistic infections. In addition, nutritional assessment including measurement of weight and height was conducted. Anthropometric computations and comparisons were conducted using the WHO anthro software [10] which is based on WHO child growth standards. Underweight was defined as a weight for age z-score (WAZ-score) less than -2 standard deviations (SD) from the WHO reference median values. Stunting was defined as height for age z-score (HAZ-score) less than -2SD from the reference values and weight for height z-score (WHZ-score) less than -2SD from the WHO reference median defined wasting. Adherence to medication was encouraged by both the physician and a trained counselor.\n\nAntiretroviral therapy was considered the exposure variable and the primary outcome variable was viral suppression 6 months after ART initiation. Other outcomes of interest included change in CD4 cell count; occurrence of ART-related adverse events; death during follow-up; and change in nutritional status as measured by weight-for-age, height-for-age and weight for height z-scores. Virologic suppression was defined as the attainment of HIV viral loads less than 400 copies/ml after 6 months of ART.\n\nPatients’ age, sex, WHO clinical stage, ART combination, presence of opportunistic infections and concurrent use of other medication, were considered potential confounders and were therefore documented and considered in the analysis.\n\nAll patient information was recorded in structured forms and was subsequently entered into the clinics electronic medical database which is designed to check for consistency of the data.\n\nWritten approval to conduct the study was granted by Makerere University College of Health Sciences’ Research and Ethics committee, Uganda National Council of Science and Technology, and Baylor College of Medicine Institutional Review Board (USA). The parents or caretakers gave written informed consent to participate in the study.\n\nStatistical analysis\nDescriptive analyses of baseline and follow-up characteristics are presented as proportions, medians with inter-quartile ranges (IQR), and means with standard deviations (SD).We used the paired t-test to compare the mean CD4 cell counts at baseline and during follow-up. Virologic suppression was categorized as ‘successful’ for viral loads less than 400 copies per milliliter and as ‘unsuccessful’ if otherwise. We used bivariate and multivariable logistic regression models to identify predictors of successful virologic suppression. Proportions of infants developing ART related adverse events were computed. For all analyses, confidence intervals (CI) were set at the 95% level and p-values less than 0.05 were considered statistically significant.\n\nResults\nOf 91 HIV-infected infants enrolled into the cohort during the study period, 53(58.2%) patients were female; 43(47.3%) were 6 months of age or younger, and 57 (62.7%) were moderate or severely underweight (Table 1). The median time from initial registration at the clinic to ART initiation was 57 days (IQR: 34.5-89). This duration varied according to ART initiation guidelines used at the clinic. The median time to ART initiation for patients that were started based on 2006 WHO treatment guidelines was 69 days (IQR=47-115); whereas the duration to ART initiation for patients that were started based on the revised 2010 guidelines was 33 days(IQR=28-44). The median follow-up time after initiating ART was 752 days (IQR= 531-980). The median age at ART initiation was 28.3 weeks (IQR=19.7-39) for infants started under the 2006 guidelines and 22.6 weeks (IQR=17.1-34.7) for infants that were started under 2010 WHO treatment guidelines.\n\nTable 1 Baseline characteristics of a cohort of 91 HIV-infected infants followed up at Baylor-Uganda\n\nVariable\tMedian (IQR)\tN (%)\t\nAge (months)\t6.2 (4.04-9.0)\t \t\n 0-6\t \t43 (47.3)\t\n 7-12\t \t48 (52.7)\t\nSex\t \t \t\n Male\t \t38 (41.8)\t\n Female\t \t53 (58.2)\t\nCD4 Percent\t20 (15-29)\t \t\nViral load (copies/ml)\t \t \t\n <100,000\t \t14 (18.2)\t\n 100,000-750,000\t \t29 (37.7)\t\n >750,000\t \t34 (44.1)\t\nWHO clinical stage\t \t \t\n 1\t \t13 (14.4)\t\n 2\t \t27 (30.0)\t\n 3\t \t32 (35.6)\t\n 4\t \t18 (20.0)\t\nART regimen\t \t \t\n ZDV+3TC+NVP\t \t14 (16.7)\t\n ZDV+3TC+Lop/r\t \t13 (15.5)\t\n D4T+3TC+NVP\t \t30 (35.7)\t\n D4T+3TC+Lop/r\t \t16 (19.0)\t\n Other\t \t11 (13.1)\t\nWeight/Age z-score\t \t \t\n Median (IQR)\t−2.2 (-3.89 - -1)\t \t\n <-3SD score\t \t33 (36.3)\t\n ≥-3SD to <-2SD\t \t24 (26.4)\t\n ≥-2≤SD to < -1SD\t \t11 (12.1)\t\n ≥-1SD\t \t23 (25.2)\t\nHeight/Age z-score\t \t \t\n Median\t−1.92 (-3.05 - -1.02)\t \t\n <-3SD score\t \t23 (25.3)\t\n ≥-3SD to<-2SD\t \t20 (21.9)\t\n ≥-2SD to<-1SD\t \t26 (28.6)\t\n ≥-1SD\t \t22 (24.2)\t\nIQR= Inter-quartile range, SD= standard deviation, WHO= World Health Organization, ART=antiretroviral therapy, ZDV=zidovudine, 3TC=lamivudine, D4T=stavudine, NVP=nevirapine, Lop/r= Lopinavir/ritonavir.\n\nDuring the follow-up period, a total of 84 patients were started on ART; 59 (70.2%) infants were started based on the 2006 WHO treatment guidelines and 25(29.8%) were started based on the revised 2010 treatment guidelines. Seven infants were not started on treatment because 4 of them died shortly after enrolment and 3 were lost to follow-up before ART could be initiated. Among infants that started ART, 78 (92.9%) were in active care at the end of the first 6 months of therapy; 4 patients died and 2 were lost to follow-up within the 6 month period. At the end of the study period, 70, 62 and 47 patients had received ART for at least 12, 18 and 24 months respectively.\n\nVirologic response\nOf the 78 infants that had ART for at least 6 months, successful viral suppression was seen in 56(71.8%) infants. Twenty two (28.2%) infants continued to have detectable viremia at month-6 of treatment. In univariate and multivariable regression analysis; none of the baseline factors such as age, gender, CD4 cell percent, WHO clinical stage, choice of antiretroviral agent, weight for age or height for age z-scores could predict treatment success at month-6 of therapy (Table 2).\n\nTable 2 Baseline predictors of treatment success (viral load<400 copies) among HIV-infected infants 6 months after ART initiation\n\nCharacteristic\tUnivariate OR\tP-value\tMultivariable OR\tP-value\t\n \t(95% CI)\t \t(95% CI)\t \t\nAge (>6 months)\t0.83 (0.31-2.24)\t0.718\t1.20 (0.33-4.37)\t0.785\t\nSex (Male)\t1.01 (0.37-2.74)\t0.990\t0.77 (0.24-2.45)\t0.657\t\nCD4 percent (every 1%)\t0.99 (0.94-1.04)\t0.670\t0.95 (0.89-1.01)\t0.123\t\nWHO stage (stage3&4)\t0.43 (0.15-1.23)\t0.116\t0.33 (0.08-1.14)\t0.078\t\nProtease Inhibitor\t1.34 (0.45-4.02)\t0.603\t1.33 (038-4.65)\t0.657\t\nWeight for Age Z-score (<-2)\t0.63 (0.21-1.85)\t0.395\t0.40 (0.09-1.76)\t0.227\t\nHeight for age Z-score (<-2)\t1.44 (0.50-4.12)\t0.500\t2.08 (0.58-7.47)\t0.260\t\nART= antiretroviral therapy; OR= Odds Ratio; CI= Confidence Interval; WHO= World Health Organization.\n\nAt month-12 of ART, 8 of the 22 patients that had detectable viremia at month-6, attained viral suppression; 1 patient got lost to follow-up, 1 was switched to second line ART, and 12 patients continued to have detectable viremia. On subsequent clinic visits, 6 of the 12 patients were switched to second-line ART, 4 were lost to follow-up and 2 died (Table 3). Among patients that attained viral suppression at month-6, no viral rebound was seen at month-12 of ART.\n\nTable 3 Characteristics of 12 children with virologic treatment failure after 12 months of antiretroviral therapy\n\nSerial number\tAge at ART initiation(months)\tWHO clinical stage\tART regimen\tOther significant OIs/social issues\tOutcome\t\n1\t4\t2\tZDV-3TC-NVP\tNone\tLost to follow-up\t\n2\t4\t3\tD4T-3TC-LPV/r\tNone\tSwitched to second line ART\t\n3\t5\t3\tZDV-3TC-NVP\t3 Pneumonia episodes\tSwitched to second line ART\t\n4\t7\t3\tD4T-3TC-ABC\tTuberculosis\tDied\t\n5\t11\t3\tZDV-3TC-ABC\tTuberculosis\tLost to follow-up\t\n6\t6\t3\tD4T-3TC-NVP\tChronic suppurative otitis media\tSwitched to second line ART\t\n7\t6\t3\tD4T-3TC-NVP\tNone\tLost to follow-up\t\n8\t4\t2\tZDV-3TC-NVP\tNone\tSwitched to second line ART\t\n9\t10\t3\tD4T-3TC-NVP\tPoor adherence to ART\tSwitched to second line ART\t\n10\t10\t2\tD4T-3TC-LPV/r\tTeenage Mother\tLost to follow-up\t\n11\t8\t3\tD4T-3TC-NVP\tNone\tSwitched to second line ART\t\n12\t10\t4\tZDV-3TC-NVP\tAnemia probably due to ZDV\tDied\t\nWHO= World Health Organization; ART= Antiretroviral therapy; OI= opportunistic infections.\n\nOf 47 patients that completed 24 months of ART; 44(93.6%) were still on first line treatment. Of these, 37(84.1%) continued to have viral suppression; and 7 patients had detectable viremia, all of whom had earlier achieved viral suppression.\n\nAltogether 7 patients were switched to second-line treatment (Abacavir + 3TC + Lopinavir/ritonavir) as a result of persistent viremia;5 out of the 7 attained viral suppression 6 months after starting second-line ART, and 2 patients were yet to complete 6 months of second-line ART.\n\nThe cumulative probabilities of attaining viral suppression at month-6 and month-12 of ART were 71.8% (95% CI: 61.6-81.3) and 83.1% (95% CI: 73.8-90.5) respectively.\n\nThe choice of third agent (Nevirapine versus Lopinavir/r) was not associated with risk of viremia at month-6, even after adjusting for the choice of NRTI backbone and baseline WHO clinical stage, Risk Ratio(RR)=1.1 (95% CI: 0.8-1.5), P=0.152. There was no association between WHO guideline used for patient treatment (2006 versus 2010) and risk of virologic failure at month-6 of ART; RR=1.24 (95% CI: 0.9-1.6).\n\nImmunologic response\nThere was a significant increase in CD4 cells from a baseline mean of 23% (SD=10.1) to 30% (SD=9.6) at month-6, P<0.001; and to 33% (SD=8.9) at month-12 of ART; (P=0.009, for the change between month-6 and month-12). By the end of the second year of ART, the mean CD4 cell percentage rose to 36% (SD=8.05) (Figure 1). The proportion of infants with very low CD4 cell counts (<15%) dropped from 23.8% at baseline to 8.5% at 6 months of treatment, and by the end of the second year, only one patient continued to have CD4 cell percentage below 15%. This patient was an infant, with no prior exposure to nevirapine for PMTCT, who started ART (D4T+3TC+NVP) at the age of 4 months with a baseline CD4 of 16%. His CD4 percentage dropped to 15% at month-6 and to 14% at month-24 of ART. He never attained virologic suppression and was considered a case of treatment failure due to possible primary HIV resistance. He was subsequently started on second-line ART.\n\nFigure 1 Change in CD4 cell counts in a cohort of children receiving antiretroviral therapy at Baylor-Uganda.\n\nClinical response\nTen (11.9%) of the 84 patients that started ART were diagnosed with tuberculosis at baseline or shortly after ART initiation. Anti-tuberculosis treatment was started but one patient died after 5 months of ART and tuberculosis medication. One 7-month old infant was diagnosed with disseminated Bacillus Calmette-Guerin (BCG) infection 3 months after starting ART. He was treated as a case of immune reconstitution inflammatory syndrome (IRIS) and improved.\n\nAt ART initiation, 54 (64.3%) of 84 patients had a WAZ-score below -2SD of the WHO reference median. This prevalence of underweight varied according to age and clinical stage of the disease. Thirty six (80%) of 45 older infants (7-12 months of age) compared to 18(46.2%) of 39 younger infants (1-6 months of age) were underweight at baseline; prevalence ratio= 1.7 (95% CI: 1.19-2.51). Of 47 infants with baseline advanced HIV disease (WHO clinical stage 3&4), 36 (76.6%) were underweight; and among 37 infants with milder clinical disease (WHO clinical stage 1&2), 18 (48.6%) were found to be underweight at baseline; prevalence ratio= 1.6 (95% CI: 1.09-2.27). There was no association between baseline underweight and gender or baseline CD4 cell counts.\n\nAmong the 78 infants that received ART for at least 6 months, the proportion that were underweight reduced from 65.4% at baseline to 30.8% at 6 month of ART, p<0.001\n\nEighty one patients were included in the analysis of height for age z-scores (HAZ-score). Of these, 32 (39.5%) patients had baseline HAZ-score less than -2. Twenty (46.5%) out of 43 infants aged 6-12 months compared to 12 (31.5%) out of 38 infants younger than 6 months of age were stunted; prevalence ratio=1.5 (95% CI: 0.84-2.60). Twenty three (51.1%) of 45 patients in WHO stage 3or 4 compared to 9 (25%) of 36 patients in WHO stage 1 or 2 were stunted at baseline; prevalence ratio=2 (95% CI: 1.08-3.85).\n\nThere was no significant change in stunting in the first 6 month of ART. Of 75 patients that had both baseline and follow-up HAZ-score measurements, the prevalence of stunting increased from 40% at baseline to 48% after 6 months of ART, p=0.134.\n\nOf 65 patients that were included in the analysis of weight for height z-scores (WHZ-score), 22 (33.8%) had baseline WHZ-scores less than -2. However, after 6 months of ART, only 9 (13.8%) patients continued to have WHZ-scores less than -2; p=0.007.\n\nDeaths and other adverse events\nA total of 11 (12.1%) patients died during the follow-up period. Four of the 11 died before ART could be initiated. All 4 patients were in WHO clinical stage 4; between 6-12 months of age at the time of death; and had been in care for 6-11.7 weeks. The illness preceding death was tuberculous pericarditis for one female infant, dysentery and lymphoma for other 2 female infants and Pneumocystis Jirovecii Pneumonia for the only male infant. Of the 7 infants that died while on ART, 4 died within the first 6 months, 1 died in the 8th month and 2 died in the second year of ART. The overall mortality rate among children on ART was 4.09 (95% CI: 1.95-8.58) per 100 child-years. Post mortem examinations were not carried out; however, the majority of patients that died had underlying malnutrition (Table 4).\n\nTable 4 Characteristics of 7 HIV-infected Children that died while on antiretroviral therapy at Baylor-Uganda clinic\n\nSerial number\tAge(months) at ART initiation\tSex\tWHO clinical stage\tART combination\tDuration on ART (months)\tClinical events preceding death\t\n1\t7\tMale\t3\tD4T-3TC-ABC\t18.3\tTuberculosis\t\n2\t7\tFemale\t4\tD4T-3TC-NVP\t16.3\tMalnutrition\t\n3\t6\tFemale\t3\tD4T-3TC-NVP\t7.8\tPneumonia\t\n4\t7\tMale\t4\tD4T-3TC-NVP\t0.8\tMalnutrition/Anemia\t\n5\t11\tMale\t4\tD4T-3TC-NVP\t1.3\tMalnutrition\t\n6\t7\tFemale\t3\tD4T-3TC-NVP\t1.7\tOral Candidiasis\t\n7\t10\tMale\t4\tD4T-3TC-NVP\t5.3\tMalnutrition\t\nART= Antiretroviral therapy; WHO= World Health Organization; D4T= Stavudine; 3TC= Lamivudine; ABC= Abacavir; NVP= Nevirapine.\n\nWithin the first 6 months of ART, adverse events were reported in 7 (8.3%) of the 84 patients that started treatment. Of the seven, 3 patients developed diarrhea, 1 had nausea and vomiting, 2 had anemia and 1 developed a skin rash. One of the 3 infants with diarrhea and the one infant with nausea and vomiting were on a PI based regimen. All patients with anemia were on ZDV and the one patient with skin rash was on nevirapine. All patients that developed anemia or skin rash had ART regimen change. Patients with diarrhea, nausea and vomiting had mild and transient illness not requiring ART regimen change.\n\nDiscussion\nIn this study, which involved a cohort of HIV-infected infants receiving first-line antiretroviral therapy in an outpatient setting in Uganda, we found that 71% of infants attained virologic suppression by 6 months of ART. In general, the infants had good immune recovery and experienced low levels of drug toxicity, with only 8% of patients reporting adverse events during the study period. Our results show that, even among very young infants from resource constrained settings, ART dramatically suppresses HIV replication, allows immune recovery and clinical improvement, and is safe.\n\nIn sub-Saharan Africa, the treatment of HIV-infected infants has lagged behind that of older children and adults largely as a result of delays in diagnosis [11], restricted choice of ART, lack of appropriate drug formulations and inadequate levels of trained medical personnel [12,13]. These difficulties coupled with the high rates of viral resistance among infants that received nevirapine for PMTCT, complicate the attainment of treatment success [14,15]. However, despite these challenges, the majority of infants in our cohort were adequately able to suppress the virus, increase their level of immunity and significantly gain weight. Our findings on growth recovery provide further evidence on the benefits of early initiation of ART. Recent reports by Shiau et al suggest that growth recovery is faster among young infants compared to older children [16].\n\nCompared to participants of the CHER study [7], infants in our cohort were enrolled into care at an older age, and were started on ART after several weeks of delay. This may have partly contributed to the mortality and loss to follow up seen before ART initiation. The 2010 revision of WHO treatment guidelines led to a notable reduction in ART initiation delay, with much younger infants being enrolled into care. The implementation of the 2010 treatment guidelines together with the increased adoption of strategies for early infant diagnosis (EID) across Uganda and other parts of Africa, are likely to lead to further reduction in ART initiation delays and early enrollment of infants into care.\n\nAmong several cohorts of HIV-infected African children currently undergoing treatment, viral suppression within the first 6 months of ART has been reported in 60% to 89% of patients [17-21]. Our results, though purely from infants, are in agreement with results from these studies. Studies conducted in Europe and primarily focusing on infants have reported much lower responses to therapy [22].\n\nIn all patients on ART, the initial rapid attainment of viral suppression is critical for the long term success of treatment. Viral suppression permits immune recovery and often delays the development of viral resistance [20]. Persistence of HIV viremia among patients on ART leads to early development of viral resistance ultimately leading to treatment failure. With the achievement of viral suppression, immune recovery and clinical improvement often occur. However, attainment of HIV viral suppression and immune rebound is often dependent on several factors including; the choice of ART regimen, prior treatment or exposure to antiretroviral drugs for PMTCT, adherence to medication, drug dosage, concurrent use of other drugs, presence of other infections and a host of other factors [23-25]. Our study did not assess all these factors; however, among baseline variables measured, we did not find any associations between infant characteristics and viral suppression. Neither was there any association between viral suppression and ART regimen used. Viral suppression was seen irrespective of age, sex, WHO clinical stage or baseline CD4 cell counts.\n\nThe immune recovery that occurred in our cohort was remarkable. The change from a baseline mean of 22% to 30% after 6 months of ART compares favorably with results seen among cohorts of children receiving treatment elsewhere in Africa [5]. In general, the increase in CD4 cell count continued even during the second year of therapy.\n\nDespite this general success in treatment, several children failed to attain viral suppression, even after 6-12 month of first-line treatment. We presume that these children may have been infected with mutant resistant viruses from mothers that were already on treatment with first-line ART. Though HIV resistance tests were not carried out, our conclusion is that these children may have been cases of primary HIV resistance, or cases of resistance resulting from prior use of antiretroviral agents for PMTCT. Once switched to second line ART, viral suppression was quickly attained. These results are worrying since it implies that either the mothers on treatment are passing on resistant virus to their infants, or prior administration of PMTCT medication to infants maybe contributing to the development of viral resistance. This development further limits the treatment options available for these children. With more adults accessing and failing first-line ART, these results underscore the need for HIV resistance testing among HIV-infected infants born to such adults.\n\nThe viral rebound that occurred in 7 patients after initial suppression may have been due to early viral resistance or due to poor adherence to medication at the time the viral load tests were carried out.\n\nWe noted a high level of acute and chronic malnutrition in this cohort and this may have been due to a combination of clinical and social factors that ultimately led to reduced caloric intake, reduced absorption and increased loss of nutrients needed for growth. This high prevalence of malnutrition underscores the need for an integrated HIV treatment approach that incorporates interventions focusing on reducing malnutrition.\n\nAs reported in previous studies [21,26], deaths were mainly reported in the first 6 months of ART. Early deaths in HIV-infected children are often a result of overwhelming infections in a setting of severe immunodeficiency and malnutrition [27,28]. Due to the rapid progression of disease and the delays in diagnosis, many infants enroll for medical care when infection, malnutrition and severe immunodeficiency have set in. For such patients, death occurs before the beneficial effects of ART are realized. Mortality rates reported from several African cohorts vary considerably; in 2 South African cohorts, rates of 4.2 deaths per 100 child years [21] and 43.7 deaths per 1000 child-years were reported [5]. In Kenya, 8.4 deaths/100 child-years were seen [29] and in Zambia 6.94 deaths per 100 person years were reported [30]. The mortality rate of 4.09 deaths per 100 child-years seen in our cohort compares favorably with these results.\n\nOur study had several limitations: We were not able to accurately document PMTCT history; neither were we able to carry out HIV resistance testing. In addition, we were unable to carry out postmortem examination of patients that died, and we did not measure adherence to medication though it was emphasized at every clinic visit. Despite these limitations and the possibility of failing to detect significant differences due to the small sample size, the results presented here draw attention to a vulnerable group of HIV-infected children and highlight the feasibility of treatment success even in resource constraint settings.\n\nConclusion\nOur results indicate that despite the high prevalence of malnutrition and the probable transmission of resistant virus from mothers to infants, treatment success for HIV-infected infants living in resource-constrained settings is possible. We recommend an integrated approach to early infant diagnosis and treatment that takes into consideration early detection of viral resistance especially among infants whose mothers received ART during pregnancy and a robust nutritional intervention plan for every infant.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nVJT participated in the design of the study, acquisition of data, data cleaning and analysis, and drafting, revision and final submission of the manuscript. MM participated is data acquisition and in the critical revision of the manuscript. ARA was involved in study design, submissions for ethical approval and critical revision of the draft manuscript. DM participated in the design of the study and acquisition of data. AM was involved in the initial design of the study and critical revision of the draft manuscript. SBK, IK and PM all participated in the initial design of the study, interpretation of the data and critical revision of the draft manuscript. AK participated in all stages of the study from design, data acquisition, interpretation of collected data, and final revision of the draft manuscript. All authors read and approved the final manuscript.\n\nPre-publication history\nThe pre-publication history for this paper can be accessed here:\n\nhttp://www.biomedcentral.com/1471-2431/13/42/prepub\n\nAcknowledgements\nThis work was supported by Cooperative agreement Number 5U2GPS000942 from Centers for Disease Control and Prevention (CDC). Its contents are solely the responsibility of the authors and do not necessarily represent the views of CDC. We also appreciate Abbott Fund who provided the test kits used in this program, Baylor International Pediatric AIDS Initiative (BIPAI) for the technical support, Clinton Foundation and Ministry of Health of Uganda who provided the drugs used.\n\nWe thank the children and their caregivers, together with the entire staff of Baylor-Uganda for their participation in this study. Special thanks to Jane Nakimuli, Betty Kasule, Susan Nakayiza, Gala Moses, Kenneth Musononwa, Albert Asiimwe, and the Cohort Team for their dedication to data collection and patient care.\n==== Refs\nAhuja TS Borucki M Grady J Highly active antiretroviral therapy improves survival of HIV-infected hemodialysis patients Am J Kidney Dis 2000 36 574 580 10.1053/ajkd.2000.16196 10977790 \nMurphy EL Collier AC Kalish LA Assmann SF Para MF Flanigan TP Kumar PN Mintz L Wallach FR Nemo GJ Highly active antiretroviral therapy decreases mortality and morbidity in patients with advanced HIV disease Ann Intern Med 2001 135 17 26 11434728 \nMbuagbaw LC Irlam JH Spaulding A Rutherford GW Siegfried N Efavirenz or nevirapine in three-drug combination therapy with two nucleoside-reverse transcriptase inhibitors for initial treatment of HIV infection in antiretroviral-naive individuals Cochrane Database Syst Rev 2010 12 CD004246 21154355 \nPalombi L Dorrucci M Zimba I Scarcella P Mancinelli S Buonomo E Guidotti G Marazzi MC Rezza G Immunologic response to highly active antiretroviral therapy and mortality reduction in a cohort of human immunodeficiency virus-positive persons in Mozambique AmJTrop Med Hyg 2010 83 1128 1132 10.4269/ajtmh.2010.09-0705 \nJanssen N Ndirangu J Newell ML Bland RM Successful paediatric HIV treatment in rural primary care in Africa Arch Dis Child 2010 95 414 421 10.1136/adc.2009.169367 19880392 \nSauvageot D Schaefer M Olson D Pujades-Rodriguez M O’Brien DP Antiretroviral therapy outcomes in resource-limited settings for HIV-infected children <5 years of age Pediatrics 2010 125 e1039 e1047 10.1542/peds.2009-1062 20385636 \nViolari A Cotton MF Gibb DM Babiker AG Steyn J Madhi SA Jean-Philippe P McIntyre JA Team CS Early antiretroviral therapy and mortality among HIV-infected infants N Engl J Med 2008 359 2233 2244 10.1056/NEJMoa0800971 19020325 \nAntiretroviral therapy for HIV infection in infants and children: Towards universal access http://www.who.int/hiv/pub/paediatric/infants2010/en/index.html \nWHO Recommendations on the diagnosis of HIV infection in infants and children http://www.who.int/hiv/pub/paediatric/diagnosis/en/index.html \nWHO Anthro for personal computers, version 3.2.2, 2011: Software for assessing growth and development of the world’s children http://www.who.int/childgrowth/software/en/ \nKellerman S Essajee S HIV testing for children in resource-limited settings: what are we waiting for? PLoS Med 2010 7 e1000285 10.1371/journal.pmed.1000285 20652012 \nHavens PL Gibb DM Increasing antiretroviral drug access for children with HIV infection Pediatrics 2007 119 838 845 17403860 \nLallemant M Chang S Cohen R Pecoul B Pediatric HIV–a neglected disease? N Engl J Med 2011 365 581 583 10.1056/NEJMp1107275 21848457 \nCharpentier C Gody JC Tisserand P Matta M Pere H Fournier J Mbitikon O Belec L Surveillance of antiretroviral drug resistance mutations in untreated young children living in the Central African Republic Antivir Ther 2011 16 1347 1350 10.3851/IMP1896 22155917 \nPalumbo P Lindsey JC Hughes MD Cotton MF Bobat R Meyers T Bwakura-Dangarembizi M Chi BH Musoke P Kamthunzi P Antiretroviral treatment for children with peripartum nevirapine exposure N Engl J Med 2010 363 1510 1520 10.1056/NEJMoa1000931 20942667 \nShiau S Arpadi S Strehlau R Martens L Patel F Coovadia A Abrams EJ Kuhn L Initiation of Antiretroviral Therapy Before 6 Months of Age is Associated with Faster Growth Recovery in South African Children Perinatally Infected with Human Immunodeficiency Virus J Pediatr 2013 [Epub ahead of print] \nPurchase SE Van der Linden DJ McKerrow NH Feasibility and Effectiveness of Early Initiation of Combination Antiretroviral Therapy in HIV-infected Infants in a Government Clinic of Kwazulu-Natal, South Africa J Trop Pediatr 2012 58 114 119 10.1093/tropej/fmr053 21705764 \nKekitiinwa A Lee KJ Walker AS Maganda A Doerholt K Kitaka SB Asiimwe A Judd A Musoke P Gibb DM Differences in factors associated with initial growth, CD4, and viral load responses to ART in HIV-infected children in Kampala, Uganda, and the United Kingdom/Ireland J Acquir Immune Defic Syndr 2008 49 384 392 10.1097/QAI.0b013e31818cdef5 18931630 \nvan Dijk JH Sutcliffe CG Munsanje B Sinywimaanzi P Hamangaba F Thuma PE Moss WJ HIV-infected children in rural Zambia achieve good immunologic and virologic outcomes two years after initiating antiretroviral therapy PLoS One 2011 6 e19006 10.1371/journal.pone.0019006 21552521 \nZanoni BC Phungula T Zanoni HM France H Cook EF Feeney ME Predictors of poor CD4 and weight recovery in HIV-infected children initiating ART in South Africa PLoS One 2012 7 e33611 10.1371/journal.pone.0033611 22438965 \nMeyers TM Yotebieng M Kuhn L Moultrie H Antiretroviral therapy responses among children attending a large public clinic in Soweto, South Africa Pediatr Infect Dis J 2011 30 974 979 10.1097/INF.0b013e31822539f6 21734620 \nJudd A Early antiretroviral therapy in HIV-1-infected infants, 1996-2008: treatment response and duration of first-line regimens AIDS 2011 25 2279 2287 21971357 \nChao C Tang B Hurley L Silverberg MJ Towner W Preciado M Horberg M Risk Factors for Short-Term Virologic Outcomes Among HIV-Infected Patients Undergoing Regimen Switch of Combination Antiretroviral Therapy AIDS Res Hum Retroviruses 2012 28 1630 1636 10.1089/aid.2012.0005 22475276 \nBagenda A Barlow-Mosha L Bagenda D Sakwa R Fowler MG Musoke PM Adherence to tablet and liquid formulations of antiretroviral medication for paediatric HIV treatment at an urban clinic in Uganda Ann Trop Paediatr 2011 31 235 245 10.1179/1465328111Y.0000000025 21781419 \nHeidari S Mofenson LM Hobbs CV Cotton MF Marlink R Katabira E Unresolved antiretroviral treatment management issues in HIV-infected children J Acquir Immune Defic Syndr 2012 59 161 169 10.1097/QAI.0b013e3182427029 22138766 \nWeigel R Estill J Egger M Harries AD Makombe S Tweya H Jahn A Keiser O Mortality and loss to follow-up in the first year of ART: Malawi national ART programme AIDS 2012 26 365 373 10.1097/QAD.0b013e32834ed814 22095194 \nSartorius BK Kahn K Vounatsou P Collinson MA Tollman SM Young and vulnerable: spatial-temporal trends and risk factors for infant mortality in rural South Africa (Agincourt), 1992-2007 BMC Publ Health 2010 10 645 10.1186/1471-2458-10-645 \nKwara A Shah D Renner LA Outcome of hospital admissions in HIV-infected children at the Korle Bu Teaching Hospital, Accra, Ghana West Afr J Med 2010 29 379 383 21465444 \nWamalwa DC Obimbo EM Farquhar C Richardson BA Mbori-Ngacha DA Inwani I Benki-Nugent S John-Stewart G Predictors of mortality in HIV-1 infected children on antiretroviral therapy in Kenya: a prospective cohort BMC Pediatr 2010 10 33 10.1186/1471-2431-10-33 20482796 \nSutcliffe CG van Dijk JH Bolton-Moore C Cotham M Tambatamba B Moss WJ Differences in presentation, treatment initiation, and response among children infected with human immunodeficiency virus in urban and rural Zambia Pediatr Infect Dis J 2010 29 849 854 10.1097/INF.0b013e3181e753a8 20526227\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2431",
"issue": "13()",
"journal": "BMC pediatrics",
"keywords": null,
"medline_ta": "BMC Pediatr",
"mesh_terms": "D019380:Anti-HIV Agents; D018791:CD4 Lymphocyte Count; D003906:Developing Countries; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D006801:Humans; D007223:Infant; D016015:Logistic Models; D008297:Male; D015999:Multivariate Analysis; D011446:Prospective Studies; D016896:Treatment Outcome; D014454:Uganda; D019562:Viral Load",
"nlm_unique_id": "100967804",
"other_id": null,
"pages": "42",
"pmc": null,
"pmid": "23536976",
"pubdate": "2013-03-27",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "22138766;20385636;19020325;21465444;21781419;22438965;22475276;19880392;20977724;21734620;21848457;21552521;21154355;23312691;21705764;17403860;22155917;22095194;20482796;20942667;18931630;21036851;21971357;11434728;10977790;20652012;20526227",
"title": "Virologic, immunologic and clinical response of infants to antiretroviral therapy in Kampala, Uganda.",
"title_normalized": "virologic immunologic and clinical response of infants to antiretroviral therapy in kampala uganda"
} | [
{
"companynumb": "UG-ROXANE LABORATORIES, INC.-2015-RO-00222RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "UG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditi... |
{
"abstract": "BACKGROUND\nDrug-induced long QT syndrome is generally ascribed to inhibition of the cardiac rapid delayed rectifier potassium current (IKr). Effects on the slow delayed rectifier potassium current (IKs) are less recognized. Triggered by a patient who carried the K422T mutation in KCNQ1 (encoding the α-subunit of the IKs channel), who presented with excessive QT prolongation and high serum levels of norfluoxetine, we investigated the effects of fluoxetine and its metabolite norfluoxetine on IKs.\n\n\nRESULTS\nECG data from mutation carriers and noncarriers revealed that the K422T mutation per se had mild clinical effects. Patch clamp studies, performed on HEK293 cells, showed that heterozygously expressed K422T KCNQ1/KCNE1 channels had a positive shift in voltage dependence of activation and an increase in deactivation rate. Fluoxetine and its metabolite norfluoxetine both inhibited KCNQ1/KCNE1 current, with norfluoxetine being the most potent. Moreover, norfluoxetine increased activation and deactivation rates. Computer simulations of the effects of norfluoxetine on IKs and IKr demonstrated significant action potential prolongation, to which IKs block contributed importantly. Although the effects of the mutation per se were small, additional IKs blockade by norfluoxetine resulted in more prominent QTc prolongation in mutation carriers than in noncarriers, demonstrating synergistic effects of innate and drug-induced IKs blockade on QTc prolongation.\n\n\nCONCLUSIONS\nIKs blockade contributes importantly to drug-induced long QT syndrome, especially when repolarization reserve is reduced. Drug safety tests might have to include screening for IKs blockade.",
"affiliations": "Heart Center, and Departments of Anatomy, Embryology, and Physiology, Cardiology, Hospital Pharmacy, Academic Medical Center, University of Amsterdam, the Netherlands; and Department of Hospital Pharmacy, Reinier de Graaf Group Hospitals, Delft, the Netherlands.",
"authors": "Veerman|Christiaan C|CC|;Verkerk|Arie O|AO|;Blom|Marieke T|MT|;Klemens|Christine A|CA|;Langendijk|Pim N J|PN|;van Ginneken|Antoni C G|AC|;Wilders|Ronald|R|;Tan|Hanno L|HL|",
"chemical_list": "C489622:KCNE1 protein, human; D051657:KCNQ1 Potassium Channel; D024642:Potassium Channels, Voltage-Gated; D017367:Serotonin Uptake Inhibitors; D005473:Fluoxetine",
"country": "United States",
"delete": false,
"doi": "10.1161/CIRCEP.113.000239",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-3084",
"issue": "6(5)",
"journal": "Circulation. Arrhythmia and electrophysiology",
"keywords": "drug-induced long QT syndrome; fluoxetine; long QT syndrome; potassium channels; torsade de pointes",
"medline_ta": "Circ Arrhythm Electrophysiol",
"mesh_terms": "D000200:Action Potentials; D002478:Cells, Cultured; D003198:Computer Simulation; D004452:Echocardiography; D004562:Electrocardiography; D005080:Exercise Test; D005260:Female; D005473:Fluoxetine; D006801:Humans; D051657:KCNQ1 Potassium Channel; D008133:Long QT Syndrome; D008875:Middle Aged; D016296:Mutagenesis; D009154:Mutation; D018408:Patch-Clamp Techniques; D010375:Pedigree; D024642:Potassium Channels, Voltage-Gated; D012307:Risk Factors; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "101474365",
"other_id": null,
"pages": "1002-9",
"pmc": null,
"pmid": "23995305",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Slow delayed rectifier potassium current blockade contributes importantly to drug-induced long QT syndrome.",
"title_normalized": "slow delayed rectifier potassium current blockade contributes importantly to drug induced long qt syndrome"
} | [
{
"companynumb": "PHHY2014NL130661",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOXETINE\\FLUOXETINE HYDROCHLORIDE"
},
"drugaddition... |
{
"abstract": "AbstractRecently, reports of delayed hemolytic anemia after treatment with artemisinin and its derivatives have emerged. Here we report two cases of delayed hemolytic anemia in a patient with severe falciparum malaria after treatment with oral artemether-lumefantrine (AL). The first patient, a 20-year-old Japanese male student, was diagnosed with falciparum malaria and was administered AL. As having a high parasitemia rate (20.6%) was the only severe malaria criterion met in this case and his general condition was stable, we continued with AL treatment. Despite disappearance of malarial parasites after 4 days of AL administration, a persistent fever remained. On days 13 and 16, a diagnosis of hemolytic anemia was made (lactate dehydrogenase [LDH]: 1,466 U/L, hemoglobin [Hb]: 7.2 g/dL). A blood smear at that time revealed no parasites. He recovered naturally from delayed hemolysis. The second patient, a 27-year-old Japanese female student, was diagnosed with falciparum malaria (parasitemia: 4.5%) and treated initially with oral quinine hydrochloride and doxycycline. The following day, parasitemia increased to 7.9% and oral AL was initiated. She was discharged on day 4 after achieving parasite clearance and afebrility. However, on day 5, fever (body temperature > 38°C) recurred, and on day 11, a diagnosis of hemolytic anemia was made (LDH: 712 U/L, Hb: 8.8 g/dL). A follow-up confirmed that her condition improved gradually. AL treatment of severe malaria can cause delayed hemolytic anemia. Patients should be followed up for up to 4 weeks to detect signs of hemolysis and provide appropriate symptomatic treatment.",
"affiliations": "Department of Infectious Diseases, Kyoto City Hospital, Kyoto, Japan.;Center for Infectious Diseases, Nara Medical University, Nara, Japan.;Center for Infectious Diseases, Nara Medical University, Nara, Japan.;Department of Tropical Medicine and Malaria, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.;Department of Infectious Diseases, Kyoto City Hospital, Kyoto, Japan.;Department of Infectious Diseases, Kyoto City Hospital, Kyoto, Japan.;Center for Infectious Diseases, Nara Medical University, Nara, Japan.;Center for Infectious Diseases, Nara Medical University, Nara, Japan.;Center for Infectious Diseases, Nara Medical University, Nara, Japan.;Center for Infectious Diseases, Nara Medical University, Nara, Japan.;Department of Pathogen, Infection and Immunity, Nara Medical University, Nara, Japan.;Department of Tropical Medicine and Malaria, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan.;Center for Infectious Diseases, Nara Medical University, Nara, Japan.;Department of Infectious Diseases, Kyoto City Hospital, Kyoto, Japan.;Department of Pathogen, Infection and Immunity, Nara Medical University, Nara, Japan.;Department of Infectious Diseases, Division of Parasitology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.",
"authors": "Tsuchido|Yasuhiro|Y|;Nakamura-Uchiyama|Fukumi|F|;Toyoda|Kasumi|K|;Iwagami|Moritoshi|M|;Tochitani|Kentaro|K|;Shinohara|Koh|K|;Hishiya|Naokuni|N|;Ogawa|Taku|T|;Uno|Kenji|K|;Kasahara|Kei|K|;Ouji|Yukiteru|Y|;Kano|Shigeyuki|S|;Mikasa|Keiichi|K|;Shimizu|Tsunehiro|T|;Yoshikawa|Masahide|M|;Maruyama|Haruhiko|H|",
"chemical_list": "D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D006454:Hemoglobins; D007770:L-Lactate Dehydrogenase",
"country": "United States",
"delete": false,
"doi": "10.4269/ajtmh.16-0460",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9637",
"issue": "96(5)",
"journal": "The American journal of tropical medicine and hygiene",
"keywords": null,
"medline_ta": "Am J Trop Med Hyg",
"mesh_terms": "D000328:Adult; D000743:Anemia, Hemolytic; D000962:Antimalarials; D000077611:Artemether, Lumefantrine Drug Combination; D037621:Artemisinins; D001772:Blood Cell Count; D003289:Convalescence; D004338:Drug Combinations; D004983:Ethanolamines; D005260:Female; D005449:Fluorenes; D006454:Hemoglobins; D006801:Humans; D007770:L-Lactate Dehydrogenase; D016778:Malaria, Falciparum; D008297:Male; D018512:Parasitemia; D010963:Plasmodium falciparum; D013997:Time Factors",
"nlm_unique_id": "0370507",
"other_id": null,
"pages": "1185-1189",
"pmc": null,
"pmid": "28193740",
"pubdate": "2017-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19083297;24376273;23302816;25013158;23265377;23553281;8953071;25812775;24354627;22453057;25796960;22523307;24859359;25166926;21529383;25306236;23849926;20650555;25448338;25163809;22462806;25071004;7871987;9735933",
"title": "Development of Delayed Hemolytic Anemia After Treatment with Oral Artemether-Lumefantrine in Two Patients with Severe Falciparum Malaria.",
"title_normalized": "development of delayed hemolytic anemia after treatment with oral artemether lumefantrine in two patients with severe falciparum malaria"
} | [
{
"companynumb": "PHJP2015JP006925",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARTEMETHER\\LUMEFANTRINE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo compare alternative class-sparing antiretroviral regimens in treatment-naive subjects.\n\n\nMETHODS\nOpen-label, multicenter, randomized trial of up to 3 consecutive treatment regimens over 96 weeks.\n\n\nMETHODS\nTwo hundred ninety-one subjects received abacavir (ABC) and lamivudine and efavirenz (nonnucleoside reverse transcriptase inhibitors [NNRTIs]), ritonavir-boosted amprenavir (protease inhibitor [PI]), or stavudine (nucleoside reverse transcriptase inhibitor [NRTI]) by random assignment. The primary end points were the percentages of subjects with plasma HIV-1 RNA levels <400 copies/mL and time to treatment failure over 96 weeks.\n\n\nRESULTS\nNinety percent of subjects completed 96 weeks of follow-up, and 79% remained on study treatment. At week 96, there were no differences between arms in the percentages of subjects with plasma HIV-1 RNA levels <400 and <50 copies/mL, mean changes in plasma HIV-1 RNA levels, time to treatment failure, time to first or second virologic failure, or CD4 cell counts. The NNRTI arm had a greater percentages of subjects with RNA levels <or=50 copies/mL at weeks 24 and 48 and a greater overall duration of plasma HIV-1 RNA levels <400 copies/mL. Three subjects in the NNRTI arm had treatment failure on their first regimen and switched therapy compared with 16 in the NRTI arm and 13 in the PI arm. Twenty-one subjects had hypersensitivity reactions attributed to ABC (7.3%). Fewer drugs were used by subjects in the NNRTI arm, and fewer subjects in the NNRTI arm used 3 drug classes.\n\n\nCONCLUSIONS\nAll treatment regimens demonstrated excellent 96-week results. Secondary analyses favored the NNRTI regimen over the PI and NRTI regimens.",
"affiliations": "Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA. jab5@duke.edu",
"authors": "Bartlett|John A|JA|;Johnson|Judy|J|;Herrera|Gisela|G|;Sosa|Nestor|N|;Rodriguez|Alan|A|;Liao|Qiming|Q|;Griffith|Sandy|S|;Irlbeck|David|D|;Shaefer|Mark S|MS|;|||",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D017320:HIV Protease Inhibitors; D010078:Oxazines; D019259:Lamivudine; D018119:Stavudine; C098320:efavirenz; D019438:Ritonavir",
"country": "United States",
"delete": false,
"doi": "10.1097/01.qai.0000243092.40490.26",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-4135",
"issue": "43(3)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D006801:Humans; D019259:Lamivudine; D008297:Male; D010078:Oxazines; D019438:Ritonavir; D018119:Stavudine; D016896:Treatment Outcome",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "284-92",
"pmc": null,
"pmid": "16967040",
"pubdate": "2006-11-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term results of initial therapy with abacavir and Lamivudine combined with Efavirenz, Amprenavir/Ritonavir, or Stavudine.",
"title_normalized": "long term results of initial therapy with abacavir and lamivudine combined with efavirenz amprenavir ritonavir or stavudine"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US03826",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ABACAVIR"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo evaluate the efficacy of 2 dexamethasone intravitreal implants and 1 ranibizumab intravitreal injection after a bilateral postoperative complication of cataract surgery as pseudophakic cystoid macular edema.\n\n\nMETHODS\nA 70-year-old male patient with systemic hypertension developed a progressive cystoid macular edema (CME) in both eyes starting between 10 and 20 days after cataract surgery. Two intravitreal dexamethasone implants and 1 ranibizumab injection were administered; first in the right eye (RE) and then in the left eye (LE). The patient was checked for 1 whole week and then once a month for 5 months after the injections.\n\n\nRESULTS\nOne month after the first dexamethasone implant in his RE, the spectral domain optical coherence tomography (SD-OCT) showed a progressive reduction of the foveal thickness until a complete resolution of the CME occurred, which was associated with an improvement of visual acuity. After 3 months, the SD-OCT showed a relapse of the CME, which was then treated with 1 injection of ranibizumab. One month after this injection, there was a complete resolution of the CME. A new CME in his RE was diagnosed 2 months after the last ranibizumab injection; it was treated with a new dexamethasone implant. A complete resolution of the CME was obtained; a normal foveal profile was still present 5 months after the last injection, and the best-corrected visual acuity was 20/20. His LE developed a CME 40 days after surgery. One intravitreal injection of ranibizumab was first administered in his LE, with a complete resolution of the CME at SD-OCT 2 weeks later. As observed in his RE, 40 days after the ranibizumab injection, there was a relapse of the CME that was treated with 1 intravitreal injection of dexamethasone implant. Five months later, the patient showed a worsening of the CME, but it was completely resolved with a second dexamethasone injection. After 3 months, the foveal thickness was back to normal with a BCVA of 20/20.\n\n\nCONCLUSIONS\nTreatment with dexamethasone implants (Ozurdex(®)) and ranibizumab injections (Lucentis(®)) induced a progressive reduction of our patient's CME after cataract surgery (Irvine-Gass syndrome) until a complete normal foveal thickness was restored and his visual function was improved despite the order of injections.",
"affiliations": "Ophthalmology Unit, NESMOS Department, S. Andrea Hospital, Faculty of Medicine and Psychology, 'Sapienza' University of Rome, Rome, Italy.;Ophthalmology Unit, NESMOS Department, S. Andrea Hospital, Faculty of Medicine and Psychology, 'Sapienza' University of Rome, Rome, Italy.;Ophthalmology Unit, NESMOS Department, S. Andrea Hospital, Faculty of Medicine and Psychology, 'Sapienza' University of Rome, Rome, Italy.;Ophthalmology Unit, NESMOS Department, S. Andrea Hospital, Faculty of Medicine and Psychology, 'Sapienza' University of Rome, Rome, Italy.;Ophthalmology Unit, NESMOS Department, S. Andrea Hospital, Faculty of Medicine and Psychology, 'Sapienza' University of Rome, Rome, Italy.;Ophthalmology Unit, NESMOS Department, S. Andrea Hospital, Faculty of Medicine and Psychology, 'Sapienza' University of Rome, Rome, Italy.",
"authors": "Fenicia|Vito|V|;Balestrieri|Marco|M|;Perdicchi|Andrea|A|;MauriziEnrici|Maurizio|M|;DelleFave|Martina|M|;Recupero|Santi Maria|SM|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000365945",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1663-2699",
"issue": "5(2)",
"journal": "Case reports in ophthalmology",
"keywords": "Cataract; Complication; Cystoid macular edema; Dexamethasone; Intravitreal injection; Irvine-Gass syndrome; Ranibizumab; Surgery",
"medline_ta": "Case Rep Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101532006",
"other_id": null,
"pages": "243-8",
"pmc": null,
"pmid": "25232337",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports",
"references": "12566041;21494891;20853257;12544809;17294379;24696869;19545901;19268890;22134362;20057303;13040458;23006995;23766636;15035387",
"title": "Intravitreal injection of dexamethasone implant and ranibizumab in cystoid macular edema in the course of irvine-gass syndrome.",
"title_normalized": "intravitreal injection of dexamethasone implant and ranibizumab in cystoid macular edema in the course of irvine gass syndrome"
} | [
{
"companynumb": "IT-ROCHE-1591830",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RANIBIZUMAB"
},
"drugadditional": null,
"dru... |
{
"abstract": "Mantle cell lymphoma has a dismal prognosis at relapse or in the refractory setting. Among therapies, mTor pathway targeting by temsirolimus has been the first strategy approved for relapse in Europe. While its efficacy in monotherapy has long been demonstrated, its use remains limited. In the T3 phase Ib clinical trial, we investigated the recommended dose of temsirolimus in association with R-CHOP (R-CHOP-T), or high-dose cytarabine plus rituximab (R-DHA-T), or fludarabine, cyclophosphamide plus rituximab (R-FC-T). From November 11, 2011 to February 26, 2015, forty-one patients were enrolled. Patients presented with high MIPI (47.5%) at relapse and a median number of treatments of 1 (1-3). Patients were treated by R-CHOP-T (n = 10), R-FC-T (n = 14), or R-DHA-T (n = 17) according to the choice of local investigators. The maximum tolerated dose (MTD) was 15 mg in the R-CHOP-T arm and has not been determined in other treatment arms because of toxicities. All patients experienced ≥ Grade 3 adverse events, mainly thrombocytopenia (76%). Twenty-six patients discontinued prematurely the treatment, mostly for toxicity (n = 12) and progression of the disease (n = 8). Of note, 6 patients of the R-DHA-T arm reached complete remission (35%). Temsirolimus with immuno-chemotherapy is associated with a high rate of toxicities. Determination of MTD could only be achieved for R-CHOP-T arm. Associations between temsirolimus and other targeted therapies may be warranted for R/R MCL patients.",
"affiliations": "Department of Hematology, CHU de Nantes, University Hospital of Nantes, Nantes, France.;Haematology, CHU de Bordeaux, Bordeaux, France.;Pathology Department, Cochin University Hospital, AP-HP, Paris, France.;INSERM U917, CHU Pontchaillou, Rennes, France.;Hematology, CHU Grenoble, Grenoble, Grenoble, France.;Department of clinical hematology, University Hospital Montpellier, Montpellier, France.;Hôpital Saint-Louis, Paris, France.;Hematology, Hospices Civils de Lyon, Pierre Bénite, Lyon, France.;Lymphoid Malignancies Unit, AP-HP, Groupe Hospitalier Mondor, Croéteil, France.;Hematology Department, Hopital Le Bocage, CHU Dijon, Dijon, France.;Department of Biostatistics, LYSARC, Lyon, France.;Service d'Hématologie et thérapie cellulaire, Centre Hospitalier Universitaire, Tours, France.;Hematology Department, Necker University Hospital, AP-HP, Paris, France.;Department of Hematology, CHU de Nantes, University Hospital of Nantes, Nantes, France. steven.legouill@chu-nantes.fr.",
"authors": "Tessoulin|Benoît|B|http://orcid.org/0000-0001-7600-3329;Bouabdallah|Kamal|K|;Burroni|Barbara|B|;Lamy|Thierry|T|;Gressin|Remy|R|;Cartron|Guillaume|G|;Thieblemont|Catherine|C|;Sarkozy|Clémentine|C|;Haioun|Corinne|C|;Casasnovas|Olivier|O|;Joubert|Clementine|C|;Gyan|Emmanuel|E|;Hermine|Olivier|O|;Le Gouill|Steven|S|",
"chemical_list": "C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; C401859:temsirolimus; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone; D020123:Sirolimus",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-020-04159-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "99(8)",
"journal": "Annals of hematology",
"keywords": "Immuno-chemotherapy; Mantle cell lymphoma; Temsirolimus",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007167:Immunotherapy; D020522:Lymphoma, Mantle-Cell; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D000069283:Rituximab; D020123:Sirolimus; D015996:Survival Rate; D013921:Thrombocytopenia; D014750:Vincristine",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1771-1778",
"pmc": null,
"pmid": "32601796",
"pubdate": "2020-08",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Safety and efficacy of temsirolimus in combination with three different immuno-chemotherapy regimens in relapse and refractory mantle cell lymphoma, final results of the T3 phase IB trial of the LYSA.",
"title_normalized": "safety and efficacy of temsirolimus in combination with three different immuno chemotherapy regimens in relapse and refractory mantle cell lymphoma final results of the t3 phase ib trial of the lysa"
} | [
{
"companynumb": "FR-PFIZER INC-2020264169",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nIn the inpatient psychiatric setting, one treatment strategy used to manage acute agitation in youth includes administration of IM antipsychotics. The aim of this study was to compare the effectiveness and safety of IM chlorpromazine versus IM olanzapine in treating aggression in youth.\n\n\nMETHODS\nWe conducted a retrospective chart review of patients younger than 18 years hospitalized in the inpatient psychiatric unit who received either IM chlorpromazine or IM olanzapine for acute agitation. Demographic, efficacy, and tolerability data were collected using the electronic health record EPIC. The primary outcome was change from baseline to end point in the Behavioral Activity Rating Scale (BARS) score. BARS was applied retrospectively using nursing and physician documentation to evaluate for clinical response.\n\n\nRESULTS\nAmong 145 patients who met the inclusion criteria, 72 received IM chlorpromazine, compared with 73 who received IM olanzapine. The mean change in BARS score (before and after IM antipsychotic) was greater with olanzapine (3.58 ± 0.99) than with chlorpromazine (3.07 ± 1.18, p = 0.006). The target BARS score of 4 was achieved more frequently with chlorpromazine (45.8%) than with olanzapine (24.7%, p < 0.008). Coadministration of IM diphenhydramine occurred significantly more often in the olanzapine group than in the chlorpromazine group (71.2% vs 36.1%, p < 0.001).\n\n\nCONCLUSIONS\nManagement of acute agitation with IM olanzapine resulted in a greater change in BARS score, despite more youth requiring coadministration with diphenhydramine. In comparison, IM chlorpromazine demonstrated a higher likelihood of returning patients to baseline. Study results suggest tolerability of IM chlorpromazine and olanzapine.",
"affiliations": null,
"authors": "Snyder|Sabrina Domicoli|SD|;Williams|Andrew|A|;Mitchell|Melissa|M|;Kneebusch|Jamie|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-26.1.33",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "26(1)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "adolescents; aggression; agitation; chlorpromazine; injections, intramuscular; olanzapine",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "33-41",
"pmc": null,
"pmid": "33424498",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": "15662151;10648310;5650165;2321713;12421260;8839521;15021203;11982448;20837212;21288118;17822344;16583125;8673189;23649219;7977894;2719364;1984724;18216715;20376274;19284622;8092591;16278769;8427433;17201611;2039103;15650504;11777497;30129244;28697164;28205446;30881565",
"title": "Use of Intramuscular Chlorpromazine Versus Intramuscular Olanzapine for the Management of Acute Agitation and Aggression in Youth.",
"title_normalized": "use of intramuscular chlorpromazine versus intramuscular olanzapine for the management of acute agitation and aggression in youth"
} | [
{
"companynumb": "US-OTSUKA-2021_011292",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Vitreomacular traction and vitreomacular traction with macular hole are conditions associated with visual disturbance and decreased visual acuity. Recent studies have demonstrated that ocriplasmin is effective and safe in specific patient groups with vitreomacular traction, and hence is recommended as a treatment option. We present here a case report of a patient treated with intravitreal ocriplasmin associated with severe loss of vision and delayed resolution of vitreomacular traction. This report highlights that it is important for patients to be made fully aware of the risks of intravitreal ocriplasmin and the prognosis for visual improvement.",
"affiliations": "The Western Eye Hospital, Imperial College Healthcare National Health Service Trust, London, United Kingdom ; Barts Health National Health Service Trust, St Bartholomew's Hospital, West Smithfield, London, United Kingdom.;The Western Eye Hospital, Imperial College Healthcare National Health Service Trust, London, United Kingdom.",
"authors": "DaCosta|Joanna|J|;Younis|Saad|S|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/DHPS.S75244",
"fulltext": "\n==== Front\nDrug Healthc Patient SafDrug Healthc Patient SafDrug, Healthcare and Patient SafetyDrug, Healthcare and Patient Safety1179-1365Dove Medical Press 10.2147/DHPS.S75244dhps-6-175Case ReportTransient visual loss and delayed resolution of vitreomacular traction after intravitreal ocriplasmin DaCosta Joanna 12Younis Saad 11 The Western Eye Hospital, Imperial College Healthcare National Health Service Trust, London, United Kingdom2 Barts Health National Health Service Trust, St Bartholomew’s Hospital, West Smithfield, London, United KingdomCorrespondence: Joanna DaCosta, Ocular Oncology Service, Barts Health National Health Service Trust, St Bartholomew’s Hospital, West Smithfield, London EC1A 7BE, United Kingdom, Tel +44 20 3465 6863, Fax +44 20 3465 5936, Email dacostajoanna@hotmail.co.uk2014 25 11 2014 6 175 178 © 2014 DaCosta and Younis. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2014The 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.Vitreomacular traction and vitreomacular traction with macular hole are conditions associated with visual disturbance and decreased visual acuity. Recent studies have demonstrated that ocriplasmin is effective and safe in specific patient groups with vitreomacular traction, and hence is recommended as a treatment option. We present here a case report of a patient treated with intravitreal ocriplasmin associated with severe loss of vision and delayed resolution of vitreomacular traction. This report highlights that it is important for patients to be made fully aware of the risks of intravitreal ocriplasmin and the prognosis for visual improvement.\n\nKeywords\nocriplasminmacular holevisual lossvitreoretinal\n==== Body\nCase report\nA 97-year-old woman developed decreased vision in her left eye over a period of 4 weeks. Past ocular history included uneventful bilateral cataract surgery and bilateral early dry age-related macular degeneration (AMD). Vision was 6/30 on the right and 6/38 LogMAR on the left. Spectral domain optical coherence tomography (SD-OCT; Cirrus, Carl Zeiss Meditec, Dublin, CA, USA) of the left eye showed vitreomacular traction with a small stage 2 macular hole1,2 and no epiretinal membrane (Figure 1). The patient was informed that ocriplasmin had been shown to statistically significantly resolve vitreomacular adhesion when compared with placebo in clinical trials, and the option of vitrectomy was discussed. Fully informed consent was obtained, and the risk for complications with intravitreal injections such as loss of vision, retinal detachment, lens damage, and endophthalmitis was documented on the consent form. The patient was made aware that there would be a guarded prognosis for visual improvement. She proceeded to receive treatment with intravitreal ocriplasmin 0.125 mg (0.1 mL) to her left eye.\n\nOne day after treatment, vision had reduced to hand movements, with symptoms of blue and dark spots in the left eye. Ocular examination revealed normal intraocular pressure and no sign of endophthalmitis, retinal detachment, or hemorrhage. No other cause of reduced vision was identified. Repeat SD-OCT revealed subretinal fluid with vitreomacular traction (Figure 2). There is a small irregular area of retinal pigment epithelium elevation (Figure 2). The patient declined fluorescein and indocyanine green angiography, and clinically, this appeared to be related to dry age-related macular changes. There appeared to be attenuation and discontinuation of the inner segment/outer segment, ellipsoid layer.\n\nTwenty-eight days after treatment, the patient’s vision had improved to 6/48 LogMAR (Figure 3), and the subretinal fluid had resolved with persistent vitreomacular traction.\n\nThe patient elected not to proceed with pars plana vitrectomy.\n\nAt 56 days after treatment, the vitreomacular traction had resolved with sustained improvement of vision (Figure 4). This appeared to be associated with improved continuity of the inner segment/outer segment (ellipsoid layer).\n\nDiscussion\nOur case report shows that ocriplasmin caused severe visual loss postinjection associated with subretinal fluid, and that vitreomacular traction may resolve up to 2 months after ocriplasmin injection.\n\nNormal aging is accompanied by physiological changes in the vitreous gel of the eye. After the age of 40 years, the vitreous undergoes progressive liquefaction (synchysis).3 Typically, by the age of 80 years, about 50% of the vitreous gel has been liquefied, resulting in weakened adhesion between the vitreous and retina.3 Posterior vitreous detachment is more common in postmenopausal women than men; this is postulated to be a result of the effects of decreased estrogen on connective tissue, such as that present within the vitreous gel.4\n\nThe patient in our case report was an elderly woman, aged 97 years, with early dry AMD. Clinically, AMD appears to primarily involve the retinal pigment epithelium and outer retinal layers. However, evidence suggests that the vitreous may contribute to the pathogenesis and progression of AMD. For example, Mojana et al5 conducted a retrospective study with SD-OCT to compare vitreoretinal adhesions in three groups: eyes with wet AMD, eyes with dry AMD, and control eyes. Eyes with wet AMD were significantly more likely to show evidence of vitreomacular adhesion. The patient described in our case report was elderly and female, which would suggest weakened vitreomacular adhesion; however, in the context of early AMD, this may have contributed to increased vitreomacular adhesion.\n\nResults of clinical trials6 and the package insert of ocriplasmin7 (Jetrea®, ThromboGenics, Leuven, Belgium) report transient blindness, photopsia, dyschromatopsia, and electroretinogram (ERG) changes occurring more frequently in those patients treated compared with in placebo-treated patients.\n\nFreund et al8 described a 67-year-old woman with a macular hole associated with vitreomacular adhesion and epiretinal membrane who developed transient loss of vision 1 week after intravitreal ocriplasmin. Eye-tracked SD-OCT demonstrated resolution of vitreomacular adhesion with disruption of the ellipsoid zone, indicating damaged photoreceptor outer segments. Despite the persistence of the macular hole, the patient’s vision recovered 3 weeks later. This was associated with improvement of the integrity of the ellipsoid zone, which is suggestive of partial recovery of photoreceptor outer segment function. It was proposed that ocriplasmin exerts a disruptive effect on the photoreceptor outer segments, which appears to be partially reversible.8 Singh et al9 was the first study to quantify the extent of outer retinal changes seen in patients receiving ocriplasmin. Seven of 17 patients experienced transient outer segment ellipsoid zone loss on SD-OCT, which resolved after an average period of 29.3 days. This was also correlated with subretinal fluid, which resolved after an average period of 30 days.\n\nRecent case reports such as Tibbetts et al10 and Fahim et al11 have described a more diffuse effect of ocriplasmin on the photoreceptors. Tibbetts et al10 described a 71-year-old woman with symptomatic vitreomacular traction who experienced persistent darkening of vision for 4 months after receiving intravitreal ocriplasmin. The symptoms of darkened vision corresponded with disruption of the photoreceptor inner segment-outer segment (ellipsoid) layer and reduce a- and b-wave ERG amplitudes. However, this was not related to persistent vitreomacular traction, as there was an immediate release of vitreomacular traction.\n\nFull-field ERG revealed a greater reduction in the amplitude of the scotopic compared with the photopic ERG, suggesting rod photoreceptors may be more susceptible to the effects of ocriplasmin. These effects may only occur in patients who are susceptible to prolonged reduction in photoreceptor activity. It was postulated that a diffuse protease enzymatic effect of ocriplasmin throughout the retina may account for the visual darkening adverse effects of ocriplasmin.\n\nFahim et al11 reported a case of persistent visual loss associated with acute severe panretinal dysfunction after ocriplasmin injection for a small macular hole with vitreomacular adhesion. This was associated with Goldmann visual field constriction, anisocoria, attenuated retinal vessels, disruption of outer retinal signals on SD-OCT, and severely reduced ERG responses. Fahim et al11 postulated that possible mechanisms of retinal injury from ocriplasmin injection included either enzymatic activity of ocriplasmin on the retinal extracellular matrix or other toxic effects not specific to the proteinase activity of ocriplasmin.\n\nThe enzymatic effects of ocriplasmin on the cleavage of laminin, a component of the photoreceptor-bipolar synapse, were consistent with ERG findings of reduced b-waves compared with a-waves. This suggests postreceptor (eg, bipolar cell) cell dysfunction in addition to decreased photoreceptor activity.\n\nThe results of clinical trials6 were statistically significant, showing that vitreomacular adhesion resolved in 26.5% of ocriplasmin-injected eyes compared with in 10.1% of placebo-injected eyes. The primary end point of the study6 was resolution of vitreomacular adhesion at 28 days, determined by OCT evaluation. Visual improvements with ocriplasmin were less encouraging, demonstrating that anatomical resolution of vitreomacular traction noted with OCT is not a surrogate marker for functional visual improvement.6\n\nThe National Institute of Health and Care Excellence has recommended ocriplasmin as a treatment option for patients with vitreomacular traction if no epiretinal membrane is present and a stage 2 macular hole is present (with a diameter of ≤400 μm) and/or the patient has severe symptoms.12 After our experience with this patient, we have sought to make the consent process for intravitreal ocriplasmin more explicit and to explain to patients that there appear to be specific risks for severe visual loss associated with this drug, in addition to the well-described risks of the intravitreal injection process.\n\nIt is important that patients are made fully aware of the risks of ocriplasmin and the prognosis for visual improvement.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Vitreomacular traction with a small stage 2 macular hole (arrow).\n\nFigure 2 Persistent vitreomacular traction with subretinal fluid; arrows show attenuation and discontinuation of the ellipsoid layer.\n\nFigure 3 Persistent vitreomacular traction with resolved subretinal fluid.\n\nFigure 4 Resolution of vitreomacular traction, with the arrow showing improved continuity of the ellipsoid layer.\n==== Refs\nReferences\n1 Gass JD Idiopathic senile macular hole. Its early stages and pathogenesis Arch Ophthalmol 1988 106 5 629 639 3358729 \n2 Gass JD Reappraisal of biomicroscopic classification of stages of development of a macular hole Am J Ophthalmol 1995 119 6 752 759 7785690 \n3 Le Goff MM Bishop PN Adult vitreous structure and postnatal changes Eye (Lond) 2008 22 10 1214 1222 18309340 \n4 Chuo JY Lee TYY Hollands H Risk factors for posterior vitreous detachment: a case-control study Am J Ophthalmol 2006 142 6 931 937 17157578 \n5 Mojana F Cheng L Bartsch DU The role of abnormal vitreomacular adhesion in age-related macular degeneration: spectral optical coherence tomography and surgical results Am J Ophthalmol 2008 146 2 218 227 18538742 \n6 Stalmans P Benz MS Gandorfer A MIVI-TRUST Study Group Enzymatic vitreolysis with ocriplasmin for vitreomacular traction and macular holes N Engl J Med 2012 367 7 606 615 22894573 \n7 Jetrea® (ocriplasmin) [package insert] Iselin, NJ ThromboGenics 2013 \n8 Freund KB Shah SA Shah VP Correlation of transient vision loss with outer retinal disruption following intravitreal ocriplasmin Eye (Lond) 2013 27 6 773 774 23640609 \n9 Singh RP Li A Bedi R Anatomical and visual outcomes following ocriplasmin treatment for symptomatic vitreomacular traction syndrome Br J Ophthalmol 2014 98 3 356 360 24357495 \n10 Tibbetts MD Reichel E Witkin AJ Vision loss after intravitreal ocriplasmin: correlation of spectral-domain optical coherence tomography and electroretinography JAMA Ophthalmol 2014 132 4 487 490 24577286 \n11 Fahim AT Khan NW Johnson MW Acute panretinal structural and functional abnormalities after intravitreous ocriplasmin injection JAMA Ophthalmol 2014 132 4 484 486 24577241 \n12 National Institute for Health and Care Excellence Ocriplasmin for Treating Vitreomacular Traction NICE technology appraisal guidance 297 London, UK National Institute for Health and Care Excellence 10 2013 Available from: http://www.nice.org.uk/guidance/ta297/documents/vitreomacular-traction-ocriplasmin-final-appraisal-determination-document2 Accessed October 1, 2014\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1179-1365",
"issue": "6()",
"journal": "Drug, healthcare and patient safety",
"keywords": "macular hole; ocriplasmin; visual loss; vitreoretinal",
"medline_ta": "Drug Healthc Patient Saf",
"mesh_terms": null,
"nlm_unique_id": "101544775",
"other_id": null,
"pages": "175-8",
"pmc": null,
"pmid": "25473315",
"pubdate": "2014",
"publication_types": "D002363:Case Reports",
"references": "3358729;18309340;7785690;18538742;22894573;24577241;24357495;17157578;23640609;24577286",
"title": "Transient visual loss and delayed resolution of vitreomacular traction after intravitreal ocriplasmin.",
"title_normalized": "transient visual loss and delayed resolution of vitreomacular traction after intravitreal ocriplasmin"
} | [
{
"companynumb": "GB-THROMBOGENICS NV-SPO-2014-1555",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OCRIPLASMIN"
},
"drugadditional": nu... |
{
"abstract": "Polytrauma patients are at high risk for neurologic complications as a result of the primary mechanism of their trauma and/or delirium caused by subsequent pain, sedatives and analgesic exposure, sleep disturbances, infections, metabolic derangements, organ dysfunctions, withdrawal syndromes, or other factors. The high prevalence of delirium within trauma intensive care units increases risks for both patients and providers and is associated with worsened patient outcomes. This case report explains the rationale and utilization of continuous intrathecal morphine administration to improve pain control while reducing and eliminating intravenous (IV) analgesics and sedatives to enable wakefulness in a polytrauma patient with refractory agitated delirium.",
"affiliations": "From the Department of Anesthesiology.;From the Department of Anesthesiology.;Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee.;From the Department of Anesthesiology.",
"authors": "Boncyk|Christina S|CS|;Brennan|Kaitlyn A|KA|;Guillamondegui|Oscar|O|;Benson|Clayne|C|",
"chemical_list": "D009020:Morphine",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000001338",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2575-3126",
"issue": "14(13)",
"journal": "A&A practice",
"keywords": null,
"medline_ta": "A A Pract",
"mesh_terms": "D006801:Humans; D007278:Injections, Spinal; D009020:Morphine; D009104:Multiple Trauma; D010146:Pain; D059408:Pain Management",
"nlm_unique_id": "101714112",
"other_id": null,
"pages": "e01338",
"pmc": null,
"pmid": "33185403",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Continuous Intrathecal Morphine Infusion for Pain Management in a Polytrauma Patient: A Case Report.",
"title_normalized": "continuous intrathecal morphine infusion for pain management in a polytrauma patient a case report"
} | [
{
"companynumb": "US-drreddys-LIT/USA/21/0144781",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FENTANYL CITRATE"
},
"drugadditional": "... |
{
"abstract": "OBJECTIVE\nAmlodipine overdose is common; however, the dose and timing of intravenous lipid emulsion (ILE) therapy as a management strategy remain debatable.\n\n\nMETHODS\nA 73-year-old man received a single bolus (1.5 mL/kg) of ILE therapy following massive ingestion of multiple drugs, including amlodipine. After approximately 20 hours of ILE therapy, the serum amlodipine level that had decreased from 90.2 to 49.9 ng/mL increased to 70.8 ng/mL.\n\n\nCONCLUSIONS\nA single bolus (1.5 mL/kg) of ILE therapy is probably insufficient to completely capture and partition serum amlodipine following amlodipine overdose.",
"affiliations": "Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.;Department of Pharmacy, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Emergency Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Clinical Laboratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Clinical Laboratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Clinical Laboratory Medicine, Kobe City Medical Center General Hospital, Kobe, Japan.;Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.;Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Kobe, Japan.;Department of Pharmacy, Kobe City Medical Center General Hospital, Kobe, Japan.",
"authors": "Ando|Motozumi|M|https://orcid.org/0000-0003-2473-0588;Nakasako|Shinji|S|;Ariyoshi|Koichi|K|;Yamaguchi|Marie|M|;Sakizono|Kenji|K|;Minowa|Kazushi|K|;Fukushima|Shoji|S|;Sugioka|Nobuyuki|N|;Hashida|Tohru|T|",
"chemical_list": "D002121:Calcium Channel Blockers; D005217:Fat Emulsions, Intravenous; D008055:Lipids; D017311:Amlodipine",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.13018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "44(6)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "amlodipine; calcium channel antagonist; emergency; intravenous lipid emulsion therapy; liquid chromatography-mass spectrometry",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000368:Aged; D017311:Amlodipine; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D005217:Fat Emulsions, Intravenous; D006801:Humans; D008055:Lipids; D008297:Male",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "970-973",
"pmc": null,
"pmid": "31436900",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Re-elevation of serum amlodipine level after lipid emulsion therapy in an overdose case.",
"title_normalized": "re elevation of serum amlodipine level after lipid emulsion therapy in an overdose case"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1146360",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GLIMEPIRIDE"
},
"drugadditional": null,
... |
{
"abstract": "To describe the prevalent side effects of prostaglandin analogues (PA) in a Hispanic population and their effect on quality of life (QOL).\n\n\n\nThis is a cross-sectional study conducted in a tertiary medical facility in which patients were evaluated in a single visit. Total of 14 participants in the study, 10 women and 4 men. Ages ranged from 26-78 years old. Subjects underwent a single full Oculoplastic evaluation by two physicians; one was blinded on patient medical history and assessed for PA side effects. After evaluation, each study subject was asked to answer a self reported QOL questionnaire.\n\n\n\nStudy participants had used or were currently using Bimatoprost (28.6%), Latanoprost (50%) or Travoprost (21.4%). After evaluate periorbital changes, 2 patients (14.3%) had ptosis, 2 (14.3%) had periorbital skin hyperpigmentation, 11 (78.6%) had periorbital fat show, 11 (78.6%) had eyelash elongation, 1 (7.1%) had injected conjunctiva, 5 (35.7%) had iris hyperpigmentation. 10 (71.4%) noted changes in the size/shape of their eyes. The questionnaire show that 10 (71.4%) disliked how their eyes looked. 9 (62.4%) reported dry eyes, 3 (21.4%) noted increased need to blink, 5 (35.7%) reported foreign body sensation, 7 (50%) reported burning sensation, 2 (14.2%) reported secretions and 3 (21.4%) reported sticky eyes. Mean QOL was 3.50, 2.14, and 2.00 in the Bimatroprost, Latanoprost, and Travoprost users respectively.\n\n\n\nQOL questionnaire showed that Bimatoprost side effects had the most negative impact in QOL, followed by the Latanoprost and Travoprost groups.",
"affiliations": "Department of Ophthalmology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.;Department of Ophthalmology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.;Department of Ophthalmology, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.",
"authors": "Rodríguez-Agramonte|Ferdinand|F|;Jiménez|Juan Carlos|JC|;Montes|José Raúl|JR|",
"chemical_list": "D000959:Antihypertensive Agents; D000077338:Latanoprost; D000069580:Bimatoprost; D000069557:Travoprost",
"country": "Puerto Rico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0738-0658",
"issue": "36(4)",
"journal": "Puerto Rico health sciences journal",
"keywords": "Periorbital; Prostaglandin analogues; Quality of Life",
"medline_ta": "P R Health Sci J",
"mesh_terms": "D060433:Administration, Ophthalmic; D000328:Adult; D000368:Aged; D000959:Antihypertensive Agents; D000069580:Bimatoprost; D003430:Cross-Sectional Studies; D005260:Female; D006630:Hispanic or Latino; D006801:Humans; D000077338:Latanoprost; D008297:Male; D008875:Middle Aged; D011788:Quality of Life; D011795:Surveys and Questionnaires; D062606:Tertiary Care Centers; D000069557:Travoprost",
"nlm_unique_id": "8303541",
"other_id": null,
"pages": "218-222",
"pmc": null,
"pmid": "29220066",
"pubdate": "2017-12",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Periorbital Changes associated with Topical Prostaglandins Analogues in a Hispanic Population.",
"title_normalized": "periorbital changes associated with topical prostaglandins analogues in a hispanic population"
} | [
{
"companynumb": "PR-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-217424",
"fulfillexpeditecriteria": "1",
"occurcountry": "PR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LATANOPROST"
},
"dru... |
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